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       BETA (Bulletin of Experiment Treatments for AIDS) Online - No. 21
       Published by the San Francisco AIDS Foundation - June 1994
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       Electronically distributed for the Global Electronic Network for
   AIDS (GENA) by AEGIS/San Juan Capistrano  *  714.248.2836  *  8N1
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       Table of Contents

       The Use of Alternative Medicine in the Treatment of HIV Infection and
       AIDS
            Jason Heyman
       Aggressive Intervention in HIV Disease: An Interview with 4 San
       Francisco Physicians
            Mark Bowers
       Human Herpesvirus Type 6 (HHV-6): Cofactor or Opportunistic  Infection
       in AIDS?
            Ronald A. Baker, PhD
       Recommended Reading
            Ronald A. Baker, PhD
       Vitamin and Nutritional Supplements in HIV Disease
       1994 BETA Readership Survey: Readers' Comments
       Acyclovir Increases Survival! ∙ FDA Approval of d4T ∙ Alternative
       Therapies: Hope and Hype
            Ronald A. Baker,PhD
       Mycobacteria and HIV Infection
            Leslie Hanna
       Mycobacterium avium Complex (MAC): An Interview with Stephen D.
       Nightingale, MD
            Leslie Hanna
       A Master Protocol to Evaluate the Safety and Efficacy of Triple
       Combination Antiretroviral Therapy for HIV Infection
            David Barry, MD,
       Research Notes
            Ronald A. Baker, PhD

       *********

 The Use of Alternative
 Medicine in the Treatment of
 HIV Infection and AIDS
 Jason Heyman

 Jason Heyman is a free-lance medical writer.

 A walk down the aisles of any health-food store will reveal a large number
of popular alternative treatments from the past and present. In fact, some
treatments that have been studied in multi-million dollar clinical trials
were originally found on these shelves. In an effort to find effective
treatments for HIV and related illnesses, the AIDS community has spent the
past 12 years exploring many possible treatments. Before allopathic
treatments such as AZT, ddI and ddC were available, people with AIDS sought
help from healers of all types.

 Although more widely available today than ever before, reliable information
on alternative treatments is still difficult to find. This article will
explore both the history of alternative treatments for HIV infection and
AIDS, and current research on a variety of alternative and holistic
therapies. Since there is such an abundance of alternative treatments, this
article will focus on the most popular herbal remedies and holistic
approaches. The use of vitamins and nutritional supplements, and the
off-label use of pharmaceutical drugs for HIV/AIDS will not be covered here.

 Terminology

 The terminology used to describe this field of medicine can be confusing
since many terms are used interchangeably. Alternative medicine generally
refers to all healing modalities that are not considered part of orthodox
western medicine. The field of alternative medicine can be separated into 2
categories: alternative treatments, which are usually individual herbs or
therapeutic activities such as massage, and holistic approaches, which are
systems of healing that incorporate the body, mind and spirit. Holistic
approaches such as traditional Chinese medicine usually derive from the
healing traditions of indigenous cultures.

 Western medicine relies upon allopathy as an approach to healing. In the
allopathic school of thought, treatments are designed to produce a condition
antagonistic to the primary condition being treated. For example, if a
patient is suffering from inflammation, a treatment is applied that reduces
inflammation. The pervasiveness of this approach to medicine may make it hard
to conceptualize any other. In contrast to allopathy, homeopathy attempts to
treat conditions with therapies that mimic the condition being treated.
Homeopathy will be discussed in more detail later.

 There are a variety of terms currently in use that describe alternative
treatments. The term complementary applies to treatments that are used in
conjunction with allopathic treatment, and is used in Europe in place of
"alternative." Experimental refers to all treatments that have not been
studied in controlled clinical trials and have not been approved for use by
the U.S. Food and Drug Administration (FDA). Sometimes alternative treatments
are referred to as natural treatments even though they do not have an organic
basis (Smith, 1993).

 History and Politics

 The precise beginning of the alternative HIV/AIDS treatment movement is hard
to establish, since at one time all treatments were considered experimental.
Donald Abrams, MD, of San Francisco General Hospital, watched many of his
patients try alternative treatments over the years, and observed their rise
in popularity:

 "Born into the generation when smallpox and polio had been conquered with
vaccines and the mysteries of Legionnaire's disease and toxic shock syndrome
had been rapidly unraveled, many of the young adults threatened by HIV were
surprised at the doggedly slow velocity of medical research....It was from
within this community that the seeds were planted from which would grow an
increasingly vocal and assertive alternative therapy movement" (Abrams,
1990).

 The popularity of alternative medicine among people with HIV/AIDS has
fluctuated greatly over the years, particularly when AZT and other
antiretroviral drugs became available. Recently, with disappointing results
from clinical trials of antiretroviral drugs (such as the Concorde AZT
study), many people have turned once again to alternative treatments.

 The research establishment has been slow to acknowledge the significance of
alternative treatments and their widespread usage, but some changes have been
made. At the 1992 VIII International Conference on AIDS in Amsterdam, for the
first time in its history and under pressure from AIDS activists, alternative
medicine was officially included among the oral presentations. That same year
the Office of Alternative Medicine (OAM) was founded at the National
Institutes of Health (NIH) to study the use of alternative medicine in the
U.S. This includes treatments for both AIDS-related and non-AIDS-related
conditions. The OAM has a relatively small budget of 2 million dollars, but
its creation was a milestone in the history of alternative medicine.

 A survey published in the New England Journal of Medicine in January 1993
estimated that 34% of all Americans had used at least one form of alternative
medicine in the previous year (Eisenberg, 1993). Although the survey was not
limited to HIV and AIDS, the current popularity of alternative medicine is
due in part to the increased attention it has received from people with AIDS.


 Most herbs and plant extracts that have been used to treat HIV and its
related conditions, such as bitter melon, licorice root and aloe vera, have
long been used in various indigenous medical systems. These systems usually
combine a variety of herbs into a single treatment, in an effort to diminish
side effects. Currently, however, and in keeping with the approach of
allopathic medicine, herbs are being taken like pharmaceutical drugs_alone
and in high doses. Used in this manner, herbs can have side effects that are
just as dangerous as potent drugs. For example, licorice root has been known
to cause high blood pressure, and mistletoe can cause liver toxicity
(Kassler, 1991).

 The anecdotal experiences of individuals offer important insights into which
treatments may be effective, but many people with HIV and AIDS have put
themselves at risk by trying unproven or dangerous treatments. Anecdotal
reports about the effectiveness of a treatment often spread by word-of-mouth
and may create intense interest in a treatment. Information is also spread
through AIDS treatment newsletters, and by buyers' clubs that specialize in
selling alternative treatments. Despite little or no notice from the
mainstream medical establishment or media, a treatment can become popular in
the HIV/AIDS community within a short period of time.

 The impact of the use of alternative treatments on people with HIV and AIDS
is often downplayed, but there can be serious repercussions. Other than the
possibility of toxic side effects, alternative treatments can also drain
financial resources. The costs of these treatments are almost never covered
by health insurance, and some may be very expensive even though they come
from inexpensive sources. A one-month supply of both bitter melon capsules
and curcumin tablets costs approximately $60 per month (Healing Alternatives
Foundation, 1994). A recent survey of health-food stores in New Orleans found
that most stores recommend a combination of products that costs an average of
$35 per month (Phillips, 1994).

 The difficulty of finding reliable information and reliable (i.e.,
non-fraudulent) alternative treatments provokes skepticism about their use.
A debate has raged within the AIDS community for years about how to stay open
to new, potentially helpful treatments without putting people's health and
financial security at risk. In 1987 John James described the dilemma that
still faces us today: "With so much unknown about AIDS, and with existing
treatments so unsatisfactory, it will be hard to find consensus on how to
distinguish legitimate, unproven and unconventional treatment attempts from
unconscionable schemes to exploit people's desperation" (James, 1987).

 There is also an ongoing debate about the roles of government and business
in the development of alternative treatments. Some people believe that the
use of effective alternative treatments has been actively repressed by the
research establishment; others believe that a self-selecting process is at
work, whereby effective treatments become popular through their own successes
in the community.  Since alternative treatments by definition cannot be
patented, money is an important element that is lacking in the development of
these treatments. Since alternative treatments are of little interest to
pharmaceutical companies, they are not pushed through the multi-million
dollar development process the way that commercially viable pharmaceutical
products are. In a few rare cases, drugs developed from alternative
treatments have been patented, but these efforts have largely failed. An
example of this is pseudohypericin, a form of hypericin, which showed
disappointing results in a recent clinical trial.

 Of the millions of dollars that have been spent studying potential AIDS
treatments, only a fraction of the money has gone into studying alternative
treatments that do not have pharmaceutical backing. The few treatments
studied with government funding include Compound Q (GLQ223), pseudohypericin,
N-acetylcysteine (NAC) and marijuana (Marinol). Currently, there are plans
for a small number of studies through the OAM, including a study of
traditional Chinese medicine for the treatment of HIV-related sinusitis.

 For years, AIDS activists have demanded well-conducted clinical trials of
treatments that are widely used in the AIDS community. One activist, Jon
Greenberg, who died of AIDS in 1993, was intent on having alternative
treatments undergo the same scrutiny as other drugs:

 "When questioned, most honest alternative practitioners will confess that
their prescriptions of a specific dose of an herbal compound are based more
on intuition than science. Although this may be acceptable in the hands of a
gifted practitioner, too often these same treatments are sold
over-the-counter with no more information than can be found on a jar of
instant coffee" (Greenberg, 1992).

  A Review of Popular Alternative Treatments

 Acemannan

 Acemannan is a polysaccharide, or complex sugar, extracted from the aloe
vera plant, Aloe barbardensis Miller. Aloe vera has been long noted for its
healing properties, and is used in many cultures as a treatment for burns.
Acemannan, which comes in an injectable form, was patented by Carrington
Laboratories under the brand name Carrisyn. It has been FDA-approved for the
treatment of fibrosarcoma, a form of cancer, in cats and dogs.

 People with HIV and AIDS sometimes use the raw form of aloe vera juice, but
the concentrations of the active proteins may not be high enough to be
effective (Korsia, 1991). Laboratory studies have shown that Carrisyn is
active against HIV and enhances the efficacy of AZT (Kahlon, 1991). Carrisyn
is also thought to stimulate the immune system, and has been promoted for use
in combination with dinitrochlorobenzene (DNCB). There is much controversy
about how these 2 treatments work, but perhaps as they become more widely
used, better clinical studies will reveal more information (Andriote, 1993).

 Clinical studies of Carrisyn have generated contradictory results. In a
trial conducted for Carrington Labs, half of the participants taking 250 mg
four times a day had a 10% increase in CD4 cell counts (McDaniel, 1990). In
contrast, a clinical trial conducted more recently by the Canadian HIV
Clinical Trials group did not have similar findings. This placebo-controlled
trial, which enrolled 62 patients with CD4 counts between 50 and 300, looked
at whether Carrisyn was synergistic with AZT or ddI. The results showed that
the CD4 counts of people taking Carrisyn declined more slowly than those on
placebo but, by the end of the 48-week study, both groups had similar losses
in CD4 cells. No difference was noted for p24 antigen, and no synergistic
interaction with the antiretroviral drugs was observed (Singer, 1993).

 Bitter Melon

 Bitter melon, Momordica charantia, was first used for treating HIV by a
Filipino man who was familiar with its traditional use as a treatment for
leukemia in the Philippines. By 1992 bitter melon had become extremely
popular, and support groups for people using it formed in many major cities
around the country. Juice and/or tea made from the leaves and vines are used
as a retention enema. Coated capsules of a freeze-dried powder are also
available through buyers' clubs. Recently, the popularity of bitter melon has
declined, even though there have been anecdotal reports of patients
experiencing large increases in CD4 cells (Zhang, 1992). However, these
findings have not been duplicated in a well-designed clinical trial.

 A protein from bitter melon, MAP 30, has been shown in laboratory tests to
effectively kill HIV-infected cells and to inhibit a common herpesvirus
(HSV-1) without causing cellular toxicity. It also stops cell-to-cell
infection and inhibits viral replication (Lee-Huang, 1990). No clinical
studies of MAP 30 have been implemented. Two other proteins isolated from the
bitter melon plant have been found to have immunological effects. Although
their modes of action are unclear, these proteins may work synergistically
(Leung, 1987).

 Curcumin

 In 1993 reports began to circulate throughout the AIDS community about the
alleged anti-HIV properties of curcumin, a compound found in the food spice
turmeric. Interest was fueled by anecdotal experiences and laboratory studies
that seemed to show that curcumin was a relatively safe and effective
anti-HIV agent.

 A mainstay of traditional Indian and Chinese medicine, turmeric is now under
study for its possible anti-cancer, anti-inflammatory and antioxidant
properties. Due to its wide availability, turmeric could be important for the
treatment of HIV infection in developing countries. Search Alliance in Los
Angeles has recently completed the first study of curcumin in people with
AIDS. No results have been released.

 DNCB

 Recently, there has been a resurgence in the popularity of DNCB
(dinitrochlorobenzene), an alternative treatment that first became popular in
the AIDS community in 1986. In fact, DNCB is now the most popular treatment
sold at the Healing Alternatives Foundation buyers' club in San Francisco.
This renewed interest can mostly be attributed to a group of zealous
supporters in San Francisco.

 In recent years there have been anecdotal reports of individuals having good
results with DNCB, particularly for the treatment of Kaposi's sarcoma
lesions, but scientific research on the drug has shown negative results. In
a recent study of 24 HIV positive gay men, CD4 cells dropped from a mean of
353 to 251, after 12 months of treatment with DNCB (Stricker, 1993). Using an
unconventional theory to explain AIDS pathogenesis, supporters look at this
same study and declare it a success.

 While most alternative treatments are derived from natural sources, DNCB is
a chemical that was first used in photographic development. It was later used
as a treatment for warts. Painted onto a patch of skin, DNCB causes an immune
response known as delayed-type hypersensitivity. This is believed to cause a
type of immune suppression that is desirable when fighting an autoimmune
disease (Stricker, 1991).

 DNCB supporters argue that all treatments for HIV/AIDS except for PCP
prophylaxis should be discontinued. Considering the many questions regarding
the therapeutic effectiveness of DNCB, it may be dangerous to stop using
other treatments that have shown beneficial effects (Gilden, 1993).

 Glycyrrhizin

 Glycyrrhizin is an extract from the root of the licorice plant Glycyrrhiza
radix, which is sometimes referred to by the brand name Stronger
Neo-Minophagen C (SNMC). Licorice root is a common ingredient in traditional
Chinese herbal remedies, recommended for its anti-inflammatory properties.
Currently, glycyrryzin is used in Japan as a treatment for hepatitis (Berger,
1990). Laboratory studies have found that it is also has a strong anti-HIV
effect, and clinical studies have shown similar results (Ito, 1987; Hattori,
1989). Glycyrrhizin is administered intravenously, which is one reason why
the treatment has not become very popular in the United States. Glycyrrhizin
may cause serious side effects, including high blood pressure and heart
complications (Kassler, 1991).

 A number of clinical studies of glycyrrhizin conducted in Japan have shown
promising results, but a more recent study was less convincing. In 1993,
researchers from 9 different Japanese universities followed 42 hemophilia
patients with HIV. They found that glycyrrhizin at high doses (over 400 ml
per day) caused increases in CD4 counts and improvements in clinical
symptoms, but these changes were not statistically significant. More
encouragingly, researchers observed improvement in liver function, which is
damaged in many HIV positive hemophilia patients (Mori, 1993).

 Homeopathy

 Homeopathy, created in Germany in the nineteenth century by Dr. Samuel
Hahnemann, remains popular in Europe to this day. It is believed that up to
25% of European doctors prescribe homeopathic remedies in their practice
(Horvilleur, 1986).

 The scientific rationale behind homeopathy causes confusion because it is in
direct opposition to the standard allopathic medical model prevalent in the
U.S. Homeopathy ascribes to "the 'law of similars'-_that is, a substance
which creates in overdose a specific set of symptoms in a healthy person will
cure these similar symptoms in a sick person when given in very small doses"
(Homeopathic Education Services, 1993). Apparently, homeopathy depends upon
the ability of the immune system to mount a response. In people with advanced
HIV disease such an immune response may not be possible.

 Homeopathic treatments, which usually come from herbs or flowers, were
discovered by Hahnemann through trial and error. Oddly, he found that using
less of an antigen provoked a proportionally stronger reaction. Therefore,
the resulting remedy is usually a small sugar pill that no longer contains
any of the actual antigen, since it has been extracted thousands of times.
Therefore, these remedies are generally considered safe. Although there is no
standardized training for homeopathic practitioners, it may be helpful to
consult someone knowledgeable before beginning treatment (Horvilleur, 1986).

 Hypericin

 Extracted from the plant St. John's Wort (Hypericum perforatum), hypericin
was used in Europe in the 1940s as a treatment for depression
(Scott-Hartland, 1993-94). In laboratory studies, hypericin inhibits HIV
replication in infected cells, protects laboratory animals from infection
with some retroviruses, and is not toxic to cells. Hypericin has also been
found to be effective against cytomegalovirus (CMV) and human papillomavirus
(HPV), suggesting a wide range of uses in the treatment of people with HIV
and AIDS (Meruelo, 1988; Schinazi, 1990). Compared to other alternative
treatments, hypericin was on a drug development fast-track. Pharmaceutical
backing eventually led to a government- funded clinical trial of
pseudohypericin, an intravenous formulation made by VIMRx Pharmaceuticals.
Unfortunately, this study showed that pseudohypericin caused phototoxicity
(abnormal sensitivity to sunlight or other strong light) in patients taking
2 mg twice a week. The trial was stopped and restarted with lower doses (0.25
mg/kg, 2 or 3 times weekly.) This dose also caused light sensitivity, and the
study was generally regarded as a failure (James, 1992). A new study of an
orally administered version of pseudohypericin is currently underway at New
York University (call 212-263-8724 for more information).

 These side effects were not reported in anecdotal use of the natural form of
hypericin. It is possible that the natural form contains some important
element that is lacking in the synthetic version. Plant extracts sold in
health-food stores are rarely pure enough to contain only the desired
chemical components; the more primitive form of a product may actually
contain a synergistic combination of active agents. However, it is difficult
to standardize the doses of natural hypericin, which lacks the financial
backing of pseudohypericin.

 Iscador

 Iscador is an extract of the mistletoe plant, Viscum album. Animal studies
of Iscador indicate that it has anti-tumor properties, and is active against
lung cancer (Hajto, 1989; Khwaja, 1983). There also have been claims that
Iscador has anti-HIV and immune-stimulatory properties (Gorter, 1992).

 Iscador is the first and only whole plant substance to be given
Investigational New Drug (IND) status by the FDA for a clinical trial in
people with AIDS. This means that the chemical components of this plant
extract do not have to be analyzed separately, which could save millions of
dollars and years of research. The IND has not been followed by a clinical
trial, and research in the United States has stalled. Research has continued
in Europe, where Iscador has been a popular alternative cancer therapy since
the 1960s.

 The brand name Iscador is applied to the fermented and unfermented extracts
of both European and Korean mistletoe. Mistletoe, a parasitic plant that
lives on trees, can also be classified by the type of tree on which it grows.
These different varieties of mistletoe may have different medicinal
properties. According to one researcher, patients are not receiving the same
type of mistletoe used in the laboratory research (Khwaja, 1992).

 In one laboratory study, researchers found that a lectin from  mistletoe
promotes the expression of tumor necrosis factor (TNF), a cytokine that has
been associated with increased HIV replication and wasting syndrome in people
with AIDS. These contradictory findings may be partially explained by the
complex nature of plant extracts (Mannel, 1991).

 Iscador is administered by intramuscular injection, which may cause welts at
the site of injection and fevers. At the IX International Conference on AIDS
researchers released data on 40 patients who gave themselves injections of
0.01 to 10 mg of Iscador twice a week for 18 weeks. They reported that 77% of
the patients had CD4 cell increases of greater than 20%. This unblinded study
has not been published, leaving these results questionable.

 Shark Cartilage

 Kaposi's sarcoma (KS) involves a proliferation of blood vessels
(angiogenesis) that is similar to the network of blood vessels that grow
around cancerous tumors. Although pharmaceutical companies have been testing
angiogenesis inhibitors for some time, they still are not available for
general use. In the meantime, a natural angiogenesis inhibitor has been found
in shark cartilage, a discovery made partially on the basis of scientists'
observation that sharks rarely get cancer. In one study, tumors introduced
into the eyes of rabbits failed to grow in the presence of shark cartilage
(Oikawa, 1991).

 Anecdotal reports of the use of shark cartilage in humans generally have
been positive (Callen, 1992), but one study showed mixed results. Search
Alliance in Los Angeles conducted a study of shark cartilage for the
treatment of KS. Since oral administration had not been shown to produce
effective blood levels, they compared an oral formulation to retention
enemas. Upon completion of the study, all the participants switched to oral
administration, and half dropped out of the study because they couldn't
tolerate the treatment's foul taste or because they experienced intense
nausea. The study results showed that patients did not improve by taking
shark cartilage alone, but using it in combination with radiation therapy had
a synergistic anti-tumor effect. Much less radiation was needed when used in
combination with the shark cartilage (Fleischman, 1993).

 Soybean

 Recently there has been some discussion about the possible anti-angiogenetic
qualities of a protein found in soybeans called genistein. In a laboratory
study, genistein was found to inhibit angiogenesis, the abnormal growth of
blood vessels seen in Kaposi's sarcoma and other cancerous tumors.

 Genistein occurs naturally in the body as a result of eating soy products.
Researchers found that patients on a traditional Japanese vegetarian diet
have 30 times more genistein in their urine than patients on a typical
western diet. According to the laboratory study results, this concentration
would be high enough to have activity against angiogenesis. But conclusions
cannot be drawn until the effects of genistein in patients with KS have been
studied.

 Unlike the other treatments discussed in this article, genistein does not
have a history of use in the AIDS community. Nutritional approaches to the
treatment of AIDS have been explored, but diet is a difficult area to study,
and so far little research has been done (James, 1994; Fotsis, 1993).

 Therapeutic Activities (exercise, massage)

 In his book Immune Power: A Comprehensive Treatment Program for HIV, Jon
Kaiser, MD, discusses the importance of combining alternative approaches with
standard allopathic treatment regimens. He also emphasizes the importance of
a holistic approach that goes beyond the medicinal herbs that are usually
associated with alternative medicine:

 "It is important to realize that these herbs should comprise one component
of an overall treatment program that includes a healthful diet, vitamins,
exercise, stress reduction, and, when indicated, standard pharmaceutical
medications. This type of overall approach will enable your herbal program to
work much more effectively_The immune strengthening value of each of the
individual therapies potentiates the other therapies. This enables the
overall program to more effectively keep HIV dormant" (Kaiser, 1993).

 Clinical trials to evaluate the therapeutic benefit of activities such as
exercise, massage and meditation are difficult to conduct. Recently, however,
the Office of Alternative Medicine (OAM) made 2 grants for the study of the
possible immune-enhancing effects of massage. One study will be in preterm
newborns of HIV-infected mothers and the other will be in patients with
advanced AIDS (Burroughs, 1993-94). If done carefully, therapeutic activities
have neither contraindications with drug treatments nor noticeable
toxicities, indicating they can be an effective complement to an HIV
treatment strategy.

 Holism and Indigenous Medicines

 One aspect shared by most non-western healing traditions is a belief   in
holism_the idea that the physical body is inseparable from the mind,
emotions and spirit. In this thought system, all beings possess an
essential healthy balance that in illness is somehow lost. Treatments
usually focus on restoring that balance so that the body can then heal
itself with its own natural abilities (Chopra, 1991).

 Unlike allopathic medicine, traditional medical systems usually focus   on
resolving symptoms of illness instead of attacking a specific   pathogen.
This difference highlights a complementary relationship that   can develop
between holistic treatments and western medicine that, when   used together,
addresses all aspects of the patient (Kaiser, 1993). In a   sense,
traditional medical systems focus on "who you are," while western   medicine
focuses on "what you have" (Ryan, 1994).

 Allopathic medicine tends to view the body as a war zone where   battles
against invading organisms are fought, and won or lost. From   this
foundation, therapeutic approaches are usually based on our   intellectual
ability to understand the nature of the battle being fought   and to employ
an effective arsenal of weapons.

 For some HIV-related opportunistic infections, allopathic treatments   such
as the use of antibiotics for fighting Pneumocystis carinii   pneumonia (PCP)
are effective. But with other conditions the allopathic   approach has been
less successful.

 Perceptions of mortality also influence a culture's medical traditions. For
instance, a given culture may use medicine to fight off   death, or to make
a limited lifespan as comfortable as possible. The   prognosis of a disease
is affected by these different philosophical   approaches, as are the
eventual course and outcome of a disease.

 African Herbal Medicine

 With the onset of illness, almost all Africans with HIV go to   traditional
healers before they visit western-trained doctors. With   their direct access
to the general population, traditional practitioners   could play important
roles in education, prevention and treatment.   Unfortunately, this
potentially invaluable resource is not being put to   efficient use
(brochure, VII International Conference on AIDS in Africa,   1992).
Traditional African medicine uses a variety of different healing
techniques, including spiritual and mystical practices, dance and herbal
medicines (International Organization of Traditional and Medical
Practitioners and Researchers, 1991).

 Fokoundang Adam Usumanu, a traditional healer from Cameroon, uses the   bark
of the Corynanthe johimbe tree for treating impotence in men   (Usumanu,
1992). In the United States, yohimbine, an extract from this   same tree, is
a prescription drug used for the same purpose. There have   been reports of
people with HIV who have had positive results using   yohimbine for the
treatment of HIV-related fatigue (James, 1992). This   coincidence supports
the idea that traditional healers have knowledge of   useful treatments that
may be unknown to western pharmacists.

 In Tanzania, research has been conducted on the effects of herbal   remedies
in Africans with HIV infection and AIDS. In 2 cases,   traditional African
healers teamed up with western-trained doctors to   study African herbal
remedies (the ingredients of which were not   described). They conducted
preliminary, uncontrolled clinical studies   with over 100 participants. In
both studies, over 75% of the patients   showed improvement. Unfortunately,
these studies are too vague to permit   the drawing of conclusions other than
the need for more studies   (Lugakingira, 1992; Scheinman, 1992).

 Ayurveda

 The indigenous healing tradition of India, Ayurvedic medicine, is   said to
be over 5,000 years old. Like other forms of traditional   medicine, Ayurveda
is based on a holistic model. The goal of Ayurveda is   to return the body to
a state of balance and health by emphasizing the   body's natural healing
abilities. Treatment may include herbal remedies   and teas, nutrition,
exercise (yoga), meditation, aromatherapy, music   therapy, massage and
detoxification through the use of enemas or other   cleansing techniques
(Ayurveda Health and Education Resources of San   Francisco, 1993).

 Ayurveda has received a lot of attention recently with the popularity   of
books by Deepak Chopra, a medical doctor and traditional Ayurvedic
practitioner, who has attempted to combine the 2 approaches into a   single,
comprehensive view of health:

 "The guiding principle of Ayurveda is that the mind exerts the   deepest
influence on the body, and freedom from sickness depends upon   contacting
our own awareness, bringing it into balance, and then   extending that
balance to the body. This state of balanced awareness,   more than any kind
of physical immunity, creates a higher state of   health" (Chopra, 1991).

 Traditional Chinese Medicine

 When the first cases of AIDS were diagnosed, western medicine had   little
to offer people who were suffering from a disease that seemed to   come from
nowhere, i.e., had no readily identifiable cause. In contrast,
practitioners of traditional Chinese medicine (TCM) then and now focus   on
the symptoms of AIDS, fitting it into their models of disease as best   they
can (Cohen, 1990).

 In TCM, health is understood to be a balance between a variety of
constantly changing variables. "TCM emphasizes treatments which enhance   the
body's natural immunities so that it may more effectively resist   disease.
Specifically, the fundamental principles of TCM for the   treatment of
infectious diseases are: fu zheng (supporting the body's   natural order,
i.e., enhancing immunity), and quxie (eliminating   external evil, i.e.,
reducing the potency of the pathogen)" (Zhang,   1990).

 Treatment with TCM generally consists of drinking brewed medicinal   herbs
(similar to a very strong tea), and acupuncture, but may include   breathing
exercises (qigong) and massage. Acupuncture is used to control   pain or, in
combination with qigong, to increase the circulation of qi   (life energy).

 There is some confusion about the effects of the medicinal herbs on   the
immune systems of people with HIV and AIDS. "Some of the herbs which   are
used to treat depressed immunity also appear to successfully treat
autoimmune diseases (which in western medicine are treated by inhibiting
rather than enhancing immune function). This suggests that the complex
herbal ingredients effectively modulate or regulate the immune functions
instead of simply stimulating them" (Dharmananda, 1989).

 Some of the herbs most commonly used in Chinese medicine for the   treatment
of immune disorders are Astragalus membranaceous and different   forms of
ginseng (Eleutherococcus senticosus and Panax notoginseng)   (Sun, 1983; Liu,
1992). Some Chinese herbs have been found to be active   against HIV in
laboratory studies, including Viola Yedoensis, Arctium   lappa and
Andrographis paniculata (Chang, 1988). The precise mode of   action of these
herbs in unknown, but they are very potent-_and   therefore as dangerous as
some pharmaceutical drugs with severe toxic   side effects. Anyone
considering using Chinese herbal medicine should   see a qualified Chinese
herbalist.

 A few clinical studies of TCM in the treatment of HIV-specific   disorders
have been conducted. A study of acupuncture for the treatment   of
HIV-related peripheral neuropathy showed a small improvement in
"quantitative sensory testing" (a test of sensitivity to applied
stimulation in the hands and feet). TCM also caused self-reported
improvement in quality of life. Although preliminary, these findings
attempt to systematically study the effects of a treatment that is
difficult to measure by western medical standards (Tosches, 1993).

 Over the years a number of observational studies have been done on   the
effects of Chinese herbal formulas on patients with HIV and AIDS.   These
studies show improvements in symptoms, but because they are   generally
unblinded and without control groups, the results have to be   viewed with
skepticism (Young, 1993; James, 1987; Hawkins, 1993).

 San Francisco General Hospital recently concluded the first double-blinded,
controlled clinical trial at a major research   institution of a Chinese
herbal compound for the treatment of AIDS.   Misha Cohen, director of Quan
Yin Chinese Herbal Clinic in San   Francisco, formulated the compound and
collaborated with western-trained   researchers in this ground-breaking study
(Burack, 1993). This   placebo-controlled study had 30 symptomatic subjects
whose CD4 counts   were between 200-500, but who did not have an AIDS
diagnosis. For 12   weeks participants took 28 pills per day of a Chinese
herbal formula   similar to Enhance, a popular Chinese herbal compound.

 The pilot study showed that there was a statistically significant
improvement in the areas of "life satisfaction," fatigue,   gastrointestinal
symptoms and neurological symptoms, all of which were   measured by
standardized questionnaires. The small sample size limits   the scope of
these findings, but these 4 outcome variables are all areas   that western
medicine has been particularly unsuccessful in treating. If   future
research, undertaken on a larger scale, can reproduce these   results, it
would have a serious impact on the standard of care in AIDS   treatment.

 According to a new book entitled, Treating AIDS with Chinese Medicine,
"Western science has yet to arrive at a satisfactory or   complete
explanation of TCM. Although acupuncture and Chinese herbs are   understood
to have measurable, biochemical effects, these effects do not   fully, or
often adequately, explain the therapeutic efficacy of the   system. In
addition, acupuncture and Chinese herbs can be very difficult   to test via
standard western methods because the treatment approach is   based on
entirely different concepts. The result has been that TCM has   been ignored,
underestimated as nothing more than a pain-reliever, and   under-utilized"
(Ryan, 1994).

 One of the studies approved this year by the OAM is a study of TCM   for the
treatment of HIV sinusitis. This will be a blinded study with 40
participants receiving either the standard pharmaceutical treatment
(augmentin) for 28 days, or a Chinese herbal formula and weekly   acupuncture
for 12 weeks. This study will be conducted by Tom Sinclair   at the Immune
Enhancement Program in San Francisco (415-252-8711).

 Psychoneuroimmunology

 Another positive aspect of alternative treatments, which may not be
discernible in clinical trials, is the placebo effect, which occurs   because
one believes that a treatment being used will be helpful.   Similarly, the
process of taking an active role in one's own health care   may play an
important role in the success of alternative treatments. In   fact, emotional
status and general state of mind both seem to have an   effect on physical
well-being.

 Both of these effects are being studied in a new field of science   called
psychoneuroimmunology (PNI), which examines the relationships   between
psychology, neurology and immunology. PNI seems to be western   science's
attempt to understand and integrate the concept of holism. The   word
psychoneuroimmunology can itself be understood as a reflection of   the 3
aspects of holism: spirit (psyche), mind (neuro) and body   (immuno).

 The results of a well-known study of women with breast cancer at   Stanford
University depict the impact that emotions have on health. In   this study,
women who were involved in a support group with other   patients benefitted
from the emotional support of the other women and   had an increased lifespan
of 2 years (Spiegel, 1989).

 This approach is also being used by people with HIV and AIDS. At   UCLA,
Margaret Kemeny, PhD, found that chronically depressed people with   HIV had
much steeper declines in their immune systems over a 5-year   period than
those who were not depressed (Kemeny, 1991).

 It will be some time before the research techniques used to study PNI   are
standardized. Until then, studies will have to be scrutinized with   extra
care. A general review of research in the area shows that while   results are
often contradictory, there is enough evidence of a positive   correlation
between emotional health and immune status to support   further study
(Solomon, 1990; Antoni, 1992).

 The relationship between depression and immune function has come   under
question after the results of 2 major studies were recently   published. The
Journal of the American Medical Association reports that   while a study
completed at the University of California at San Francisco   showed a
positive correlation between depression and immune system   decline, a more
thorough study conducted at John Hopkins University   showed the opposite,
i.e., no correlation (Lyketsos, 1993; Burack,   1993).

  Conclusion

 In many ways the alternative treatment movement has been in reaction   to
perceived limitations of western medicine. This has caused   re-examination
of some of the basic elements of clinical research and   treatment, and
created some changes. One result is that many people with   AIDS have taken
their healthcare decisions into their own hands, using   themselves as guinea
pigs to try out new and unproven treatments.   Patients also are educating
themselves, and becoming more involved in   planning their treatment
strategy. In another divergence from standard   medicine, alternative
treatments are being employed as preventive   measures, to support and
prolong health.

 Political changes have also occurred, such as the creation of the   Office
of Alternative Medicine at the NIH, which bodes well for the   integration of
alternative treatments into the standard western model.   But it is unlikely
that indigenous medical systems can be integrated as   easily since they are
based on different philosophical approaches to   healing. Perhaps new fields
of medicine, such as psychoneuroimmunology,   will begin to bridge the gaps
between allopathic medicine and holistic   approaches.

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 Lyketsos CG and others. Depressive symptoms as predictors of medical
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lectin from Viscum album. Cancer Immunology & Immunotherapy 33(3): 177-182.
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 Mori K and others. Effects of glycyrrhizin (SNMC) in hemophilia patients
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 Ryan MK and Shattuck AD. Treating AIDS with Chinese Medicine. Pacific View
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 Schinazi RF and others. Anthraquinones as a new class of antiviral agents
against HIV. Antiviral Research 13(5): 265-272. May 1990.

 Scott-Hartland B. Common alternative therapies. Treatment Issues 7(11/12):
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 Tosches W and others. A pilot study of acupuncture for the symptomatic
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  Guidelines for Using Alternative Treatments

       ∙ Research the treatment that you are interested in, including
         information on dosing amount, dosing regimen and side effects.
         Local buyers' clubs, AIDS organization libraries and treatment
         newsletters may have useful information. Be skeptical about what
         you read since the author may be biased in some way. Also, the
         media has a tendency to focus on or create a "drug-of-the-month,"
         which can be dangerous because little is usually known about
         treatments that become big news this way. Peer-reviewed journals
         are the best source for medical information, because articles in
         these publications have to pass a qualified board of knowledgeable
         individuals.

       ∙ Seek out people who have had both good and bad experiences
         with the treatment you are interested in. It is always a good idea
         to investigate possible negative side effects of a treatment. AIDS
         organizations in some cities have support groups for people using
         alternative treatments.

