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[Electronic distribution for GENA/aegis by the Sisters of St. Elizabeth]

 Volume 8 no. 8

 Gay Men's Health Crisis: Treatment Issues
 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
> Treatment Highlights from Yokohama Conference
  >> New Ways to Measure Viral Burden
  >> HIV in the Lymph System
  >> Protease Inhibitors
  >> Little Benefit to "Early" Use of AZT, again
  >> A More Promising NNRTI?
  >> Other New Anti-HIV Drugs
  >> Mono, Combo or Sequential Therapy
  >> Opportunisitic Infections
  >> Long Term Survivors
  >> Reducing Maternal-Fetal HIV Transmission
 > HIV-Related Weight Loss and Wasting
 > Nutritional and Wasting Reports at the 10th Int'l Conference
 > Donald Kotler on the Gut, Inflammation and HIV

 ==============================
 ==============================

Treatment Highlights from Yokohama Conference
 by David Gold

The Tenth International Conference on AIDS, held in Yokohama, Japan
from August 7 to 12, included a total of 709 oral presentations and
2,760 poster presentations. Numerous satellite conferences,
community meetings and press conferences also took place.
Treatment Issues this month presents an overview of the major
treatment themes emerging at the conference. Next month's edition
will provide in-depth coverage of the presentations on antivirals,
immune therapies, opportunistic infections, HIV pathogenesis,
diagnostics and alternative therapies.

New Ways to Measure Viral Burden

Diagnostic techniques that measure the amount of HIV in the blood
were a major focus at this year's International Conference. The two
products receiving the greatest attention were Hoffmann-LaRoche's
HIV RNA polymerase chain reaction (PCR) and Chiron's "branched-
chain DNA" (bDNA). These two assays measure the same thing - the
RNA that forms HIV genes in free virus particles.

Both methods may be useful in clinical trials, where they could
provide a quick assessment of the effectiveness of anti-viral
therapies without having to wait for clinical endpoints (the onset of
opportunistic infections or death). For individual patients and their
physicians, these tests ultimately may provide a way to track
disease progression more clearly. An increase in someone's HIV
population might indicate that their current treatment had lost its
effectiveness and thus point to the need to alter antiviral therapy.
Both Roche's PCR and Chiron's bDNA are now available for use by
physicians, but these assays are not approved by the FDA for
diagnostic use in HIV disease, and "research or scientific use" must
be claimed. The price of these tests is steep for now -- at least
$200.

Analyzing Viral Load Decreases

Currently approved anti-HIV therapies (AZT, ddI, ddC, d4T) can
decrease HIV levels in the blood, at least temporarily. It is hoped
that these decreases will translate into slower disease progression
and increased survival for patients. This relationship has yet to be
demonstrated, though.

In Yokohama, several studies did suggest that a drop in viral load
caused by anti-viral therapy predicts clinical improvement in human
beings. The NIH-sponsored trial ACTG 116B/117 produced data
indicating that individuals whose HIV levels go down by 50 percent
or more during the first month of therapy also experience a
reduction in new opportunistic infections. A 254-person Veterans
Affairs (VA) study similarly found evidence that decreases in viral
load after starting AZT correlate with improved health.

HIV in the Lymph System

The new viral burden tests so far have been used almost exclusively
to measure HIV levels in the blood. Yet, researchers have come to
realize over the past few years that much of the early HIV
replication occurs not in the blood but in the lymph system. Dr.
Ashley Hasse presented data suggesting that approximately 25
percent of the CD4 cells in the lymph nodes are infected by HIV. This
is a much larger portion than previously thought. Using a new type of
molecular technology, Hasse detected a "staggeringly large" amount
of HIV-infected CD4 lymphocytes and macrophages in the lymph
system.

Yet, a small study by NIH researchers suggested that current
antiretroviral therapies may have a very minimal impact on HIV
levels in the lymph system. When asymptomatic, HIV-positive
individuals were given AZT monotherapy, the amount of HIV found in
lymphoid tissue remained largely unchanged. In more advanced
patients who added ddI to AZT therapy, there was a "temporary
reduction" in HIV replication in the lymph tissue in four of six
patients.