       ∙ Consult your doctor before you begin an alternative treatment
         to make sure that it is not contraindicated with any medication
         that you are currently using. Contrary to popular opinion, herbs
         and vitamins can have very serious side effects and can be
         dangerous in combination with other drugs. People often mistakenly
         believe that a "natural" substance cannot do them any harm.

       ∙ Be cautious of "secret formulas." Anyone unwilling to say
         what is in their product, thereby avoiding public discussion about
         their treatment, could be hiding something. Be wary of questionable
         scientific explanations for the way a treatment is supposed to
         work.

         In some cases it is appropriate for someone not to disclose the
         ingredients of their treatment. For example, some traditional
         healers do not like to give out their formulas because that is how
         they make a living.

       ∙ Shop around to get the best price, particularly since the
         cost of alternative treatments is not reimbursed by insurance or
         government programs. Supposed AIDS "cures," sold in the U.S. and
         abroad for huge amounts of money, often turn out to be frauds.

         Before making a large financial investment, consider lower-priced
         alternative treatments that are available locally. San Francisco
         currently has programs for free or low-cost traditional Chinese
         medicine and acupuncture for people with HIV/AIDS (see resource
         list, page 8). Some health food stores give a discount to people
         with HIV/AIDS, but buyers' clubs, which are usually run as nonprofit
         organizations, generally have the lowest prices around.

       ∙ Buyer beware. The manufacturers of alternative treatments
         have no watchdog agency to monitor the accuracy of product contents
         and labels. Products may be contaminated with other, possibly
         dangerous, substances.

       ∙ Take an organized approach. Try one treatment at a time, for
         a set period of time, so that you can monitor yourself to see if it
         is working. Starting multiple treatments at once can make it hard
         to determine the effect of a particular treatment. Since many
         alternative treatments are expensive, careful monitoring of your
         health can save you money by allowing you to weed out those that do
         not work.

         Keeping a journal of how you feel and fluctuations in your
         weight can be helpful. Having your blood work done before and after
         using a treatment can also be useful, but the length of time it
         takes a treatment to work often varies. Some community
         organizations are doing their own studies of alternative
         treatments. (A survey of alternative treatments is being conducted
         currently by a community research group in Toronto. For more
         information contact the Toronto Community Research Initiative,
         416-324-9505 (phone), or 416-324-9921 (fax).)

       ∙ Use common sense about what feels right for your body. You
         are the only judge of how something makes you feel. Discontinue a
         treatment if you develop an unexpected rash or if you have
         difficulty breathing_these could be signs of a dangerous allergic
         reaction.

  Resources For More Information On Alternative Treatments

  American College of Traditional Chinese Medicine Community Clinic,
  San Francisco, CA, 415-282-9603.

  Carl Vogel Center, buyers' club, Washington, DC, 202-289-4898.
  Center for Natural and Traditional Medicines/The NATC Caucus of the

  International AIDS Society, 1601 Connecticut Ave. Suite 201C,
  Washington, DC, 20009, 202-234-9632. This group works mainly on
  political issues and on organizing conferences, particularly the
  International Conferences on AIDS.

  Direct AIDS Alternative Information Resources (DAAIR), buyers'
  club, New York, NY, 212-689-8140.

  Healing Alternatives Foundation, buyers' club, 1748 Market Street
  #204, San Francisco, CA, 94102, 415-626-4053. (Contact local AIDS
  organizations to find out about local buyers' clubs.)

  Immune Enhancement Program, Chinese medical clinic, San Francisco,
  CA, 415-252-8711.

  PWA Health Group, buyers' club, New York, NY, 212-255-0520.

  Quan Yin Chinese Herbal Clinic, San Francisco, CA, 415-861-4964.
  San Francisco Center for Living, 4054 18th St., San Francisco, CA,
  415-252-1666. This nonprofit institution assists people with
  life-challenging illnesses (and their families and friends) by
  offering support groups, individual counseling, healing circles,
  meditation classes and bodywork (massage). Also, in New York City
  at 212-533-3550 and Los Angeles at 213-655-4802.


       **********

 Aggressive Intervention
  in HIV Disease:
 An Interview with 4 San
  Francisco Physicians
 Mark Bowers

 Mark Bowers is a medical writer and AIDS treatment activist.

  BETA asked 4 San Francisco physicians who treat adult patients with
 HIV disease to provide a template for aggressive early intervention to
 slow disease progression and possibly extend life. We also asked for
 their views on other treatment issues: which vaccines are recommended
 for HIV positive people? What measures of disease progression are most
 reliable? What opportunistic infections warrant prophylaxis?

  Paul Volberding, MD, is Director of the AIDS Activities Division at
 San Francisco General Hospital. Mary Romeyn, MD, an internist with an
 HIV practice in San Francisco, is the author of a forthcoming book
 entitled Nutrition and AIDS: a New Model for Treatment. Gifford Leoung,
 MD, is Medical Director of HIVCare at Saint Francis Memorial Hospital.
 Stephen Follansbee, MD, is Medical Director of the Institute of HIV
 Treatment and Research at Davies Medical Center in San Francisco.
 Drs. Volberding and Romeyn see many patients in the early stage of
 HIV disease, and both have strong views about the value of early
 intervention and aggressive treatment for HIV infection. Drs. Leoung and
 Follansbee specialize in infectious diseases; most of their patients are
 symptomatic.

 BETA: What are the most aggressive early strategies that you offer to
 your HIV positive patients?

 VOLBERDING: What do we mean by early intervention? I think one of the
 big changes in the past year and a half is the sense that our definition
 of early treatment has broadened. Early intervention used to be offered
 to all asymptomatics with CD4 counts below 500. We now know from
 research on the pathogenesis of HIV disease that true early intervention
 is therapy applied as soon as possible after HIV infection occurs,
 before the virus damages the lymph nodes. In fact, the breakdown of the
 lymphoid system and the resultant release of virus [into the
 bloodstream] occurs at a count of about 500 CD4 cells.

 There are many health-promoting activities that can be started before
 antiretroviral drug therapy is considered. One issue that keeps coming
 up is the realization that physicians should discuss lifestyle issues
 with HIV positive individuals. The provider can work with each patient
 in a one-on-one, confidential manner to ensure that the individual
 understands how the virus is transmitted and is not engaging in
 behaviors that will put other people at risk for becoming HIV positive.
 So one important aspect of early intervention is prevention of HIV
 transmission.

 In terms of preventing disease progression, there are ways to empower
 patients to decrease their risk of progression. We talk about stress
 reduction, appropriate diet and the necessity of avoiding excessive use
 of recreational drugs, including alcohol. These are important parts of a
 program of early HIV care.

 Optimal drug treatment for people with HIV infection continues to be
 a source of controversy. Although a substantial amount of new data on
 the safety and efficacy of the nucleoside analogs [AZT, ddI, ddC, d4T]
 has been released during the past year, it is difficult to develop
 specific treatment algorithms that represent a consensus of most
 treating physicians. Increasingly, patients are prescribed combinations
 of nucleoside analogs as initial and, more commonly, secondary
 treatments. Because AZT plus ddC is [FDA-] approved for such an
 indication, there is more clinical experience with this combination. In
 both clinical trials and clinical practice, this combination apparently
 has not increased the toxicity anticipated from each drug given
 separately.

 AZT is the drug of first choice for patients beginning antiretroviral
 therapy. If patients are absolutely unable to tolerate AZT, then the
 decision to initiate a second antiviral, either ddI or ddC, is
 straightforward. If the patient tolerates AZT easily, there is the
 option of adding a second agent in continuous combination. On the other
 hand, if the patient experiences toxicity after beginning combination
 antiretroviral therapy, it is possible to initiate intermittent therapy.
 The patient could be continuously treated with the better-tolerated drug
 and the more toxic agent could be added, for example, on alternating
 months. Problems of drug toxicity require individualized treatment.

 ROMEYN: I discuss 7 basic principles with all my HIV positive patients.
 First, based on the results from new studies, we strongly recommend not
 smoking and not drinking alcohol. These activities create an environment
 of oxidative stress that encourages HIV replication. The in vitro data
 on alcohol and HIV is impressive. Social drugs that expend an
 individual's energy also are discouraged: we have all seen how quickly
 speed (methamphetamine) and cocaine can bring the immune system to its
 knees.

 Second, we inquire about the patient's work situation. If and when
 there is disease progression, we address chronic stress in the
 workplace. We work with the patient on an individual basis to minimize
 work-related stressors.

 Third, we ask whether the patient is having sex, and what kind of sex
 he or she is having. We strongly discourage unprotected oral sex and
 unprotected insertive sex, especially receptive anal sex. There is
 another dimension to this line of questioning: we want to know something
 about the emotional health and the support systems of our patients. We
 work especially hard on behavior modification with bipolar couples (one
 positive and one negative partner). We are currently treating one couple
 where the negative partner recently caught hepatitis B from the positive
 partner but, thankfully, did not seroconvert for HIV. We always test the
 negative partner at least yearly for HIV antibodies.

 Fourth, we test HIV positive patients and their partners for
 hepatitis B antibodies. If either person tests negative, we give a
 recombinant vaccine course as soon as possible. It would be
 irresponsible to do otherwise.

 Fifth, for all male gay patients, we test 3 times at intake for
 intestinal ova and parasites, even if they do not acknowledge having
 receptive anal intercourse. Sometimes a patient will not immediately
 feel comfortable telling me that. We look for cryptosporidium in
 patients with fewer than 500 T-cells. Perhaps we should look even
 sooner. When we find a pathogen, we treat for eradication if we can. In
 late-stage HIV disease, eradication of Giardia or Entamoeba histolytica
 is very difficult; it is more prudent to eliminate these problems early,
 if possible.

 Sixth, an important part of our approach to HIV management is through
 close monitoring of nutritional status and prevention of the wasting
 syndrome. We attempt to preserve or increase lean body mass. To do this,
 we need to be aggressive in the early identification and treatment of
 secondary infections that induce the endocrine and metabolic changes
 characteristic of HIV disease. Lean body mass is estimated by caliper
 measurements, although we hope to use an impedance monitor soon. A
 nutritional consultation is arranged for each HIV positive patient at
 intake.

 Triglycerides are monitored regularly, as a screen for increasing
 metabolic abnormalities. One of the earliest changes that we see in the
 gut of HIV positive patients is lactose deficiency. Therefore, we do not
 rely on milk products for nutritional value, although we support their
 use as comfort foods for pleasure. In contrast with dietary
 recommendations for other conditions, we recommend eggs and meat
 (excellent sources of protein) for patients in early-stage HIV disease.
 Also, we check vitamin B-12 and folate levels in every patient. When
 there are deficiencies, we supplement them. All of our patients are
 urged to take 2 multivitamins per day, as supplementation is shown in
 the literature to be of benefit. We also recommend a trace element
 supplement, because zinc and selenium levels may be reduced. AZT also
 lowers zinc levels. We are careful about not over-recommending beta
 carotene, because of the dangers of hypervitaminosis. Our conservative
 recommendation on antioxidants is to start with 1,000 mg of vitamin C
 and 800 units of vitamin E. Many of our patients take more.

 Seventh, we aggressively promote progressive resistance exercise for
 the early asymptomatic patient. Some patients have personal trainers;
 others join gyms; for those who cannot afford either, there are plans
 underway to connect them with trainers who offer free services to HIV
 positive clients. Aerobics are good early on, but not all of the results
 are in; we do know that there can be a drop in the immune status of
 marathon runners. We want to avoid continued stress from aerobic
 exercise, especially if and when there is disease progression. We are
 interested in the new attention being paid to the role of testosterone
 supplementation, and look forward to studies of its use in late-stage
 HIV disease.

 BETA: Setting aside candidate vaccines for HIV, which vaccines do you
 offer to your HIV positive patients?

 LEOUNG: All patients, if possible, should try to complete the usual
 childhood series of vaccines, if they haven't already. The only concern
 is the attenuated vaccines, like polio. These are not recommended,
 particularly for people who are symptomatic. Otherwise, people should
 try to complete the normal series. An annual influenza vaccine may be
 useful, although it's not clear how useful, particularly in people who
 have advanced HIV disease. But there is no evidence that it is
 clinically harmful.

 Other things worth considering are the pneumococcal and hemophilus
 vaccines. It is very clear that people with HIV at some stage have more
 and more problems clearing these organisms. They are both encapsulated
 organisms. We have good data to show that there is an increase in
 pneumococcal bacteremia and probably invasive pneumococcal disease, and
 we have data to show that there is an increase in hemophilus sinusitis
 and bronchitis/pneumonia. I think that it's worth it to offer those 2
 vaccines to patients even if they have not had any significant problem
 with these organisms before.

 FOLLANSBEE: We avoid live vaccines like BCG [a tuberculosis vaccine
 invented by the French researcher Calmette-Guerin_ Ed.], for example. We
 are using killed vaccines or subtype vaccines. The problem in adult HIV
 disease has been to assess the risks and consequences of some of these
 other bacterial infections, or of influenza. There is very little known
 about the consequences of viral influenza in someone with HIV disease.
 The literature has been contradictory. The official recommendation has
 been to vaccinate all HIV positive people for influenza on a yearly
 basis. I follow that recommendation, but there are a lot of unanswered
 questions.

 The pilot study done by the Gladstone Institute in conjunction with
 the Community Consortium looked at the possibility that vaccination with
 influenza vaccine may lead to a burst of HIV production. We looked at 30
 HIV positive individuals divided into 3 cohorts and 10 HIV negative
 controls. One cohort of 10 had more than 500 CD4 cells, one cohort had
 between 200 and 500 CD4 cells, and one cohort had fewer than 200. By
 using the current investigative methods for assessing HIV viral load,
 Chiron's branched DNA assay and QC-PCR, it appears that there is a short
 burst of virus activity in response to the influenza vaccination. This
 burst was detectable in all 3 cohorts; it appeared generally within 7
 days and maxed out at 14 days. This effect had been predicted, but not
 documented before. The increased replication began to diminish at 28
 days. The study was initially a 28-day study, so we brought almost
 everyone back for a repeat analysis at 13 weeks. Most individuals had
 returned to baseline. No fevers, sweats, chills or swollen lymph nodes
 were reported. There was no symptomatic change during the period of the
 study. No one came down with influenza, but there was no true epidemic
 in the Bay Area.

 Influenza itself, or any external challenge, may produce a similar
 viral burst or one that is logarithmically worse and prolonged. If a
 relatively weak vaccine of killed virus can do this, who knows what
 other challenges do. Most people were on antiretroviral therapy at the
 same time, except for the ones with more than 500 CD4 cells. The pilot
 study was so small that we can't really make any hard and fast
 conclusions.

 ROMEYN: We are giving the Pneumovax vaccination to any HIV positive
 patient as early as possible. We give tetanus and annual influenza
 vaccines. At this point in time we are not giving hemophilus influenza
 vaccination, although there is some interest in doing that with kids. We
 haven't seen a lot of hemophilus influenza in adults. We do a yearly PPD
 test for tuberculosis, and controls for comparison. Many physicians
 forget to do the controls and do not discover anergy until it is too
 late.

 BETA: Do you consider markers of progression other than CD4 counts? If
 so, how do you evaluate them when you are deciding to offer therapeutic
 interventions to your patients?

 VOLBERDING: This is probably the most interesting question in the field
 of AIDS research right now. However, it is a little premature to give a
 complete answer. At San Francisco General Hospital, we are investigating
 methods of viral quantitation. In our laboratory we have been evaluating
 both the Chiron branched DNA assay (bDNA) and qualitative competitive
 polymerase chain reaction (QC-PCR) from Genelabs. There is now
 absolutely no doubt that we can reproducibly measure how much virus most
 of our patients are carrying in their blood.

 My belief is that the information that these 2 new assays provide
 will prove to be extremely useful, both in estimating the risk of
 disease progression and in following the response to therapy. We do not
 yet know whether tracking the amount of HIV will improve the way that we
 use current antiretrovirals, because the drugs we have may not be potent
 enough to have much impact on the quantity of virus in the blood.
 However, we are designing clinical trials to answer that question. At
 San Francisco General Hospital, we plan to do these quantitation tests
 on a large population of patients in order to gain some experience with
 the assays. My hope is that these new tools will help us to manage our
 patients more effectively.

 FOLLANSBEE: I try not to rely on any one test: p24 alone, CD4 cell
 counts alone, a single CD4 cell count, or simply molluscum in the
 absence of anything else. I look at CD4 cell counts, but I also look at
 the CD4 percentage, as well as suppressor counts and the ratio. And I
 still follow p24 antigens. They're not perfect markers, but changes from
 undetectable to detectable levels of virus cannot be a good sign. I'm
 impressed that p24 levels are relatively constant from blood draw to
 blood draw in any given individual, without changing interventions. The
 main problem with respect to treatment is what can we really do about
 some of these endpoints. Some individuals are very cognizant of soft
 endpoints like the appearance of molluscum, for example, and will become
 quite concerned_and there may be reason for concern. The appearance of
 oral candidiasis or hairy leukoplakia also triggers my attention. In
 contrast, the resolution of chronic lymphadenopathy may not be good
 news. Resolution of lymphadenopathy may herald further seeding of the
 virus to other parts of the body. Those may seem like "soft endpoints"
 but, in fact, if they are changing at the same time that laboratory
 parameters are changing, then I think it's time to change therapy.

 LEOUNG: HIV positive people have always been concerned about weight
 loss, thrush and prolonged fevers. I think these symptoms are an
 indication that there is something going on. There can be considerable
 disagreement about whether or not to start someone on antivirals who has
 some of these findings intermittently but who has good T-cell counts. I
 am more concerned about people who have good T-cell counts with other
 infections such as Neisseria meningitis. We can treat the meningitis,
 and the patient recovers completely. Even though he had very good T-cell
 counts, to my mind, this person has an AIDS diagnosis. A person with a
 T-cell count of 500 or 600 who has significant illness deserves
 antiretroviral therapy much more than someone with a high T-cell count
 who has no additional illness.

 ROMEYN: Certainly, an abrupt drop in CD4 count or an abrupt change in
 ratio would catch my attention, but I don't check CD4 counts on sick
 people. If patients are in an acute state, we know their counts are
 going to be low, and we don't need to give people reasons to think that
 they are even sicker. I treat them, and then I check their CD4 counts.
 Under these circumstances, drops in CD4 counts are more meaningful. The
 last thing people need to hear when they are sick with pharyngitis or
 diarrhea, or some perfectly normal garden-variety bug, is that their CD4
 count is now 300 when it was 585 two months ago.

 I want to be very aggressive up front. I always start by telling
 people what the basic recommendations are, and then I explain how
 essentially proactive we are. We start by looking for things. I get
 almost every test in the world the first time. When I initiate
 treatment, I often recommend initiating double [combination] treatment.
 I tend to do double treatment with AZT and ddI. There's a new study that
 maybe makes ddC look a little better. I have patients with very high CD4
 counts who are on combinations of regimens, because they can afford it
 and they want it. These tend to be very proactive people.
 We monitor triglycerides very closely. We've seen that triglycerides
 are elevated as a result of the activation of an acute phase response to
 infection. For that reason, if triglycerides are up, I want to know why.
 I look for an underlying pathogen.

 I don't mind seeing people with hairy leukoplakia, because it gives
 me an excuse to put them on acyclovir to suppress Epstein-Barr virus
 (EBV). Acyclovir is shown to increase survival, whether or not people
 have herpes [herpes simplex]. But no managed care company will let me
 give a patient acyclovir if they don't have herpes simplex or
 Epstein-Barr. So, if I find hairy leukoplakia, I can write a script for
 acyclovir.

 BETA: Do you prescribe drugs for prophylaxis against opportunistic
 infections?

 LEOUNG: It has been clearly established that prophylaxis against
 Pneumocystis [PCP] is good. I participated in the first study that
 demonstrated that aerosolized pentamidine was useful. Since then there
 have been a number of studies that look at other agents, including
 trimethoprim-sulfamethoxazole, or TMP-SMX (Bactrim, Septra), and
 dapsone. It is clear that TMP-SMX works better than anything else that
 we have now for PCP prophylaxis. Because Pneumocystis only rarely occurs
 at CD4 counts above 200 in adults, I usually start prophylaxis at that
 point. Whether you use TMP-SMX or dapsone may not make any difference,
 although some evidence suggests Septra has greater efficacy against
 Pneumocystis, and it's cheaper. Therefore, if patients can tolerate
 Septra, there is no reason why they should not be on it.

 My personal feeling is that we should direct our antifungal therapies
 against Candida (thrush) because that is most common. I prefer to treat
 thrush with agents such as clotrimazole (Mycelex) or ketoconazole
 (Nizoral). I think you can get good therapy with those without having to
 go to fluconazole (Diflucan). I don't use fluconazole as prophylaxis
 against Cryptococcus. I feel that I can monitor patients for fungal
 diseases, catch them early when they occur, and treat them with a
 variety of means, including intravenous amphotericin plus or minus
 5-flucytosine, oral fluconazole plus or minus 5-flucytosine, and even
 itraconazole (Sporanox). And if I monitor my patients closely enough,
 then I can treat them early and effectively when they get fevers, which
 is one of the hallmarks of cryptococcal disease.

 Last year rifabutin (Mycobutin) was approved by the FDA for
 prophylaxis against MAC [in individuals with fewer than 100 CD4 cells].
 In the interim months, there has been a lot of concern from physicians,
 particularly infectious disease physicians, regarding the use of
 rifabutin for MAC prophylaxis, for a variety of reasons. One reason is
 that the studies do not actually show a change in survival [for those
 using prophylaxis]. They basically show that there was some decrease in
 some of the symptoms among some patients treated with rifabutin,
 compared with those who did not take rifabutin. There also appeared to
 be a delay in the onset of MAC-positive blood cultures in people
 receiving rifabutin, but this delay was temporary.
 My concern is that widespread use of rifabutin may cause resistance
 that will cross over to rifampin. If we lose rifampin as a useful agent
 against TB, we are going to be in big trouble.

 FOLLANSBEE: In the last year, despite the prevalence of fluconazole
 usage, we saw more cryptococcal disease. Fluconazole may in fact
 prophylax against cryptococcal disease. I believe it was [the results
 of] ACTG 098 that suggested there was some prophylactic value with
 fluconazole for Cryptococcus as well as for endemic mycoses, such as
 histoplasmosis or coccidioidomycosis. But I'm still relatively
 conservative, because I'm concerned about the other side of the coin
 with fluconazole, which is basically drug resistance, as well as drug
 interactions. I think that as we increasingly get into polypharmacy,
 particularly with many of the new antiretroviral drugs such as protease
 inhibitors, and some of the non-nucleoside reverse transcriptase
 inhibitors that are metabolized through the same hepatic enzyme system
 as fluconazole, itraconazole and ketoconazole, we're going to see more
 and more drug interactions. We need to be aware of this up front. I tend
 to use fluconazole in more of a pulse for the treatment of oral
 candidiasis or indicated diseases, and not on a regular prophylactic
 schedule.

 I'm involved in the CMV prophylaxis studies with oral ganciclovir
 (Cytovene). I think oral ganciclovir has a role in the maintenance of
 people with CMV retinitis. Studies are emerging that suggest efficacy.
 Whether the drug will have a prophylactic advantage is not clear to me
 at this point, but there is no other prophylaxis. I'm quite clear that
 acyclovir does not prophylax against CMV disease.

 ROMEYN: We offer PCP prophylaxis to anyone with under 500 CD4 cells. I
 know that's high, but I've seen PCP in people who have 400 CD4 cells.
 Usually, I prophylax with Bactrim 3 times a week. If and/or when someone
 develops a reaction to Bactrim, I switch them over to dapsone. I don't
 treat through a rash. Unfortunately, we don't yet have the answers on
 atovaquone (Mepron) prophylaxis.

 The other thing that is important about starting Bactrim early is
 that you see less of an allergic response to a continuous regimen than
 you see to a start-and-stop regimen. I let my patients choose a regimen
 and then keep them on it. I have them on Bactrim 3, 5 or 7 times a week.
 I think Bactrim 3 times a week is enough.

 Another technique that we use here is borrowed from my large
 geriatric practice: I make an effort not to change more than one
 medication at a time. If you add 2 medicines and you see a rash
 reaction, you don't know where it came from. Wherever possible, I make
 only one change in a regimen at a time. We can often do this by phone.

 The other strategy we use to build tolerance is to start people on
 half-doses of AZT, 100 mg 3 times a day. Side effects, if they occur,
 usually resolve within a few weeks. Then you can up the dose. If people
 are interested in combination antiretroviral prophylaxis, I start the
 second drug a month later. I don't start both at once.

 I also prophylax against the ongoing adrenal response to this
 illness. With HIV infection, the body is in a chronically stressed
 state. This stress activates the immune system in ways that are harmful
 and allow for progression of the virus. I'm quick to write a
 prescription for the treatment of depression or anxiety. I'm slow to do
 this for patients who are not HIV positive. I don't think people with
 HIV can afford to be crazy; they have to maintain their sanity.

 BETA: What are the major changes you have made in your HIV practice in
 the last year?

 FOLLANSBEE: I am becoming increasingly convinced that acyclovir does
 play a role in HIV treatment. There are now 2 prospective studies that
 unfortunately haven't made it to press, which were designed to look at
 the role of acyclovir for CMV prophylaxis and in fact showed no such
 role. But both studies did show a survival benefit in those people who
 received acyclovir. I understand that a retrospective analysis of
 patients in the Multicenter AIDS Cohort Study (MACS) has now been
 completed that shows the same survival benefit. There does not appear to
 be a dose response, and there is no proposed mechanism to explain why
 acyclovir may improve longevity. From discussions that I've had with
 some of the investigators, it does not appear that this is related to a
 specific antiretroviral regimen. It seems to be an independent survival
 advantage. It may be through a cofactor role.

 Acyclovir probably will not be an early treatment, because most of
 these studies are done with people who are at risk for CMV disease. So
 it is probably a strategy to reserve for later on, unless of course the
 patients have recurrent herpes. I am now putting patients on acyclovir,
 which is a change for me.

 VOLBERDING: We have a unique situation at San Francisco General
 Hospital. About 20 providers work in the HIV/AIDS clinic. Each clinician
 has a personal style and approach. We have come to appreciate that
 therapy has to be individualized. What is appropriate for one person
 might very well be inappropriate for another. Some patients prefer to
 follow a more aggressive course, and feel less reluctant to use drugs to
 treat their HIV infection. Those who are concerned about the limitations
 and side effects of the drugs tend not to use drug therapy. It is
 important for each provider to learn each patient's attitude about the
 wide spectrum of treatment options. We need to find ways to work with
 patients without compromising our own professional standards.

 We all agree that PCP prophylaxis is necessary, and strongly
 recommend it. It is much more difficult to come to consensus regarding
 antiretroviral therapy. From what we know about the biology of HIV, I
 still believe that asymptomatics should be treated. The perceptions of
 other providers in our clinic have been swayed by the Concorde data;
 they tend to recommend later initiation of antiretroviral therapy. Most
 importantly, providers need to work with patients and allow them a
 central role in discussions about treatment. If they are going to be in
 this field, providers need to know the data well enough to actually make
 recommendations. It is a confusing time, but I hope that professionals
 will not run away from this important responsibility to their patients.

 ROMEYN: In researching and writing my book, Nutrition and AIDS, I looked
 at growth hormone, cytokine blockers and progressive resistance
 exercise, as well as vitamins and antioxidants.

 In the last year we've also begun to recognize that progressive
 resistance exercise is a means to build lean body mass in early
 asymptomatic patients. Not only can they build lean body mass early on,
 so that you have a higher mountain to slide down, but it also gives your
 highly motivated, highly anxious, newly diagnosed, healthy HIV patients
 something to do for themselves. We strongly recommend weightlifting. I
 hope to get my own impedance monitor so I can measure lean body mass.
 I'd like to get one for me and one for Project Open Hand. Then we can
 appropriately measure lean body mass instead of weight, and monitor how
 people are really doing.

 The Kotler studies show statistically that at 54% or 66% of lean body
 mass, people die. We say that they died of MAC or lymphoma, but they
 really die because they only have 54% of lean body mass. If you can
 build up lean body mass early and reduce the episodes of acute drop-off
 of lean body mass by getting a head start on infection, and if you can
 replete lean body mass by watching for malabsorption and aggressively
 attending to calories during a period of secondary infection, then you
 may greatly lengthen the time between diagnosis and death.

 LEOUNG: Over the last year the likelihood has become greater that we
 will come up with new, more effective antiretroviral drugs. A number of
 agents of different types and with different mechanisms of action are
 being investigated simultaneously in several places in this country.
 With the promise of these new modalities, I think that we are drawing
 closer to truly controlling HIV. What is different this year is that we
 have more reason to be hopeful about that.

       *********

 Human Herpesvirus Type 6
 (HHV-6):
 Cofactor or Opportunistic
  Infection in AIDS?
 Ronald A. Baker, PhD

 Ronald Baker is editor of BETA.

 A recent post-mortem study of lung, lymph node, spleen, liver and
 kidney tissues of 9 people with AIDS revealed that every tissue examined
 (34 of 34) was positive for active HHV-6 infection (Knox and Carrigan,
 1994). Based on these and other results from their study, a research
 team at the Medical College of Wisconsin concludes that HHV-6 is an
 important disease-causing agent in people with AIDS.

 The HHV-6 infection rate was significantly higher in the tissues
 examined than that for cytomegalovirus (CMV), which was present in only
 9 of the 34 tissues. HHV-6 infection of the lung of one individual was
 extensive enough to account for his fatal pneumonitis, according to the
 investigators.

 Background

 HHV-6 is a commonly found virus that infects at least 90% of the
 general population in the U.S. by age 2, and is widely and highly
 prevalent in many parts of the world. HHV-6 was first discovered in 1986
 at the Tumor Cell Biology Laboratory of the National Cancer Institute
 (Bethesda, Maryland) by Dr. Zaki Salahuddin and colleagues (Salahuddin,
 1986).

 The potential pathogenic role of HHV-6 is not yet clearly understood,
 but there is suggestive evidence that the virus may play a significant
 role in several diseases. Researchers have conclusively linked the virus
 to only one disease_exanthem subitum (roseola), a benign illness of
 early childhood associated with primary HHV-6 infection. As with other
 herpesviruses, available serologic tests have limited value in
 differentiating between latent (inactive) and active infection with
 HHV-6. Only recently have researchers developed and employed special
 techniques that can detect HHV-6 replication in vivo
 (immunohistochemical staining with a specific polyclonal antiserum).

 Dr. Robert Gallo and colleagues at the National Cancer Institute
 (NCI) suggested 5 years ago that HHV-6 might contribute to the depletion
 of CD4 cells (T-helper cells) in people with AIDS. These government
 researchers found that, like HIV (but unlike CMV), HHV-6 selectively
 infects CD4 cells. They also discovered that, in laboratory tests of HIV
 and HHV-6 coinfected cells, HHV-6 stimulates the release of cytokines
 that activate HIV replication. Thus, HHV-6 and HIV can coinfect
 individual lymphocytes and cause increased cytopathic changes in these
 immune system white blood cells, when compared to lymphocytes infected
 only with HIV. HHV-6 also induces CD8 cells and natural killer (NK)
 cells to express the CD4 receptor (the major receptor of HIV), thus
 increasing the number of cells susceptible to infection with HIV.

 Natural Killer Cellsand HHV-6

 Natural killer cells provide the body with an important mechanism of
 primary defense against infection with viruses. When natural killer cell
 functioning is significantly compromised or reduced (as in AIDS), the
 natural immunity of the individual is seriously impaired. For example,
 multiple herpesvirus infections occur in individuals who congenitally
 lack natural killer cells. [Ed. note: a reduced natural killer cell
 function has been documented not only in AIDS but also in chronic
 fatigue syndrome (CFS), a disorder of unknown cause that often presents
 with signs of active HHV-6 infection.]

 In laboratory tests, HHV-6 can directly target and kill natural
 killer cells. In humans, this could result in the suppression of the
 individual's natural antiviral immunity. HHV-6 is the only virus known
 that efficently infects and kills natural killer cells, according to NCI
 researchers.

 Disseminated, Active HHV-6 Infection

 Researchers in the Department of Pathology at the Medical College of
 Wisconsin evaluated the frequency of active HHV-6 infection in 9 people
 who died of AIDS. The demographic data of these individuals closely
 resembled that of the general population of HIV positive individuals in
 Wisconsin. As mentioned above, every tissue examined was positive for
 active HHV-6 infection, while CMV infection was found in only 9 of the
 34 tissues examined.

 The investigators conclude that HHV-6 was probably the cause of one
 individual's fatal pneumonitis. They point out that respiratory failure
 is the main cause of death in AIDS patients, with pneumonitis of unknown
 cause being the primary cause of death in 5-10% of people with AIDS.
 They suggest that HHV-6 infection may be the cause of the fatal
 pneumonitis in some of these individuals.

 Most of the HHV-6-infected cells in tissues of AIDS patients examined
 were lymphocytes. HHV-6-infected lymphocytes located within areas of
 inflammation, suggest the researchers, could transfer the infection to
 other lymphocytes, thereby perpetuating the inflammation and causing a
 significant systemic destruction of lymphocytes.

 The lymphoid organs are important reservoirs of HIV infection, and
 recent studies have demonstrated that HIV infection is active and
 progressive in lymphoid tissue during the clinically latent stage of HIV
 disease. The Wisconsin pathologists note that HHV-6-infected lymphocytes
 account for the increased density of HHV-6 infection found in the
 lymphoid organs. HHV-6 can infect and destroy CD4 cells, and when HHV-6
 and HIV infect the same CD4 cells, the destruction of these cells is
 enhanced by mechanisms not yet understood.

 Other Evidence of the Interaction between HHV-6 and HIV-1

 Many isolates of HHV-6 have been drawn from the lymphocytes of people
 with an AIDS diagnosis. Because the primary cellular target of both
 HHV-6 and HIV is CD4 cells, it has been suggested that HHV-6 may be a
 cofactor in progression to AIDS. The manifestations of such a role might
 include the following criteria: (1) changes in HHV-6 antibody levels as
 AIDS progresses; (2) changes in levels of HHV-6 in tissues or bodily
 fluids; and (3) evidence for interactions between the viruses at the
 cellular or molecular levels (Pellet, 1992).

 The study of HHV-6 in people with HIV disease has yielded uncertain
 results. Published reports include evidence of a high seroprevalence of
 HHV-6 and/or increased antibody titers in people with AIDS (Levy, 1990);
 no differences in immune profiles (Balachandran, 1991); no significant
 differences in HHV-6 antibody titer between HIV positive and random male
 blood donors (Brown, 1988); lower prevalence of HHV-6 in AIDS patients;
 and no difference between antibody titers of HIV positive
 lymphadenopathy patients who did or did not progress to AIDS (Spira,
 1990).

 In laboratory tests of cell cultures coinfected with HIV and HHV-6, a
 wide range of effects have been found. Individual CD4 cells can be
 simultaneously infected with both viruses, with the coinfected cells
 demonstrating increased HIV activity, increased reverse transcriptase
 levels and earlier cell death (Lusso, 1989). Lusso and colleagues found
 that HHV-6 induced the expression of the CD4 receptor in lymphocytes,
 making these cells more susceptible to infection with HIV (Lusso, 1991).
 Other experiments have shown suppression of HIV replication in cells
 coinfected with HHV-6 and HIV (Carrigan, 1990). HHV-6 replication in
 these cells was unaffected or only slightly enhanced. It was even
 suggested that HHV-6 may slow the progression of disease in some HIV
 positive individuals.

  Chronic Fatigue Syndrome

 Several studies have noted higher HHV-6 antibody titers or
 seroprevalence in people diagnosed with chronic fatigue syndrome
 (Krueger, 1987; Read, 1988; Balachandran, 1991). In a controlled study,
 HHV-6 antibodies were detected in 69% of the cases and in only 12.5% of
 the controls (Dale, 1989). In contrast, one study found no difference in
 seroprevalence between cases and controls (Wakefield, 1988), and another
 noted no correlation between HHV-6 seroprevalence or antibody titers and
 chronic fatigue syndrome (Gold, 1990).

   Immune Response

 HHV-6 induces the increased expression of several cytokines,
 including interferon alpha, interleukin-1B and tumor necrosis factor
 (Kikuta, 1990; Flamand, 1991). HHV-6 may produce an immunomodulatory
 effect by stimulating the production of these cytokines, which, in turn,
 may result in disease progression (Carrigan, 1991), viral avoidance of
 immune surveillance (Flammand, 1991) or stimulation of viral activity
 (Folks, 1989).