Protease Inhibitors

Much of the discussion about new antiviral therapies centered
around HIV protease inhibitor compounds. Approximately twenty of
these compounds are now under development, but most are not yet in
human trials. Of those that are in human trials, virtually no new data
were reported. Hoffmann-LaRoche presented previously released
data on saquinavir from ACTG 229 (see Treatment Issues, June
1994). Researchers from Merck discussed the company's overall
development program in only general terms. Preclinical data
measuring antiviral effect in test tubes and bioavailibility (how
much of the drug gets into the bloodstream) in animals were
presented by at least eight companies.

Viral Resistance to Protease Inhibitors

The most important new information about protease inhibitors came
from the Third International Workshop on Resistance, held in Kauai,
Hawaii immediately preceding the International Conference.
There, researchers from Wellcome Research Labs presented viral
resistance profiles based on test-tube studies of five protease
inhibitor compounds under development. Of concern, similar
resistance patterns were seen in many of the compounds. In fact,
two key mutations were associated with resistance to four of the
five compounds.

Interestingly, HIV resistant to Merck's compound, L-735,524, was
still sensitive to Roche's saquinavir, though. Dr. Emillio Emini of
Merck Research Laboratories reported that after six to eight months,
the HIV in most patients on L-735,524 is resistant to the protease
inhibitor compounds created by Abbot and DuPont-Merck, but not to
saquinavir. However, one patient, among the first given L-735,524,
eventually developed virus that was ten times more resistant than
normal to all protease compounds tested, including the Roche,
Vertex and Searle compounds.

Roche researchers reported that after one year of treatment with
saquinavir at 600 mg three times per day, 50 percent of patients
showed evidence of harboring resistant HIV with a mutation at one
of two points in the virus's genes. Stefano Vella, M.D., summarized
data indicating that the combination of saquinavir and AZT delayed
the emergence of resistance to both drugs.

Little Benefit to "Early" Use of AZT, again

New data was released from ACTG 019, a long running, placebo-
controlled study of AZT in over 3,200 HIV-positive patients. Paul
Volberding, M.D., of the University of California San Francisco
presented data on 1,637 individuals who began the study with over
500 CD4 cells and were randomized to either AZT or placebo. After a
median follow-up of five years, patients randomized to AZT had
higher median CD4 cells, but there was no significant difference in
disease progression or death. The results of this study, which will
be discussed in greater detail next month, appear to be consistent
with results from the Concorde study announced last year. In that
study, the use of "early" AZT in asymptomatic HIV-positive
individuals provided measurable increases in levels of CD4 cells but
no significant advantage in terms of disease progression or survival.

A More Promising NNRTI?

Some have already written off the class of drugs known as non-
nucleoside reverse transcriptase inhibitors (NNRTIs). Yet, a number
of reports at Yokohama suggested that these compounds may still be
promising, especially when used in combination with two nucleoside
analogs. Although resistance seems to develop rapidly with both
nevirapine and delavirdine, a European study reported that
resistance may develop less quickly with loviride, an NNRTI
manufactured by Janssen Pharmaceuticals.

Other New Anti-HIV Drugs

Aside from the reports about the protease inhibitor compounds,
there was little data about new anti-HIV therapies. Dr. Robert Gallo
reported that hydroxyurea, a drug already approved as a treatment
for some forms of chronic leukemia, inhibits a cellular enzyme
necessary for HIV to reproduce. Hydroxyurea seems synergistic with
AZT. Burroughs Wellcome reported that it is developing three new
nucleoside analogs, all now in clinical trials, and an
immunomodulator compound known as "Tucaresol," which should
begin phase I trials by the end of 1994. A small study of interleukin-
4 suggested that the compound, although unimpressive as a Kaposi's
sarcoma therapy, increased CD4 levels and decreased HIV levels.

Mono, Combo or Sequential Therapy

A number of small studies suggested that switching (sequential)
therapy from AZT to ddI may be more beneficial than continued long-
term AZT monotherapy. An retrospective analysis conducted by the
U.S. Multicenter AIDS Cohort Study (MACS) found that men with
intermediate stage HIV infection and on long-term AZT had a one-
third better survival rate if they added ddI or ddC to the AZT. Men
who exchanged monotherapies did no better than those who stayed on
AZT. Yet, the issue of combining versus switching drugs remains
unsettled and probably awaits the results of larger trials now
underway (ACTG 175 and the Delta trial). For more advanced patients
with very low CD4 counts, combination therapy still has not proven
better than monotherapy and may be associated with more toxicity.

Opportunisitic Infections

The leading story in terms of OI treatment was data about Serrano
Labs' human growth hormone (see below). Unfortunately, no data was
presented about the use of oral ganciclovir for CMV prophylaxis.
Shortly before the conference, Treatment Issues reported that a
placebo-controlled study of oral ganciclovir had been halted after
initial results indicated a significantly lower level of CMV disease
and a "trend toward increased survival" in patients given the drug.
The drug's manufacturer, Syntex, was unable to put together the data
quickly enough to be presented at the international conference as
late-breaking news. The data are now scheduled for release at a U.S.
conference in October.

Long Term Survivors

"Long-term nonprogressors" (individuals infected with HIV for at
least seven to twelve years with no decline in CD4 counts) elicited a
flurry of reports this year. David Ho, M.D., of the Aaron Diamond
Research Center in New York, reported that the long term
nonprogressors he is observing have extremely low levels of HIV in
their blood and that their CD8 cells may be playing a critical role in
suppressing HIV replication. Neutralizing antibodies to HIV also
remained high, indicating some continued viral replication in
nonprogressors. The viral strains from two of Dr. Ho's subjects grew
poorly in cell cultures and seemed defective in some way.

Reducing Maternal-Fetal HIV Transmission

While the conference was in session, the Food and Drug
Administration approved the use of AZT to reduce perinatal
transmission. Guidelines were issued in the CDC's Morbidity and
Mortality Weekly Report (August 5, 1994; vol. 43, no. RR-11).
A presentation by Yvonne Bryson, M.D., reported that HIV-positive
mothers with higher viral burden, lower CD4 counts and more
advanced disease were more likely to transmit HIV to their infants.
Efforts are now underway to initiate trials using Merck's protease
inhibitor to see whether this drug's comparatively large initial
reduction in viral load further reduces mother-to-child
transmission.

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


HIV-Related Weight Loss and Wasting
 by David Pieribone

HIV-associated weight loss, or wasting syndrome, is a major cause
of illness and death in patients with late-stage HIV infection. It can
be divided into two categories: acute weight loss, which often
rebounds after an opportunistic infection is brought under control,
and chronic weight loss, which is more difficult to reverse. Either
decreased nutrient intake or alterations in metabolism can lead to
weight loss. These factors can arise directly from HIV infection as
well as from opportunistic infections, cancers or pre-existing
gastrointestinal disease.

It is important to differentiate between mere loss in weight and the
loss of protein stores (in lean tissue) that occurs during HIV
infection. When acute weight loss is halted by treating an
opportunistic infection, an individual may regain lost weight by
adding fat rather than rebuilding lean tissue. Simply taking in more
nutrients does not automatically produce recovery from wasting.
AIDS-related wasting differs qualitatively from starvation. In
starvation, the body's protein stores and muscle mass is conserved
while basic metabolic rates slow and fat deposits are broken down
for energy. During AIDS, the reverse happens. Studies by Kotler and
others meanwhile indicate that death from wasting is related to the
loss of lean body mass rather than just the amount of weight loss.[1]

Alterations in Metabolism

Primary infection with HIV or secondary opportunistic infections
changes the body's metabolic pathways. Abnormal patterns of
protein and lipid metabolism result, with nutrients transferred from
lean to adipose (fat) tissue. Some inflammatory cytokines
(intercellular immune regulators), such as tumor necrosis factor
(TNF) and interleukin-1, have been associated with metabolic
dysregulation and wasting.[2] Their chronic release during HIV
infection seems to play a major role in HIV-related wasting.
Endocrine abnormalities, including changes in gonadal, adrenal and
thyroid function, have been noted in HIV-infected individuals and are
another possible cause of weight loss and wasting.[3,4] One recent
paper reported that people with AIDS-related wasting syndrome had
significantly less testosterone and more prolactin and cortisol than
similar people without wasting.[5] Testosterone promotes the growth
and maintenance of muscle tissue. The decrease in testosterone may
be related to the increased prolactin. Cortisol is an adrenal hormone
that modulates stress. One of its functions is to free existing
protein stores to repair tissue damage elsewhere in the body.
Finally, progressive muscle weakness (myopathy), is an ill-defined
condition that may be caused by HIV itself or extended use of AZT. It
is reversible in the latter case.

Approved Treatments for Wasting

Two appetite stimulants are the only FDA-approved therapies
specifically for AIDS-related wasting syndrome.