  Other Disease Associations

 As mentioned above, HHV-6 infection occurs early in life, and has
 been shown to be the cause of a mild disease in children, exanthem
 subitum (roseola or sixth disease). In addition, significant increases
 in anti-HHV-6 titers have been found in several types of transplant
 recipients whose immune systems were suppressed by chemotherapy: cardiac
 (Irving, 1988), bone marrow (Asano, 1991), liver (Ward, 1989) and renal
 (Asano, 1989).

 In a study of 15 bone marrow recipients, only one participant was
 culture-positive for HHV-6, suggesting that active HHV-6 infection is
 not common among this patient population. HHV-6-infected lymphocytes
 were detected in the lungs of 2 bone marrow transplant recipients who
 developed pneumonitis, but the lung tissue cells had no evidence of
 HHV-6 infection, suggesting that disease resulted from HHV-6-associated
 inflammation rather than cell destruction by the virus. It is clear that
 HHV-6 can become active due to post-transplant immunosuppression, but
 its role in causing complications following transplantation is unclear.
 There is evidence suggesting a role for HHV-6 in some adult cases of
 hepatitis (Dubedat and Kappagoda, 1989). Researchers also have reported
 an association of HHV-6 with cases of mononucleosis-like illnesses that
 did not appear to result from infection with Epstein-Barr virus (EBV) or
 CMV (Irving and Cunningham, 1990). HHV-6 was cultured from the blood of
 a patient with a severe mononucleosis-like illness, elevated numbers of
 activated B cells, depressed numbers of T-cells, extremely high titers
 of anti-HHV-6 antibodies, and who met the case definition of chronic
 fatigue syndrome (Buchwald and others, 1991).

 Immune Disorders and Lymphoproliferative Diseases

 The first 6 isolates of HHV-6 were taken from individuals with
 lymphoproliferative disorders (Salahuddin, 1986), but the role of HHV-6
 in immune disorders and lymphoproliferative diseases is uncertain.
 Individuals with autoimmune diseases (e.g., sarcoidosis, Sjogren's
 syndrome and systemic lupus erythematosis) reportedly have higher than
 normal HHV-6 antibody titers (Ablashi, 1988). Researchers found that
 patients with leukemia and lymphoma had higher anti-HHV-6 titers than
 controls, with the highest titers among those with acute myeloid
 leukemia, Hodgkin's disease and non-Hodgkin's lymphoma (Clark, 1990).
 Others have also noted higher HHV-6 antibody titers in people with
 Hodgkin's disease (Balachandran, 1991). It is possible that, even if
 HHV-6 does not play a direct causative role, the virus may be a cofactor
 in the progression of these diseases. Some researchers have suggested
 that HHV-6 may stimulate the production and activation of B-cells, thus
 expanding the population of cells targeted by another pathogen or event
 that gives rise to malignant lymphomas.

  Treatment Implications

 The possible involvement of HHV-6 in serious illnesses has motivated
 a search for antivirals to inhibit its replication. The results of HHV-6
 susceptibility to antivirals is summarized in Table I. Although it is
 difficult to compare the results due to the variety of assays, viral
 strains and culture conditions, some conclusions can be drawn.
 Ganciclovir (GCV), foscarnet (PFA) and phosphonoacetic acid clearly
 inhibit almost all HHV-6 replication, indicating that the virus is
 susceptible to similar antivirals as cytomegalovirus. HHV-6 is also
 sensitive to acyclovir (ACV), although somewhat less than to the other
 antivirals shown. It is possible that acyclovir (Zovirax) at doses
 adequate to suppress herpes simplex virus infection (oral and genital
 herpes) also might have an inhibitory effect on the reactivation of
 HHV-6. The effect of the new acyclovir prodrug valacyclovir (Valtrex) in
 HHV-6 has not yet been studied. Because Valtrex produces significantly
 higher blood levels of acyclovir than Zovirax, it may effectively
 suppress the activity of HHV-6.

  Commentary

 If the destruction of CD4 cells caused by coinfection with HHV-6 and
 HIV seen in laboratory tests also occurs in vivo, the result of this
 coinfection in the lymphoid organs could be the synergistic destruction
 of CD4 lymphocyte cells. This process, in turn, would eventually result
 in the progressive disintegration of the immune system.

 Conclusive evidence demonstrating an immunosuppressive role for HHV-6
 in AIDS is not yet available. It is possible that the widespread
 reactivation of HHV-6 infection shown by Knox and Carrigan may result
 from the immunodeficiency caused by HIV infection, but in his commentary
 on the Wisconsin post-mortem study, Dr. Gallo suggests that the
 reactivation of HHV-6 over the course of HIV infection may significantly
 increase disease progression: "...the unique biological properties of
 HHV-6, especially its 'immunotropic' nature and its positive
 interactions with HIV, strongly suggest that, once reactivated in the
 course of HIV infection, it may have detrimental effects on the immune
 system and expedite progression of the disease."

 "How can we solve this puzzle that may have critical implications for
 the prophylaxis and management of AIDS? Longitudinal studies of HHV-6
 replication in HIV-infected people are essential to establish a solid
 association with disease progression. Nevertheless, valuable information
 can be expected from other approaches_for example, coinfection studies
 in animal model systems...and therapeutic trials of drugs with selective
 activity against HHV-6" (Gallo and Lusso, 1994).

  Conclusion

 Although a good deal has been learned about HHV-6 in a short period
 of time, much significant information remains unclear or unknown.
 Researchers have presented data suggesting HHV-6 involvement in a number
 of diseases, but it is unlikely that the virus plays a causative or
 cofactor role in all of them. The evidence for a cofactor role for HHV-6
 in HIV disease progression is suggestive, but inconclusive. HHV-6 may be
 an opportunistic infection, like so many others in AIDS. Controlled
 clinical trials will be necessary to clarify further what role, if any,
 HHV-6 plays in HIV-associated immune dysfunction.

  Sources

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1391. 1989.

 Asano Y and others. Reactivation of herpesvirus type 6 in children receiving
bone marrow transplants for leukemia. New England Journal of Medicine 324:
634-635. 1991.

 Balachandrian N and others. Electrophoretic analysis of human herpesvirus 6
polypeptides immunoprecipitated from infected cells with human sera. Journal
of Infectious Diseases 163: 29-34. 1991.

 Brown NA and others. Prevalence of antibody to human herpesvirus 6 among
blood donors infected with HIV. The Lancet ii: 1146. 1988.

 Carrigan DR and others. Suppression of human immunodeficiency virus type-1
replication by human herpesvirus-6. Journal of Infectious Diseases 162:
844-851. 1990.

 Carrigan DR and others. Interstitial pneumonitis associated with human
herpesvirus-6 infection after marrow transplantation. The Lancet 338:
147-149. 1991.

 Corbellino M and others. Disseminated human herpesvirus 6 infection in AIDS.
The Lancet 342: 1242. 1993.

 Dale JK and others. The Inoue-Melnick virus, human herpesvirus type 6, and
the chronic fatigue syndrome. Annals of Internal Medicine 110: 92-93. 1989.

 Drobyski WRR and others. Human herpesvirus 6 (HHV-6) infection in allogeneic
bone marrow transplant recipients I: evidence for a marrow-suppressive role
for HHV-6 in vivo. Journal of Infectious Diseases 167: 735-739. 1993.

 Dubedat S and Kappagoda N. Hepatitis due to human herpesvirus-6. The Lancet
ii: 1463-1464.

 Flamand L. Human herpesvirus 6 induces interleukin-1B and tumor necrosis
factor alpha, but not interleukin-6, in peripheral blood mononuclear cell
cultures. Journal of Virology 65: 5105-5110. 1991.

 Folks TM and others. Tumor necrosis factor alpha induces expression of human
immunodeficiency virus in a chronically infected T-cell clone. Proceedings of
the National Academy of Sciences USA 86: 2365-2368. 1989.

 Gallo RC and Lusso P. Human herpesvirus 6 in AIDS (commentary). The Lancet
343: 555-556. March 5, 1994.

 Gold D and others. Chronic fatigue. A prospective clinical and virologic
study. American Medical Association 264: 48-53. 1990.

 Knox KK and Carrigan DR. Disseminated active HHV-6 infections in patients
with AIDS. The Lancet 343: 577-578. March 5, 1994.

 Krueger GRF. Persistent fatigue and depression in a patient with antibody to
human B-lymphotropic virus. The Lancet ii: 36. 1987.

 Levy JA and others. Frequent isolation of HHV-6 from saliva and high
seroprevalence of the virus in the population. The Lancet 335: 1047-1050.
1990.

 Lusso P and others. Productive dual infection of human CD4 T lymphocytes by
HIV-1 and HHV-6. Nature (London) 337: 370-373. 1989.

 Lusso P and others. Induction of CD4 and susceptibility to HIV-1 infection
in human CD8+ T lymphocytes by human herpesvirus 6. Nature (London) 349:
533-555. 1991.

 Lusso P and others. Infection of natural killer cells by human herpesvirus
6.

 Nature 362: 458-462. April 1, 1993.

 Lusso P and Gallo RC. Human herpesvirus 6 in AIDS. The Lancet 343: 555-556.
March 5, 1994.

 Lusso P. Interactions between HHV-6 and HIV: HHV-6 as a potential cofactor
in AIDS. In: Interactions between retroviruses and herpesviruses. Kung HJ,
Wood C, eds. River Edge, New Jersey. World Scientific Publishing (in press).

 Pellet PE and others. Human herpesvirus 6: the virus and the search for its
role as a human pathogen. Advances in Viral Research 41: 1-51. 1992.

 Salahuddin SZ and others. Isolation of a new virus, HBLV, in patients with
lymphoproliferative disorders. Science 234: 596-601. 1986.

 Wakefield D. Human herpesvirus 6 and myalgic encephalomyelitis. The Lancet
i: 1059. 1988.

 Ward KN and others. Brief report: primary human herpesvirus 6 infection in
a patient following liver transplantation from a seropositive donor. Journal
of Medical Virology 28: 69-72. 1989.

       ---------
 Inhibition of HHV-6 Growth by Antiviral Drugs

                                Inhibitory
 Drug    Virus strain   Cells    dose (µM)   Inhibition  (%)

 PFAa    African        PBL           83            100
         HBLV           HSB-2        104            100
 PAAb    Z29            PBL         2141             88
         Z29            CBL          714            100
         Roseola        CBL          357            100
         Z29            CBL          200            100
 ACVc    Z29            PBL          400             85
         OK             CBL          444            100
         Z29            CBL           50             88
         KF             PBL          128             90
         African        PBL          100            100
         HBLV           HSB-2e       0.4             80
 GCVd    African        PBL           10            100
         KF             PBL            6            100
         Z29            CBL           25             94
         HBLV           HSB-2        0.6              0

 a Phosphonoformate       c Acyclovir     e Drug was cytotoxic
 b Phosphonoacetic acid   d Ganciclovir

       **********

  Recommended Reading
 Ronald A. Baker, PhD

 Treating AIDS with Chinese Medicine.
 Mary Kay Ryan and Arthur D. Shattuck.
 Published by Pacific View Press (1994).
 364 pages. Paperback. $29.95.

 This easy-to-read book offers an excellent introduction to the use of
 Traditional Chinese Medicine (TCM) in the treatment of HIV infection and
 AIDS. The book opens with a description of the differences between
 western and Chinese medicine and a synopsis of how TCM understands the
 human body. Basic TCM concepts are discussed, including Qi ("vital
 energy"), Channels ("internal and external routes"), Yin and Yang
 ("types of bodily activities, developments, processes and outcomes"),
 Xue (blood) Jin and Ye (fluids).

 The authors, cofounders and codirectors of the North Side HIV
 Treatment Center in Chicago, combine both western and Chinese medical
 treatment. In their view, both systems have value, and they use them in
 tandem. At the Chicago clinic, patients are evaluated by a team of
 providers that includes a physican, but also an acupuncturist, a message
 specialist and an expert in the use of Chinese herbal treatments.
 Sometimes western medicine is the therapy of choice, for example, in the
 treatment of AIDS-associated opportunistic infections. As a result of
 western medications, however, adverse side effects often occur that, in
 their view, are best helped by TCM.

 The book contains a lengthy chapter on the appropriate TCM treatments
 to accompany western drug treatment for opportunistic infections, as
 well as a detailed section on the management of symptoms associated with
 HIV disease (diarrhea, fatigue, fever, headaches, night sweats), using
 both TCM and western treatments. The authors also address the special
 problems of certain groups coping with AIDS_women, hemophilics and IV
 drug users_and then propose specific TCM approaches to treating problems
 unique to these groups.

 The use of dietary supplements is also discussed, including many now
 familiar to the HIV/AIDS community: beta carotene, egg lecithin,
 selenium, vitamins A, B and C, zinc and germanium. Less familiar herbs
 and plants are also outlined, such as bitter melon, chaparral, comfrey
 root, hops, mistletoe, licorice root, Siberian ginseng and turmeric.

 In the chapter entitled "Addressing the Crisis of AIDS," Ryan and
 Shattuck write, "There are long-term survivors of AIDS. There are people
 who have beaten other usually terminal illnesses. How can we know any
 given patient won't be among these miracles? The work of medicine is to
 support the quality of life in the living and to help and support
 patients through death_"

 "Patients' lives are often prolonged by their involvement in fighting
 for their rights. If, as many people think, there will come a time when
 AIDS, like diabetes, is debilitating and serious, but not consistently
 terminal, then any prolonging of life may get a patient to that time. We
 hope they are right. In the meantime, we see our job as supporting
 quality of life, prolonging life when possible, and respecting death
 when it comes."

       *********

 Vitamin and Nutritional Supplements in HIV Disease

 The following text is an edited transcript of 3 BETA LIVE!
 teleconferences held April 5, 7 and 12, 1994.

 BAKER: Good evening, everyone, and welcome to the first BETA LIVE!
 teleconference. Thanks to the miracle of the information super-highway,
 there are about 200 of us online together from cities and towns across
 the U.S., and from Canada, Puerto Rico and Spain. I'm Ronald Baker,
 editor of BETA and the moderator of this evening's program. I'm speaking
 to you from the offices of BETA at the San Francisco AIDS Foundation. We
 have online with us this evening 3 distinguished guest panelists who
 will take your questions about the main subject of our teleconference:
 "Vitamin and Nutritional Supplements in HIV Disease." The format of
 tonight's teleconference is this: I'll start with some questions for the
 panelists, and after about 20 minutes we'll take questions from callers.
 Later I'll report briefly on recent drug developments and review
 important drug studies that are now open to enrollment. We'll close the
 program with a preview of upcoming BETA LIVE! teleconferences. Let me
 introduce you now to our guest panelists.

 Dr. Jon Kaiser is a San Francisco physician who specializes in
 treating people with immune disorders. He is also the author of a new
 book entitled Immune Power: A Comprehensive Treatment Program for HIV.
 Dr. Kaiser joins us tonight from his office in San Francisco.

 Cade Fields is a registered dietician who specializes in nutrition
 and AIDS. She joins us from her home in Cary, Illinois.

 Dr. Howard Greenspan is a researcher and expert on oxidative stress.
 Last November he chaired a conference on oxidative stress in AIDS that
 was sponsored by the National Institutes of Health [NIH]. Dr. Greenspan
 joins us tonight from his home in Clinton, New Jersey.

 Dr. Kaiser, let's begin with a question for you. Why do you believe
 that vitamins and nutritional supplements can make a significant
 difference in the treatment of HIV infection in AIDS?

 KAISER: Well, Ron, I think that whenever we're talking about supporting
 the immune system, we have to understand that its strength is connected
 to, and dependent on, the nutritional status of the individual. We knew
 even before HIV came on the scene that nutrient deficiencies were
 responsible for promoting a weakened immune state and more frequent
 infections. And Pneumocystis pneumonia, which we attribute to the
 effects of HIV, is often found in profoundly malnourished children. So
 there's a direct link between T-cell function, T-cell numbers, antibody
 production and the amount of nutrients_vitamins, minerals, protein and
 calories_that are available to the body. We also know that the stress of
 infection creates a need for higher levels of the nutrients that I just
 mentioned.

 When we take a look at people who have chronic infections, or who
 have sepsis, we see that those with a higher nutritional state do much
 better than those that are in a weakened nutritional state. Separate
 studies by Marianna Baum and by Richard Beech, both at the University of
 Miami, showed that there was a high prevalence of these nutritional
 deficiencies in HIV positive patients who were asymptomatic,
 well-nourished, taking nutritional supplements of 3 to 5 times the RDA,
 and with as high as over 500 T-cells. They found that 67% of this
 population of patients had at least one nutrient deficiency, and a third
 had several nutrient deficiencies in the bloodstream. We also see that
 some of the drug therapies that are used in HIV, namely AZT, can also
 precipitate deficiencies of copper and zinc. So we are starting to get
 evidence that relative deficiencies exist in HIV positive people despite
 their high levels of intake. The deficiency is due either to poor
 absorption or to greater utilization of nutrients because of higher
 metabolism. We're also starting to find out that there are systems of
 the body that are designed to keep the immune system healthy_such as the
 antioxidant pathways_and that they are inordinately sensitive to
 deficiencies of some of the compounds we're going to be talking about,
 such as vitamins C and E, zinc, selenium and the amino acid glutathione.
 So we need further research into this area to find out whether high-dose
 nutrient supplementation of these antioxidant vitamins and
 minerals_either alone or in combination with antivirals_can have a
 significant therapeutic effect, can slow the trend of decreasing immune
 function, and can help support the immune system. Another issue is
 whether or not lower drug dosages can be utilized in combination with
 these vitamins for better overall results, fewer toxic side effects and
 resistance.

 Evidence from published studies and from my clinical practice, in
 which I use a lot of nutrient supplementation, has proven to me that a
 lot of potential exists in this area. Except for a couple of nutrients
 that I'm sure we'll talk about today, we really haven't found the upper
 limit of what benefits HIV positive individuals. All of these studies
 reveal that there are deficiencies, and that higher intakes of many of
 these supplements seems to decrease the immune system deterioration over
 time. With much more information and emphasis on nutrition and nutrient
 therapy, we will be able to lessen the dosages of some of the more toxic
 antiviral medications and prevent some undesirable side effects of the
 drugs by keeping people stronger and healthier through good nutrition.
 This will make a significant impact on helping people live long and
 healthy lives while being HIV positive.

 So I would like to say to the listeners that this is a real fertile
 area for you to gather as much information as possible. As much as your
 resources allow, work with a nutritionist to look into the possibilities
 of vitamin supplementation and to make decisions that hopefully will
 make a big impact in keeping you healthy for as long as possible.

 BAKER: Thank you, Dr. Kaiser. Dr. Greenspan, will you explain, in
 layman's terms, what antioxidants are and tell us about their possible
 role in the treatment of HIV infection?

 GREENSPAN: There's so much information flying around these days about
 antioxidants, and the good and bad aspects of their use, that it has
 become quite confusing. The use of antioxidants has been promoted to
 help fight against the excess production of what we call "free
 radicals," or reactive forms of oxygen. They are formed in the body as
 natural by-products of oxygen metabolism and are essential components of
 our immune system. The problem with free radicals arises when the
 natural balance between their production and the buffering, protective
 mechanism of antioxidants is lost. Then damage can occur. This is
 commonly seen in cardiovascular disease and cancer, and may even be the
 main component of aging. So some people may say antioxidants are very
 important, while others say that they may compromise our ability to
 utilize our immune system.

 In the HIV-infected individual, the virus compromises the delicate
 balance between free radicals and antioxidants in a number of ways. The
 virus may change the absorption level of certain nutrients from the
 bowel, including antioxidant vitamins and amino acids essential in the
 body's production of antioxidants. In fact, the virus can effectively
 inhibit the cellular production of essential antioxidant enzymes.

 The result in the HIV-infected patient is this excess activity of
 free radicals, a condition that we call "oxidative stress." The research
 published in the last 2 years shows that oxidative stress can increase
 the rate of replication of the HIV virus. Perhaps more importantly,
 oxidative stress can also initiate a cascade of events that results in
 the destruction or premature death of immune cells, particularly
 T-lymphocytes. So if you are able to bring this oxidative activity under
 control, you may be able to slow viral replication and preserve the
 T-cell population. In fact, evidence that was presented at the NIH
 conference last November supported both of these premises: that using
 certain types of antioxidants can decrease viral replication and can
 help to maintain, and even raise, T-cell levels.

 BAKER: What antioxidants do you recommend, Dr. Greenspan, and could you
 give us some examples of dosages?

 GREENSPAN: I can give you some recommendations that I would use for
 myself if I was an infected individual, but I caution that every
 individual is different, and that dietary intake and stage of illness
 may govern what type of supplemental therapy would be recommended.
 Generally, with beta carotene I would probably stay with a dosage
 somewhere around 50,000 units/day; with vitamin E, I would try to work
 up to 1,200 units/day. I normally go to bowel tolerance on oral vitamin
 C; flavonoids usually come in combination with the vitamin C, and 300 to
 600 mg/day of flavonoids is probably adequate. Certain individual
 flavonoids, such as quercetin, may be prescribed on an individual dosage
 basis.

 BAKER: What about NAC [N-acetylcysteine] which is very commonly used in
 the HIV community now? What dose would you recommend for most
 individuals?

 GREENSPAN: I happen to be one of those who feel that NAC, which is a
 precursor to glutathione, has very limited toxicity. I use it in fairly
 high doses, between 3 and 5 grams/day, although certain of my colleagues
 will dose twice that amount. Most of the studies that have been done_and
 there have been quite a few_have shown very little, if any, toxicity at
 reasonably high levels. I know that there is controversy in this area
 and that's why there are so many researchers doing work on
 N-acetylcysteine here at NIH, at Stanford University, the Pasteur
 Institute and Heidelburg University. It's quite an open subject for
 debate but I myself don't hesitate to use it.

 BAKER: Thank you, Dr. Greenspan. I know there will be more questions
 from our callers about antioxidants.

 Miss Fields, as a specialist in nutrition in AIDS, what's the most
 important nutritional advice you have for people living with HIV
 infection and AIDS?

 FIELDS: First I would like to stress that nutritional supplements are
 just that, supplements. So the most important advice I can give a person
 who is HIV positive is to make sure to have the necessary nutritional
 foundation before starting with supplements, which unfortunately won't
 work without this foundation.

 Building the foundation requires knowing your nutritional priorities
 and making the commitment to fulfill them. The most important priority
 is fluids, which doesn't have to mean water and which can contain
 calories. The amounts that people need are anywhere from 16 to 17 cc per
 pound of body weight, which works out to about 1 cup of fluids for every
 15 pounds, or 32-35 cc per kg of body weight. Calories are your second
 priority. Men need approximately 16 calories per pound and women need
 between 13 and 14 calories for every pound of body weight. The third
 priority is protein. You need at least 0.6 grams of protein per pound of
 body weight. Your fourth priority is micronutrients and making sure,
 before looking into nutrient supplements, that you get an adequate
 amount of them.

 Natural and traditional medicine is not nontoxic, and I think it's
 important to remember that. Also there are a number of antioxidants in
 food which may work synergistically with a supplement program. Certainly
 there are more specific recommendations that a clinician can make for
 you after assessment.

 The second piece of advice is that it is important to monitor trends
 in your status. It is important to get baselines on basic things like
 albumin, prealbumin, creatinine and others that you can get tested on a
 regular visit to a physician. Since every person has different baseline
 values, knowing your own numbers is more useful than comparing yourself
 to a range. Weight, height and body composition measurements are very
 important. Don't guess. Get a baseline on your nutrient intake and
 compare it to your estimated needs. Get a body composition done by means
 of caliper measurements or mid-arm circumference measurements. Make sure
 that the person is trained in the area and knows what he or she is doing
 because measurements taken by different people can vary greatly. Also
 get a baseline on your daily activity. When you have all these baseline
 values, take a look at any symptoms, or interactions of drugs you may be
 taking, and see how they affect your nutritional status.

 The third piece of advice I'd have is to develop a plan together with
 your healthcare professional for intake and supplementation, and to
 follow it wisely. Know what your options are for the future in terms of
 specialized nutrition support, things like tube-feeding and TPN [total
 parenteral nutrition], which during rough times can help you get back to
 your normal regimen. Include exercise in this regimen because it could
 play one of the most important roles in your body functioning normally
 and in controlling all of the related events in HIV seropositivity.

 BAKER: Thank you, Miss Fields. Jennifer, I'll turn the program over to
 you to take questions from our audience.

 JENNIFER: Thank you, Dr. Baker. Our first caller is from Los Angeles.

 LOS ANGELES: This question is for Dr. Greenspan. Hi, Howard, we've
 spoken in the past. My name is Steve Franco. As an HIV positive
 individual aware of vitamin deficiencies and possible oxidative stress
 damage, my question to you is whether there is a test, other than the
 standard T-cell test, that can be done regularly to monitor specific
 vitamin deficiencies or to test for the state or rate of oxidative
 stress?

 GREENSPAN: Well, there's quite a number of tests that are available, but
 not necessarily all physicians know about them. They certainly can be
 ascertained by some investigation. The tests measure vitamin levels,
 levels of amino acids, levels of superoxide dismutase, catalase and
 peroxidase. You can check actual levels of free radicals such as
 hydroxyl free radicals. You can check for products of oxidation fairly
 easily. In fact, now there's a new method of determining the degree of
 oxidative damage to DNA, which may be a very significant site of the
 oxidative damage in T-cells. So those types of tests are readily
 available if you know who to speak to and where to go.

 LOS ANGELES: So individuals need to approach a medical practitioner who
 has that capability or is willing to do those tests.

 GREENSPAN: Right. And as I've said, if they can't be found, you could
 probably check with BETA or come directly to me. And I can certainly
 give BETA a list of where these tests can be done.

 HOUSTON: Hi, this question could go to any of the panelists. This is
 Clint Stevens. I'm a dietician working with HIV positive patients in
 Houston, and I get a lot of questions on how to structure a supplement
 program. Like Cade, I prefer to emphasize food sources.

 With some of the recent studies suggesting zinc may speed progression
 of HIV disease, I'd like some comments about maximum levels of zinc and
 selenium that could be recommended with some comfort for
 supplementation.

 KAISER: Zinc is a double-edged sword. There are a fair number of studies
 which show that inordinately high levels cause depressed lymphocyte
 function and, like the caller suggested, can decrease the time before
 symptoms and immune suppression is evident. On the other hand, in Dr.
 Beech's study, 50% of the participants were found to be zinc-deficient,
 and zinc deficiency is also associated with impaired phagocytic
 function, as well as cellular and humoral immune dysfunction. So what we
 need to do is to find a dosage that will give individuals the optimum
 level of the nutrient. It might need to be individualized based on a
 person's diet and exercise level, and whether or not he or she is taking
 antiviral medications (which can decrease absorption). What I usually
 recommend is somewhere between 50-75 mg/day, and I caution my patients
 not to exceed 100 mg/day in supplement form. The zinc level in the
 bloodstream is easily tested, and anybody who questions whether they're
 getting too much or too little should have their level tested by a
 reputable laboratory.

 FIELDS: I'd like to add that the level of some nutrients is very
 dependent on other components in the blood. A person with a low zinc
 level also should have a very low albumin level, which will be
 associated with an acute phase of infection as well as with low zinc. It
 may have little to do with the actual true level of zinc itself. There
 have also been some studies that have tried to establish whether or not
 blood levels of nutrients, especially for individuals with some degree
 of infection, are really accurate. So it's just a note of caution for
 the interpretation of those laboratory values.

 KAISER: Yes, I would agree with that. As far as selenium goes, 200
 micrograms (mcg)/day is the usual upper limit of dietary tolerance, and
 the dose we often use. However, there have been some research studies
 published in which subjects have supplemented selenium up to 400 mcg and
 have increased immune function without any incidence of toxic side
 effects. Again, it depends on your diet, and on what part of the country
 you live in because, for example, some rural areas already have a lot of
 selenium in the ground water, and supplementing may cause toxicity. As a
 moderate dosage, I recommend no more than 200 mcg in supplemental form
 per day.

 PHOENIX: My question is for anyone on the panel. I became HIV positive
 in 1989 and started taking just about all the vitamins and supplements
 that you've mentioned. However, I have another complication. I have
 hepatitis B and I also took an experimental drug at the NIH, the FIAU
 drug. So I'm interested in where the test in Dr. Greenspan's area would
 be since I am only temporarily here in Phoenix. Also, what vitamins I
 should be extremely careful of since I have hepatitis B?

 GREENSPAN: As far as where the various tests can be done, I will furnish
 that to BETA rather than go through a whole list on the phone. As far as
 knowing what level of vitamins you can tolerate, it's determined by the
 extent of liver damage that you may have experienced either from the
 hepatitis or from drug therapy. Taken in reasonable dosages, most of the
 antioxidant vitamins really work to decrease inflammatory processes, and
 hepatitis is an inflammatory-type process. Yours is a very individual
 case, though, and someone would have to look at your blood and liver
 function to really give you aa appropriate answer. But in general, most
 of these substances have no known toxicity, taken at reasonable levels.

 NEW YORK CITY: My question is for Dr. Kaiser. It's about NAC. I was
 wondering, is there any difference between NAC bought in the underground
 and the NAC vitamin supplement? I read that if you have gastrointestinal
 problems or if you have a tendency to get ulcers or gastritis, that you
 should stay away from NAC. Is that true?

 KAISER: I'll take the second part of your question first. Probably the
 most common, though not extremely common, side effect from taking high
 doses of NAC is gastric irritation. It does have a thinning effect on
 the mucous. We call it a mucolytic effect. If you have problems with
 gastric or esophageal reflux or ulcers, be cautious of the NAC dosage
 that you take, especially because it's meant to be taken on an empty
 stomach. Take it at a low dosage first and then gradually increase the
 dosage to make sure that it doesn't exacerbate a previous condition.

 As far as the different formulations, antioxidants, and especially
 NAC, by their very nature are very reactive with the oxygen in the air.
 Make sure that the source you get it from keeps it very fresh and that
 the bottle is well sealed. I know that there are some companies that put
 it out in a foil packet so that it is protected from the light and air.
 I'll defer to Dr. Greenspan to find out more on particular formulations,
 but I would advise that you keep it tightly closed and protected from
 the light and air as much as possible, and that you obtain it as fresh
 as possible.

 GREENSPAN: I might add that when taking supplements, and especially
 something like NAC, which has become quite popular, you should stay with
 companies that have longer-term experience in producing these types of
 substances, rather than go with someone who is new on the market and
 trying to mimic an existing product. I don't want to endorse one product
 or another, but most of the good underground organizations, certainly
 the ones I'm familiar with in New York City, like DAAIR, are very well
 versed on which products are good. I would go along with their advice.

 DISCUSSION GROUP: This is a question for Dr. Greenspan. I'm curious
 whether he sees any role for the use of BHT as an antioxidant.

 GREENSPAN: Certainly BHT has been used for many years as a preservative
 in foods and in early antioxidant therapies. In the mid-70's it was a
 very popular antioxidant. Much of the work that we are seeing now has
 been moving somewhat away from use of BHT and towards some of the more
 updated forms such as the flavonoids and quinones that I've mentioned.
 I'm not saying that BHT is necessarily bad, but there are not many
 research groups now establishing clinical data on its use in HIV
 patients.

 SITE #17: Dr. Fields, would you address the nutritional value of
 lecithin, sugar and sunlight? As for protein supplements, how much
 additional protein powder might be necessary to take as a supplement?

 FIELDS: First, let me recommend that you check the type of protein that
 you use, see whether it's complete or not, and whether it complements
 what you have in your current diet. Protein has a nasty habit of
 dehydrating, so make sure that you get adequate amounts of fluid in at
 the same time. Overdoses of protein have shown no particular benefit,
 but just end up as extra adipose tissue [fat]. Your body has to tear
 apart the protein in order to store it as adipose, which creates a bit
 of a load on nitrogen. If you want to build body protein, one way to do
 that is through exercise. You have to have an adequate amount of
 calories, fluids and protein in order to do the type of exercise that
 you would need to build mass. Without activity you would see that
 providing protein to your body won't necessarily improve your lean body
 mass.

 As far as sunlight, I'm assuming you're talking about vitamin D and
 its production, which requires sunlight. Perhaps one of the other
 speakers has more information on this.

 Regarding sugar, there are some interesting relations between sugar
 and immune toxicity. Once again, I would recommend you prioritize in
 terms of getting an adequate amount of nutrition before concerning
 yourself with micromodulation. To my knowledge, there is not a sound
 basis for sugar being a problem, or at least not a high-risk problem,
 with toxicity to the immune system.

 In terms of lecithin, I'm not sure what particular aspect the caller
 is interested in. In the past lecithin has been used to alter the
 permeability of cells, and it has sort of waxed and waned in popularity.

 BARCELONA, SPAIN: I have 2 questions. Dr. Greenspan, what is the best
 way to take vitamin E? I understand that the epitope form might not be
 as useful as an antioxidant. And one question for Dr. Kaiser: you
 mentioned that in high doses vitamin A and zinc have adverse effects.
 What would be safe doses?

 GREENSPAN: Basically, we recommend that people try to get the
 alpha-tocopherol form. Succinate seems to be an adequate format to use,
 as well, depending upon the individual. The dosages that I gave before
 are what I would use for myself, but there are some potential risks for
 certain individuals in using high-dose vitamin E.

 KAISER: Overdosage of zinc and vitamin A can cause significant
 toxicities. If an individual consumes beta carotene, which the body uses
 to form vitamin A, there is very little chance of toxicity from as high
 as 100,000 or 200,000 units/day. The reported toxicity at that level has
 been the skin turning an orange color, which resolves when the person
 cuts back on it. Now I'm certainly not suggesting that most individuals
 take dosages that high. I'm more comfortable in general with what Dr.
 Greenspan recommended, which is from 25,000 to 50,000 units/day. As far
 as zinc goes, there's a significant body of research that has shown that
 both elevations in dosage above 100 mg/day as well as deficiencies can
 have immunosuppressive effects. So take a look at what's in the multiple
 vitamin and at what you're getting from your diet, and shoot for between
 50 and 75 mg of zinc per day.

 ST. PETERSBURG, FL: Yes, my question is for Ms. Fields, who was
 discussing the use of TPN [total parenteral nutrition]. Who could we
 address to lobby to get TPN into earlier usage for HIV-infected persons?
 I don't know if it would be the companies that make the TPN or someone
 else.

 FIELDS: There are 2 key players to address, and one is the physician.
 It's important to talk with the physician to find out when, in fact, TPN
 should be used. This means that close self-monitoring will be important.
 Based on studies, we recommend that people keep in close touch with
 their physicians, and, if 2 days go by where intake is very difficult,
 to go in and address the problem.

 The other key player is the insurance case manager. As much as we
 would like to think that insurance is not a factor, case management has
 had a lot to do with the medical decisions that are made for individual
 patients. So I think that educating insurance case managers as well as
 physicians about the use of TPN and when it's most appropriate will be
 helpful. We've talked with a number of insurance groups that have said
 we are not going to be reducing the cost of care with nutrition
 therapies, and my answer to them at this point is, "you're right, we're
 not. We're going to increase the cost of care because we haven't agreed
 on where it is appropriate to provide that particular care." So, anyway,
 those are the 2 groups to educate about valuable and not-so-valuable use
 of TPN and TPN dollars.

 DISCUSSION GROUP: I would like to address a question to whichever member
 of the panel is best able to answer it. It concerns the level of
 cholesterol. It is noticed that people who are in advanced stages of
 AIDS or HIV infection have very low levels, if not zero, of cholesterol.
 Has any study been done to determine the benefit of supplemental intake
 of cholesterol, if any?

 FIELDS: Cholesterol laboratory levels in your blood have very little to
 do with the intake of dietary cholesterol. Though my gut feeling about
 that is that there wouldn't be any significant benefit from dietary
 cholesterol intake.

 DISCUSSION GROUP: I've been told that getting infusions or injections of
 certain vitamins is superior to taking them orally. I would like to know
 which vitamins you would recommend taking orally and which you would
 recommend taking intravenously. And also I would like to know, is there
 a certain time you should take certain vitamins_should you take certain
 ones in the morning and certain ones in the evening? Should you mix them
 together? Should you take all the vitamins at once, along with the
 minerals?