Dronabinol (Marinol) is the psychoactive component of marijuana. In
trials, dronabinol improved appetite and weight gain (mostly body
fat) in about half of the participants. Side effects associated with
Dronabinol include dizziness, thinking abnormalities, asthenia
(weakness or loss of strength) and euphoria.

Megestrol acetate (Megace) is a synthetic progesterone (steroid
hormone) in oral suspension. A twelve-week, placebo-controlled
study conducted in patients with AIDS-related wasting provided the
basis for its approval. Weight gains of five to seven pounds were
observed in the megestrol acetate group, and two-pound losses were
observed in the placebo group.[6] Phase II studies are underway to
evaluate the combination of Marinol and Megace.

Side effects of Megace include high blood pressure, leg swelling,
diabetes and impotence. (In addition, there was a trend toward a
higher death rate in one study's treatment arm.) Megace, like
Marinol, is widely considered to increase weight without adding to
lean body mass (see article on the Tenth International Conference on
AIDS). Appetite stimulants alone may not be able to
overcome the basic metabolic changes wrought by the chronic
response to HIV and the concurrent opportunistic infections.
Reversing wasting may require "anabolic" agents that, like
testosterone, promote muscle formation and discourage fat buildup.

Human Growth Hormone

Recombinant human growth hormone (rHGH) and insulin-like growth
factor (IGF-1) are two growth stimulators currently under study as
therapies for wasting.

rHGH is a synthetic version of pituitary gland-derived human growth
hormone. It is made by genetic engineering and used for the
treatment of dwarfism. rHGH can induce positive nitrogen balance,
promote protein sparing and increase weight gain and lean body mass
in patients with AIDS-related wasting.[7] Side effects of rHGH
include joint aches, fevers and high blood pressure.

Two preliminary studies published last year found that human
growth hormone triggered significant weight gain in people with HIV
wasting.[8,9] See the box on the International Conference on AIDS for
the first analysis of a much larger, more extended trial of rHGH. The
presentation on this trial was very encouraging.

IGF-1 is produced by the liver in response to human growth hormone.
Many, but not all, of growth hormone's effects seem to really be the
result of IGF-1. A trial comparing growth hormone and insulin-like
growth factor is being conducted at the National Cancer Institute,
but a trial examining the combination of the two yielded negative
results (see below).

Anabolic Steroids

Testosterone and the chemically similar synthetic anabolic steroids
have been used by athletes and body builders to increase their
muscle mass and stamina. Anabolic steroids can be dangerous,
though, and medical supervision is desirable.

Community doctors have found that testosterone replacement
therapy can improve patients' mood, sexual function, appetite and
energy, although the long-term effects on immune function are not
known. Testosterone replacement is generally not sufficient to
manage weight loss and increasing testosterone levels to above
normal can have adverse effects, including liver damage.
A limited number of studies indicates that some of the newer
synthetic oral testosterone derivatives have fewer side effects, and
anecdotal reports claim that they increase immune cell populations
(CD8 and CD4). Dr. Kotler, at St. Luke's/Roosevelt Hospital in New
York, is conducting trials with oral oxandrolone, a synthetic
anabolic. Early results indicate that patients taking oxandrolone
experience weight gain. Upon termination of treatment, weight loss
resumed, however. There was no evidence of CD8 or CD4 cell
increases resulting from oxandrolone therapy. During short-term
use, no overt side effects were noted but studies examining long-
term use have not been done. The effects of anabolic steroids on
women in particular need further monitoring, although oxandrolone
is reputed to have few masculinizing effects.

Anabolic steroids such as deca-durabolin have become popular as an
underground therapy among people with AIDS. Many feel that these
compounds work much better when accompanied by a rigorous
exercise program. Future studies should be conducted to evaluate the
combination of anabolic steroids with growth hormone and
testosterone replacement. The ideal therapy may well be an
individualized one that includes hormone- and cytokine-modulating
agents as needed but starts with such simple supportive measures
as exercise and food supplements.

Cytokine Modulators

Pentoxifylline is a medication for blood circulation disorders. It
also inhibits the activity of TNF and might in this way help reverse
wasting syndrome. An NIH-sponsored study has found that after
eight weeks on pentoxifylline, triglycerides (lipids) in blood serum
dropped significantly and TNF production went down.[10] Researchers
at the Veterans Affairs Hospital in Brooklyn, New York studied the
drug's effect on wasting syndrome in patients with AIDS but were
not able to detect any weight gain or reversal of wasting.[11] Another
recent study found that pentoxifylline at a dose of 800 mg three
times daily did not affect the T-cell counts, viral load or TNF in
eight patients treated for three weeks.[12]

Thalidomide is enjoying a revival as a TNF blocker. Recently, two
separate studies, one in France and another at Rockefeller University
in New York City, have shown significant weight gain in patients
receiving thalidomide. Thalidomide's abilities in this area are now
the subject of further study. For the latest results, see the article on
the AIDS Conference.

OP-1, a mixture of polypeptides, glycopeptides and glycosides, is
another reputed TNF inhibitor. Its developer, Omega
Pharmaceuticals, is just now beginning clinical trials of OP-1 for
AIDS-related wasting.

Malabsorption

Cells in the GI tract are particularly prone to damage during HIV
infection, and this results in reduced absorption of nutrients. The
HIV virus itself, intestinal parasites, and colitis induced by
cytomegalovirus (CMV) are the main sources of tissue damage. The
diarrhea connected with these conditions also may result in
malabsorption. Fat, carbohydrate, protein and micronutrient (vitamin
and mineral) malabsorption can occur. Malabsorption may also be a
condition that pre-exists infection with HIV.

Infection by intestinal parasites triggers diarrhea and
malabsorption in persons with AIDS by causing atrophy of the villi
- the small threadlike projections on the interior of the small
intestines which absorb nutrients when working properly. Given the
variety of intestinal parasites, electron microscopic analysis of
intestinal biopsy is required for a conclusive diagnosis. This
procedure is both uncomfortable and expensive. It is also difficult to
perform and may be unavailable in many places.

The protozoa Cryptosporidium parvum, the most commonly identified
parasite in people with AIDS, causes massive secretory diarrhea.
Paramomycin (Humatin) at 500 mg four times a day has
demonstrated positive results in some patients although relapse is
common after the drug is discontinued.[14] For persons with a more
mild infection, a lactose-free, low-fat diet with a high calorie,
protein-rich fluid supplementation is helpful. The large amounts of
sugars or long-chain proteins found in some nutritional drinks tend
to engender bloating and heightened diarrhea. Persons with severe
untreatable diarrhea may also require parenteral (intravenous) fluid
administration to maintain a normal state of hydration and
electrolyte balance.

Among the drugs under investigation for cryptosporidiosis is
intravenous azithromycin. This formulation of the drug is available
directly from the manufacturer, Pfizer, on a compassionate use
basis (call 800/742-3029 for further information). Side effects of
IV azithromycin include nausea and abdominal pain. Oral
azithromycin failed to show an effect on the frequency of bowel
movements, parasite shedding in the stool or overall clinical
response in a placebo-controlled study of 90 patients with
cryptosporidiosis conducted at Cornell Medical Center.[15]

Another anti-crypto agent in development consists of concentrated
antibodies derived from cow's milk. Bioimmune Systems of Salt Lake
City is just beginning preliminary human trials in HIV-negative
individuals of its oral, milk-derived antibody product, known as
Immuno-C. An efficacy trial for 40 people with AIDS-related
cryptosporidiosis is expected later in the fall and will include six to
eight sites around the country. More information may be obtained by
calling Joy Erickson of Bioimmune Systems at 801/582-2345.

A second cow's milk preparation is called CryptoGAM. It is
manufactured by Immucell and licensed by Univax. CryptoGAM failed
as an oral agent in several early trials apparently because it was
broken down in the stomach before it reached the intestines. A new
open label trial is currently being conducted by Louis Fries, M.D.,
from Univax. Very high dose CryptoGAM (40 grams per day) is
introduced directly into the duodenum via a nasogastric tube.
Patients interested in the trial can contact Dr. Fries at 301/770-
3099.

Microsporidia (Enterocytozoon bieneusi or Septata intestinalis) is a
second common GI parasite in people with AIDS. Infection can cause
diarrhea and decreased intestinal absorption.[16] The drug albendazole
has shown some promise and is currently the subject of an NIH-
sponsored trial. A preliminary report on eight patients from Dr.
Dominique Anwar of Grady Memorial Hospital in Atlanta indicates
that atovaquone (an approved treatment for pneumocystis
pneumonia) may be effective in reducing diarrhea.[17]

As a preventive measure, HIV-infected people with low CD4 counts
should be extremely careful about the water they consume. There are
only three acceptable forms: distilled, deionized or boiled. Water
filters, standing water (wells), spa waters and bottled spring water
can be contaminated with intestinal parasites. Ice cubes and soda
fountain-type drinks which mix tap water with syrup can also be
contaminated. Use distilled, deionized or boiled water in all foods
that will not be cooked and require water for their preparation.
Because even the smallest amount of contaminated water can cause
infection, fruits and vegetables rinsed with tap water could be a
source of parasistes.