 GREENSPAN: There are only certain types of vitamins that are available
 in an injectable form, such as vitamin C and the B complex vitamins.
 Taking those on an injectable basis would give you higher doses than you
 normally could tolerate orally, especially vitamin C. Other substances
 such as beta carotene, vitamin E, flavonoids and quinones are only
 available in an oral form.

 As far as combinations of vitamins, I tend to advise patients to take
 their vitamins all together, although they may want to take the vitamin
 E in the evening. That's one of the only substances that may interact
 with other antioxidants. I always advise people to take vitamins on a
 stomach with food already in it so that there is a decrease in the
 potential for gastric upset. The only substance that we advise taking on
 an empty stomach is NAC.

 KAISER: I agree with Dr. Greenspan's comments on when to take the
 vitamins. As far as the choice of intravenous or intramuscular, there
 really haven't been any studies which have looked at the type of
 administration of high dosages of B vitamins, vitamin C and some of the
 antioxidant minerals.

 I am currently preparing a protocol for a Phase I-II study here in
 San Francisco to look at a 2-month course of twice-a-week IV
 administration of higher than normal dosages of vitamin C, B vitamins
 and some of the antioxidant minerals. The study is intended to answer
 the question that I think you are asking, and that is whether nutrients
 in dosages this high become drugs, and whether they have the potential
 to cause side effects. That's why I really think before anybody takes
 them that they need to be looked at in a controlled, scientific manner.
 The theory is that if you provide the antioxidant system of the body
 with nutrient compounds, you may in fact be able to tip the balance back
 from a high level of oxidative stress, increased HIV activity and cell
 death, to a more balanced situation where the body has the ability to
 hold its own against this infection. I think it's an interesting
 direction for research to go and hopefully we'll have at least some
 preliminary information over the next 6 months.

 FIELDS: I'd like to mention one thing. I recently was talking with a
 patient who told me that one of his clinicians recommended injections of
 B12 twice a day. The only concern I really have about that is every time
 you puncture your skin, you are putting yourself at a little more risk
 of infection. That should be taken into consideration.

 DISCUSSION GROUP: Regarding the fluid status in the body composition,
 you said there was a test to look at how much total body water there
 was. Would you talk about that some more? And for the people who have to
 get rehydrated at the hospital, would you discuss what they need to do
 to better maintain hydration?

 FIELDS: There are a number of ways to test body composition and the one
 I think you're interested in involves an electronic sort of "mini-jolt"
 to test total body water. A machine shoots a single frequency through
 the body and measures the water level inside and outside the cell. It
 doesn't tell you specifically how much is either inside or outside the
 cell. What you're concerned with is how much is inside the cell because
 that is more likely to be associated with protein stores. So in order to
 differentiate between the total body water and the amount that's inside
 the cells, a number of people have turned to multifrequency meters.
 However, they're not good clinical tools at this time because they're
 not transportable and they're difficult to use.

 If you have to go into the hospital for rehydration, there's a
 serious problem. Maintaining hydration is always important, but
 especially so during times of fever, for example. To get something that
 is tailored to your needs, you would need to see a clinician to make
 sure that the amount of fluid that you get meets the amount that you
 need. Taking in about 2 to 2 1/2 quarts of fluid a day, not necessarily
 water but some fluid, is a good baseline.

 OMAHA, NEBRASKA: Glad to talk to everyone on the teleconference. The
 question I want to ask is about the importance of massive dosages of
 vitamin C, such as 40,000 to 80,000 mg, and high dosages of vitamin E to
 keep the immune system functioning well. And secondly, I'd like to know
 what resources are available to help people with the cost of vitamins.
 Vitamins are not cheap, as you all know, and some people can barely
 afford them. Is there some kind of a program to help? My last question
 is, what are the foods that naturally contain antioxidants?

 KAISER: Well, I think the person on the other end brought up some
 excellent points, and I think we could probably talk about the answers
 for the rest of the hour. But just to address a few things that he
 brought up_first of all, I think that if I had to pick one category of
 food that contains the most antioxidants_and I hope Cade will say more
 about this_it would be fruits and vegetables. There was an article in
 the newspaper today about a component of broccoli that had been shown in
 an animal study to significantly block the occurrence of cancer in rats,
 compared to a control group, when both groups were exposed to heavy
 doses of carcinogens. So getting at least 5 large servings of fruits and
 vegetables each day would be, I think, your best food source for
 antioxidants.

 As far as the cost of vitamins, with continued research hopefully we
 will get some recommendations that nutrient and vitamin supplementation
 is a valid, even at times an indicated, form of medical therapy, and it
 will be covered by insurance. Unfortunately that's not the case right
 now, so if your finances are stretched, what I would recommend is
 finding the least expensive source of many of these. They come in
 generic forms. You can get a generic multivitamin. You can get generic
 vitamin C. Seek out the least expensive forms of these individual
 nutrients, and try to balance whatever dollars you have both on food and
 these nutrient supplements.

 FIELDS: Before we go on, I'm thrilled that the subject of food sources
 of certain vitamins and minerals was mentioned. I'd like to add a couple
 of things that may be helpful. One medium baked sweet potato has about
 14-15,000 IUs of beta carotene; one large carrot has 11,000 IUs. So you
 can see that food can be a real good source of this. Vitamin C in a
 medium orange is about 80 mg. A less common fruit source is an acerola
 [a cherry-like fruit produced by various West Indian shrubs] which in 3
 1/2 ounces has 1,300 mg of vitamin C, but I don't think too many people
 will find that in their stores. A large green pepper can have 128 mg of
 vitamin C.

 KAISER: These food sources may actually have better bioavailability than
 supplement forms, so you don't have to take as high doses.

 FIELDS: They may have some items that synergistically work along with,
 say, beta carotene, for instance. Carrots have canthaxanthin [an orange
 pigment] in them, which actually may prove to be a little more powerful
 than beta carotene alone, and which may not be found in the beta
 carotene supplement.

 GREENSPAN: There are citrus bioflavonoids which are very prevalent in
 some citrus fruits. They have been studied by the National Cancer
 Institute and shown to be very effective anticancer substances, and are
 known to be among the substances with the highest antioxidant activity.

 NEW YORK CITY: This is addressed to all 3 parties. Regarding various
 extracts, vitamins and even drugs like Bactrim, if the body can't absorb
 them, or develops toxicities, what can you do to try to get them into
 the system?

 KAISER: In my holistic medical practice I do everything as naturally as
 possible before resorting to drugs. In about 3 1/2 years' experience of
 people taking 1 Bactrim double-strength tablet 3 times a week to prevent
 Pneumocystis, the only people in my practice who have come down with
 Pneumocystis have been those who either refused to take Bactrim or who
 decided that, due to allergic reactions, they needed to use an
 alternative. The other thing is that, as expected, if a person wasn't
 allergic but refused Bactrim, there was a higher incidence of fungal
 infections, viral infections and gastrointestinal distress. As it turns
 out, 1 Bactrim tablet 3 times a week has been associated with very, very
 few of these long-term side effects that I was concerned about when I
 started. So my experience has been that it's very safe and effective,
 and I recommend it highly.

 FIELDS: People often look for a single answer but really, because HIV
 affects so many different systems and mechanisms in the body, there's
 probably not going to be a single answer. Antioxidant supplements are
 not the answer to everything that happens in HIV infection. Since there
 is no good single answer, it's going to be multifactorial approach that
 includes a lot of the available medications, some nutritional
 interventions, exercise and a number of other things. Looking to solve
 everything with one answer will probably be more risky than beneficial.

 GREENSPAN: I support Cade on that point. Although much of my work now
 concentrates on antioxidants, I have to say that in my 18 years of
 clinical practice, regardless of the disease situation, good nutrition,
 proper care of the body, just an overall good program is really the
 answer. No one nutrient or set of nutrients is going to be the answer.
 As every day goes by we find new pieces of the puzzle, and new answers.

 KAISER: Ron, I have one more comment for people who are taking
 antibiotics over the long term for prophylaxis. It's very important that
 the quality of the diet be extremely high, and that people consider
 supplementing with acidophilus preparations. If you have these things,
 you'll have a much lower chance of developing side effects from chronic
 antibiotic use.

 BAKER: Excellent comments. Thank you. Jennifer, let's take a question
 from one of the discussion groups.

 WASHINGTON, DC: My question is regarding the juicing of vegetables and
 fruits, which makes it easier to get 6 servings per day. Does juicing
 affect the nutrients in those fruits and vegetables?

 FIELDS: There are 2 ways to think about that. One is that in juicing you
 can get a lot of stuff in a good amount of fluid, and it may be easier
 for some people to deal with. The other thing is that, juicing things
 does allow for an oxidative reaction in a number of the nutrients. For
 instance, if you were to juice an orange and leave it sitting for a
 while, you would lose a great deal of the activity of vitamin C, which
 is why most of the commercial orange juices add vitamin C back. I would
 say if you're going to drink juice, consume it very shortly after you
 juice for optimal nutritional value. The fact that you're using juice to
 get a number of the nutrients at once is an excellent idea. Juice can
 also help if you have problems digesting more solid food.

 NEW YORK CITY: I've been associated with the Gay Men's Health Crisis in
 New York, as a staff nutritionist. I just wanted to say that, with beta
 carotene in particular, the nutrition is mostly in the pulp. If you
 figure that a cup of carrot juice contains roughly the juice of five
 carrots, you're still only getting the beta carotene of about one carrot
 since about 4/5 of the beta carotene stays in the pulp. So,
 unfortunately, it isn't an efficient way of getting beta carotene.

 GREENSPAN: Likewise for most of the citrus fruits. Much of the nutrient
 value is in the fibrous material.

 NEW HAVEN, CT: Dr. Kaiser mentioned that patients taking 3 to 5 times
 the RDA still showed nutritional deficiencies in things like zinc. I'm
 interested to know what's really causing these nutritional deficiencies.

 KAISER: I have 3 quick comments on that. One is, I think that RDA
 requirements for most of the nutrients are woefully inadequate when
 you're talking about people who are under the stress of HIV infection.
 The RDA are effective at keeping people just above the level where an
 individual who doesn't have a health problem, who is not overly
 stressed, will not come down with a disease related to nutrient
 deficiencies. But for someone with HIV infection RDA are woefully
 inadequate, due to increased metabolic requirements, due to increased
 stress.

 The second point is that HIV itself tends to cause changes in the
 bowel that may influence the absorption. In different individuals the
 absorption will be affected to different degrees. Without doing very
 expensive and sometimes inaccurate tests, we need to shoot for a level
 that in most HIV positive people will provide sufficient levels of
 absorption and that help with the deficiencies that the condition
 causes.

 There are people who are bypassing the absorptive mechanism of the
 gut and who are taking nutrients in intravenous form. I really don't
 think we have enough data on whether or not that is effective or whether
 it's safe. It's a personal decision, but I think one should try to take
 as much as possible orally and naturally.

 WHARTON, NEW JERSEY: What sort of supplementation would you recommend to
 a diabetic, HIV-infected person on a restricted diet?

 FIELDS: A diabetic diet allows a person to get an adequate amount of
 nutrients, including micronutrients, without requiring additional
 supplementation. If you're having a problem getting an adequate amount
 of nutrients with a diabetic diet, then you probably need to talk with a
 diabetic educator on an individual basis.

 SAN FRANCISCO: I'm a physician's assistant for Marcus Conant's Medical
 Group in San Francisco. This question is for any of the panelists who
 would like to answer. We see, almost universally, increased
 triglycerides in our HIV patients, and we were wondering whether the
 amino acid carnitine has been shown to be effective in reducing these
 levels. We really haven't found much else that has worked for some of
 these patients.

 GREENSPAN: Certainly carnitine has been used in that capacity, although
 I've not seen any studies that verify its activity. We do know that one
 of the primary causes of the elevations in triglycerides has to do with
 the production of TNF [tumor necrosis factor] from macrophages and
 monocytes, which are prevalent in HIV infection. More progressive
 infection has higher levels of TNF. And one of the things we are looking
 at are mechanisms of reducing the levels of tumor necrosis factor
 production.

 BAKER: There have been several studies suggesting that use of the drug
 Trental (pentoxifylline) reduces levels of tumor necrosis factor in
 people with AIDS. Patients might want to discuss use of the drug with
 their doctors. Trental has shown no significant adverse side effects.

 Thank you all for your excellent questions. Now I'm going to report
 briefly on recent AIDS drug developments and also tell you about some
 important clinical studies which are open for enrollment.

   D4T

 Although there haven't been any new antiviral drugs approved by the
 Food and Drug Administration for a long time now, there is one anti-HIV
 drug called D4T that is currently awaiting FDA approval. Bristol-Myers
 Squibb, the manufacturer of D4T has asked the FDA to approve this drug
 for HIV positive adults who have previously taken AZT. The FDA Antiviral
 Advisory Committee, which makes recommendations on drug approvals, will
 meet in May to make a recommendation for or against approval of this
 drug. Right now D4T is only available to people who have failed or are
 intolerant to both AZT and ddI. If you fall into that category, you
 should speak with your doctor about the possibility of getting the drug.

  Acyclovir

 There's quite a bit recently to report about the anti-herpes drug
 acyclovir, especially its use in HIV. Government health officials in
 Australia have approved acyclovir as a treatment for people with
 symptomatic HIV infection who have fewer than 150 T-helper (CD4+) cells.
 Several studies, as many of you know, have shown a significant survival
 benefit for people with AIDS who take acyclovir daily. This survival
 benefit may not be related to the use of high doses of acyclovir, as was
 previously thought, but rather to the drug's use for a longer time
 without interruption and at doses between 600 and 800 mg/day. One study
 found that acyclovir produces an increased survival rate in people with
 AIDS taking it in combination with AZT, compared to people taking AZT by
 itself. Another study concluded that acyclovir increases survival when
 it's started after the individual receives an AIDS diagnosis, but not in
 people who started before they received an AIDS diagnosis.
 There's more news on acyclovir. In May the FDA will consider a
 request to make acyclovir an over-the-counter drug in the U.S. If
 granted, this would mean that no prescription would be necessary to buy
 acyclovir.

   AZT

 The most important news recently regarding AZT, as I'm sure many of
 you read, is that a recent government-sponsored trial has demonstrated
 that AZT significantly reduces the transmission of the virus from HIV
 positive pregnant women to their newborn infants. Because of this study
 result, the manufacturer, Burroughs Wellcome, has asked the FDA to
 approve AZT to treat HIV positive pregnant women. This is a
 controversial area, and the NIH will probably soon convene a national
 conference to come up with recommendations regarding AZT use for
 pregnant women who are HIV positive.

  HIV and HSV

 Researchers have long suspected that there may be an interaction
 between HIV and the herpes simplex virus. Now a new study has shown that
 when these 2 viruses are present together, they can infect many more
 cells then when either is present alone. HIV positive individuals may
 benefit from daily use of acyclovir.

  HHV-6

 Another herpesvirus, which was discovered just a few years ago, is
 also in the news. It is called human herpes virus type 6, or HHV-6 for
 short. More than 90% of the population of the U.S. has become infected
 with HHV-6 by the time they are 2 years old. Like other herpesviruses
 such as herpes simplex and varicella zoster, HHV-6 can remain inactive
 for many years and then reactivate, causing disease in people with
 weakened immune systems such as people with HIV disease and AIDS.

 Researchers in Wisconsin say they have found a significant link
 between HHV-6 and AIDS. Most of the cells in the individuals infected
 with HHV-6 were T-helper cells, which are the same cells that HIV
 infects and destroys. These researchers concluded that HHV-6 may be an
 important disease-causing agent in people with AIDS. In an editorial on
 this subject, Dr. Robert Gallo, the co-discoverer of HIV, pointed out
 that HHV-6 is the only virus known that can effectively infect and
 destroy the body's natural killer cells. Losing the protective effect of
 natural killer cells is one of the hallmarks of HIV disease progression.
 In the June issue, BETA will examine the question of whether HHV-6 is a
 significant contributor to HIV disease progression or whether it is an
 opportunistic infection that may cause disease in people with AIDS.

   Interleukin-12

 I want to mention a new development in the area of immunotherapy for
 HIV infection. Immunotherapy is treatment to help restore normal immune
 function. In June of this year the first human study of the
 immunomodulating drug interleukin-12 will begin. The results of animal
 studies using this drug have made some researchers optimistic about the
 ability of interleukin-12 to stop the growth of cancerous tumors in
 humans without causing severe toxicity. AIDS researchers are excited
 about the potential of this drug to restore normal immune function in
 people with HIV. If the drug can do this without causing severe
 toxicity, it may help to slow disease progression. One of the
 manufacturers of interleukin-12, Genetics Institute in Cambridge,
 Massachusetts, has announced that a Phase I study of interleukin-12 in
 people with HIV will start by June of this year. Hoffman-La Roche also
 will begin a Phase I study of interleukin-12 as a treatment for cancer
 some time this year. Roche scientists have said that interleukin-12 is
 active against a widespread group of cancers, including the dangerous
 skin cancer, melanoma, and 14 other malignancy types. BETA will continue
 to follow the development of this drug very closely.

  Septra

 One of the callers tonight mentioned the anti-Pneumocystis drug
 Bactrim, also commonly called by the brand name Septra. Researchers have
 found that HIV positive people using the drug to prevent Pneumocystis
 also avoided toxoplasmosis, a life-threatening infection in people with
 AIDS. We summarized the results of this study in the March issue of BETA
 and we wanted to stress that Septra or Bactrim is very clearly the best
 drug to prevent these dangerous infections. It's important for people
 with HIV who are at risk for these diseases to seriously consider using
 the drug.

 Because Septra often causes serious side effects in people with HIV,
 it's best for a patient and physician to discuss using a
 "desensitization protocol" for Septra before starting preventive
 treatment. This involves taking very small doses of the drug at the
 beginning of therapy and gradually increasing the dose until the
 full-strength dose for prophylaxis is reached. By using such a
 desensitization procedure, many people who otherwise cannot tolerate
 Septra may be able to do so. We know of 2 successful desensitization
 protocols, one from Dr. Marcus Conant in San Francisco. For more
 information on this protocol you may call 415-923-1333. The other was
 developed by Dr. Brian Lipson in Redwood City, California; his number is
 415-365-6300.

  Peptide T

 Researchers have concluded from a Phase II trial recently that
 peptide T, which is a widely used experimental drug sold by AIDS buyers'
 clubs, is not effective in reducing the pain and discomfort caused by
 HIV-related peripheral neuropathy. A 12-week study of about 100 people
 in Miami showed that there was no significant difference between peptide
 T and a placebo in treating the pain caused by peripheral neuropathy.
 Although peptide T is nontoxic, a month's supply costs about $250 when
 purchased from an AIDS buyers' club, so buyer beware!

   Protease Drugs

 I want to mention briefly a couple of important drug studies that are
 currently open to enrollment for people with HIV infection and AIDS. As
 many of you may have heard or read recently, the most promising anti-HIV
 drugs that are likely to be approved in the near future are called
 protease inhibitors. These drugs attack HIV in an entirely different way
 than currently available anti-HIV drugs do. Their most effective use may
 be in combination with AZT and/or ddI and ddC, or with each other. The
 protease inhibitor that is farthest along in development is the Roche
 protease, which has been given the name saquinavir. The results of a
 government-sponsored study of saquinavir used in a triple combination
 with AZT and ddC will be released in the near future. This significant
 study will give us the first information on whether the combination of a
 protease inhibiting drug with currently available anti-HIV drugs
 produces more benefit than taking the drugs alone. Another interesting
 aspect of the study is that researchers are measuring the effect of the
 combination treatment on viral load in people taking the drug. It will
 be important to know how effectively and for how long this combination
 treatment may reduce the amount of HIV in the body.

  Saquinavir

 Saquinavir is just now entering Phase III trials in North America.
 About 40 medical centers are currently recruiting for 1,200 HIV positive
 individuals with T-helper cell counts between 50 and 300, who have
 previously used AZT but no other anti-HIV drug. In this study,
 saquinavir will be evaluated as single-agent therapy and in combination
 with ddC and compared to results with ddC alone. Study sites are open
 for enrollment in the following states: California (in the San Francisco
 Bay Area and in Southern California), Illinois, the District of
 Columbia, Florida, Georgia, Massachusetts, Missouri, New York (including
 New York City), Oregon, Pennsylvania (Philadelphia) and Texas. The
 toll-free number to call for more information about this study is
 800-526-6367.

 An international trial of saquinavir, scheduled to begin this month,
 has been postponed. That trial will eventually recruit about 1,800
 people who have never taken AZT or any other anti-HIV drug. About 600
 people will be recruited in the U.S. and about 1,200 in Europe. Again,
 the number to call for more information is 800-526-6367.

  Interleukin-4 for KS

 For the first time people with Kaposi's sarcoma (KS) are now being
 treated with an experimental therapy that may allow them to avoid
 chemotherapy and its adverse side effects. The therapy involves
 interleukin-4. Laboratory tests show that this drug interferes with the
 growth of KS. For more information about this study in the Southern
 California area, call [phone]; in the Boston area, call (617)
 632-8528.

  Marijuana and Weight Gain

 The last study I'll mention involves the use of marijuana against
 weight loss in people with AIDS who are suffering from wasting syndrome.
 An FDA-approved pilot study will compare use of inhaled marijuana to the
 synthetic THC oral drug called Marinol which is already FDA-approved for
 weight loss in people with AIDS. For information about this trial in the
 San Francisco Bay Area, call 415-476-9554.

 We hope that you can participate in future BETA LIVE!
 teleconferences. We've tentatively scheduled another teleconference for
 July. The subject will be "Aggressive Treatment for HIV Infection."
 Please call the 800-707-BETA number anytime after May 1st to find out
 dates, times and panelists. We've also tentatively planned a third
 teleconference in August to report on treatment updates from the
 International AIDS Conference in Yokohoma, Japan.

  Ms. Fields, Dr. Greenspan and Dr. Kaiser, thank you so
 much for your participation. Thanks to Hoffmann-La Roche for
 providing the educational grant that supports the BETA LIVE!
 teleconferences, and thanks to you, our audience, for
 joining us this evening. We hope to talk with you again in
 July. Good-bye for now, and stay well.

       **********
  Nutrition for HIV-Associated Wasting Syndrome

 Serono Laboratories soon will produce the following text as a free
 educational brochure.

 If you are HIV positive and losing weight, you are not alone.
 HIV-associated weight loss, known as wasting syndrome, is a common
 manifestation of HIV infection. Although much needs to be learned about
 wasting syndrome, there are certain nutrition and fitness strategies
 from which all people with HIV-associated weight loss can benefit.
 Why is wasting important?

 The key to understanding wasting is to recognize that HIV-associated
 weight loss differs from ordinary weight loss. With ordinary weight
 loss, fat is initially depleted more than muscle. In wasting syndrome,
 however, muscle and other protein stores are significantly affected.
 Without these essential protein stores, the body cannot function at
 optimal levels. In fact, when more than 45% of lean tissue, such as
 muscle, is depleted, wasting can become life-threatening.

 If you are HIV positive, you may be losing vital muscle mass for
 several reasons. You may have lost your appetite due to such factors as
 infection or depression. You may have metabolic disorders that cause
 changes in the way the body transforms food into energy. Or, you may not
 be able to absorb the nutrients in the food you eat due to an infection
 that affects the function of your gastrointestinal tract, including
 vomiting and/or diarrhea.

 What's the best nutrition plan?

 The importance of proper nutrition cannot be emphasized enough. When the
 body is malnourished, as is the case with wasting, immune system
 function is impaired. Because HIV infection itself jeopardizes the
 immune system, it is especially important for people who are HIV
 positive to maintain proper nutrition.

 What foods are recommended?

 You should eat a balanced diet that includes foods from a variety of
 food groups, being sure to include adequate protein. Protein is
 essential to help build up muscle mass that is lost because of wasting.

 To reach the proper balance of fat, protein and other foods, it is
 helpful to eat foods from a variety of categories. If you are HIV
 positive, however, you need more calories than people who are HIV
 negative. Therefore, you should not restrict your diet to limited
 servings, but eat as much as you can when you are hungry. Select foods
 from the following categories, which are recommended for all people by
 the American Dietetic Association:

 Bread, Cereal, Rice, Pasta:

 These foods, like potatoes and corn, are high in carbohydrates and low
 in fat, which means that you will derive significant energy from
 starches without gaining undesirable weight from fat. For this reason,
 these foods, along with protein-containing foods, should form a large
 part of your diet.

 Dairy:

 Milk, eggs, yogurt and ice cream are just some of the foods that
 comprise the dairy group. It is not uncommon for people who are HIV
 positive to have problems digesting dairy products because of lactose
 intolerance. Lactose-free dairy products are available for this problem.
 Even if you tolerate dairy products well, you should always drink
 pasteurized milk and milk products, and you should not eat raw eggs
 (often present in Caesar salad dressing and uncooked cookie dough).
 People who are lactose-intolerant may take Lactaid, an oral,
 over-the-counter product, to aid in lactose digestion.

 Protein:

 Meat, poultry, fish, nuts, beans, eggs and peanut butter provide
 protein, which is essential for building muscle. Meat provides more
 complete proteins than nuts and beans, but there are ways to form
 complete proteins by combining foods such as rice and beans. Your
 physician or a nutritionist can help you plan meals that meet protein
 requirements if you do not want to eat meat.

 Vegetables:

 Thoroughly washed fresh and frozen vegetables are rich sources of
 vitamins. All vitamins are essential to your diet, but because those who
 are HIV positive are often deficient in vitamins C and A, these vitamins
 are especially important for people who are HIV positive. Vitamin C is
 provided by such vegetables as tomatoes, potatoes, broccoli, green
 pepper and cabbage. Vitamin A is provided by such foods as carrots,
 broccoli, spinach, yams and pumpkins. Some methods of food preparation,
 such as boiling, can deplete the vitamins in vegetables.

 Fruit:

 Fruit also is an important source of vitamins. Vitamin C is provided by
 such fruits as oranges, tangerines and grapefruits. Apricots are an
 excellent source of Vitamin A. Thorough washing is as important for
 fruit as for vegetables.

 Fats, Oils, Sweets:

 Although some fat is necessary in your diet, you should eat very limited
 quantities. Fat is present in great amounts in foods such as butter,
 cream, ice cream, mayonnaise, avocado, salad dressing and fried foods.
 How can I make my food safe to eat?

 HIV infection weakens the immune system, making people who are HIV
 positive more vulnerable to infection than those who are not. For this
 reason, the common bacteria found on food presents a significant risk to
 people who are HIV positive. Therefore, you should take certain
 precautions when you select and prepare food. With the proper steps, you
 can greatly increase your chances of eating safely:

 ∙ Be sure all foods that require refrigeration are properly stored.

 ∙  Wash your hands in hot, soapy water before handling food.

 ∙ Avoid tap water because it may contain bacteria that may adversely
   affect people with HIV; buy bottled water or purify water from the
   tap.

 ∙ Use only pasteurized milk and milk products.

 ∙ Never consume any product after the "sell-by" date has passed.

 ∙ Cook foods as soon as they thaw, and never thaw them at room
   temperature. Use a microwave oven set on the defrost setting, or
   place frozen food in the refrigerator to thaw.

 ∙ Do not eat raw vegetables and salads at restaurants.

 ∙ If you eat raw vegetables and fruits, the safest method to use is to
   wash and peel them at home before eating. Let vegetables or fruit
   stand in a disinfected mixture 10 minutes before rinsing. A mixture
   of one gallon water to 20 drops of 2% iodine tincture solution is
   recommended. The mixture may turn blue, but the food is still safe to
   eat. Discard the mixture after each use.

 ∙ Use paper or cloth towels only once before discarding.

 ∙ Cook all meats, poultry, fish and eggs thoroughly.

 ∙ Heat leftovers to an internal temperature of 165°F and do not leave
   any cooked food in the refrigerator longer than 3 days.

 ∙ Place meats, poultry and seafood in double plastic bags before
   refrigeration. Keep them out of contact with other foods.

 ∙ Clean all reusable items (cutting board, utensils, plates, pots,
   countertops, etc.) that come into contact with your food after each
   use with hot water and soap or diluted bleach (2 tablespoons/gallon of
   water). Follow the same process when preparing food. For example, a
   knife that has been used to clean chicken should be thoroughly cleaned
   before using the same utensil on other food.

 ∙ Do not drink or eat directly from a storage container (milk carton,
   peanut butter jar).

 What if eating is painful?

 If you have an infection that makes eating painful, there are steps you
 can take to make food easier to swallow. Eating soft foods, such as
 yogurt and bananas, can minimize discomfort. Additionally, you or your
 caregiver can chop or puree food in a blender. It may also help to chill
 blended foods, such as fruit shakes, because the cool temperature is
 soothing. There are also medicinal approaches to decreasing painful
 chewing or swallowing. Of course, be sure to talk with your doctor about
 any unexplained pain during eating.

 Exercise: an Important Part of Your Regimen

 Although exercise is frequently seen as a way to lose weight, you should
 view exercise as an opportunity to increase muscle mass. The foremost
 objective of exercise is to use and build muscle, which can be achieved
 by including walking, performing resistance exercises and stretching,
 among other activities. Strenuous aerobic exercise is not recommended
 because it burns a great deal of calories.

 No matter what activity you enjoy, the key to a successful program is
 consistency. On days that you feel stronger, increase the level of
 difficulty and duration of exercise. Even when you feel fatigued, mild
 exercise may help to give you more energy while maintaining and building
 muscle. Exercise often has the added benefit of decreasing stress,
 improving sleep and increasing your appetite.

 Before you begin an exercise regimen, talk to your physician. He or
 she will be able to help you select appropriate exercises and compensate
 for additional calorie use by adding foods to your diet.

 Managing problems that contribute to weight loss

 Problems such as diarrhea or taste changes can make it difficult to
 consume or enjoy food. There are ways to alleviate or lessen the
 severity of these problems and encourage weight maintenance or gain. If
 you feel so fatigued that it is impossible to prepare your own food, you
 may want to utilize food delivery services in your community or have a
 caregiver assist you in meal preparation. Following are some guidelines
 for dealing with several common problems associated with HIV infection
 that can interfere with optimal food intake.

  Diarrhea

 Do:

 Drink plenty of fluids. Apple, grape, peach and nectar drinks are
 recommended. However, fruit juices can cause diarrhea. Non-citrus
 juices may be diluted with water to help alleviate this problem.

 Eat foods high in soluble fiber. Oatmeal, potatoes, apples/applesauce,
 bananas, peaches, pears and apricots are recommended.

 Eat small, frequent meals served at room temperature.
 Consult with your physician if the diarrhea lasts for more than 2 days.

 Do not:

 Consume high fat foods, such as cream, bacon, sausage, cheese, oil,
 avocados and salad dressing.

 Consume lactose-containing foods such as milk, ice cream and dairy
 products.

 Eat foods high in insoluble fiber, such as granola, whole grain
 breads/cereals and wheat germ.

 Eat citrus fruits or drink citrus juices such as orange, lemon or
 grapefruit.

 Drink alcohol.

 Drink caffeinated drinks.

   Loss of appetite

 Do:

 Choose high-calorie and protein foods.

 Keep track of what and how much you eat.

 Eat small meals frequently.

 Keep easy-to-prepare foods on hand.

 Plan meals with friends.

 Eat a lot on days you feel like eating.

 Ventilate the area in which you prepare food_stale odors can decrease
 appetite.

 Do not:

 Drink liquids just before or during meals because they can be filling
 and can result in a bloated feeling.

 Eat high-fat foods, which empty out of your stomach more slowly than
 other foods.

 Mouth sores/Difficulty swallowing

 Do:

 Keep your mouth clean by rinsing often with a dilute solution of
 hydrogen peroxide and water or other solution recommended by your
 dentist or physician.

 Eat soft foods such as pudding, custard and mashed potatoes.

 Use a straw.

 Do not:

 Eat steaming hot foods.

 Eat deep fried, salty, sticky and sour foods.

 Use commercial mouthwash.
   Taste changes

 Do:

 Eat a variety of foods.

 Keep your mouth clean.

 Try increasing aroma in foods by using spices, lemon and vinegar.
   Nausea/Vomiting

 Do:

 Eat dry and liquid foods separately.

 Eat smaller portions, more often.

 Eat saltine crackers, pretzels or dry toast.

 Consult with your physician if symptoms persist.

 Do not:

 Eat high-fat foods.

 Eat very sweet or spicy foods.

 Eat foods with strong aromas.

 Lie down after eating.

 Creating Your Own Strategy

 Eating a proper diet, maximizing food safety and engaging in a regular
 exercise program are important steps in managing wasting syndrome. These
 suggestions are intended to help you in this regard. Your physician can
 help you create a plan that meets your individual needs.

 This information is provided as an educational service by Serono
 Laboratories, Inc., a subsidiary of the Ares-Serono Group.

 We gratefully acknowledge the assistance of Donald P. Kotler and Viva
 Tai.

  Sources

 Jensen J. Controlling wasting and tasting. Being Alive: 5. September 1993.

 Kotler DP and others. Magnitude of body-cell-mass depletion and the timing
of death from wasting in AIDS. American Journal of Clinical Nutrition 50:
444-447. September 1989.

 Kraak V. You are what you eat. The Body Positive. October 1993.

 Weber J. Gastrointestinal disease in AIDS. Clinics in Immunology and Allergy
6: 519-541. 1986.

       *********

 1994 BETA Readership Survey:
  Readers' Comments

 The marketing research firm Communications Technologies is
 now analyzing the surveys returned by over 1,500 BETA
 readers. Their report will be published in the September
 issue of BETA. The comments below were drawn from the
 hundreds of handwritten notes returned by readers with their
 completed surveys.