Nutritional Support

Nutritional support is very important for individuals with HIV
infection. Anabolic drugs will have little effect without sufficient
diet. Studies also indicate that diets high in protein and complex
carbohydrates, moderate in fats and sugars are important for good
immune function.

Use of nutritional drinks such as Nutren, Ensure Plus, and Sustacal
can increase caloric intake for individuals who are having trouble
consuming enough calories. Because both individuals' needs and the
products' compositions vary, one supplement may be better suited
than another for a particular situation. Patients should consult their
physicians or a nutritional counselor before adding nutritional
drinks to their diets. Little data from controlled trials exist, though,
so it is difficult to assess the actual benefit of supplementation.
Lipisorb is a food supplement containing medium chain triglycerides
that may benefit patients with fat malabsorption. Elemental
(predigested) diets are comparatively easy to absorb in the GI tract
and reportedly have helped lessen diarrhea and stabilize weight.[18]
In patients unable to eat, data from two studies suggest that enteral
gastrostomy feeding (feeding through a tube placed directly into the
stomach through the skin) can result in weight gain and increased
lean body mass.[19]

Total parenteral nutrition (TPN) is a form of liquid nutrition infused
directly into the bloodstream. Studies indicate that patients
receiving TPN gain significant amounts of body cell mass and weight
if they are free of systemic infections. Other studies have shown
that administering TPN during secondary infection can increase
weight gain and improve the quality of life by improving the
individual's ability to fight infection.[20] Investigators also have
reported that TPN has favorable effects on immune cell
responsiveness.[21] But TPN can cost up to $13,000 a month in a home
care environment. It is usually used to support someone through a
limited period of acute illness but may be required for more lengthy
periods.

Exercise

Exercise can promote protein formation in tissues throughout the
body. It is a helpful therapy when physical health permits. To build
up lean body mass, resistance exercises (such as weight lifting) are
more important than aerobic exercises, although aerobic exercise
can also be beneficial. Exercise promotes muscle formation by
increasing the number of testosterone receptors. Proper timing of
food intake is also important in weight lifting. It is a good idea to
eat well but not immediately prior to lifting weights and to eat a
high protein food one to two hours after lifting.

Conclusion

A variety of therapeutic strategies are available for different
aspects of HIV-associated wasting. There is a strong correlation
between proper weight, good nutritional status and survival.[22]
Individuals should chart their weight, noting any significant change,
and physicians should take determined steps to diagnose and treat
major weight loss. Correct diagnosis and aggressive treatment can
improve quality of life and prolong survival.

1 Kotler DP et al. American Journal of Clinical Nutrition. Sept 1989;
50(12):444-7.

2 Lombard RP et al. Clinical Immunology and Immunopathology. 1989;
50:374-84.

3 Jones PD et al. Journal of Acquired Immune Deficiency Syndromes.
Dec 1992; 5:1266-71.

4 Landman A et al. Thirty-second Interscience Conference on
Antimicrobial Agents and Chemotherapy. Oct 1992; abstract 568.

5 Coodley GO et al. Journal of Acquired Immune Deficiency
Syndromes. Jan 1994; 7(1):46-51.

6 Flynn N et al Eighth International Conference on AIDS Jul 1992;
8(2): B205. abstract PoB3687.

7 Grunfeld C et al. Eighth International Conference on AIDS Jul 1992;
8(2): B230. abstract PoB3835.

8 Krentz AJ et al. Journal of Acquired Immune Deficiency Syndromes.
Mar 1993; 6(3):245-251.

9 Mulligan K et al. Journal of Clinical Endocrinology and Metabolism.
Oct 1993; 77(4):956-62.

10 Dezube BJ et al. Journal of Acquired Immune Deficiency
Syndromes. Jul 1993; 6(7): 787-94.

11 Landman A et al. Thirty-second Interscience Conference on
Antimicrobial Agents and Chemotherapy. Oct 1992; abstract 568.