 "I am grateful for your publication. I share the information in it with
 HIV positive females in recovery from alcohol and drugs_it has been most
 helpful. I also do inservices on HIV at work and I use your magazine for
 that as well. I believe it is critical that accurate information is
 passed along to all people, positive or negative."
 Alameda, California

 "Living in Indiana makes it very difficult to obtain information on
 alternative treatments. Because I have just started ddI I would greatly
 appreciate as much information on herbs, massage, acupuncture_and
 contact numbers. BETA has helped me over the past 2 years to make
 informed decisions about my treatment. Thanks."
 Evansville, Indiana

 "I enjoy reading BETA very much! I wish it was published monthly, but
 your quarterly published volumes still provide much information. I read
 it faithfully and feel that I have survived this long due to
 experimenting with therapies that you have written about. Thank you very
 much."
 Las Cruces, New Mexico

 "I greatly appreciate that BETA is provided to me by scholarship. The
 information is extremely helpful. I have advanced AIDS and used to work
 as an AIDS educator and substance abuse counselor. I also started and
 facilitated an HIV support group for addicts. I have found BETA to be
 helpful both personally and professionally in my life and work. I would
 like to see some articles about drug use and HIV."
 Van Nuys, California

 "Keep on keeping on_I know there must be some days you feel like it's
 hopeless, not worth the effort_but it is! Particularly you help us out
 here in small towns and rural areas. We have to educate the physicians
 here, not the other way around. You are our lifeline and all the latest
 news."
 Fayetteville, Arkansas

 "In the year that I've been receiving BETA, I have been able to make
 several significant suggestions to my doctor. Quite often what I offered
 was new to them as well. Thanks for the good work_please keep it up."
 Baton Rouge, Louisiana

 "We could benefit from a computerized research/retrieval, archive and
 current information system."
 San Quentin, California

 "I am the Executive Director of an AIDS support organization that
 focuses on mental health and education. Over the seven years I have been
 involved with this organization, your publication has been among the
 best we have ever received. Keep up the excellent work. You are helping
 so many. Thank you!"
 Orlando, Florida

 "Your publication helps to keep me informed of new treatments and to ask
 more intelligent questions of my physicians. I believe my continued
 participation in my treatment has helped me retain my status as a
 longtime survivor. Please continue to keep up the good work."
 Richmond, Virginia

 "Would greatly appreciate more information on pediatric AIDS. This last
 BETA was very helpful! Thanks, a concerned mom."
 West Palm Beach, Florida

 "More information on women, please!"
 Nevada City, California

 "Thank you for providing an invaluable information source for AIDS
 patients, especially for those of us who do not live in big cities. Many
 doctors in smaller cities and public health clinics do not have much
 information on treating AIDS and related illnesses."
 Reno, Nevada

 "I live in a city which is behind in most of their alternative therapy
 information. BETA has not only enabled me to learn what else is being
 used, but to show this valuable information [to others]. You're doing a
 great job! Keep it up!"
 Buffalo, New York

 "Rural America is about to suffer a big loss as people ignore the fact
 that AIDS does not discriminate. We need to educate rural teenagers
 immediately."
 Trinidad, Colorado

 "BETA is the first thing we show HIV positive people who come to our
 health education center to ask for information."
 South San Francisco, California

 "My interest in HIV/AIDS is because my son died in January 1993 of
 Kaposi's sarcoma in his lungs. We (he and I) read every issue and were
 informed and aware. We thought that being educated would put off his
 ultimate death. Perhaps it did. He lived 3 years after his AIDS
 diagnosis. He had no skin lesions so doctors didn't know he had KS. Keep
 informing people_every day an AIDS sufferer lives is a gift to those who
 love him."
 Tucson, Arizona

 "I find your journal an excellent source of information that prepares me
 for my doctor's visits by supplying ideas and questions."
 New Hyde Park, New York

 "Excellent publication overall. I used to live on Maui, and BETA was a
 lifeline for me. One criticism: I'd like to see more explanation and
 discussion of alternative treatments/theories."
 Albany, California

 "I've only been reading BETA for 2 months and look forward to each
 issue. My husband and I are both HIV positive."
 Sacramento, California

 "People must be made aware of how important nutrition and lifestyles
 are. My doctor just gave me drugs (AZT, ddI) and didn't even mention
 smoking and drinking! That's not right. Please print as much as possible
 about taking care of ourselves. It's really all we've got."
 Phoenix, Arizona

 "More on women, also more alternative therapies, great publication.
 Thank you all!"
 Lakeland, Florida

 "By far, BETA is my best information source. It is more technical than
 most, but I feel this is necessary to fully explain a bodily process or
 experiment. Please keep up the good work. I look forward to each issue
 and modify my health program based on your reports. I would particularly
 like to see more articles on Chinese medicine, herbs, acupuncture and
 nutritional supplements."
 Chicago, Illinois

 "This publication is invaluable for me living in northern New England. A
 physician recommended this publication. Medical books become outdated
 soon so keep up the good work. It helps a great deal to stay informed."
 Manchester, New Hampshire

 "Excellent publication! I look forward to every issue and often use
 articles in current and past issues to council recently symptomatic HIV
 individuals and even AIDS patients dealing with new complications."
 San Diego, California

 "Excellent, highly useful publication The technical orientation is hard
 to understand for a layperson, but I prefer to make the effort because
 the result is so precise and unambiguous. BETA is my primary source for
 authoritative AIDS information."
 San Francisco, California

 "The information has proven invaluable in managing the course of my
 health care. Understandably, your publishing costs and overhead are
 significant but subscriptions to BETA for myself and friends on limited
 incomes are simply not possible. Fortunately, I live in the Bay Area and
 most times can obtain my quarterly issues without incidence. However, I
 do not hesitate to photocopy and forward to others. Still, I cannot help
 but sympathize with the countless individuals on all levels who could
 benefit as I have. Please increase your circulation. And first and
 foremost, thank you!"
 San Francisco, California

 "I wait for your issue of BETA every month from the AIDS Assistance
 Association. When they come and see me here in jail it is basically all
 I have to look forward to. I've written a lot of agencies and have not
 had a response except for 2 or 3 out of 50. So what you put in BETA is
 my lifeline. Thank you!"
 Anchorage, Alaska

 "The information you provide in BETA I cannot get anywhere else. You
 have a very complete and wide range of information and test studies.
 Thank you for making it available to those of us who are financially
 strapped and could use any extra help in our everyday lives."
 Medford, Oregon

 "I truly believe I've lived so long because BETA helped me decide my own
 treatment. I've tried everything I could use in BETA. I still learn.
 BETA keeps up my hope with knowledge."
 Fort Smith, Arizona


       **********
 Acyclovir Increases Survival!
 ∙ FDA Approval of d4T ∙
 Alternative Therapies: Hope
 and Hype
 Ronald A. Baker,PhD

 Ronald Baker is editor of BETA.

 Acyclovir Increases Survival!

 There is a growing consensus among clinicians that, in addition to
 anti-HIV therapy, acyclovir (Zovirax) should be offered to all
 individuals with advanced HIV disease to increase their survival time.
 Several studies have concluded that daily use of acyclovir significantly
 increases the lifespan of people with AIDS who are also on
 antiretroviral treatment (Cooper, 1993; Stein, 1993;
 Youle, 1994).

 No one knows why acyclovir confers a survival benefit; it may be
 related to the ability of the drug to suppress reactivation of one or
 more of the herpesviruses. It is also possible that the drug interferes
 with the activity of an as yet unidentified cofactor for HIV disease
 progression.

 The optimal dose of acyclovir for increasing lifespan is unclear. One
 recent study suggests that 600-800 mg/day is sufficent (Stein, 1993).
 Other studies showing a survival advantage from acyclovir plus AZT used
 3,200 mg/day acyclovir (Cooper, 1993; Youle, 1994). Stein and colleagues
 conclude that longer, uninterrupted periods of acyclovir use are
 associated with longer survival. In their study group, acyclovir
 conferred significantly increased survival time when used following an
 AIDS diagnosis, but not pre-AIDS.

 An important unanswered question is whether HIV positive individuals
 at earlier stages of infection will also experience a survival benefit
 from acyclovir use, even if they do not have recurrent genital or oral
 herpes simplex.

 The Australian government has approved acyclovir use for all HIV
 positive individuals with fewer than 150 CD4 cells.

 Based on the weight of the available evidence, Marcus Conant, MD, now
 recommends lifetime treatment with oral acyclovir (400 mg twice daily)
 to all his HIV positive patients, regardless of CD4 count or disease
 stage (Conant, 1994). Dr. Conant is an AIDS researcher and community
 physician with a large HIV practice in San Francisco, CA.

 "It is important for physicans to discuss with
 their HIV positive patients the potential benefits
 and risks of lifelong treatment with acyclovir as
   soon as possible."

 Because acyclovir appears to significantly increase survival time, it
 is important for physicans to discuss with their HIV positive patients
 the potential benefits and risks of lifelong treatment with acyclovir as
 soon as possible.

 Conant MA. Director of the Conant Medical Group, San Francisco, CA. Personal
Communication. May 25, 1994.

 Cooper DA and others. The efficacy and safety of zidovudine alone or as
co-therapy with acyclovir for the treatment of patients with AIDS and
AIDS-related complex: a double-blind, randomized trial. AIDS 7(2): 197-207.
1993.

 Stein DS and the MACS. The interaction of acyclovir (ACV) with zidovudine
(ZDV) on survival in HIV infection. The First National Conference on Human
 Retroviruses and Related Infections, December 12-16, 1993. Abstract #527.

 Youle MS and others. Effects of high-dose oral acyclovir on herpesvirus
disease and survival in patients with advanced HIV disease: a double-blind,
placebo-controlled study. AIDS 8(5): 641-649. May 1994.

 FDA Approval of d4T

 On May 20 the Antiviral Advisory Committee of the U.S. Food and Drug
 Administration (FDA) recommended that the government grant accelerated
 approval of the anti-HIV drug d4T (see Research Notes, page 50 of this
 issue). Although d4T is not a breakthrough treatment, its approval
 definitely will benefit many people living with HIV infection and AIDS.
 HIV positive individuals desperately need access to new treatment
 options. Currently d4T is available only to people with AIDS who have
 failed or are intolerant to all 3 licensed anti-HIV drugs: AZT, ddC and
 ddI. Although d4T likely will be licensed with this same restriction,
 following FDA approval, physicians will be able to prescribe the drug to
 patients at all stages of HIV disease.

 Community groups that spoke to the FDA panel raised legitimate
 concerns about the safety and effectiveness of d4T, citing a lack of
 knowledge about how to use the drug and questions about its adverse side
 effects. Although these concerns deserve attention, d4T appears to be
 reasonably safe and has demonstrated some promise of efficacy. With so
 few treatment options, d4T is a welcome addition to the short list of
 anti-HIV agents now available by prescription.

 Preliminary data suggest that d4T is about as effective as AZT (the
 first-line treatment for HIV infection), yet causes less severe side
 effects. For these reasons alone, d4T should be made available by
 prescription as soon as possible.

 Several activists and advisory panel members strongly criticized a
 new FDA policy that allows AIDS drugs to be evaluated using CD4 counts
 as a marker for HIV disease progression. The best evidence presented for
 approval of d4T was its ability to raise CD4 counts by 20-30 cells among
 former AZT users, compared to a decline in CD4 cells among people who
 continued on AZT. Although changes in CD4 counts are not the ideal
 method for evaluating anti-HIV drug effectiveness, their use is both
 appropriate and necessary until more reliable markers (such as PCR
 measurement of HIV load) become widely available.

 The potential for benefit in making d4T available by prescription far
 outweighs the potential for harm from the drug, particularly if
 physicians and patients closely monitor for the drug's most serious side
 effect, peripheral neuropathy. The risk of experiencing this adverse
 side effect from d4T is no greater nor more harmful that the risk of
 bone marrow toxicity from AZT, pancreatitis from ddI or peripheral
 neuropathy from ddC.

 While making d4T available by prescription is not a major treatment
 development, it is a step forward from the current restriction that
 limits access to the drug only to those who have already failed on AZT,
 ddI and ddC. These are the least likely people to benefit from d4T. The
 drug may prove far more useful to asymptomatic or mildly symptomatic
 individuals and to people with AIDS who have not yet exhausted all other
 anti-HIV treatment options.

 Alternative Therapies:Hope and
 Hype

 The term "alternative treatment" has 2 distinctly different meanings.
 For some individuals, the term literally means an alternative that
 excludes the use of orthodox therapies. For others, it implies
 "complementary" treatment, i.e., used in addition to standard therapies.
 The distinction is important, since strict adherence to the first
 definition could be life-threatening to people with advanced HIV
 disease.

 A recent survey of HIV positive individuals who regularly visit a
 London medical clinic revealed that 44% were using one or more
 alternative therapies (Barton, 1994). Of these people, 27% were also
 participants in a clinical trial of some standard therapy. As this
 report indicates, the use of alternative treatments appears to be
 increasing among HIV positive individuals, probably due to widespread
 disappointment and pessimism about the limited benefits of available
 standard treatments.

 "DNCB is reportedly the current 'best-seller' in
 U.S. AIDS buyers' clubs, despite the lack of
  scientificevidence for its efficacy."

 Given the renewed popularity of alternative treatments, it is
 important for HIV positive individuals and their caregivers to educate
 themselves about these agents. One or more of these therapies may prove
 useful in HIV disease. Official acknowledgement of their potential
 importance occurred in 1992, when the National Institutes of Health
 founded the Office of Alternative Medicine to study the use of
 alternative treatments for both AIDS-related and non-AIDS-related
 illnesses.

 A few alternative therapies, once considered unorthodox and
 "underground," have entered FDA-sanctioned clinical studies: Compound Q
 (GLQ223), hypericin and acupuncture are prominent examples. Recent
 research results suggest a benefit to HIV positive individuals from
 daily use of high-dose nutrients such as beta carotene (provitamin A),
 vitamin E, L-carnitine and the antioxidant agent N-acetylcysteine (NAC).
 A study in San Francisco will evaluate whether inhaled marijuana
 stimulates appetite and promotes weight gain among individuals with
 HIV-related wasting syndrome.

 A number of AIDS "buyers' clubs" in the U.S. sell and distribute
 dozens of alternative compounds that supporters claim will work
 effectively against HIV and/or AIDS-related illnesses. The number and
 variety of substances sold is extensive. Some of these products, such as
 vitamin C and Chinese herbs, have been used for decades as alternative
 therapies for certain cancers and other incurable diseases. Others, like
 DNCB (dinitrochlorobenzene), have become popular only since the advent
 of the HIV pandemic.

 DNCB is reportedly the current "best-seller" in U.S. AIDS buyers'
 clubs, despite the lack of scientific evidence for its efficacy (Gilden,
 1993). Although DNCB is inexpensive and relatively nontoxic, its more
 zealous supporters have advocated a dangerous policy, namely that DNCB
 users abandon all standard HIV/AIDS treatments except PCP prophylaxis.
 Individuals using DNCB are urged to discuss with an AIDS-knowledgeable
 physician the potential for harm of this action.

 ACT-UP/San Francisco reportedly will meet with officials of the
 National Institutes of Health (NIH) to present study findings and
 anecdotal information from current DNCB users.

 The history of the AIDS alternative therapies movement is strewn with
 examples of treatments once considered promising, now discredited:
 AL-721, ribavirin, dextran sulfate, isoprinosine, oral alpha interferon
 and DTC (diethyl-dithiocarbamate), to name only a few. Despite the
 failed promise of these products, a commercial market for alternative
 therapies likely will continue to flourish so long as HIV disease
 remains incurable.

 Abrams DA. Dealing with alternative therapies for HIV. In: The Medical
Management of AIDS, 3rd edition. Sande and Volberding, editors. W.B. Saunders
Company. 1992.

 Barton SE and others. Complementary therapies used by people with HIV
infection (letter). AIDS 8(4): 561. April 1994.

 Gilden D. DNCB treatment today. AIDS Treatment News 182: 3-8. September 3,
1993.

 Ryan MK and Shattuck AD. Treating AIDS with Chinese

 Medicine. Pacific View Press, Berkeley. 1994.


       *********
Mycobacteria and HIV Infection
 Leslie Hanna

 Leslie Hanna is associate editor of BETA.

 BETA spoke about AIDS-related mycobacterial infections with
 researcher Stephen Nightingale, MD. This introduction to the subject
 precedes the interview.

  General Characteristics of Mycobacteria

 Mycobacteria are a major cause of human diseases. This category of
 bacteria includes normal human flora as well as the microorganisms that
 cause the diseases tuberculosis, leprosy and Mycobacterium avium
 complex, or MAC.

 Mycobacteria are rod-shaped, aerobic, "acid-fast" bacteria, i.e.,
 they hold onto particular laboratory stains, once stained, despite acid
 or alcohol rinsing. This staining technique is used for identification
 purposes. Mycobacteria contain large amounts of lipids, or fats. Their
 waxy, hydrophobic cell surfaces cause them to form masses or clumps that
 help them to resist chemical attack.

 Mycobacteria are generally slow-growing, and the diseases they cause
 typically develop slowly as well. Disease results from the ability of
 the microorganisms to take up residence inside the cells of the host
 organism. This intracellular location affords them protection from
 chemical agents and encourages their persistence. They most frequently
 reside inside monocytes or macrophages (white blood cells). Once
 established inside the cell, mycobacteria interfere with normal cell
 function and immune response. Mycobacterial diseases are generally
 chronic and often involve the formation of characteristic infectious
 granulomas (lesions). These lesions may appear externally, on the skin,
 or internally, affecting various tissues and organs.

  Atypical Mycobacteria

 Mycobacterium tuberculosis and Mycobacterium leprae, the organisms
 that cause tuberculosis and leprosy, respectively, have been the 2
 species of mycobacteria of greatest historic concern for humans, who are
 considered the "natural" hosts for both organisms. Mycobacterium
 tuberculosis has caused severe epidemics probably for thousands of
 years. In contrast, the so-called atypical mycobacteria are species of
 mycobacteria that do not reside in humans as natural hosts but which can
 adapt to cause disease in humans. Although infections due to atypical
 mycobacteria have long been known to occur in immunosuppressed
 individuals, they were previously rare and aroused little scientific
 interest. Now, however, atypical mycobacteria are of increasing medical
 concern because of their ability to infect and cause disease in people
 with HIV.

 Most of the so-called atypical mycobacteria are found in the
 environment: in soil, dust and water. They are not easily transmitted
 from one person to another. Atypical mycobacteria include Mycobacterium
 avium and Mycobacterium intracellulare, the organisms responsible for
 causing MAC, the mycobacterial infection of greatest HIV-related
 concern. Birds and swine also carry these organisms. Other atypical
 species continue to emerge as pathogens, as the numbers of HIV
 infections rise and as survival time among individuals infected with HIV
 increases. The Centers for Disease Control and Prevention (CDC) reports
 that M. kansasii, M. gordonae, M. fortuitum and M. chelonei, in that
 order of frequency, are all known to cause infection in people with HIV.
 Mycobacterium haemophilum is another emerging pathogen in people with
 AIDS. Infections caused by a recently appearing species, M. xenopi,
 occur more commonly in the Northeast (compared to infections caused by
 M. kansasii, which occur more frequently in the Midwest).

 Diagnosis of and differentiation between mycobacterial infections can
 be difficult. Some species of atypical mycobacteria are cross-reactive
 with M. tuberculosis, making accurate diagnosis as challenging as it is
 critical. Another species of atypical bacteria, Mycobacterium genavense,
 has been noted to cause infection closely resembling MAC in people with
 HIV. An article about M. genavense in American Journal of Clinical
 Pathology (AJCP) concludes that "scrupulous microbiologic
 investigations, including molecular biologic techniques, are necessary
 in cases with mycobacterial infections."

 Mycobacterium avium Complex (MAC)

 At this time, the organisms that cause MAC, M. avium and M.
 intracellulare, remain of greatest practical concern for people with
 HIV. It is estimated that up to nearly one-half of people with AIDS will
 develop MAC at some point. The U.S. Public Health Service recommends MAC
 prophylaxis and therapy (summarized in the next section) for people with
 fewer than 100 CD4 (T-helper) cells. While many experts feel that the
 actual risks of developing MAC develop at CD4 counts lower than 100,
 what is certain is that the risk of MAC increases with worsening
 immunosuppression.

 MAC can occur in a specific organ or become disseminated throughout
 the body, indicating a more severe infection. The symptoms of MAC
 include fever, night sweats, weight loss, weakness and gastrointestinal
 disturbances and, occasionally, chest pain. Diagnosis is usually made on
 the basis of cultures taken from sterile sites such as the blood or bone
 marrow. The clinical significance of the presence of MAC in sputum or
 stool cultures is unclear.

  U.S. Public Health Service Recommendations

 In 1993, a U.S. Public Health Service Task Force on MAC published
 recommendations on prophylaxis and therapy for disseminated MAC, based
 on 2 clinical trials that found that therapy with rifabutin reduced by
 50% the number of MAC organisms in blood. The following is a summary of
 the recommendations:

 Prophylaxis should be given to people with HIV and fewer than 100
 T-helper cells. Three hundred (300) mg of rifabutin per day is
 recommended (after screening for tuberculosis with chest x-ray and PPD
 skin test). Before beginning a prophylactic regimen, the individual
 should be evaluated to eliminate the possibility of active mycobacterial
 disease (MAC, tuberculosis, etc.). Prophylaxis continues for the
 individual's lifetime unless MAC disease develops, which would
 necessitate the use of multiple drugs.

 Diagnosis of active, disseminated MAC disease is best made on the
 basis of one positive blood culture. Blood cultures are indicated in
 people who have clinical or laboratory abnormalities suggestive of
 mycobacterial infection.

 Treatment (for disseminated MAC) should include at least 2 agents,
 one of which should be clarithromycin or azithromycin. Effective
 treatment should continue for life.

 The recommendations note that many clinicians use ethambutol as the
 second drug, and that other candidate second, third or fourth drug(s)
 include: clofazimine, rifabutin, rifampin, ciprofloxacin and amikacin.
 The recommendations do not support the use of isoniazid (INH) or
 pyrazinamide for MAC therapy.

  Uveitis

 Uveitis, an unanticipated side effect associated with the use of
 rifabutin in multidrug regimens, recently emerged in the context of a
 clinical trial of MAC prevention strategies. Uveitis is an inflammation
 of portions of the eye, including the iris. Symptoms of uveitis include
 blurred vision, eye pain, redness and sensitivity to light. Fortunately,
 uveitis is reversible. Uveitis seems to occur when blood levels of
 rifabutin become very high, which may be caused by combining rifabutin
 with other drugs such as clarithromycin (Biaxin) or fluconazole. So far,
 only 12 cases have been reported, but anyone taking rifabutin should
 report any changes in vision to his/her doctor.

 Since the release of these guidelines, the FDA has approved
 clarithromycin for the treatment of disseminated MAC; questions remain
 unanswered about which drug or drugs to pair with clarithromycin for
 treatment. Recent reports of uveitis in connection with clarithromycin
 plus rifabutin point out some of the complications that may arise as
 experimental treatments are used. Still more general concerns and
 questions about MAC, such as the optimal time to begin prophylaxis, the
 significance of various diagnostic tests, resistance, whether treatment
 prolongs life, and more, remain to be elucidated.

   Selected Sources
 Georgii A and others. Mycobacterium genavense: autopsy findings in three
patiets. American Journal of Clinical Pathology 101(1): 95-99. January 1994.

 MAC (Mycobacterium avium Complex). AmFAR AIDS/HIV Treatment Directory 7(1):
90-92.

 Mycobacterium. In Fundamentals of Medical Bacteriology & Mycology, 2d ed.
Myrvik QN and Weiser RS, editors. Philadelphia. Lea & Febiger. 1988.

 Recommendations on prophylaxis and therapy for disseminated Mycobacterium
avium complex for adults and adolescents infected with human immunodeficiency
virus.  Morbidity and Mortality Weekly Report 42(RR-9): 17-19. June 25, 1993.

 Review of Medical Microbiology, 17th ed. Jawetz E, Melnick JL and Adelberg
EA, editors. Appleton & Lange. 1987.

 Strauss and others. Clinical and epidemiological characteristics of
Mycobacterium haemophilum, an emerging pathogen in immunocompromised
patients. Annals of Internal Medicine 120(1): 118-125. January 1, 1994.

 Young LS. Atypical mycobacteria. In Textbook of AIDS Medicines. Broder S,
 Merigan TC and Bolognesi D, editors. Baltimore. Williams & Wilkins. 1994.

       *********
 Mycobacterium avium Complex
 (MAC): An Interview with Stephen D.
  Nightingale, MD
 Leslie Hanna

 Leslie Hanna is associate editor of BETA.

 Stephen D. Nightingale, MD, teaches at the University of Texas
 Southwestern Medical Center, where he was director of its HIV clinic
 from 1988 to 1992. He now directs the North Texas and Oklahoma AIDS
 Education and Training Center, where he is researching prophylaxis and
 treatment for AIDS-related opportunistic illnesses.

 BETA recently spoke with Dr. Nightingale about prophylaxis and
 treatment for Mycobacterium avium complex (MAC).

   Treatment for MAC

 BETA: What do you consider to be the first-line treatment for
 established MAC infection?

 Stephen D. Nightingale: The first-line treatment for established MAC
 infection is clarithromycin (Biaxin). However, we're not yet sure of the
 correct dose. Some people feel that 1,000 milligrams (mg) twice a day
 clears the blood faster than 1,000 mg once a day. Others stress that
 1,000 mg twice a day is more toxic than 1,000 mg once a day.
 In my experience the 2 grams/day dose is a little harder on the
 gastrointestinal tract, so I use 1 gram/day as initial therapy. I
 combine clarithromycin with at least one other drug and what I use is
 ethambutol (Myambutol). I use 400 mg of ethambutol 3 times a day for all
 patients who have MAC that I've cultured from an ordinarily sterile site
 like blood or bone marrow.

 BETA: Is ethambutol the drug most often used in combination with
 clarithromycin?

 SDN: Yes, I think that is standard practice right now. Some people are
 using azithromycin (Zithromax) for treatment as a first drug instead of
 clarithromycin. In fact, the U.S. Public Health Service expert panel
 said that azithromycin could be an alternative to clarithromycin. At the
 moment I only use azithromycin for the rare patient who cannot tolerate
 clarithromycin. I wouldn't recommend azithromycin as the first drug
 until more information about it comes out.

 BETA: The FDA recently approved clarithromycin for the treatment of
 disseminated MAC but recommend using it in combination with at least 1
 other drug. Since the other drug hasn't been specified, what does the
 FDA's approval mean?

 SDN: The FDA has said, "You've got to use clarithromycin plus something
 else," but they don't know what else. In other words, the FDA in its
 approval of clarithromycin explicitly told doctors to use some other
 drug that they had not yet approved in combination with clarithromycin.
 That doesn't mean that the FDA is stupid. What it actually means is that
 the FDA recognizes that medicine is changing faster than the regulatory
 apparatus can keep up with it, and that people have a strong interest in
 getting good medicine. FDA has a strong interest in being good
 regulators but they're also being much more responsive to the needs of
 the public than they might have been, or have been in the past. So I
 like the approval. I think it's objective proof that the FDA is trying
 to respond to AIDS.

 BETA: You said you use at least one drug in addition to clarithromycin
 to treat disseminated MAC. Do you ever use more than one? The
 recommendations are tentative, suggesting merely that a "minimum of 2
 drugs" be used for treatment.

 SDN: At the moment I don't know whether or not a third drug is necessary
 for all patients, but I generally do prescribe a third drug for
 treatment. There are several drugs you can use, but I use rifabutin
 (Mycobutin). I only use rifabutin at a dose of 300 mg/day, although some
 doctors use up to 600 mg/day. The reason I use the lower dose of
 rifabutin is to avoid the possibility of uveitis, inflammation of the
 eye.

 Uveitis has occurred only at 600 and 900 mg doses of rifabutin, and
 only in association with clarithromycin or fluconazole (Diflucan). [SN:
 Since this statement was made, uveitis has been reported in patients
 taking only 300 mg rifabutin a day.] Over the next year there likely
 will be a lot of new evidence or at least new experience with
 combination drugs.

 BETA: Has anyone considered using more than 3 drugs?

 SDN: Well, 4 might be better than 3 but we don't know. With 4 drugs you
 have even more toxicity. Uveitis is an important example of what can
 happen with additional drugs. Fluconazole, clarithromycin and rifabutin
 by themselves are safe. Compared to AZT, their safety profiles are
 phenomenal. But when you start mixing these drugs together, bang! This
 serious and unanticipated side effect [uveitis] appeared.

 BETA: Leaving side effects and toxicity aside for the moment, is it
 correct to say that you feel that 3 drugs are the optimal number to use
 for treating MAC?

 SDN: I'm still using 3 drugs (clarithromycin, ethambutol and rifabutin)
 but I can certainly understand why other physicians might now choose 2.
  Prophylaxis vs Treatment

 BETA: Clinical trials have shown that the development of MAC bacteremia
 is highly associated with disseminated MAC. What is the difference
 between MAC bacteremia and disseminated MAC?

 SDN: MAC bacteremia is a sign of disseminated MAC disease, but you can
 have MAC bacteremia before you have all the symptoms of disseminated
 MAC. The MAC organisms seem to get into the bloodstream relatively early
 in infection. Organ damage appears to occur 2, 3 or even 4 months after
 the organisms can be isolated from the blood.

 BETA: The mortality associated with MAC would seem to support
 aggressive, early intervention. How do you decide exactly when to start
 prophylaxis against or treatment for dMAC?

 SDN: There are a couple of ways to go: (1) start prophylaxis at 100
 T-cells [CD4 cells] before anyone gets it, which is what the U.S. Public
 Health Service Task Force recommends; (2) start at 50 T-cells before
 just about anyone gets it, which is what I currently recommend; (3) at
 100 T-cells, do lots of tests, or (4) wait and then treat active
 infection.

  Decisions about when to treat are based on several
 considerations_including financial ones since these are expensive
 drugs_and opinions vary. We all know that as the T-cell count goes down
 towards zero, the incidence of disseminated MAC increases. The lower the
 T-cell count, the more likely the person is to develop infection. Of
 course, people want to start prophylaxis before subclinical infection
 starts. The question is, how long can an infection be subclinical?
 One hypothesis is that patients have a prolonged period during which
 they are colonized with a large number of the organisms that cause MAC,
 but are not infected. In this view, as T-cells go down, the individual
 becomes colonized with more and more organisms until active infection
 breaks through, something that takes months to happen. The numbers of
 organisms present and the length of time they're in the body before
 getting into the blood are important points if you are worried about
 resistance.

 BETA: What concerns are there about resistance and MAC?

 SDN: If there are hundreds of millions of organisms in the sputum or in
 the stool before they get into the blood, and you give somebody
 prophylaxis that doesn't kill all of those organisms, the organisms that
 survive are likely to be the ones that are resistant to that
 prophylactic agent. If, on the other hand, there are only a few
 organisms in the stool or in the blood, when those organisms get into
 the blood the chance that one or more of them will be resistant to the
 prophylactic agent is very small.

 However, we don't see resistance during asymptomatic infection. I
 believe this is because people don't have a large number of organisms in
 their body when they are asymptomatic. There will be a few hundred or
 maybe a few thousand but not a few hundred million organisms. And the
 fewer organisms there are the less likely you are to develop resistance.
 (You also need less drug.)

 BETA: Why do you favor beginning prophylaxis later, at 50 T-cells,
 particularly if resistance is less of a concern when the numbers of
 organisms in the body are fewer?

 SDN: There are 2 important published studies right now, one from Atlanta
 and the other from San Francisco General Hospital (Havlik and others,
 Journal of Infectious Diseases, October 1993; Chin and others, Journal
 of Infectious Diseases, February 1994). Both studies tried to follow
 patients prospectively to see if they had organisms in their sputum or
 organisms in their stool before they developed organisms in their blood.
 Neither study was able to find that.

 I personally no longer believe that people with AIDS have long
 periods of latent MAC infection, although I'm not sure how many other
 people would agree with me. People with 50 T-cells cannot suppress MAC
 infection very well. Based on the work of Chin and Havlik, and based on
 the failure to detect resistance in prophylaxis trials, I feel that the
 period from when colonization begins to active infection is brief, a
 matter of days or a few weeks, rather than weeks to months. This is one
 of the best explanations for why, so far, prophylaxis has not appeared
 to promote the development of resistant organisms.

 However, these are relatively new conditions and areas of research,
 and the information changes rapidly. Treatment decisions should be made
 on the basis of all currently available information, which is subject to
 change without notice.

 BETA: How would you proceed with someone whose sputum or stool cultures
 come back positive for MAC?

 SDN: I think if you detect MAC on [a diagnostic test] smear, until you
 have it cultured, the big question actually is "Is it MAC or is it
 tuberculosis?" While there are many pathologists who believe they can
 differentiate between MAC and tuberculosis, nobody has published how to
 do so yet. This is something that you want to be real sure about, not
 just a little sure. If I find acid-fast organisms that might be MAC or
 might be Tb then, frankly, I treat for Tb not MAC.

 If I find acid-fast organisms in the sputum, I order a blood culture.
 If I were the patient I would have a bone marrow exam done, even if the
 chest x-ray was normal. If the bone marrow was negative and the blood
 was negative I would not continue Tb treatment for the rest of my life.
 I might go on prophylaxis, however, for the rest of my life.
 I'm giving you a complicated recommendation right now that is really
 patient-specific because I don't think there's enough data to give a
 simple answer for all patients. I make decisions about MAC found in
 sputum on a case-to-case basis. Until I'm sure it's MAC and not Tb I
 treat for Tb. Meanwhile I do lots of cultures of the patient and, if all
 the bone marrow and blood cultures are negative and the patient's
 feeling O.K., then I think I'd do prophylaxis with 1 drug rather than
 treatment with 3.

  Prophylaxis

 BETA: The current approved prophylactic strategy for MAC is monotherapy
 with rifabutin [in people with equal to or less than 100 T-cells]. When
 or to whom do you recommend prophylaxis?

 SDN: I would recommend prophylaxis to someone who has had an
 AIDS-defining OI and less than 200 T-cells, especially to someone who's
 had PCP. Those were the people we had in the rifabutin prophylaxis
 trials. That's different than saying everybody with less than 200
 T-cells, though. I emphatically don't recommend it to someone with 200
 T-cells who hasn't had an OI. If you haven't had an OI, my own
 recommendation is to consider prophylaxis at 50 T-cells, because it's at
 50 T-cells that it seems to me that the benefits exceed the risks and
 justify the cost [of the drug] for such patients.

 Again, the recommendations of the Public Health Service are different
 from mine. They recommend prophylaxis at 100 T-cells, AIDS or no AIDS. I
 respectfully disagree_neither the investigative evidence nor any
 economic rationale supports that recommendation, to my way of thinking.
 This drug costs a lot of money. When I look at the evidence of the
 studies to date, what I see is if you've had an AIDS-defining event,
 then you've got a 20% chance of getting it in a year. If you have less
 than 50 T-cells you have a 16% chance of getting it in a year. These are
 risks that justify MAC prophylaxis for me.

 If my own patients get MAC between 50 and 100 T-cells, which they
 hardly ever do, then I treat them. I suspect that somebody with 70
 T-cells is much more likely to respond to therapy for MAC than somebody
 with 7 T-cells. To me somebody with no prior OI and more than 50 T-cells
 who shows up with MAC in their blood or in their sputum is probably
 someone you're better off treating than preventing. But once you get
 under 50 T-cells, you have less immune function, and MAC becomes more
 inevitable.

 As far as I can tell, clarithromycin will be about as effective as
 rifabutin for prophylaxis. The difference between clarithromycin and
 rifabutin is that clarithromycin is not effective against tuberculosis,
 and rifabutin is, or seems to be. Although it remains to be proven, the
 available evidence suggests that rifabutin will protect against
 tuberculosis as well as protect against MAC. For that reason more than
 the lack of FDA approval, I still favor rifabutin over clarithromycin.
 But for anyone who can't take rifabutin then I think clarithromycin is a
 definite second choice. I personally do not recommend the combination.

 BETA: What doses would you use for prophylaxis with clarithromycin?

 SDN: The trials are being done with 500 mg twice a day, which is what I
 would go with. I suspect that a lower dose of clarithromycin, 500 mg
 once a day, would be effective, but I don't know that for a fact. If
 clarithromycin at 1 gram/day works, I'd like to see a trial of 1
 gram/day versus 500 mg/day. I'd like to see the AIDS Clinical Trials
 Group (ACTG) focus more on getting down to the minimum dose, seeing how
 low the dose can be pushed, rather than seeing how high it can be
 pushed.

 BETA: You did say that you would not advocate using clarithromycin and
 rifabutin together as prophylaxis at any doses?

 SDN: Yes, in any combination. There are studies of the combination going
 on, and if those studies show that the combination is a lot better, then
 I would revise what I say. But at the moment I see no evidence to
 recommend giving 2 drugs when 1 is effective. I think it's much more
 important to push compliance with 1 drug. In my experience, if you take
 this drug it usually works. And if it doesn't work, you just treat them
 with a combination of drugs that often includes the drug that "failed"
 as a prophylaxis agent. There's a point at which prophylaxis is more
 trouble than its worth.

 Lots of people are using clarithromycin and are having good luck with
 it. When there's more data on rifabutin my guess is that it will be
 shown to be equivalent to clarithromycin. The issue is going to revolve
 around whether clarithromycin is good for tuberculosis, which it isn't,
 or what kind of resistance to normal flora clarithromycin induces. But
 that's a year down the road.

 BETA: Is anyone considering combinations for prophylaxis?

 SDN: Combinations are being tried right now. I myself don't think that
 combinations will prove preferable to monotherapy for prophylaxis. I
 think the reason that most prophylaxis regimens fail is that people
 don't take them right. I'm not sure that giving 2 drugs instead of 1
 will increase compliance. I think increasing patient understanding of
 the benefits as well as the risk of the study is what will increase
 compliance.

 The breakthrough cases in the rifabutin prophylaxis study were not
 with resistant organisms. The breakthrough cases broke through with
 sensitive organisms and the only explanation that I can come up with for
 that is that people who broke through weren't taking it or didn't absorb
 it.

 BETA: Isn't it difficult to say then what the real risk of breakthrough
 MAC with rifabutin prophylaxis is?

 SDN: It's difficult to answer. The first risk is that you don't take it,
 the second risk is that if you take it, you don't absorb it, and the
 third is that in any population someone is going to be less responsive.

 BETA: One study suggests that rifabutin has the potential to decrease
 the blood concentration of AZT.

 SDN: I am the second author on that abstract, and that abstract has a
 problem: the conclusion was based on only 6 patients, which makes the
 clinical significance of the study highly questionable. For example, our
 study suggests that rifabutin drops AZT levels, but a bigger and better
 study showed that rifabutin didn't do anything to ddI levels. There was
 no difference in the outcome of our patients in the rifabutin
 prophylaxis trials who were on AZT or on ddI_if the rifabutin effect on
 AZT had been clinically significant you would have expected to see a
 difference between those on ddI and AZT, but it wasn't there.
 That conclusion was included in the paper because Adria
 Pharmaceuticals has tried hard to be honest and accurate in their
 presentation of the data, but more work needs to be done before it's
 widely accepted.