12 Mole L et al. Journal of Acquired Immune Deficiency Syndromes.
May 1994; 7(5):520-1.

13 Lahdevirta J et al. American Journal of Medicine. Sept 1988;
85(3):289-91.

14 Armitage K et al. Archives of Internal Medicine. Dec 1992;
152(12):2497-9.

15 Soave R et al. Thirty-third Interscience Conference on
Antimicrobial Agents and Chemotherapy. October 1993; abstract
405.

16 Hecker LM et al. Nutrition Reviews. Nov 1990; 48(11):393-401.

17 Torres G, personal communication.

18 Hickey MS. Surgical Clinics of North America. Jun 1991;
71(3):645-64.

19 Kotler DP et al. American Journal of Clinical Nutrition. 1991;
53(1):149-54.

20 Campelli A et al Eighth International Conference on AIDS. Jul
1992; 8(2): 63.

21 Singer P et al. Journal of Parenteral and Enteral Nutrition. Jan-
Feb 1991; 15(1):75-9.

22 Guenter P et al. Journal of Acquired Immunodeficiency
Syndromes. Oct 1993; 6(10):1130-8.

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

Nutritional and Wasting Reports at the Tenth International Conference
 by Dave Gilden

Although the Tenth International Conference on AIDS in Yokohama
last month was particularly poor in information about the
nutritional aspects of AIDS, researchers did present several
significant reports on treating AIDS wasting syndrome.
Morris Schambelan, M.D., of the University of California San
Francisco described very positive results from a trial utilizing
recombinant human growth hormone (rHGH) produced by Serono
Laboratories.[1] Although rumors about this trial had circulated
before, Dr. Schambelan's account was the first official disclosure of
the data, which covered an initial twelve weeks of placebo-controlled
observation and up to two years of further follow-up in which all
trial participants received rHGH.

In the trial's first phase, the 90 trial participants receiving human
growth hormone (at a rate of 0.1 mg per kilogram of body weight)
gained an average of 1.5 kilograms. Their lean body mass went up
three kilograms, and they lost 1.5 kilograms of fat. These people's
treadmill performance also increased ten percent. A full quality of
life assessment has yet to be done. In comparison, the 88 people
originally on placebo at first gained a pound in weight on average,
but by the end of the twelve weeks, their weight was back to
baseline.

These figures suggest that rHGH works as expected, by reorienting
the body's metabolism to building protein stores and breaking down
fat rather than just adding weight. During the extended follow-up
period, trial participants continued to regain weight, with some
increasing by more than twenty pounds to reach their pre-illness
mass. Since human growth hormone is very expensive to produce, the
question now is whether the extra weight and lean tissue can be
maintained if therapy is stopped.

Dr. Schambelan further noted that levels of insulin-like growth
factor (IGF) rose substantially during the first twelve weeks of
rHGH therapy. Much of growth hormone's effect may be due to IGF.
But in another presentation at the conference, researchers from
Genentech, Inc. reported negative results from a trial using small
amounts of its version of rHGH plus IGF.[2] The effects on 52 trial
participants appeared to be minimal after six weeks, and Genentech
says it has no plans for further trials concerning wasting syndrome.

A cheaper alternative to human growth factor and insulin-like
growth factor may be thalidomide. Thalidomide interferes with the
production of tumor necrosis factor (TNF), excessive amounts of
which are suspected of accelerating weight loss as well as HIV
replication. In a small study conducted in Mexico City,[4] an average
weight gain of eight percent was recorded after twelve weeks on
thalidomide, compared to an average loss of eight percent in the
trial's placebo arm. A similar study conducted in Thailand[3] found
that trial participants increased their weight by 4.5 percent after
21 days. Nearly half the people in the Thai trial also had
tuberculosis, which like HIV is known to cause very high TNF
production. Neither trial could measure any effect on HIV levels or
CD4 counts. The trials also did not collect detailed body composition
data.

(A trial of thalidomide for HIV wasting is just getting under way at
Rockefeller University in New York and several other sites around
the country. Note that because of thalidomide's notorious history of
causing birth defects, women "of child-bearing potential" have been
excluded from thalidomide trials. This is an issue that raised
considerable controversy during one of the Conference sessions.)
The necessity of analyzing body composition and not just weight
gain was underscored by two posters at the conference concerning
the appetite stimulant Megace.[5,6] Both studies found that although
Megace triggered significant weight gains in men with HIV-related
wasting, most or all of that gain was composed of fat. The lack of
increase in lean tissue may be at least partly explained by the
reduction in serum testosterone associated with Megace that the
first study detected.