 MAC Treatment and the Side Effect of Uveitis

 BETA: When was uveitis first observed?

 SDN: Late October 1993. The Adria Data Safety Committee met on December
 3, 1993, and the letter by Steven Shafran was published in the February
 7, 1994 New England Journal of Medicine. We're still collecting cases.

 BETA: How was uveitis first detected? Or, with what drug combinations
 did or does the condition occur?

 SDN: The first reports were with rifabutin and clarithromycin. One of my
 cases, and some other cases, were of rifabutin and fluconazole. Both
 clarithromycin and fluconazole raise rifabutin levels. The common
 denominator in most people who developed uveitis is rifabutin plus some
 other drug or rifabutin at high levels, like 600 or 900 mg/day.
 But I have to emphasize to you that this is very preliminary. This
 isn't going to be at a scientific meeting until the fall. Adria has been
 exceptionally good at getting out information. They have a list of every
 doctor in the U.S. who has prescribed AZT, and they have sent to each of
 those doctors a letter saying, "This is the possibility, and here's the
 data_" If more companies understood that doctors really appreciate this,
 maybe they would be a little more forthcoming about side effects.

 BETA: Side effects that no one is aware of until after marketing?

 SDN: More than 6,000 people have received rifabutin before it was out on
 the market but the condition only appeared after we started doing
 combination therapy. This is a dangerous business. Right now there are
 30,000 people out there who got rifabutin and it looks like 30 or 40 of
 those 30,000 people have gotten uveitis. I'm projecting up from some
 cases that haven't been reported yet. That's not a high percentage, but
 30 eyes are a lot of eyes.

 Studies are being redesigned right now because of the uveitis. I
 think there are 5 studies currently in progress just for MAC treatment
 that use rifabutin and other drugs. Uveitis and the redesigns will set
 back the results by a year, probably.

 BETA: What is the second-line choice for treatment for someone who
 develops uveitis?

 SDN: For uveitis the prudent thing to do is to discontinue rifabutin. If
 I had to discontinue rifabutin, I would try to continue clarithromycin
 and continue ethambutol.

 Ethambutol is a drug that probably works by making other drugs more
 effective. Ethambutol is a really neat compound but there's a lot that
 we don't know about it. We know that ethambutol in very high doses can
 induce blindness (called optic neuritis). For this reason I am very
 careful to keep the dose of ethambutol below 20 mg/kilogram (kg). So if
 you weigh 132 pounds or about 60 kg, then you get 1200 mg/day of
 ethambutol. If you weigh 70 kg I might give you a little more, but if
 you weigh 50 kg or are under 130 pounds, then I'd give only 800 mg/day.
 Alternative drugs include clofazimine. I use 100 mg/day; some people
 may use more, but it has a lot of gastrointestinal toxicity. Some people
 have found success with ciprofloxacin (Cipro)_I have not. I think
 ciprofloxacin is a good drug for tuberculosis but not for MAC. Liposomal
 gentamicin was not as successful as I had hoped it would be, at least as
 a single agent.

 Sparfloxacin is another quinalone like ciprofloxacin. Dr. Lowell
 Young has studied sparfloxacin. The development of sparfloxacin is going
 slowly. Amikacin has been around a long time. Some people feel that it
 works. I am neutral on the subject of amikacin; I don't usually use it.
 Rifampin is not effective against MAC in the test tube. When I treated
 MAC with anti-TB drugs, I did not find rifampin successful. Rifabutin is
 a second-generation rifampin; it's like rifampin in its activity against
 tuberculosis. Unlike rifampin, rifabutin is active against MAC as well.

  Next Steps: Multiple Opportunistic Infection (OI) Prophylaxis and Treatment
  for HIV Infection

 BETA: What do you see in terms of next steps?

 SDN: For the treatment of OI, the next step to take is to look for lower
 rather than higher doses. For prophylaxis, now that ACTG 981 has been
 presented, which shows that fluconazole works [for fungal infections],
 and now that the rifabutin trials show that it works [for MAC], the next
 step is to get the ganciclovir prophylaxis trials done to see if
 ganciclovir works [for CMV]. Then, we can start thinking about a combo
 trial of all 3 to look for other side effects.

 Beyond that, the next step is to find the role played by the
 Epstein-Barr virus (EBV) in lymphomas and in HIV disease overall. The
 ideal OI prophylaxis regimen right now, it seems to me, would include:
 (1) a sulfa drug like Bactrim, which as far as I can tell prevents
 toxoplasmosis as well as PCP; (2) fluconazole at some dose to prevent
 esophagitis and systemic fungal infections (the dose is uncertain but
 100 mg rather than 200 mg is probably right; (3) rifabutin for
 mycobacterial infections; and (4) hopefully a third-generation oral
 acyclovir/ganciclovir to help prevent all the herpes infections
 (including herpes simplex 1 and 2, CMV, EBV and all the other
 herpesviruses).

 I think that people who are on that kind of combo prophylaxis, with
 that 4-level moat, are the ideal candidates in which to test better
 anti-HIV strategies. Preparations are under way for a 10,000-person
 trial, natural history, kind of off-the-street. I understand the reasons
 for this study and intellectually applaud it, but I also have
 reservations about it. I think that a 10,000-patient study is going to
 be complicated by people who get CMV, and that the effect the
 investigators are looking for is going to be overridden by CMV and other
 opportunistic infections. It seems to me that progress in defining which
 antiretroviral therapies work best will be a lot easier to achieve in
 people who you can put in a "chemical coat" so that your treatment
 effect doesn't get washed away by CMV, EBV [the virus that causes hairy
 leukoplakia and mononucleosis], cryptococcal meningitis or MAC
 infection.

 You're going to have to take care of OI before you can design the
 ideal antiretroviral trial, particularly for people with less than 50
 T-cells. For people with 500 T-cells that's not the case because they
 rarely get OI, but if you want to find out if AZT alone or nevirapine
 alone works in people with 50 T-cells, you've got to have good
 prophylaxis regimens, or the OI are going to wash out your AZT effects.
 Furthermore, there is evidence that OI stimulate HIV replication, and
 this would even further counteract the effects of antivirals and make
 them look worse than they actually are. That may not be the only reason
 why we are in such a quandary about antivirals, but I think it's one of
 them.

       *********
 A Master Protocol to Evaluate
 the Safety and Efficacy of
 Triple Combination
 Antiretroviral Therapy for HIV
 Infection
   David Barry, MD,
 Director of Research, Development and Medical Affairs, Wellcome plc
 and the Clinical Trials Subcommittee of the Inter-Company
 Collaboration for AIDS Drug Development

  The Inter-Company Collaboration for AIDS Drug Development, a
 consortium of 15 pharmaceutical companies, was established in April
 1993. It will begin an unprecedented program this fall to test for
 the efficacy of various triple anti-HIV drug combinations. The
 regimens will be tested among HIV positive, asymptomatic individuals
 who have never used anti-HIV medication.

  This program is the result of an agreement among the 15 member
 pharmaceutical companies in the Collaboration to accelerate research
 into anti-HIV drugs by sharing information and compounds, and
 conducting joint research. The major objective of these studies is to
 identify triple drug combinations that demonstrate strong activity
 against HIV. Regimens that show promise will be tested further in
 traditional trials. Below is an introduction to the master protocol
 for these triple combination studies.

  The participating pharmaceutical companies are (in
 alphabetical order) AB Astra (Sweden), Aji Pharma USA (New
 Jersey and Japan), Boehringer Ingelheim (Connecticut and
 Germany), Bristol-Myers Squibb (New York), Burroughs
 Wellcome (North Carolina and Great Britain), DuPont Merck
 (Delaware), Glaxo (North Carolina and Great Britain),
 Hoechst AG (Germany), Hoffmann-La Roche (New Jersey and
 Switzerland), Miles Pharmaceuticals (Connecticut), Pfizer
 (New York), Sigma Tau (Italy), SmithKline Beecham (Great
 Britain) and Syntex (California).

 Study Rationale

 The effective treatment of serious, chronic, immunosuppressive,
 infectious or malignant diseases has generally required the
 administration of 3 or more chemotherapeutic agents. In some instances,
 such as tuberculosis or leprosy, this requirement is based primarily on
 the need to obviate the generation and eventual overgrowth of resistant
 organisms. The number of agents required to accomplish this is
 proportional to the number of organisms present in the body and to the
 probability of these organisms developing resistant mutations to each of
 the agents employed. In other instances, such as childhood acute
 lymphoblastic leukemia or Hodgkin's lymphoma, the explanations for the
 success of multiple-drug regimens are not as clear. Here, efficacy may
 depend upon synergistic effectiveness and/or differential sensitivity of
 a heterogeneous, transformed cell population, as well as the prevention
 of resistance development.

 The principles underlying successful multidrug approaches are
 straightforward and based on 2 determinative elements. First, the
 mechanism of action (and thus the presumed mechanism of resistance) of
 the various agents should be different, leading to independent
 probabilities of resistance development. Second, the toxicities of the
 drugs used should be different so that they may be used in combination
 without additive, specific end-organ toxicities.

 Even though the sum total of toxicities within a given patient may be
 greater when polytherapy rather than monotherapy is used, the number and
 dosages of the drugs can usually be adjusted so that the function of the
 patient is not seriously compromised.

 Viral Resistance

 In the case of HIV infection, it is clear that monotherapy in most
 stages of disease will lead to the development of viral resistance, and
 that this viral resistance may seriously compromise or even negate the
 effectiveness of the drug. Resistance may occur in weeks or years,
 depending on the virus numbers in the body and on the drug in question.
 The hypervariability of HIV and the lack of any DNA repair mechanism
 makes it highly likely that resistance will develop at some point with
 any single agent, no matter what its mechanism of action.

 Resistance has most commonly been described with RETROVIR
 (zidovudine) [AZT], Videx (ddI), 3TC and various non-nucleoside reverse
 transcriptase inhibitors (NNRTI). Furthermore, because antiviral agents
 are, by definition, "virustatic" rather than "virucidal," complete or
 near complete suppression of replication will need to occur in order for
 resistance development to be prevented.

 Double Combination Therapy

 For reasons that are not entirely clear, many proven anti-HIV agents
 in combination are either additive, superadditive or synergistic in
 their in vitro activity against the virus. Pilot studies in humans with
 the combinations of AZT and several other agents indicate that the in
 vitro promise of synergy may be fulfilled at least partially in vivo.
 Whether these combinations also inhibit the development of resistance is
 currently under study. Such inhibition is likely to be observed to some
 degree because the molecular basis of resistance for these agents
 appears to be different even though their general mechanism of action
 may be the same. These drugs generally have different toxicities and
 thus are likely to be useful clinical combinations, leading to the next
 significant advance in the treatment of HIV infection.

 In spite of the apparent early successes of duotherapy, the
 difficulties with relying on only 2 agents for the complete control of
 HIV infection, unfortunately, are manifold. The virus is extremely
 unstable. Mutation rates within genome segments controlling
 drug-sensitive functions may be as high as 104. In addition, the virus
 load in patients, particularly those with advanced disease, may be
 extraordinarily high.

 In fully advanced disease (AIDS), for example, the cell-free (serum)
 virus titer may average 6 X 102 per ml but can be as high as 108 per ml.
 If one assumes a patient's total blood volume to be approximately 5
 liters, then there would be 3 X 106 to 5 x 1011 infectious virus
 particles in the serum of an AIDS patient, in addition to an
 undetermined but large number of intracellular viruses in lymphocytes,
 macrophages and other mononuclear cells.

 Most mutations are unlikely to lead to resistance, and the rate of
 resistance development to single agents is not known with precision.
 Nevertheless, it is likely, given these numbers, to observe resistance
 development to agents over some period of time in patients who have high
 viral loads at the time therapy is begun. By analogy, this in fact was
 observed in mycobacterial infections in clinical conditions where
 organism counts were high, such as cavitary tuberculosis or lepromatous
 leprosy. In addition, because of prior exposure to single agents,
 partial or complete (high-level) resistance may already be present at
 the time of the addition of the second agent.

 The interactive effect of chemotherapeutic agents on HIV is extremely
 complex. Rapid mutation of the virus leads to the development of
 resistance to single and even 2-drug combinations. In vitro evidence
 points to the distinct possibility that development of resistance can be
 circumvented with the proper combination of agents. First, resistant
 strains exposed to additional agents have shown increased sensitivity to
 the initial agent. For example, AZT-resistant virus exposed to ddI or
 ddC has shown increasing sensitivity to AZT. Viral sensitivity to AZT
 was reportedly restored when AZT-resistant virus mutated to develop
 resistance to 3TC or FTC. Likewise, increased sensitivity to nevirapine
 was reported when mutation of HIV was induced in response to exposure
 and subsequent development of resistance to NNRTI.

 Triple Combination Therapy

 Additionally, development of resistance by HIV to certain
 nonnucleoside reverse transcriptase inhibitors resulted in the
 suppressed resistance to nucleoside analog reverse transcriptase
 inhibitors. Second, several in vitro studies with 3-drug combinations
 have shown complete suppression of all virus replication.

 Such combinations may not be able to induce a series of mutations
 inconsistent with continuous virus replications, as had been originally
 postulated. Still, the ability of these combinations to suppress all
 viral replication for as long as they are present in the culture could
 provide a clear clinical advantage over existing therapies. The complex
 interaction of chemotherapeutic agents and the replicative enzyme
 systems of HIV could hold the key to successful chemotherapeutic
 treatment for HIV infection. The rapid identification of the best
 combinations of antiretroviral agents which can completely suppress
 viral replication and development of resistance over an extended period
 is therefore not only possible but urgently needed.

 Only a limited number of clinical 2- and 3-drug combination studies
 have been performed. In general they support additional and continued
 benefit with the addition of the second or third drug. Unfortunately,
 the interpretation of the results of prior and ongoing 2- and 3- drug
 regimens are clouded by the fact that many of the patients in these
 studies harbored virus which was already resistant, to some degree, to 1
 or more of the agents used.

 Study Population

 Our knowledge of the in vitro details and clinical consequences of
 antiretroviral combination therapy is still in its infancy. However, it
 is not unreasonable to deduce that the potential advantages of such
 therapy with regard to additive or synergistic effectiveness are likely
 to be minimized or obviated if the viruses are already poorly sensitive
 to 1 or more of the agents employed. The ideal patient population to
 study the maximum benefits of combination therapy would be one without
 advanced disease or prior antiretroviral therapy. Rapid antiviral
 sensitivity assays are difficult to perform and would pose major
 logistical difficulties were they to be used as criteria for study
 entry.

 Fortunately, we know that virtually all wild-type HIV isolates are
 sensitive to most antiretroviral agents prior to exposure to these
 agents. Thus, appropriate patient selection with only post hoc analysis
 of sensitivity will be sufficient to conduct a study that can fairly
 evaluate the maximum benefit of multidrug therapy. These patients will
 necessarily have less advanced disease and will be exposed to the
 potential toxicities of 3 drugs. In such patients, however, these
 toxicities are expected to be minimal when appropriate dosages are
 chosen. In addition, because 3-drug combinations can suppress 93-100% of
 virus replication in in vitro assays as opposed to the 63-77%
 suppression seen in assays of 1- and 2-drug combinations, these patients
 may experience a return to normal of their immune function with 3-drug
 therapy.

 Available Triple Combinations

 There are currently 6 FDA-approved drugs with known in vitro anti-HIV
 activity: AZT, ddI, ddC, interferon, foscarnet and ribavirin, and an
 additional 2 (d4T and 3TC) with parallel-track status. Altogether, there
 are now 56 possible 3-drug combinations that could be tested. Even
 allowing for the elimination of several potential combinations because
 of antiviral antagonism (e.g., those combinations containing both AZT
 and ribavirin) or additive toxicity (e.g., those combinations containing
 both ddI and ddC), the number of remaining possible combinations exceeds
 the clinical research capacity of the U.S. and Western Europe (if any
 significant number were studied by statistically rigorous comparative
 methodology and used clinical endpoints).

 In addition, the emergence of other compounds, including protease
 inhibitors, NNRT inhibitors and therapeutic vaccines from Phase II
 studies in the coming year will raise the number of potential
 combinations to several thousand. Because antiviral resistance will
 occur to any new single drug, it is unlikely that any such agent could
 provide greater benefit for periods longer than existing 2-drug
 regimens. Thus a streamlined system of clinical research is required if
 3-drug combinations are to provide immediate and long-term benefit to
 those currently infected with HIV.

 The Master Protocol

 We have therefore designed a Continuous Cohort Variable Regimen
 (CCVR) study to rapidly evaluate current 3-drug combinations and to
 allow the addition of new agents as they become available. This design
 will provide information which could be implemented quickly into
 clinical practice. In this study, patients will be assigned to various
 3-drug combination protocols and followed until the relative efficacy of
 the treatment combination is determined.

 Although these protocols are designed as pilot Phase II studies, it
 is conceivable that they could become the basis for widespread use
 within the parallel-track system if the results are sufficiently
 impressive. Likewise, a sufficiently negative outcome would lead to
 rapid elimination of that combination from the options available to
 patients. Intermediate responses would obviously require Phase III
 studies to fully define the comparative therapeutic index of that
 combination.

 Significant and prolonged suppression of virus is likely to have
 extremely positive impacts on horizontal and vertical transmission rates
 and thus on the progress of the epidemic. Therefore, some regimens may
 be accepted as appropriate therapy if they lead only to virological and
 not immunologic benefit and if adverse reactions are minimal.
 Each 3-drug regimen will be chosen on the basis of the best
 scientific knowledge available from laboratory and Phase I studies.
 Factors to be considered when choosing a triple combination to be
 included in a treatment cohort include but are not limited to:

 ∙ in vitro evidence of synergy
 ∙ in vitro evidence of prevention of resistance patterns
 ∙ lack of expected additive toxicity

 The protocols in this series of studies will evaluate 3-drug
 combinations. The first 4 combinations to be tested have been selected;
 they are (1) AZT, ddC and saquinavir (the Hoffman La-Roche protease
 inhibitor), (2) AZT, ddI and nevirapine, (3) AZT, ddI and 3TC, and (4)
 AZT, ddC and nevirapine. These combinations were chosen because they
 show in vitro evidence of synergistic anti-HIV activity as well as no
 evidence of overlapping toxicity. Testing these first 4 regimens will
 also allow investigators to evaluate the mechanisms of the study
 protocol.

 If you would like the source references for Dr. Barry's article,
 please write to BETA: P.O. Box 426182, San Francisco, CA, 94142, ATTN:
 Master Protocol.

       *********
  Research Notes
 Ronald A. Baker, PhD

 Ronald Baker is editor of BETA.

 This issue of Research Notes is organized under 7 categories: (1)
 Basic Science, (2) Treatment for HIV Infection, (3) Treatment for
 Opportunistic Infections, (4) Nutrition, (5) Immunotherapy, (6)
 Laboratory Markers and (7) Miscellaneous.

 Basic Science

  The 10th International Conference on AIDSin
   Yokohama, Japan

 The 10th International Conference on AIDS and Sexually Transmitted
 Diseases (STD) will be held in Yokohama, Japan, from August 7-12, 1994.
 For the first time in its 10-year history the International Conference
 will take place in Asia. Although a relatively new health problem in
 Asia, HIV infection represents a serious threat to a number of Asian
 countries. By the year 2000 Asia is expected to have the world's highest
 rate of HIV infection. The World Health Organization (WHO) estimates
 there may be more new HIV infections in Asia than in either Africa or
 Latin America.

 In Thailand, between 400,000 and 600,000 individuals are HIV
 positive, and 2 to 4 million infections are expected by 2000. In India,
 approximately 1.5 million people are already HIV positive. Cambodia,
 Vietnam and Indonesia are all expected to have an enormous increase in
 new HIV infections in the coming 5 years. In Japan, 2,900 individuals
 are officially diagnosed with HIV infection, and 700 people have been
 officially diagnosed with AIDS. The Japanese Ministry of Health and
 Welfare predicts that 26,000 Japanese citizens will be HIV positive by
 1997.

 The conference organizers are attaching great importance to the
 participation of Asian and other developing countries, increased
 involvement of women and a strong focus on community activities. The
 Conference will of course include the latest findings in basic science
 and clinical medicine.

 Various groups and individuals have expressed concern about Japanese
 immigration policy toward foreigners living with HIV infection and AIDS
 entering Japan. No one will be denied a Japanese visa or entry into
 Japan because of their HIV positive serostatus, according to Naoko
 Yamamoto, MD, Deputy Director of the Infectious Diseases Control
 Division of the Japanese Ministry of Health and Welfare. Dr. Yamamoto
 added that Japanese officials do not ask visa applicants about their HIV
 status, and do not require them to take an HIV antibody test. "The
 policy applies regardless of length of stay, and it applies not only
 during the Yokohama conference, but at all times," said Dr. Yamamoto.

 For further information about the Yokohama Conference, contact:
 Secretariat for the Tenth International Conference on AIDS/STD,
 Congress Corporation
 Namiki Building, 5-3 Kamiyama-cho
 Shibuya-ku, Tokyo 150, Japan
 Tel: [phone]
 Fax: [phone]

 Triple Combination Study with Hoffmann-La Roche

  Protease Drug Yields Promising Results

  Preliminary results of a study (ACTG 229) show that using the
  triple combination of saquinavir (a protease inhibitor), AZT and
  ddC reduces HIV load significantly and produces a transient, but
  significant increase in CD4 (T-helper) counts. The study compared
  the safety and activity of the 3-drug combination to 2 double
  combinations: ddC plus AZT and saquinavir plus AZT. The triple
  combination was significantly better than the 2 double combinations
  in reducing viral load and in increasing CD4 counts.

  With 302 participants, ACTG 229 is the largest study of an HIV
  protease inhibitor yet completed. All study participants had 50-300
  CD4 cells and had used AZT for at least 4 months before enrollment.
  Participants took 600 mg saquinavir 3 times a day, 200 mg AZT 3
  times a day and/or 0.750 mg ddC 3 times a day for 24 weeks.

 Reduced HIV Load and CD4 Increases

  Viral load is the amount of HIV in circulating blood. The
  3-drug combination decreased viral load as measured by quantitative
  cell culture significantly better than the 2 double combinations.
  CD4 counts rose during the first 8 weeks of study but then
  gradually declined in all 3 treatment arms. The increase in CD4
  cells was greatest in the 3-drug combination group: 60 of 96 people
  (63%) maintained a 25 CD4 cell increase or a 25% rise from baseline
  CD4 count. Increases in the 2-drug combinations were significantly
  smaller: 52 of 98 (53%) using saquinavir plus AZT and 33 of 100
  (33%) using ddC plus AZT maintained this same CD4 increase. In
  addition, a greater proportion of patients using the triple
  combination sustained increases of 50 CD4 cells or 50% from
  baseline CD4 count.

 Adverse Side Effects

  The type, severity and frequency of adverse side effects were the
  same in all 3 treatment groups. Eleven individuals experienced a
  major clinical event (an AIDS-defining opportunistic infection or
  death). One of these individuals was on the triple combination, 6
  were on saquinavir plus AZT and 4 were on ddC plus AZT. There were
  2 deaths during the 24-week study, both of which were attributed to
  HIV-related events and not associated with drug therapy.

 Implications

  These study results, although promising, do not demonstrate a
  clinical benefit from use of the combinations studied. The study
  was not designed to evaluate the clinical effectiveness of the
  treatment regimens. The endpoints used in the study were laboratory
  values ("surrogate markers") such as CD4 count, viral load, and p24
  antigen, and not clinical endpoints, such as opportunistic
  infections or death. It remains unknown if the favorable effect of
  the 3-drug combination on laboratory markers is associated with a
  delay in disease progression or improved survival (clinical
  endpoints). The Phase III trials of saquinavir now open to
  enrollment (see Open Clinical Trials on page 62) are designed to
  evaluate the clinical effectiveness of the drug.
  Despite the limitations of ACTG 229, the study results are
  encouraging, particularly the fact that the 3-drug combination
  suppressed HIV load significantly better than either of the 2
  double combination regimens. In addition, this suppressive effect
  continued for the duration of the 24-week study. The results of the
  upcoming Phase III studies of saquinavir will provide important
  information about how long the triple combination can suppress
  viral load.

  Bassett R and others. ACTG 229: Executive Summary. May 26, 1994.
 ACTG 229: Antiviral Trial of Combination Therapy. Press Release from
 the National Institute of Allegy and Infectious Diseases.

  HIV Can Cause Cancer

 Scientists have known for some time that HIV can cause cancer
 indirectly by weakening the immune systems of infected individuals,
 leaving them susceptible to many opportunistic infections and cancers. A
 new study from the University of California at San Francisco (UCSF) now
 shows that HIV can cause cancer directly, by "turning on" the cancer
 genes in some of the cells it invades. "This is the first direct
 evidence that we have [of] a human virus causing cancer through some
 mechanism_not just indirectly by immunosuppression," said lead
 investigator Michael McGrath, MD.

 The UCSF research team reviewed 30 lymphoma cases and discovered
 that, in 4, HIV had inserted itself into the same location in the DNA of
 the infected cell. Dr. McGrath estimates that HIV may directly cause
 over 30% of all B-cell lymphomas in people with AIDS. These findings
 probably will lead researchers to search for a possible role for other
 viruses in causing cancer. Scientists currently do not know what causes
 Hodgkin's disease or lymphomas.

 Although the UCSF study appears to have important implications, many
 questions remain about the role of HIV in causing cancer, such as (1)
 what is the exact mechanism by which HIV activates the cancer genes in
 infected cells? (2) how often does HIV cause cancer? (3) how long does
 it take for cancer to develop in HIV-infected cells?

 Some scientists say the UCSF study results raise concerns about using
 retroviruses such as HIV for vaccines or gene therapy. "Hooking up a
 gene to a retrovirus and then infecting human cells might risk cancer
 [in the treated individual]," said Dr. McGrath.

 Shiramizu B and others. Identification of a common clonal human
immunodeficiency virus integration site in human immunodeficiency
virus-associated lymphomas.  Cancer Research 54(8): 2079-2072. April 15,
1994.

 TREATMENT FOR HIV INFECTION
  Advisory Panel Recommends Approval for d4T

 The FDA Antiviral Advisory Committee on May 20 recommended
 accelerated approval for for the anti-HIV drug d4T (stavudine). The FDA
 is not required to follow the recommendations of the advisory committee,
 but usually does so. The advisory panel concluded there was "an unmet
 need for d4T," and found that the drug probably offers some benefit over
 AZT, ddI and ddC, but also noted that it was unclear who would benefit
 most from the drug and how safe it is.

 In asking for acclerated approval for d4T, Bristol-Myers Squibb told
 the FDA panel that the drug appears to improve immune function among
 people with AIDS and causes less serious toxic effects than existing
 FDA-approved anti-HIV drugs. The most serious adverse side effect of d4T
 is a painful peripheral neuropathy that has occurred in about 21% of
 those using the drug. Because HIV itself can cause peripheral
 neuropathy, it is difficult to know whether this side effect is due to
 the virus or to the drug among those taking it.

 d4T versus AZT

 Preliminary results of an ongoing study of 359 people presented to the
 FDA panel suggest that d4T is beneficial for individuals who switch to
 the drug after using AZT for about 6 months. In the study, half the
 participants switched to d4T after 6 months of AZT treatment while the
 other half continued with AZT. Those who changed to d4T experienced a
 CD4 cell increase of 20-30. The participants on AZT had decreases in
 their CD4 cell counts. The d4T group also gained weight, while those on
 AZT lost weight, according to Susan Yarin, Director of Communications
 for Bristol-Myers Squibb.

 Data from Expanded Access Program

 Bristol-Myers Squibb also presented data from the ongoing expanded
 access program that has enrolled about 12,000 people with AIDS taking
 either 20 or 40 mg d4T twice daily. There appears to be no significant
 difference in effectiveness between the low and high dose, but those on
 the higher dose experienced a higher incidence of peripheral neuropathy.
 As a result of these findings, the recommended d4T dose likely will be
 20 mg twice daily.

  Access to d4T

 The advisory panel has recommended that use of d4T be restricted to
 people with AIDS who have failed or are intolerant to AZT, ddI and ddC.
 However, if the FDA approves d4T, it will become available by
 prescription, and physicians may then prescribe the drug to HIV positive
 patients at all stages of HIV disease and with or without previous use
 of AZT, ddI and ddC.

 Associated Press. FDA committee recommends new AIDS drug. Los Angeles Times.
A-21. May 21, 1994.

 Yarin, S. Director of Communications, Bristol-Myers Squibb. Personal
Communication. May 23, 1994.

   ddI versus ddC

 ddI and ddC are equally safe and effective for people with AIDS who
 have failed or are intolerant to AZT, according to the results of a
 national study of 467 volunteers published in the New England Journal of
 Medicine. "Although neither of these drugs are very effective in this
 population of patients with advanced disease, this study suggests that
 ddC alone is as good as ddI [alone], and both should be available as
 single-agent therapies," said lead investigator Donald Abrams, MD,
 assistant director of the AIDS Program at UCSF-affiliated San Francisco
 General Hospital.

 Dr. Abrams noted that there was no significant difference between ddI
 and ddC in the number of patients who had progression of disease or who
 died. Among those taking ddI (230), 157 had disease progression and 100
 died. Among those taking ddC (237), 152 progressed and 88 died. These
 results suggest a slight survival advantage for those using ddC. About
 66% of all participants experienced some significant adverse side effect
 (e.g., peripheral neuropathy among ddC users; abdominal pain and
 diarrhea among ddI users).

 Abrams DI and others. A comparative trial of didanosine or zalcitabine after
treatment with zidovudine in patients with human immunodeficiency virus
infection. New England Journal of Medicine 330(10): 657-662. March 10, 1994.

 Merck Protease Drug Suffers Setback

 The following information appeared in the March 15, 1994 edition of
 BETA BULLETIN.

 The protease inhibitors are regarded by many AIDS treatment activists
 as the most promising class of anti-HIV drugs currently in the research
 pipeline. In a small study last summer, Merck's lead protease drug,
 L-735,524, demonstrated promising results, exhibiting an anti-HIV effect
 roughly comparable to AZT. Unfortunately, study results obtained 6
 months later have proven disappointing.

 Merck announced on February 25, 1994, that L-524 failed to
 effectively suppress HIV in volunteers receiving the experimental
 compound for about 6 months. Merck researchers learned from PCR testing
 of stored plasma samples that the study volunteers' plasma HIV RNA
 levels began to rise after about 12 weeks of treatment. After 24 weeks
 of L-524 use, these levels rose to almost pretreatment levels.
 Merck scientists said they are not yet certain why the drug's initial
 promise faded so quickly, but they suspect that HIV developed resistance
 to L-524 at the doses tested. Researchers are examining blood samples
 from the study volunteers for the presence of resistant strains.
 As a result of these disappointing study results, Merck has canceled
 plans to test L-524 in several hundred HIV positive volunteers. Instead,
 researchers will modify an ongoing study (protocol 006) comparing L-524
 at low and high doses to AZT monotherapy in 60 asymptomatic,
 p24-positive volunteers.

 Dr. Linda Distlerath, Director of Public Policy at Merck, told BETA
 that 006 participants who were on the L-524 arms now will take a higher
 dose of L-524 (600 mg 4 times a day). A separate study will test the
 safety and effectiveness of L-524 plus AZT. The investigators are hoping
 that higher doses of L-524 monotherapy, or L-524 in combination with AZT
 or other nucleoside analogs will effectively suppress viral activity.
 Emilio Emini, Executive Director of Virology at the Merck Research
 Laboratories, told the Wall Street Journal that the company has other
 protease inhibitors in preclinical development that may show stronger
 activity against HIV than L-524.

 Distlerath L. Director of Public Policy, Merck and Company. Personal
Communication. March 2, 1994.

  Other Protease Drugs

 Hoffmann-La Roche

 A number of pharmaceutical companies are developing oral protease drugs
 for use in HIV infection. Hoffmann-La Roche's saquinavir (formerly
 called Ro 31-8959), now entering Phase III trials, is the farthest along
 in the drug development process. The international trial of saquinavir
 is now recruiting for 1,800 study volunteers (600 in the U.S.) with no
 previous use of any anti-HIV drug. In the North American trial of
 saquinavir, 40 medical centers will enroll a total of 1,200 HIV people
 with CD4 cell counts between 50 and 300 who have previously used AZT
 (but no other anti-HIV drug). For more information about the
 international and North American trials of saquinavir, call
 1-800-526-6367.

 Abbott

 Abbott has experienced considerable difficulties with its protease drug
 development program. Two Abbott protease candidates have failed, but a
 third, A-84538, is now entering Phase I safety studies in New York City,
 St. Louis, and at sites in Alabama and in Europe. Call 1-800-TRIALS-A
 for enrollment information.

 Monsanto Searle

 Searle has started Phase I testing of its protease drug, SC-52151, in
 Berlin. The bioavailability of this compound reportedly is high, a
 definite advantage in the ongoing race to bring a safe and effective
 protease drug to market.

 Burroughs Wellcome

 Burroughs Wellcome has made an agreement with Vertex, a small
 biotechnology company in Cambridge, Massachusetts, to develop and market
 that company's experimental protease drug, VX-478. A Phase I study of
 VX-478 sponsored by Burroughs Wellcome is expected to begin this year.
 The results of laboratory testing suggest that VX-478 may be a powerful
 inhibitor of HIV activity.

 Other Protease Developers

 Other companies developing protease inhibitors include Agouron,
 Ciba-Geigy, DuPont Merck, Hoechst-Bayer, Nippon Mining, Parke-Davis and
 Upjohn.

  AZT Reduces Spread of HIV to Newborns

 The following information appeared in the March 15, 1994 edition of
 BETA BULLETIN.

 Preliminary results of a U.S. government-sponsored study (ACTG 076)
 indicate that AZT reduces by two-thirds the risk of transmission of HIV
 from infected pregnant women to their newborn infants. The finding is
 considered so important that a monitoring board halted the study before
 its scheduled completion date. Based on these results, Burroughs
 Wellcome, manufacturer of AZT, has asked the U.S. Food and Drug
 Administration (FDA) to approve AZT for the treatment of HIV positive
 pregnant women.

 The National Institute of Allergy and Infectious Diseases (NIAID) has
 released a summary of the data as a "Clinical Alert" so that physicians
 and healthcare professionals worldwide are aware of the findings. These
 documents are available in the U.S. on request from the AIDS Clinical
 Trials Information Service (call 1-800-TRIALS-A).

 Background

 The large majority of HIV positive children become infected through
 maternal-infant transmission, either in the womb, during birth or after
 birth, from breastfeeding. The ACTG 076 study was designed to test the
 hypothesis that treatment with AZT could reduce the risk of
 maternal-infant transmission.

 Study Results

 The 477 HIV positive pregnant volunteers in the study took either AZT or
 a placebo during pregnancy and labor. After birth, the babies received a
 syrup containing either AZT or placebo for 6 weeks. Of the 364 infants
 delivered for whom at least 1 HIV culture test was available, 53 were
 HIV positive. Thirteen (8%) of these babies were born to women taking
 AZT and 40 (26%) to mothers taking the placebo.

 The researchers reported that both mothers and infants experienced no
 significant short-term adverse side effects except for a mild,
 reversible anemia. They also have found no differences in the quantity
 or type of birth defects in infants whose mothers took AZT or the
 placebo. Researchers will continue to monitor the growth and development
 of the infants and watch for any unusual illnesses. Government health
 officials are expected to convene a panel of medical experts this summer
 to consider new recommendations on the testing and treatment of pregnant
 women.

 AZT reduces rate of maternal transmission of HIV. NIAID NEWS. February 21,
1994.

 The Concorde AZT Trial Revisited

 Results of the largest study ever conducted on AZT (1,749
 participants) were published in April 1994, a year after release of the
 study's preliminary findings in a letter to The Lancet (April 3, 1993).
 The data prompted many physicians and patients to reevaluate AZT use in
 early (asymptomatic) HIV infection.

 In their published report, the Concorde researchers reaffirm their
 preliminary conclusions that asymptomatic HIV positive individuals do
 not benefit more from starting AZT early than from delaying AZT
 treatment until symptoms appear. The investigators found no significant
 differences in clinical outcome between the 2 treatment strategies of
 early versus deferred treatment, irrespective of the participants'
 initial CD4 T-cell count. They also report no significant differences in
 rates of progression of HIV disease between the 2 groups, and no
 differences in survival rates.

 CD4 T-cell counts were significantly higher for the early therapy
 group after 3 months (a 29 cell increase), a difference that continued
 for up to 3 years, although the researchers note no clinical benefit
 from the CD4 cell increase. They also state that the Concorde trial
 results cast doubt on the value of using changes over time in CD4 counts
 as a predictive measure for the effects of antiviral therapy on disease
 progression and survival.

 The results of the Concorde trial do not encourage the early use of
 AZT as monotherapy nor in combination with other antivirals among
 asymptomatic HIV positive individuals. In fact, the Concorde findings
 prompted a significant change in the "official" U.S. government
 recommendations on AZT use by asymptomatic individuals. Prior to release
 of the Concorde preliminary findings, AZT was recommended to all
 asymptomatic HIV positive individuals with fewer than 500 CD4 cells.
 Current U.S. government recommendations for this group support either
 "continued observation" (no AZT use) or initiation of AZT treatment.

 Commentary

 BETA spoke with Michael Saag, MD, Associate Professor of Medicine,
 University of Alabama at Birmingham, about the Concorde results. In
 response to the question of whether AZT should still be considered a
 viable treatment among asymptomatics, given the Concorde findings, Dr.
 Saag replied: "Absolutely. Concorde basically confirmed what we already
 knew about AZT. Specifically, AZT is an effective antiretroviral that
 has a limited durability of effect when used as monotherapy. The benefit
 of AZT appears to be of longer duration when used earlier in treatment,
 rather than when initiated later."

 "On a theoretical level and in all likelihood on a practical level,
 it makes good sense to add antiretroviral therapy as early as possible
 to help the immune system in its battle against the virus. This is
 especially true if we believe that better therapies will be available in
 the next 3-5 years." On the subject of AZT use in combination therapy,
 Dr. Saag added: "AZT has an integral role to play in combination therapy
 and is, in my view, the cornerstone of combination therapy at the
 present time."

 In response to publication of the Concorde trial results, Burroughs
 Wellcome Company, the manufacturer of AZT, released a statement
 defending the use of the drug among asymptomatics, pointing out that
 several clinical studies in the U.S. and abroad have shown that AZT
 delays HIV disease progression and slows viral replication in
 asymptomatic individuals: "In the final analysis, while Burroughs
 Wellcome believes early therapy with Retrovir [AZT] is an appropriate
 and effective strategy for managing HIV infection in asymptomatic
 patients, physicians and patients will need to weigh all available data
 and make the choices that are most appropriate for each individual."

 Seligmann M and others. Concorde: MRC/ANRS randomized double-blind
controlled trial of immediate and deferred zidovudine [AZT] in symptom-free
HIV infection. The Lancet 343: 871-867. April 9, 1994.

 Twice Daily AZT in Asymptomatics

 AZT appears to delay disease progression among asymptomatics for at
 least a year, according to results of a study of volunteers using twice
 daily AZT (500 mg 2 times/day) or placebo for 104 weeks. The study
 enrolled 329 asymptomatic individuals from 5 European countries and
 Australia. With 200-400 CD4 cells, this study population was considered
 at high risk for progression to AIDS. The primary endpoint of the study
 was the development of AIDS or severe AIDS-related complex (ARC).

 Study Results

 Progression to AIDS or severe ARC occurred in 17 people in the placebo
 group and 12 in the AZT-treated group. After 2 years, no statistically
 significant difference in progression to AIDS or severe ARC was found
 between the 2 groups. However, after 1 year of follow-up, significantly
 more placebo than AZT users had progressed to AIDS or severe ARC.

 Commentary

 The researchers emphasize that while AZT confers a clear benefit over
 placebo in the first year of treatment, it fails to do so in the second
 year. They suggest that the steady increase in the probability of
 progression in the second year for the AZT group may be related to the
 development of viral resistance to the drug. In conclusion, they write:
 "Phase I/II studies with combination treatment have shown more
 substantial and prolonged rises in CD4 cell counts than observed with
 monotherapy. It is likely that more aggressive initial treatment
 regimens than AZT monotherapy will be necessary."

 Mulder JW, Cooper DA and others. Zidovudine [AZT] twice daily in
asymptomatic subjects with HIV infection and a high risk of progression to
AIDS: a randomized, double-blind placebo-controlled study. AIDS 8: 313-321.
March 1994.

  AZT and Quality of Life

 The benefits to asymptomatics of taking AZT may be outweighed by the
 drug's adverse side effects, according to the results of a study of
 1,338 asymptomatic HIV positive individuals with fewer than 500 CD4
 cells. After 18 months, the AZT group taking 500 mg/day gained an
 average of 0.5 months without disease progression, as compared to the
 placebo group. However, the AZT group experienced severe adverse events
 an average of 0.6 month sooner than the placebo group.

 The research team concluded that, for asymptomatic patients treated
 with 500 mg/day AZT, a reduction in the quality of life due to severe
 side effects of therapy approximately equals the increase in the quality
 of life associated with a delay in the progression of HIV disease.
 Burroughs Wellcome has criticized the methodology of the study and its
 conclusions, noting that the authors did not measure overall patient
 quality of life, but focused only on the adverse side effects of AZT.
 Lenderking WR and others. Evaluation of the quality of life associated with
 zidovudine [AZT] treatment in asymptomatic human immunodeficiency virus
 infection. The New England Journal of Medicine 330: 738-743. March 17, 1994.

 How AZT Affects Progression to AIDS and Survival in People with ARC

 AZT may benefit people with ARC by significantly postponing the
 development of AIDS, but AZT use by these individuals does not appear to
 extend their survival after they develop AIDS, according to the results
 of a 3-year study of 235 Australian gay and bisexual men with ARC.
 The benefit of AZT appears to be greater in those who do not develop
 intolerance to the drug. The investigators suggest that people with ARC
 who develop clinical intolerance to AZT, or who develop AIDS while using
 AZT should immediately consider another anti-HIV regimen (e.g., adding
 ddI or ddC to AZT or switching to ddI or ddC monotherapy).

 At the time of study entry, participants had a mean CD4 cell count of
 117 and a mean age of 38.1 years. The daily dose of AZT used was 1,200
 mg/day. Eighty-two individuals (35%) were taking some prophylactic
 treatment: dapsone (33%), pyrimethamine-sulfadoxine (26%), acyclovir
 (26%) and ketaconazole (15%). Only one participant was taking
 trimethoprim-sulfamethoxazole.

 Swanson CE and others. Efficacy of zidovudine treatment in homosexual men
with AIDS-related complex: factors influencing development of AIDS, survival
and drug intolerance. AIDS 8(5): 625-634. May 1994.

  Switching from AZT to ddI

 The duration of response to treatment with AZT has been quite
 variable: some individuals experience a slow decrease in CD4 cells
 despite treatment, while others maintain a stable CD4 cell count for up
 to 3 years. This variation in response may be due, at least in part, to
 the development of HIV resistance to AZT. Laboratory studies have shown
 that viral resistance to AZT and ddI develops at different genetic
 locations, and AZT-resistant strains of HIV remain sensitive to ddI.
 A recent study of 312 individuals at 19 study sites was designed to
 examine the benefits of switching to ddI compared to continuing AZT
 among people who have used AZT for 6 or more months and who have signs
 of progressive disease. The study volunteers took either ddI tablets
 (600 mg/day adjusted for weight) or AZT (600 mg/day).

 The study results show that individuals who continued to receive AZT
 had a 50% greater risk for disease progression than those who switched
 to ddI. Patients with either a diagnosis of AIDS or AIDS-related complex
 (ARC) appeared to benefit from changing to ddI treatment. The beneficial
 effect of switching was greater in individuals with a CD4 cell count at
 study entry of 100 or greater.

 This is the first study to show a benefit for switching from AZT to
 ddI among people with AIDS or ARC, and the first to prove the clinical
 effectiveness of the tablet formulation of ddI and to validate the
 practice of using clinical signs or a decrease in the CD4 count as an
 indication for changing drug treatment.

 Spruance SL and others. Didanosine [ddI] compared with continuation of
 zidovudine [AZT] in HIV-infected patients with signs of clinical
deterioration while receiving zidovudine. Annals of Internal Medicine 120:
360-368. March 1, 1994.

 Alternating vs Simultaneous AZT and ddI Treatment

 Although both simultaneous and alternating regimens of anti-HIV drugs
 have been studied, there is little information available directly
 comparing these 2 approaches. A randomized pilot study comparing
 alternating and simultaneous regimens of AZT and ddI was conducted at
 the National Cancer Institute (NCI) in 41 individuals with AIDS or
 symptomatic HIV disease. Individuals on each regimen took the same
 overall amounts of AZT and ddI over the course of the one-year study.
 Volunteers taking the simultaneous regimen had significantly better
 responses in terms of CD4 cell count increase and weight gain over a
 year than those taking the alternating regimen. Those taking the
 simultaneous regimen also had an overall greater decrease in p24 antigen
 levels and fewer opportunistic infections, although these trends were
 not statistically significant.

 Two relatively low-dose regimens of AZT and ddI were used in this
 small study. Results of a 1992 study of combination treatment with AZT
 plus ddI suggest that CD4 cell increases are optimal from use of
 relatively high doses of each drug. However, this study shows that
 sustained CD4 cell increases can be attained with half the usual daily
 dose of AZT and ddI. In addition, recent laboratory experiments suggest
 that AZT resistance is less likely to occur when a combination of AZT
 and ddI is used. Prevention or the delay of the generation of
 AZT-resistant strains may be responsible in part for the clinical
 benefits and the CD4 increases observed in this NCI pilot study.

 Antonelli G and others. Drug combination of AZT and ddI_synergism of action
and prevention of appearance of AZT resistance. Antiviral Chemistry and
Chemotherapy 5: 51-55. January 1994.

 Yarchoan R and others. A randomized pilot study of alternating or
simultaneous zidovudine [AZT] and didanosine [ddI] therapy in patients with
symptomatic human immunodeficiency virus infection. The Journal of Infectious
Diseases 169: 9-17. January 1994.

 Combination ddI plus AZT Beneficial in Children

 HIV positive, previously untreated children who took full-dose AZT in
 combination with ddI gained weight, had increased numbers of CD4 cells
 and showed decreases in HIV load, according to the results of a 24-week
 study at the National Cancer Institute. After 24 weeks on the
 combination, children in both the previously AZT-treated and untreated
 groups experienced significant CD4 cell count increases: the median CD4
 cell count for all the children increased from 331 to 556 cells. For the
 previously untreated group, the median increase in CD4 counts was from
 386 to 726 cells.

 This study of 68 children, the first to evaluate the effects of the
 combination of AZT and ddI in children, showed the combination did not
 enhance toxic side effects. The low incidence of pancreatitis or any
 other serious toxicity suggests that full doses of ddI can be used in
 combination with AZT among children. The researchers conclude that the
 doses used in combination treatment for children could be the same as
 those currently used in monotherapy, i.e., AZT at 90-180 mg/m2 every 6
 hours combined with ddI at doses between 90-135 mg/m2 every 12 hours.

 Husson RN and others. Zidovudine [AZT] and didanosine [ddI] combination
therapy in children with human immunodeficiency virus infection. Pediatrics
93: 316-322. February 1994.

   AZT plus 3TC

 Glaxo and Burroughs Wellcome (manufacturers of 3TC and AZT,
 respectively) have made an agreement whereby Burroughs holds the option
 to develop and market 3TC for the treatment of HIV infection. 3TC is
 currently in Phase II/III studies, with one arm evaluating the safety
 and effectiveness of combination treatment with 3TC and AZT. Pending the
 results of that study, Burroughs may ask the FDA to approve AZT in
 combination with 3TC for the treatment of HIV infection in adults.
 AZT Resistance Correlates with Treatment Failure

 A study by Spanish researchers confirms the results of other
 laboratory tests suggesting that development of HIV resistance to AZT at
 codon 215 of the reverse transcriptase enzyme correlates with declining
 responsiveness to treatment with the drug. The investigators conclude
 that "the zidovudine [AZT] resistance mutation at codon 215 of reverse
 transcriptase was associated with a worse response to therapy. Absence
 of antiviral response and resistance mutations were more frequent in
 patients with lower CD4 cell counts and higher provirus loads. These
 findings support a more beneficial effect of early than late therapy."

 Luque F and others. Provirus load changes in untreated and
zidovudine-treated HIV-1 infected patients. Journal of Infectious Diseases
169(2): 267-273. February 1994.

 TREATMENT FOR OPPORTUNISTIC
 INFECTIONS

 Oral Ganciclovir: Effective Maintenance Therapy for

   CMV Retinitis

 This information is reprinted from the March 15, 1994 BETA BULLETIN.
 Many individuals with CMV retinitis become understandably upset when
 they learn that the standard treatment for their condition involves the
 permanent installation of a catheter for intravenous access to
 ganciclovir (Cytovene) or foscarnet. Fortunately, new data indicate that
 the oral formulation of ganciclovir is both safe and effective as
 maintenance therapy for CMV retinitis.

 Two studies (at the University of Alabama and Beth Israel Hospital in
 Boston) showed no statistically significant difference in effectiveness
 between intravenous (IV) and oral ganciclovir, when the assessment of
 progression was based on retinal photographs. However, a significant
 difference in the 2 approaches did emerge when the assessment of
 progression was based on examination by onsite ophthalmologists. In the
 latter case, the IV ganciclovir appeared more effective than the oral
 formulation. It has been suggested that there may be ophthalmologist
 bias against the oral drug. One of the studies also showed more adverse
 side effects (fever, neutropenia and sepsis) in individuals receiving IV
 ganciclovir.

 Based on the data from these 2 studies, Syntex, manufacturer of
 ganciclovir, will file a New Drug Application (NDA) with the FDA seeking
 approval of oral ganciclovir as maintenance therapy for CMV retinitis.
 Two ongoing studies are testing the hypothesis that oral ganciclovir may
 prevent first-episode CMV retinitis in HIV positive individuals with
 fewer than 100 CD4 cells.

 Japour AJ. Update on oral ganciclovir for CMV retinitis. AIDS Clinical Care
 6(3): 23. March 1994.

 Spector SA. A randomized, controlled study of intravenous ganciclovir
therapy for cytomegalovirus peripheral retinitis in patients with AIDS. AIDS
Clinical Trials Group and Cytomegalovirus Cooperative Study Group. Journal of
Infectious Diseases 168: 557-563. 1993.

 Interferon Gamma for Disseminated Mycobacterial
  Infection

 A study published in the New England Journal of Medicine (May 12,
 1994) suggests that treatment with interferon gamma dramatically
 benefits individuals with disseminated mycobacterial infection that is
 resistant to therapy. The study involved 7 HIV negative individuals with
 mycobacterial infection that had spread to involve at least 2 organs or
 types of body tissues. Six had disseminated Mycobacterium avium complex
 (MAC), which is difficult to treat in people with AIDS. At the beginning
 of the study all 7 participants were either unresponsive to, or
 experiencing disease progression despite standard anti-mycobacterial
 therapy.

 Interferons are a class of proteins naturally produced by the body to
 help fight infection. Previous studies had led researchers to believe
 that gamma interferon, secreted by immune system T cells, plays a
 particular role in controlling mycobacterial infection, possibly through
 cytokine-mediated signaling of T-cells and macrophages.
 All participants received subcutaneous injections of gamma interferon
 3 times weekly in doses that varied according to body weight (50
 micrograms/meter2). While there were no striking changes in CD4 cell
 counts or characteristics, all had dramatically improved clinical
 responses, which began within 8 weeks and continued for several months.
 Side effects were minimal_fever, malaise and myalgia (muscle ache or
 pain)_and resolved with dose reduction.

 Researchers conclude that interferon gamma in combination with
 standard therapy may be beneficial for treating disseminated refractory
 mycobacterial infection.

 Holland SM and others. Treatment of refractory disseminated nontuberculous
 mycobacterial infection with interferon gamma. The New England Journal of
 Medicine 330(19): 1348-1355. May 12, 1994.

  PWA Living 29 Months Longer than in 1986

 The lifespan of people with AIDS (PWA) has increased on average to 40
 months since 1986, according to a recent report in the Journal of the
 American Medical Association by a team of University of California at
 San Francisco researchers. Survival time was defined as the time the
 study participants' CD4 cells dropped below 200 until their death.
 Changes in survival time were studied through an examination of the
 medical records of 761 HIV positive men enrolled in the San Francisco
 Men's Health Study (1984 to 1993) and the San Francisco General Hospital
 Cohort Study (1983 to 1993).
 The median survival time following an AIDS diagnosis in the first 500
 people diagnosed with AIDS in San Francisco was 11 months, according to
 lead investigator Dennis Osmond, PhD. Since that time, studies have
 reported an increase in survival time ranging from 14.4 months to about
 2 years. This increase in lifespan following an AIDS diagnosis generally
 had been attributed to the beneficial effects of treatment with anti-HIV
 drugs.

 PWA who took AZT or other anti-HIV drugs alone did not have a
 statistically significant increase in survival, said Dr. Osmond: "The
 most important finding in our study was that the major contributor to
 improved survival during the past 10 years has been in HIV-infected
 individuals diagnosed with PCP, suggesting that prophylaxis and
 treatment for PCP, rather than antiretroviral therapy, were responsible
 for most of the improvement." The study showed that people treated for
 PCP who also took anti-HIV treatment did best, but that the role of
 anti-HIV drug treatment was less significant to the survival benefit
 than the anti-PCP therapy.

 The UCSF study results suggest that people with lower CD4 counts are
 living longer now because more of them have used prophylaxis and
 treatment for PCP than was the case earlier in the epidemic. "Now
 patients are diagnosed more frequently with opportunistic infections
 other than PCP as their CD4 counts drop over time. They tend to die of
 other infections or cancer, rather than PCP," according to Dr. Osmond.

 Osmond D and others. Changes in AIDS survival time in 2 San Francisco
cohorts of homosexual men, 1983 to 1993. Journal of the American Medical
Association 271(14): 1083-1087. April 13, 1994.

 Trinkl A. Survival time in some HIV-infected men has increased by
approximately one year since beginning of the AIDS epidemic, UCSF study
finds. News from SFGH/UC-San Francisco. April 12, 1994.

 The Effects of High-Dose Acyclovir on Survival and
   Herpesvirus Disease

 High-dose acyclovir (3,200 mg/day) does not reduce the incidence of
 cytomegalovirus disease (CMV), but does significantly reduce the
 probability of dying after 1 year of therapy, according to results of a
 double-blind, placebo-controlled trial of 304 men and women with AIDS in
 16 hospitals in Europe and Australia. There were 43 deaths in the
 placebo group compared to 27 deaths in the acyclovir group. As expected,
 acyclovir also significantly reduced the incidence and frequency of
 herpes simplex virus disease.

 Trial participants were seropositive for CMV and had fewer than 150
 CD4 cells at study entry. There was a steady decline in CD4 counts in
 both the acyclovir and placebo groups.

 The data showed that anti-HIV treatment significantly improved
 survival in both the acyclovir- and placebo-treated groups. Participants
 used AZT monotherapy, AZT plus ddC or ddI monotherapy. Ninety-six
 percent (96%) of individuals in both the acyclovir and placebo groups
 were on PCP prophylaxis. Taking this into account, the investigators
 still found that acyclovir therapy had an independent and significant
 beneficial effect on survival.

 Researchers chose to use a high dose of acyclovir in this trial in an
 effort to achieve drug blood levels sufficent to produce an anti-CMV
 effect similar to that reported in organ transplant patients. They note
 that if the survival benefit from acyclovir is due to the drug's ability
 to suppress acyclovir-sensitive herpesviruses, then lower doses of the
 drug might be as effective as the high dose used in this trial (3,200
 mg/day). On the other hand, use of the experimental drug valacyclovir
 may provide even greater benefit, since it produces significantly higher
 blood levels of acyclovir than acyclovir (Zovirax). An international
 study (ACTG 204) is now addressing these possibilities.

 Youle MS and others. Effects of high-dose oral acyclovir on herpesvirus
disease and survival in patients with advanced HIV disease: a double-blind,
placebo-controlled study. AIDS 8(5): 641-649. May 1994.

  Over-the-Counter Acyclovir

 On May 19, 1994, a public hearing was held by the FDA to create a
 forum for the expression of various perspectives on the proposed
 granting of over-the-counter (OTC) availability of acyclovir (Zovirax)
 200 mg for the management of recurrent genital herpes. Burroughs
 Wellcome Company, manufacturer of acyclovir, presented their case for
 approval of OTC status, citing the desirability of wider access and the
 increased opportunity approval would create for early treatment, as well
 as their intention to launch a major program to educate the public about
 genital herpes.

 The FDA heard passionate objections to allowing OTC sales of
 acyclovir from both AIDS activists and some medical experts. Their major
 concern is that people will overuse the drug and thereby increase the
 odds that the herpes simplex virus will develop resistance to it. "If
 acyclovir is used casually on and off again, the likelihood of
 resistance developing may increase and the likelihood of the disease
 [genital and oral herpes simplex] spreading may increase," according to
 Stephen Straus, a virologist at the National Institute of Allergy and
 Infectious Diseases.

 In addition to concerns about OTC acyclovir contributing to the risk
 of acyclovir-resistant herpes simplex, activists cited economic reasons
 for their opposition to the Burroughs Wellcome proposal.
 "Over-the-counter drugs are not reimbursed by insurance carriers nor are
 they included in government assistance programs," a spokesperson for San
 Francisco's ACT-UP/ Golden Gate told BETA.

 According to Kathy Bartlett of Burroughs Wellcome, the advisory panel
 expects to reconvene for continued discussion of the acyclovir OTC issue
 at the end of July.

 Bartlett K. Manager of Corporate Media Relations, Burroughs Wellcome
Company. Personal Communication. May 24, 1994.

 Bowers M. Medical Writer.Personal Communication. May 27, 1994.

 FDA Approves Septra Brand TMP-SMX to Prevent PCP

  The  FDA  has  made  it  official:  Septra  brand
 trimethoprim-sulfamethoxazole (TMP-SMX) is indicated for treatment to
 prevent Pneumocystis carinii pneumonia (PCP) in people with HIV
 infection and other immunocompromising conditions. TMP-SMX is the most
 effective prophylaxis for PCP as well as for toxoplasmosis in
 individuals who can tolerate the drug. Septra is the brand name for
 TMP-SMX manufactured by Burroughs Wellcome Company. Bactrim,
 manufactured by Hoffmann-La Roche, is another brand of TMP-SMX. There
 are also generic TMP-SMX products.

 The FDA action on Septra, applied for by Burroughs Wellcome Company,
 validates common clinical practice already in use.

  Desensitization Protocols

 Because TMP-SMX may cause adverse side effects in people with HIV
 infection (often severe enough to necessitate discontinuation of the
 drug), it may be most beneficial for these individuals to start TMP-SMX
 using a desensitization protocol. Two California physicians have
 reported success using desensitization protocols. For more information,
 call the offices of Dr. Marcus Conant in San Francisco (415-923-1333)
 and Dr. Brian Lipson in Redwood City, CA (415-365-6300).

 Steroid Therapy: a Role in the Management of MAC?

 A report in the January 1994 issue of the journal AIDS describes
 beneficial effects from adjunctive corticosteroid therapy in the
 management of 2 individuals with AIDS and disseminated MAC. The 2
 patients were adult men who both previously had an AIDS-defining
 illness. When diagnosed with MAC, both had fewer than 40 CD4 cells and
 presented with fever, night sweats and weight loss. They were treated
 first with rifampin, isoniazid and pyrazinamide, and later with
 azithromycin and clofazimine. One patient also took ciprofloxacin.
 In both cases only a partial response was achieved during the first 2
 weeks of treatment. However, the introduction of 20 mg prednisolone
 daily produced a resolution of fever and sweats and a feeling of
 well-being, according to physicians at the Heartland Hospital in
 Birmingham, U.K. During follow-up, both patients gained weight and one
 who was anemic did not require transfusion after starting prednisolone
 treatment.

 Both patients have continued to take azithromycin (with clofazimine
 in one case and ciprofloxacin in the other). One has continued to be
 free of fever and has maintained his weight gain for 5 months. His
 prednisolone dose has been halved, in an attempt to control resistant
 oral candidiasis. The second has maintained his improvement in symptoms
 and is back at work 8 months after starting prednisolone.

 The attending physicians speculate that the anti-inflammatory actions
 of prednisolone may inhibit the production of cytokines such as tumor
 necrosis factor (TNF). Excessive production of TNF, they say, is one
 cause of fever and weight loss in advanced AIDS. They also point out
 that prednisolone is commonly used in the treatment of immunocompetent
 individuals with tuberculosis to reduce their symptoms of prolonged
 fever. TNF also has been shown to stimulate HIV replication.
 Immunosuppressive treatment with prednisolone may both reduce the
 symptoms of MAC and slow disease progression in people with AIDS,
 suggest the British physicians.

 There has been concern among researchers and clinicians that use of
 corticosteroid therapy in HIV positive individuals might accelerate
 disease progression, due to the immunosuppressive action of these drugs.
 In the 2 individuals described here, prednisolone did not seem to
 promote disease progression (although one has resistant oral
 candidiasis). It would be useful to conduct a controlled study of
 prednisolone use in the treatment of MAC, and to monitor cytokine levels
 in study participants with MAC before treatment, especially for levels
 of tumor necrosis factor.

 Elliott AM and others. Use of prednisolone in the treatment of HIV positive
tuberculosis patients. Quarterly Journal of Medicine 85: 855-860. 1992.

 Steven N and others. Corticosteroid therapy for AIDS patients with
Mycobacterium avium/intracellulare infection. AIDS 8(1): 136-137. January
1994.

 Hospital and Municipal Water Systems May Be a
 Primary Source of MAC Infection

 Mycobacterium avium complex (MAC) organisms were found in 10 (30%) of
 33 water samples collected from environmental and municipal water
 sources in Boston and New Hampshire between March 1990 and February
 1992, according to results of a study by researchers at
 Dartmouth-Hitchcock Medical Center and Boston City Hospital.
 This is the first documented report of a water system that may be
 persistently colonized with a particular strain of Mycobacterium avium.

 Background

 Disseminated infection with MAC organisms occurs in up to 40% of people
 with advanced AIDS in the U.S. These environmental mycobacteria are
 found in water, soil and animals, but the specific source of human
 infection is not known. It is also unknown whether people with AIDS
 develop MAC disease from recent infection with the MAC organisms or
 through a reactivation of previous infection. The investigators of the
 study reported here believe it is likely that MAC organisms are acquired
 from an environmental source to which most people are exposed.
 The researchers collected and analyzed water samples from
 environmental sources (e.g., lakes, rivers) and water supply systems
 (e.g., home municipal water, hospital water) in New Hampshire and
 Boston. They then compared the MAC strains isolated from these sources
 to the M. avium strains of 28 individuals in New Hampshire and Boston
 with disseminated MAC infection. Four groups of strains infecting these
 patients were also isolated from 2 or more epidemiologically related
 sources. "For 3 of these [M. avium] strains, the epidemiological data
 implicate water as the source of infection, including 2 strains
 associated with nosocomial [hospital-asociated] acquisition [from hot
 water]."

 The authors implicate "recirculating hot water systems which are used
 in large institutions, including hospitals, hotels and apartment
 buildings." They also note that investigators "have not found MAC in
 single-family residential water supplies."

 The researchers report that the results of recent M. avium skin test
 studies suggest that previous infection with M. avium is not sufficently
 common in healthy populations to explain the high incidence of
 disseminated M. avium in AIDS solely on the basis of reactivation of an
 existing infection. "The identification of water as the source of
 infection for 5 patients confirms that infection was acquired recently
 and was not the result of reactivation of latent infection."
 Implications for Prevention of MAC?

 The investigators believe that their findings suggest another approach
 to the prevention of disseminated MAC in AIDS than the use of rifabutin
 in patients with fewer than 100 CD4 cells. They propose an aggressive
 program to identify (and then avoid) environmental sources of M. avium
 infection: "Patients might be advised to avoid institutional showers and
 exposure to non-sterile drinking water; colonised institutional water
 systems might be sterilised, as recommended in the prevention of
 nosocomial legionella infection."

 These proposed risk-reduction strategies may be a useful supplement
 to the use of rifabutin in HIV positive individuals at risk for
 developing disseminated MAC infection.

 du Moulin GC and others. Concentration of Mycobacterium avium by hospital
hot water systems. Journal of the American Medical Association 260:
1599-1601. 1988.

 Singh N and Yu VI. Potable water and Mycobacterium avium complex in HIV
patients: is prevention possible? (commentary). The Lancet 343: 1110-1111.
May 7, 1994.

 von Reyn and others. Persistent colonisation of potable water as a source of
Mycobacterium avium infection in AIDS. The Lancet 343: 1137-1141. May 7,
1994.

 von Reyn CF and others. Isolation of Mycobacterium avium complex from water
in the United States, Finland, Zaire, and Kenya. Journal of Clinical
Microbiology 32: 27-30. 1993.

 ISIS 2922: Promising New Drug for CMV Retinitis

 Isis Pharmaceuticals' experimental antisense drug, ISIS 2922, has
 shown promising results in a small Phase I/II study of people with CMV
 retinitis. Preliminary results suggest that ISIS 2922 halted disease
 progression (eye lesion progression) in most study participants who
 received the middle and high doses of the drug. All 10 individuals in
 the study had failed or were intolerant to either ganciclovir or
 foscarnet (or both), the standard treatments for CMV retinitis.
 As of late April, none of the participants have shown progression,
 according to the company. Two out of 3 individuals in the middle-dose
 group and all in the high-dose groups showed positive clinical
 responses. In addition, the participants experienced no significant,
 dose-related side effects from ISIS 2922. The drug is administered by
 intravitreal injection into the globe of the eye.

 CMV retinitis, a sight-threatening disease that damages the retina of
 the eye, affects up to 40% of people with AIDS. Treatment with
 ganciclovir and/or foscarnet may produce little benefit and also may
 cause severe toxicities. Individuals receiving ganciclovir frequently
 must cease taking AZT due to the synergistic toxicities of the 2 drugs.
 ISIS 2922 may be compatible in combination with anti-HIV drugs and with
 the anti-CMV drugs ganciclovir and foscarnet.

 ISIS 2922 is the first antisense drug to show activity against a
 disease-causing agent in humans. Antisense drugs are a new and unique
 class of pharmaceuticals designed to work more selectively than
 traditional drugs and to act against pathogens at a different or earlier
 stage in the disease process. The design of antisense drugs is
 "rational," i.e., based on information about the targeted pathogen. This
 "rational" approach allows for a relatively rapid and more efficient
 drug design.

 Based on the results of the initial human study, 2 randomized,
 placebo- controlled Phase II/III trials of ISIS 2922 in individuals with
 CMV retinitis are planned to begin this summer at 10 to 15 clinical
 centers in the U.S.

   Other ISIS Drugs

 Isis Pharmaceuticals is considering developing ISIS 2922 as a
 treatment for CMV pneumonia and CMV gastroenteritis. The company is also
 exploring the potential of antisense treatments for HIV infection. In
 addition, a new ISIS anti-HIV drug, ISIS 5320, is in preclinical
 development. In laboratory testing, this drug inhibits HIV from
 infecting immune cells, blocks cell-to-cell transmission of the virus
 and is active against AZT-resistant strains of HIV.

 Isis Pharmaceuticals announces clinical activity of antisense drug. Phase
I/II Preliminary Data from annual meeting of the Federation of American
Societies for Experimental Biology (FASEB) in Anaheim, CA. April 28, 1994.

 NUTRITION

 High-Dose Oral L-Carnitine in PWA

 Supplementation with high-dose oral carnitine (6 g/day) may have a
 role as a complementary therapy among people with HIV infection,
 according to the results of a small Italian study. Carnitine is a
 naturally occuring substance in the body that stimulates the oxidation
 and synthesis of fatty acids. In people with HIV infection, it may
 reduce wasting and improve immune cell production. Carnitine
 concentrations in the sera of people with AIDS are usually lower in
 those taking AZT (De Simone, 1992), and carnitine deficiency has been
 found in the skeletal muscle of people with AZT-related myopathy
 (Dalakas, 1994). In addition, people with AIDS taking L-carnitine
 supplements have demonstrated enhanced peripheral blood mononuclear cell
 (PBMC) responses to mitogens and a decrease in triglycerides and beta-2
 microglobulin levels (De Simone, 1993).

 Study Results

 The investigators enrolled 20 men with advanced AIDS (22-109 CD4 cells)
 who had normal serum levels of carnitines. The participants were
 randomly assigned to receive either L-carnitine (6 g/day) or placebo for
 2 weeks. At study entry and at the end of the study, the researchers
 measured carnitines in both sera and in PBMC, serum triglycerides, CD4
 counts and the effects of mitogen stimulation.

 Despite having normal concentrations of carnitines as measured by
 serum levels, these patients had lower concentrations of total carnitine
 in PBMC than healthy, HIV negative controls. In those participants
 treated with high-dose L-carnitine, appropriate levels of carnitine were
 restored. In addition, the immune function of the treated individuals
 also improved, as measured by an improved lymphocyte response to mitogen
 stimulation. At the end of the study, the researchers also found a
 significant reduction in serum triglyceride levels in the L-carnitine
 group compared with baseline levels.

 Increased serum levels of triglycerides are common in people with
 AIDS, and appear to result from the unregulated production of cytokines,
 particularly tumor necrosis factor (TNF). The Italian investigators
 believe that the effect of L-carnitine on serum triglyceride levels is
 probably mediated via the modulation of TNF. L-carnitine has previously
 been shown to modulate the production of TNF both in vitro and in vivo
 (Delogu, 1993; Ruggiero, 1992).

 The researchers believe their study findings suggest a significant
 relationship between carnitine status in PBMC and immune function in
 people with AIDS. They recommend that L-carnitine supplementation be
 considered as a complementary therapy for HIV positive individuals.
 "Further studies are currently in progress to address the important
 question of whether the encouraging results obtained by administering
 high-dose L-carnitine supplements for a short timespan persists, or
 whether prolonged treatment is required.

 No adverse side effects were noted in those receiving high-dose
 L-carnitine. Six patients (30%) on L-carnitine reported psychological
 well-being, weight gain, increased energy and feeling healthy. The
 investigators note that reduced serum carnitine levels have been
 associated with AZT treatment, and they conclude that supplementation
 with high-dose L-carnitine may be useful to prevent or treat AZT-related
 myopathy.

 Dalakas MC and others. The AZT-induced mitochondrial myopathy is associated
with muscle carnitine deficiency and lipid storage. Annals of Neurology. 1994
(in press).

 Delogu G and others. Anaesthetics modulate tumour necrosis factor alpha:
effects of L-carnitine supplementation in surgical patients. Preliminary
results. Medical Inflammation 2(supp): S33-S36. 1993.

 De Simone C and others. Carnitine depletion in peripheral blood mononuclear
 cells from patients with AIDS: effect of oral L-carnitine. AIDS 8(5):
655-660. May 1994.

 De Simone C and others. L-carnitine deficiency in AIDS patients. AIDS 6:
203-205. 1992.

 De Simone C and others. High-dose L-carnitine improves immunologic and
metabolic parameters. Immunopharmacologic Immunotoxicology 15: 1-12. 1993.

 Ruggiero V and others. LPS-induced serum TNF production and lethality in
mice: effect of L-carnitine and some acyl-derivatives. Medical Inflammation
2(supp): S43-S50.

 Vitamin E and Beta Carotene Have No Beneficial
 Effect on the Incidence of Lung Cancer and Other Cancers in Male Smokers

 The results of several studies over the last 10 years have suggested
 that high intake of antioxidant vitamins such as vitamin E
 (alpha-tocopherol) and beta carotene (provitamin A), either through diet
 or vitamin supplementation, might help to prevent cancer or
 cardiovascular disease (Peto, 1981; Packer, 1991). In 1993, a large
 clinical trial of 15,000 inhabitants of Linxian County in China found
 that a combination of beta carotene, vitamin E and selenium reduced the
 number of deaths from stomach cancer by 21%. More recently, several
 studies have suggested a beneficial role in the treatment of HIV
 infection for a high intake of nutrients and antioxidant vitamins
 (Abrams, 1993; Beach, 1992).

 Many epidemiologic studies have linked the intake of vegetables rich
 in beta carotene with a lower risk of cancer, especially lung cancer,
 and have suggested that certain micronutrients are inhibitors of cancer
 (Peto, 1981). Some observers have pointed out that the limitation of
 these observational studies is that the demonstrated benefits are not
 large and might be due to other, unmeasured differences in lifestyle.
 In April 1994 the New England Journal of Medicine published the first
 randomized, double-blind, placebo-controlled trial of supplementation
 with antioxidant vitamins in a large, well-nourished population (The
 Alpha Tocopherol, Beta Carotene Cancer Prevention Study Group [ATBC],
 1994). This study enrolled more than 29,000 middle-aged male smokers in
 Finland who were treated for 6 years. The purpose of the study was to
 determine if supplementation with vitamin E, beta carotene or both would
 reduce the incidence of lung cancer in male smokers. A secondary purpose
 was to see if the incidence of other cancers would be affected by this
 supplementation.

 Study Results

 The trial failed to detect any significant protective effect of either
 of the 2 vitamins on lung cancer. On the contrary, among those treated
 with beta carotene (20 mg/day), there were significantly more new cases
 of lung cancer. In regard to the incidence of other cancers, there was
 no statistically significant difference with either vitamin. Neither
 vitamin significantly affected death rates due to heart disease or
 stroke. When adjustments were made for multiple comparisons, neither
 vitamin was associated with greater increases or decreases in any
 particular cause of death than could be due to chance. The researchers
 concluded that "these supplements may actually have harmful as well as
 beneficial effects."

 Commentary

 The results of the ATBC trial should not be viewed as proving that these
 vitamins are ineffective or even hazardous. The development of lung
 cancer may require many years, possibly decades, and treatment with
 vitamin supplements sufficient to significantly affect the middle or
 late stages of the disease may require substantially longer than the
 median 6 years of the ATBC trial. In addition, although the 20 mg daily
 dose of beta carotene appeared adequate and had high bioavailability,
 increasing blood levels 10-fold, the 50 mg daily vitamin E supplement
 was a synthetic form of the vitamin that does not have a high
 bioavailability, and increased blood levels of vitamin E in study
 participants by only one third. It may be necessary to at least double
 blood levels of vitamin E to show whether it produces a significant
 benefit.

 Ongoing Trials of Antioxidant Vitamins

 Three ongoing large trials are assessing the benefit of beta carotene:
 the Carotene and Retinoid Efficacy Trial (CARET), the Women's Health
 Study (Harvard) and the Physicians' Health Study (Harvard). The safety
 monitoring committee for the CARET trial may decide to notify
 participants' of the Finnish study finding that 20 mg/day beta carotene
 could increase the risk for lung cancer among cigarette smokers. The 2
 Harvard trials are scheduled to continue without notification of the
 participants.

 Dr. Charles Hennekens, lead investigator of the Physicians' Health
 study, told Science magazine "[The Finnish trial] does not disprove the
 value of antioxidant vitamins, nor does it incriminate them as harmful.
 But it does provide support for skepticism, and a moratorium on
 unsubstantiated claims [about beta carotene and other antioxidants]."

 Abrams B and others. A prospective study of dietary intake and acquired
immune  deficiency syndrome in HIV-seropositive homosexual men. Journal of
Acquired Immune Deficiency Syndromes 6(8): 949-958. August 1993.

 Baum MK and others. Interim dietary recommendations to maintain adequate
blood nutrient levels in early HIV-1 infection. VII International Conference
on AIDS. Amsterdam, 1992. PoB 3657.

 Beach RS and others. Specific nutrient abnormalities in asymptomatic HIV-1
 infection. AIDS 6(7): 701-708. July 1992.

 Gilden D. Nutritional intervention in HIV disease. BETA: 3-11. 1994.
Nowak R. Beta-carotene: helpful or harmful? Science 264: 500-501. April 22,
1994.

 Packer L. Protective role of vitamin E in biological systems. American
Journal of Clinical Nutrition 53 (supp): S1050-S1055. 1991.

 Peto R and others. Can dietary beta carotene materially reduce human cancer
rates? Nature 290: 201-208. 1981.

 IMMUNOTHERAPY

  Impaired Response to Hepatitis B Vaccine in Asymptomatics

 Hepatitis B virus (HBV) is commonly found in HIV positive individuals
 because the 2 viruses share the same modes of transmission: parenteral
 (via shared contaminated needles), sexual and vertical (from mother to
 child during pregnancy, childbirth or from breastfeeding). HIV infection
 is associated with a high degree of HBV replication, which increases the
 potential of transmitting this often life-threatening viral infection.
 Prevention of HBV infection through use of the hepatitis B vaccine among
 previously unexposed HIV positive individuals is highly desirable.
 Researchers at the General Hospital in Newcastle, United Kingdom,
 studied the immune response (especially in relation to CD4 counts) to
 hepatitis B vaccine among asymptomatic, HIV positive gay and
 heterosexual individuals (Tayal and Saukar, 1994).

 A 20 microgram (mcg) dose of recombinant hepatitis B vaccine (Engerix
 B) was given to 20 asymptomatic, HIV positive individuals
 intramuscularly in the deltoid muscle region at 0, 1 and 6 months. An
 additional dose of vaccine was given to those who did not respond or had
 poor response to the standard regimen. Of the 20 individuals vaccinated,
 anti-HBV level was checked in 12 of 13 who completed 3 doses of
 vaccination. The remaining 7 patients had either 1 or 2 doses of vaccine
 and were not available for follow-up.

 Of the 12 patients, 2 (16.6%) had a fully protective response, 2
 (16.6 %) had a poor response and 8 (66.7 %) had no response. A fourth
 dose of vaccine was given to 5 patients. Of these, one had a poor
 response to the initial 3 doses but showed a fully protective response
 to the fourth. Of the 4 patients with no response to the 3 initial
 doses, one (33.3%) had a poor response to the fourth dose of vaccine and
 2 no response. A response was not determined in the fourth patient.
 The mean pre- and post-vaccination CD4 counts of 435 and 367,
 respectively, among the responders was not significantly higher than the
 corresponding CD4 counts of 377 and 332 among nonresponders. Two of the
 nonresponders progressed to AIDS within 3 years of diagnosis of their
 HIV infection.

 The researchers found a positive response to vaccination in 4 of 12
 patients (33.3%) with fewer than 660 CD4 cells. Hepatitis B vaccination
 results in a much higher response rate of 80-90% among HIV negative
 individuals who are immunocompetent.

 The response rates among immunocompromised individuals show a marked
 difference according to the type of vaccine used. The response rate to
 plasma-derived vaccine is 50-56% compared with a lower response range of
 20-40% following the use of recombinant hepatitis vaccine in
 asymptomatic HIV positive individuals (Loke, 1990). In the study
 reviewed here, the response rate from the Engerix B recombinant vaccine
 was 33.3%.

 Additional doses and/or higher doses of hepatitis B vaccine may be
 required to overcome the relative unresponsiveness to hepatitis B
 vaccine among HIV positive individuals, according to Drs. Tayal and
 Sankar. An optimal dose in this population might include a higher dose
 (e.g., 40 mcg/dose) or a higher number of doses (e.g., at 0, 1, 6 and 9
 or 0, 1, 2 and 12 months). Further studies are needed to determine the
 optimal regimen for hepatitis B vaccination of HIV positive individuals.

 Carne CA and others. Impaired response of homosexual men with HIV antibodies
to plasma derived hepatitis B vaccine. British Medical Journal 294: 866-868.
1987.

 Loke RHT and others. Diminished response to recombinant hepatitis B vaccine
in homosexual men with HIV antibody: an indicator of poor prognosis. Journal
of Medical Virology 31: 109-111. 1990.

 Tayal SC and Sankar KN. Impaired response to recombinant hepatitis B vaccine
in asymptomatic HIV infected individuals. AIDS 8(4): 558-559. April 1994.

 LABORATORY MARKERS

  Triglyceride Levels in Asymptomatics

  A 1993 report described elevated triglyceride  levels
 (hypertriglyceridemia) in association with lower survival rates in 58
 people with AIDS and suggested that hypertriglyceridemia might be a
 useful marker for HIV disease progression (Gonz_lez-Clemente, 1993). In
 contrast, a recent study of 94 HIV positive individuals concludes that
 mean levels of triglyceride among asymptomatics are not significantly
 different from those of healthy, HIV negative controls (Baum and
 Shor-Posner, 1994).

 Drs. Baum and Shor-Posner also conclude that serum triglyceride
 levels do not appear to be associated with indicators of immune function
 during early HIV infection. They found no significant correlation
 between triglyceride levels and CD4 count, CD8 count, CD4/CD8 ratio or
 B2-microglobulin level. Further, an analysis conducted over 18 months
 indicated that triglyceride levels were not associated with survival or
 stage of disease progression.

 Baum MK and Shor-Posner G. Normal triglyceride levels in early HIV-1
infection (letter). AIDS 8: 131-132. January 1994.

 Gonz_lez-Clemente IM and others. High triglyceride levels as a predictor of
 mortality in AIDS patients. AIDS 7: 1022-1023. 1993.

  Lowered Cholesterol in Early HIV Infection

 A 1993 study demonstrated that lowered cholesterol levels
 (hypocholesterolemia) are prevalent in early HIV infection (Shor-Posner,
 1993). Disturbances in cholesterol metabolism appear to precede the
 development of hypertriglyceridemia (elevated triglyceride levels) in
 HIV infection (Grunfeld, 1992).

 Researchers also have shown that low values of total, high-density
 and low-density cholesterol are significantly associated with elevated
 B2-microglobulin levels (Rubsamen-Waigmann, 1991). This finding suggests
 that hypocholesterolemia may contribute significantly to immune
 dysfunction in early HIV infection and therefore may be a reliable
 marker for disease progression, according to the authors.
 Grunfeld C and others. Lipids, lipoproteins, triglyceride clearance and
 cytokines in human immunodeficiency virus infection and the acquired
 immunodeficiency syndrome. Journal of Clinical Endocrinologic Metabolism 74:
1045-1052. 1992.

 Rubsamen-Waigmann H and others. Markers for HIV disease progression in
untreated patients and patients receiving AZT: evaluation of viral activity,
AZT resistance, serum cholesterol, B2-microglobulin, CD4+ cell counts, and
HIV antigen. Infection 19 (supp): S77-S82. 1992.

 Shor-Posner G and others. Hypocholesterolemia is associated with immune
dysfunction in early human immunodeficiency virus-1 infection. American
Journal of Medicine 94: 515-519. 1993.

 MISCELLANEOUS

 HSV-1 and HIV Enhance Each Other's Replication

 Coinfection of tissues by HIV and HSV-1 particles in non-genital
 herpes simplex lesions among people with AIDS significantly enhances the
 replication of both viruses, resulting in the production of increased
 numbers of both HIV and HSV-1 virions, according to study results
 published in a recent issue of The Lancet. This new finding suggests
 that HSV-1 may be a significant cofactor in HIV disease progression, and
 supports the use of suppressive therapy with acyclovir for herpes
 simplex infection among people with HIV infection.

 In the abstract of their article the authors state: "HIV uses the CD4
 molecule_as a receptor for entry into host cells. In tissues co-infected
 with herpes simplex type 1 (HSV-1), HIV virions were observed to infect
 keratinocytes, which, because they lack the CD4 molecule, are normally
 incapable of being infected by HIV."

 "Although a number of other viruses have been reported to enhance HIV
 viral transcription in vitro, this is the first in-vivo report to our
 knowledge of reciprocal enhancement of viral replication associated with
 co-infection of keratinocytes and macrophages by HIV and HSV-1 in
 patients with AIDS and non-genital herpes simplex lesions."

 Heng MCY and others. Co-infection and synergy of human immunodeficiency
virus-1 and herpes simplex virus-1. The Lancet 343: 255-258. January 29,
1994.

       **********

 Selected Open Clinical Trials
 for HIV/AIDS Treatments
 Leslie Hanna

 The following studies are actively recruiting for participants. For
 further information, call the number provided with the individual
 listing or call the AIDS Clinical Trials Information Service (ACTIS)
 toll-free at 1-800-874-2572 (1-800-TRIALS-A). This government-sponsored
 service can provide information about many of the following trials, but
 can only provide information about privately sponsored trials when the
 sponsor has elected to give ACTIS that information.

  Treatment for HIV Infection

 L-735,524 (protease inhibitor)

 This Phase II clinical trial will look at the safety and tolerability of
 a higher dose of the Merck protease inhibitor than previously studied,
 alone and in combination with other anti-HIV agents. Specifically,
 participants will be randomized to 1 of 3 treatment arms: (1) 600 mg
 L-524 plus AZT plus ddI, (2) 600 mg L-524 or (3) AZT plus ddI. The study
 lasts for 6 months. Entrance requirements include less than 500 CD4
 (T-helper) cells and no greater than 2 weeks of prior use of AZT and/or
 ddI. Individuals must discontinue using ddC 2 weeks prior to treatment,
 and d4T, 3TC or another experimental agent 30 days prior to treatment.
 There are multiple sites. In San Francisco, call the Conant Medical
 Group at 415-923-0222.

 saquinavir (protease inhibitor) high-dose study

 This study will randomize 40 people to 2 treatment arms, and will take
 place at Stanford University in Palo Alto, CA. Participants in arm 1
 will take 600 mg of Hoffman La-Roche's protease inhibitor, saquinavir, 6
 times daily; those in arm 2 will take 1,200 mg 6 times daily. Entrance
 requirements include 200-500 CD4 cells, less than 3 months prior use of
 AZT and less than 2 weeks prior use of ddC or ddI. Participants may be
 p24 antigen positive or -negative. Call Jane Norris, PA, at
 415-723-2805.

 saquinavir (protease inhibitor) and ddC

 This 40-center Phase III study will involve 1,200 participants. The
 trial is open to people with HIV with 50-300 CD4 cells who have failed
 on AZT. Prior use of ddC, ddI or d4T must not be greater than 2 weeks.
 There are 4 treatment arms: (1) saquinavir monotherapy, (2) ddC
 monotherapy, (3) ddC plus low-dose saquinavir and (4) ddC plus high-dose
 saquinavir. For more information about the international and North
 American trials of saquinavir, call 1-800-526-6367.
 saquinavir (protease inhibitor) and AZT

 This study compares saquinavir to AZT. Partipcipants will be randomized
 to take protease alone, AZT alone, or protease inhibitor in one of 2
 doses with AZT. Some sites are still open. Call 1-800-526-6367.
 A-84538 (protease inhibitor)

 A protease inhibitor manufactured by Abbott, called A-84538, is now
 entering Phase I safety studies in New York City, St. Louis, and at
 sites in Alabama and in Europe.

 HIVIG plus AZT vs IVIG plus AZT for pregnant women

 HIVIG, a solution of concentrated antibodies, is a type of passive
 immunotherapy. ACTG 185 is a Phase III trial that compares HIVIG to IVIG
 for efficacy in preventing transmission of HIV from mother to infant.
 Participants are randomized to take either HIVIG or IVIG; all
 participants take AZT. Mothers are given AZT intravenously during labor.
 Infants receive the same treatment as mothers. Newborns also receive
 either intravenous HIVIG or IVIG, within 12 hours of birth, and a syrup
 formulation of AZT for 6 weeks. There are numerous sites nationwide.

 nevirapine, AZT, ddI and ddC

 ACTG 193A is a Phase II/III, double-blind, placebo-controlled trial that
 compares various combinations of antiretrovirals. Participants are
 randomized into 4 treatment arms: (1) nevirapine, AZT and ddI, (2) AZT
 and ddC, (3) AZT and ddI, or (4) AZT and ddI taken in 1-month,
 alternating cycles. Participants have less than 50 CD4s, and do not have
 acute or chronic pancreatitis.

 HIV gene mutation and antiretroviral treatments

 ACTG 244 is a nationwide, multicenter study that compares the
 effectiveness of various antiviral regimens in people with HIV. Using a
 special test, the study will determine whether or not participants have
 developed a specific viral mutation, at codon 215 of the HIV genome,
 which is associated with the development of resistance to AZT. Thus, the
 study also will explore issues involved in determining when to switch
 from AZT to another anti-HIV drug. Participants will take one or more of
 the following drugs: AZT, ddI and nevirapine. The trial is open to
 people with 300-600 CD4 cells who have taken AZT for more than 1 month
 but less than 2 years.

 SC-49483 vs AZT for inhibition of syncytia formation

 ACTG 259 is a study of SC-49483, a new drug that may help prevent the
 formation of syncytia, which are clumps of infected and healthy immune
 cells that are targeted for elimination from the bloodstream. Syncytia
 formation is an event associated with disease progression. Entrance
 requirements include 50-350 CD4 cells and less than 6 months prior use
 of AZT.

 GS-840

 A Phase I study of an oral drug known as GS-840 (also called BIS-PON
 PMEA) is underway. Manufactured by Gilead Sciences, GS-840 is a prodrug
 of another Gilead Sciences product, GS-393, or PMEA, which is in ongoing
 Phase I/II clinical trials. GS-840 is designed to be efficiently
 converted in the body into GS 393 and to achieve the highest possible
 bioavailability. Ongoing trials of GS 393 or PMEA demonstrated an
 association between taking the drug and decreased levels of p24 as well
 as increases in CD4 cell counts. Call Dr. Paul Leitman at Johns Hopkins
 University at 410-955-9707.

 thalidomide

 Thalidomide (Synovir) inhibits tumor necrosis factor (TNF), a cytokine
 associated with HIV-related wasting syndrome and increased HIV
 replication. There are 2 open-label Phase I trials underway that look at
 the anti-HIV effects of thalidomide; one focuses on whether thalidomide
 is an effective treatment for HIV-related weight loss. Two other trials
 independently evaluate the drug for the treatment of apthous ulcers and
 of tuberculosis. Celgene, the manufacturer, and NIAID/ACTG will
 cosponsor an upcoming Phase II trial of thalidomide for the treatment of
 cachexia (HIV-related wasting), with weight gain as the primary clinical
 endpoint.

 GEM 91

 This Phase I study of an antisense therapy made by Massachussetts-based
 Hybridon called GEM 91 will evaluate its pharmacokinetic and safety
 profiles. Antisense is a new type of therapy. In preliminary studies in
 Europe, GEM 91 has shown a strong ability to inhibit HIV replication by
 disrupting the process at its genetic base. The initial U.S. studies
 will take place at the University of Alabama in Birmingham.
 935U83

 This Phase I study of 935U83 (a nucleoside analog) will evaluate the
 safety, tolerance and pharmacokinetics of various oral doses of the
 drug. The study is open to people with 200-500 CD4 cells, not more than
 1 month's prior use of nucleoside analogs (AZT, ddI, ddC, d4T) and no
 prior use of non-nucleoside reverse transcriptase inhibitors.

 delavirdine (DLV) and AZT

 A Phase II/III randomized, double-blind study of the BHAP compound
 delavirdine (DLV), a non-nucleoside reverse transcriptase inhibitor,
 will look at 3 fixed doses of DLV plus AZT vs AZT alone to examine
 safety, tolerance and preliminary efficacy of the combination. This
 6-month study will enroll asymptomatic, HIV positive individuals with
 200-500 CD4 cells. Exclusion criteria include prior use of AZT for
 longer than 4 months, AZT intolerance and prior use of ddI, ddC, d4T or
 3TC. In San Francisco, call Mark Bowers at St. Francis Memorial Hospital
 at 415-353-6215. For information on other study sites, call the Upjohn
 AIDS Hotline at 1-800-432-4702.

 delavirdine (DLV) and ddI

 This Phase II/III randomized, comparative trial will evaluate the
 safety, tolerance and efficacy of DLV in combination with ddI vs ddI
 alone. Participants have 300 or fewer CD4 cells and less than 4 months
 prior ddI experience (unlimited AZT experience is permitted). One arm
 will receive ddI and 400 mg DLV; the other arm will receive ddI and
 placebo. For study sites and more information, call 1-800-432-4702.
 Note: participants in both DLV studies described here who do not respond
 to the study treatment will be eligible for open-label, triple-drug
 therapy containing DLV.

 atevirdine

 Atevirdine, another BHAP compound manufactured by Upjohn, is synergistic
 with AZT. This one-year, multicenter Phase II trial randomizes
 participants to one of 3 arms: (1) atevirdine 600 mg/day plus AZT, (2)
 atevirdine 200 mg/day plus AZT, or (3) placebo plus AZT. Participants
 will have 50-350 CD4 cells, have had 1 or more opportunistic
 infection(s), and have been taking AZT for at least 3 months. For
 information about trial locations, call 1-800-432-4702.
 PMEA

 The National Cancer Institute (NCI) is conducting a Phase I/II
 dose-ranging study of the safety and efficacy of the combination of AZT
 and PMEA, a nucleoside analog like AZT, known to be active against
 herpesviruses and HIV. PMEA is given in IV form 3 times a week.
 Participants have less than 500 CD4 cells. Call Sergio Bauzo of NCI at
 301-496-8959.

 thymopentin

 Thymopentin, derived from a natural hormone, stimulates the immune
 system. This Phase III double-blind, placebo-controlled trial will
 evaluate the safety and efficacy of thymopentin (Timunox) in HIV
 positive individuals taking an anti-HIV drug(s). Specifically,
 participants are randomized to receive thymopentin with AZT or ddI, or
 AZT combined with ddI, or AZT combined with ddC. A previous study
 indicated that the combination of thymopentin and AZT was more effective
 than AZT alone in slowing HIV disease progression.

 A related Phase II placebo-controlled trial will look at the impact
 of various doses of thymopentin on viral load; the study is open to
 people with less than 400 CD4 cells.

 oral hypericin (VIMRxyn)

 The NIH is sponsoring a trial of oral hypericin, an antiviral compound
 made by VIMrx. The Phase I/II trial will evaluate the efficacy of a
 daily oral regimen. Eligibility requirements include being p24-positive
 and having less than 350 CD4 cells. Efficacy will be evaluated by
 measuring p24 antigen levels and viremia using cultures and PCR. Study
 sites are New York University Medical Center/Bellevue Hospital, Beth
 Israel Hospital in Boston, MA, and Johns Hopkins University in
 Baltimore, MD.

 short-term AZT for primary infection

 This NIAID trial, DATRI 002, will evaluate the effect of short-term
 daily doses of AZT in people recently infected by HIV. The p24 antigen
 test will be used to determine eligibility. Participants will be
 randomized to receive either 1,000 mg/day AZT or placebo for 24 weeks.
 CD4 cell counts will be measured during and after the 24-week period to
 determine whether or not taking AZT produced an increase in CD4 cells.

 ViRx gene therapy screening and treatment (San Francisco Bay
 Area)

 Two sequential studies will first screen and then provide a new
 treatment to people with at least 350 CD4 cells. In the screening phase,
 blood tests will determine participants' human leukocyte antigen (HLA)
 type, the type of genetic marker found on white blood cells, which has
 predictive value about certain immune system characteristics. Lab work
 and clinical evaluations are free. People who meet the HLA and CTL
 requirements, and who have never used HIV immunotherapy or vaccine
 therapy, will be eligible for the treatment study. (The treatment study
 will evaluate the ability of injected treatments derived from mouse
 virus to enhance the immune system's ability to destroy HIV-infected
 cells.) Call ViRx at 415-474-2233. The Conant Medical Group in San
 Francisco is conducting a similar screening study of 100-200 people to
 identify about 50 candidates for a future study of "gene transfer
 technology" for the treatment of HIV disease; call 415-923-0555.

 BuCast in San Francisco

 BuCast is a compound closely related to a chemical (castanospermine)
 that is naturally found in a particular variety of chestnut trees.
 Laboratory studies have shown that castanospermine prevents HIV
 replication, and prevents HIV from binding to host cells. HIVCare is
 conducting a Phase I study to establish a maximum tolerated single dose
 and to evaluate the safety and pharmacokinetics involved in using the
 agent over a period of 2 weeks. Participants have at least 500 CD4
 cells. For more information call Mark Bowers at 415-353-6215.
 N-acetylcysteine (NAC) trial in San Francisco

 Sponsored by the National Cancer Institute, this 8-week study will look
 at the effects of oral NAC on glutathione levels inside T-cells in
 people with HIV. The reduced levels of glutathione in many people with
 HIV may promote an increased rate of viral replication. NAC is a prodrug
 that is converted in the body to cysteine and then to glutathione.
 Participants will receive either NAC or placebo. Inclusion criteria
 include reduced glutathione levels and a CD4 cell count equal to or less
 than 500. Concurrent use of AZT, ddI, ddC or d4T is permitted as long as
 therapy began at least 4 months prior to the beginning of the study.
 Exclusion criteria include current use of NAC, OTC, cysteine or
 glutathione; use of Trental; B-cell lymphoma; and any acute
 opportunistic infection requiring treatment. For more information, call
 David Hook, RN, Laura Goldbaum, RN, or Greg Dubs at 415-863-8090.

  Children

 non-Hodgkin's lymphoma

 The National Cancer Institute (NCI) is conducting a pilot study of 2
 drugs, systemic cyclophosphamide and methotrexate, for the treatment of
 HIV-related non-Hodgkin's lymphoma in children. The drugs under study
 are considered the 2 most effective drugs for treating childhood
 lymphomas. During the study, participants will continue to use
 antitretroviral therapy as well as IV gamma globulin, acyclovir and PCP
 prophylaxis to minimize the risk of complicating infection. The
 treatment period is 2 1/2 months. The age range is 3 months to 18 years.

 For more information, call the NCI at 301-496-2321.

 nevirapine, AZT and ddI

 This 3-drug combination pilot study is open to children already taking
 AZT and ddI. Nevirapine will be added to the participant's ongoing
 regimen, which will continue at the same dose level. Participants must
 have been using AZT and ddI for at least 12 weeks before entering the
 study. CD4 cell requirements are: children 1-11 months, greater than
 1,750; children 12-23 months, greater than 1,000; children 24 months-5
 years, greater than 750; and children 6-18 years, greater than 500.
 Lymph node biopsies will be performed the week before adding nevirapine,
 and at 24 weeks. Call Susan Sandelli, RN, at the NCI at 310-402-1391.
 AZT, ddI and 3TC

 This Phase I/II study will evaluate the safety and tolerability of
 different combinations of all 3 agents. Participants will be assigned to
 treatment arms according to previous experience with antiretroviral
 therapy. Children with less than 6 weeks of (or no) prior therapy will
 be assigned to arm A; children with prior therapy will be assigned to
 arm B. Participants in arm A will receive combination therapy with all 3
 drugs, but will be assigned to 2 different doses of AZT. Those in arm B
 will be assigned to a treatment regimen and dose level based on their
 medical histories and prior use of antiretrovirals. Specifically, those
 with prior toxicity to ddI will take AZT and 3TC; those with prior
 toxicity to AZT will take ddI and 3TC; those with prior toxicity to both
 AZT and ddI or with progressive HIV will take all 3 drugs but a reduced
 dose of AZT. Call 301-496-4256.

   Immune Modulators

 interleukin-12 (IL-12)

 The first Phase I studies of recombinant (genetically engineered in
 the laboratory) human interleukin-12, a protein that stimulates the
 cell-mediated immune response, will take place in San Francisco and Los
 Angeles. About 40 people with HIV and 100-500 CD4 cells who are on
 stable antiretroviral therapy will be enrolled at each site.
 Investigators will evaluate the safety of a single dose of IL-12; about
 75% of the participants will receive IL-12 and about 25%, placebo. In
 Los Angeles, call Dr. Hardy, Suzette Chafey or Rob Noga of the UCLA
 Center for AIDS Research and Education at 310-206-6414. In San
 Francisco, call Anna Martinson of the UCSF AIDS Program at 415-476-9296.

 interleukin-2, CD8+ cell infusion and antiretroviral
 therapies

 This Phase II trial will compare the safety and efficacy of 5 different
 combinations of recombinant IL-2, CD8+ cell infusion and standard
 antiretroviral therapy (AZT, ddI, ddC or d4T, singly or in combation).
 Participants will be randomized to 1 of 5 arms: (1) antiretroviral
 therapy alone, (2) antiretroviral therapy plus low-dose IL-2, (3)
 antiretroviral therapy plus high-dose IL-2, (4) antiretroviral therapy
 plus low-dose IL-2 plus CD8+ infusions, or (5) antiretroviral therapy
 plus high-dose IL-2 plus CD8+ cell infusions. There is no placebo.
 Eligibility requirements include more than 250 CD4 cells and 800 CD8+
 cells, and current, stable anti-HIV therapy (at least 12 weeks before
 beginning the study). Contact Brian Camp, RN, at the AIDS Community
 Research Consortium at 415-364-6563, or call ViRx at 415-474-2233.

  Treatment for Opportunistic Infections

 oral ganciclovir for maintenance treatment of CMV retinitis
 Syntex Research is sponsoring an open-label safety study of oral
 ganciclovir for maintenance treatment for CMV retinitis. Enrollment may
 be made through any licensed physician in the U.S. and Canada.
 Participants have stable CMV retinitis; treatment with IV gancicvlovir
 or foscarnet during at least 18 of the last 21 days prior to study
 enrollment; known difficulty with tolerating the IV catheter; no known
 sensitivity to acyclovir or ganciclovir.

 oral ganciclovir to prevent CMV infection

 NIAID CPCRA 023 will evaluate the effectiveness of oral ganciclovir in
 preventing CMV infections of the retina and gastrointestinal tract, the
 most common sites of CMV infection. Oral ganciclovir is easier and safer
 to take than IV ganciclovir. Participants have CD4 counts less than 100
 and will receive either 3 grams ganciclovir per day or placebo. The
 12-month monitoring period will be followed up with 12-24 months of
 follow-up.

 azithromycin for the prevention of MAC disease

 This study evaluates the safety and effectiveness of weekly azithromycin
 for the prevention of MAC disease in people with fewer than 100 CD4
 cells. Participants take azithromycin or placebo. Criteria include not
 having had a positive MAC culture within 1 month of beginning the study,
 and no treatment with any anti-MAC drugs within the last 4 weeks.
 amphotericin B, fluconazole and itraconazole to treat
 cryptococcal meningitis

 ACTG 159 is a multicenter, Phase I/II comparative trial. For the first 2
 weeks of the study, participants will receive either amphotericin B
 alone or in combination with flucytosine. Then, for 8 weeks afterward,
 half will take fluconazole and half will take itraconazole.

  Treatment for Malignancies and Cancers

 5-FU for cervical dysplasia

 5-FU is a cream applied intravaginally for preventing and treating
 cervical cancer. ACTG 200, a Phase II/III trial of safety and efficacy,
 compares the use of intravaginal 5-FU to observation for maintenance
 treatment of cervical dysplasia. After standard treatment for high-grade
 cervical dysplasia, women participants are randomized to receive
 treatment (topical intravaginal administration of 5-FU) or to be
 observed. There are numerous sites nationwide.

 interleukin-4 (IL-4) for Kaposi's sarcoma (KS)

 ACTG 224 is a Phase I/II open-label, dose-ranging study of IL-4 for
 treating KS. In Boston call Dr. Scadden at 617-632-8528 and in Los
 Angeles call Dr. Miles at 310-206-6414. For more information about
 another Phase II open-label trial of IL-4 for KS, call Dr. Gill in Los
 Angeles at 213-343-8275.

 photodynamic therapy for KS: Tin Ethyl Etopurpin and lasers

 This Phase I/II trial looks at the safety and effectiveness of
 photodynamic therapy for cutaneous KS. The drug Tin Ethyl Etopurpin is
 injected directly into lesions, followed by irradiation of the lesions
 with a laser. All participants receive treatment for a period of only a
 few days. Participants must have at least 3 measurable KS lesions that
 have been not been treated within the last 30 days. Contact Margot
 Whitfield at UCSF/SFGH Dermatology Department at 415-206-6099.
 implants of 5-FU and MPI 5003 for KS

 This open-label, Phase II study looks at the safety and efficacy of
 intralesional drug implants for treating cutaneous lesions of Kaposi's
 sarcoma. Participants will receive implants of either of 5-FU or MPI
 5003, or of the 2 combined, or placebo, into 4 lesions. Entrance
 requirements include greater than 4, but fewer than 52 red-to-purple
 colored KS skin lesions, and no prior treatment for KS. At the UCSF/SFGH
 Dermatology Department, contact Timothy Berger at 415-206-8680 or Margot
 Whitfeld at 415-206-6099.

  Treatment for Wasting Syndrome and Myopathy

 human growth hormone

 Serono Laboratories is sponsoring a trial to evaluate the efficacy of
 their recombinant human growth hormone, Saizen, in promoting weight gain
 in people with HIV infection. Saizen stimulates lean tissue production.
 Twenty-five (25) centers nationwide will enroll 180 individuals.

 Eligibility requirements include documented unintentional weight loss
 and use of an antiretroviral drug (AZT, ddI, ddC or d4T). For the first
 3 months, one group will receive human growth hormone; the other,
 placebo. After that, all participants will receive growth hormone for an
 indefinite period of time. For information about nationwide sites, call
 Gina Cella of Serono Laboratories at 800-283-8088, extension 5251.

 inhaled marijuana vs Marinol

 An FDA-approved pilot study will compare inhaled marijuana to the
 synthetic THC drug, Marinol, for use in promoting weight gain in people
 with HIV-related wasting syndrome. For information about this San
 Francisco Bay Area trial, call 415-476-9554.

 L-carnitine for myopathy (muscle weakness/degeneration)

 L-carnitine is a natural biochemical that stimulates the oxidation and
 synthesis of fatty acids. The NIH is conducting a Phase II
 placebo-controlled trial to evaluate L-carnitine as a treatment for
 myopathy, which in some cases is a side effect associated with use of
 AZT. Call Dr. Cupler at the National Institute of Neurological Disorders
 and Stroke (NIND), a division of NIH, at 301-402-4479.

 Clinical Trials Information by Region

   SAN FRANCISCO BAY AREA
    415-476-9554

   SOUTHERN CALIFORNIA
   HIV TREATMENT DIRECTORY
    213-469-5888

  AIDS/HIV TREATMENT DIRECTORY
    FOR NEW ENGLAND
    617-424-1524

    NEW YORK,
    CONNECTICUT,
  NEW JERSEY AND PHILADELPHIA
    212-268-4196

    AIDS Institute
  Experimental Treatment Infoline
   in New York state: 800-MEDS-4-HIV
  outside New York: 212-239-5523

   DIRECTORY OF WISCONSIN
   HIV/AIDS CLINICAL TRIALS
  in Wisconsin: 800-359-9272
  outside Wisconsin: 414-291-2799

  NORTHERN GEORGIA & ALABAMA
    404-874-7926

   GULF COAST REGION
    504-584-3605

  HOUSTON CLINICAL TRIAL NETWORK
    713-520-2083

  CANADIAN HIV TRIAL NETWORK
    604-631-5327

  ACTIVELY RECRUITING U.S. TRIALS
  AmFAR Treatment Directory
    212-682-7440

 Drug information and Clinical
 Trial Hotline
  1-800-874-2572
   English and Spanish
  Monday through Friday, 9 am _ 7pm EST
  Free
 Up-to-date information and customized searches of the
 National Clinical Trials Database.

 ------------------------------------------------------------

 CORRECTIONS

 It is a policy of BETA to correct factual errors. We regret these
 errors and any misunderstanding they may have caused.

 In the March 1994 issue of BETA, the dosage units for the B vitamins
 in the chart on page 5 entitled "Therapeutic Use of Nutrients in HIV
 Infection" were mistakenly reversed.

 The RDA for vitamin B6 is 2 milligrams (mg) and the therapeutic doses
 in use are 20-100 mg/day (not micrograms). The text in the Possible
 Toxicities column should read "greater than 300 mg/day can lead to
 peripheral neuropathy."

 The RDA for Vitamin B12, on the other hand, is 2 micrograms (mcg),
 not milligrams, and the therapeutic uses in dose are 50-500 micrograms.


       Copyright 1994. Bulletin of Experimental Treatments for AIDS (BETA) is
       a quarterly publication of the San Francisco AIDS Foundation (SFAF).
       Reproduced with permission. Reproduction of this article (other than
       one copy for personal reference) requires written consent from the
       SFAF. For subscription information, please contact the BETA
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