Another nutritional strategy that received some limited support at
the Tenth International Conference on AIDS was vitamin
supplementation. An eight-year observation of 280 gay or bisexual
HIV-positive men forming part of the United States' Multicenter
AIDS Cohort Study (MACS)[7] tracked survival rates according to
intake of specific vitamins. High intakes of vitamins B1, B2, B6, C
and niacin were associated with decreased mortality rates. In
particular, those who at the beginning of the study were taking
vitamin B6 supplements equal to at least two times the RDA had a
40 percent lower death rate during the eight-year period. Zinc
supplementation, on the other hand, was associated with an
increased death rate.

1 Schambelan M et al. Tenth International Conference on AIDS
Abstract Book. Aug 7-12 1994; II:35, oral presentation 432B.

2 Bukar JG et al. II:223, poster PB0903.

3 Reyes-Terçn G et al. II:65, oral presentation 536B.

4 Klausner JD et al. I:221, poster PB0312.

5 Engelson ES et al. II:222, poster PB0900.

6 Stute A et al. II:223, poster PB0907.

7 Tang A et al. II:220, poster PB0894.

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Donald Kotler on the Gut, Inflammation and HIV

> Donald Kotler, M.D., is Associate Professor of Medicine at Columbia
University College of Physicians and Surgeons. He is one of the
world's foremost experts on AIDS-related gastrointestinal
conditions and weight loss. Over the years he has co-authored more
than 100 reports related to AIDS and HIV. His current AIDS research
concerns malnutrition, protein loss, anabolic agents, infections of
the digestive tract and the role HIV itself plays in digestive
ailments. <

Diagnosing GI Disorders

TI: Are there things that concern you about how people are being
treated for HIV-related gastrointestinal disorders?

Kotler: Yes. If a doctor says, "You have malabsorption," and the
doctor was smart enough to test for it specifically and find it, then
I think the patient should listen to whatever the doctor says. Most
doctors don't know malabsorption from hemorrhoids, and diarrhea
becomes a common wastebasket designation. Diarrhea comes from
the small intestine or the large intestine. And when it comes from
the small intestine, it may well be malabsorption. When it comes
from the large intestine, it may well not be malabsorption.
If you're trying to feed someone, it is absolutely important to know
whether the small intestine is working or not. Most doctors ignore
that. If you have a doctor who ignores it, then you probably can't
trust what he or she is going to say in terms of nutritional advice. If
you have a doctor who does not ignore it and actually makes that
determination, that's probably a doctor who will refer you to a good
nutritionist.

The biggest mistake that I've seen is that patients with
malabsorption are told to eat as much as they want of anything that
they want to try, to maximize the calories that go in.

TI: Why is that bad?

Kotler: Usually you maximize the symptoms that occur and in
maximizing the symptoms, there is a big push to not eat. So patients
are left in a horrible situation of being very hungry, but knowing
that whatever they eat is going to give really bad symptoms.
In fact, if you look at the typical malabsorption syndromes, the
amount of calories that are malabsorbed are not huge. People should
just be able to eat a little bit more and overcome that. But they do
not, either because the symptoms prevent the eating, or there are
unconscious signals not related to symptoms which prevent food
intake.

So in fact, the typical malabsorber doesn't eat enough. And the richer
the diet you give them, the less they end up eating, especially of
calories that will be absorbed. Someone who has a malabsorption
syndrome and who starts the day with a big ice cream soda because
it has a lot of calories is probably going to have great difficulty
eating lunch at all and may not get any appetite back until late at
night.

TI: So, often people are not getting proper workups?

Kotler: Right. And if they do have an assessment which shows
malabsorption, they need to be treated with a special diet, and even
that might not even work. For that, I often have to resort to
intravenous feeding, but I'm now doing a study to see if I can get
away from intravenous feeding.

TI: What does a patient need to know about getting a good GI workup?

Kotler: The workup has to lead to some answer. If it doesn't, then it's
not an actual workup. A patient who has a problem and goes for an
evaluation and is told simply, that it is not A, B, or C - that patient
hasn't finished their evaluation. It's very important to know what or
at least where it is. There must be an explanation for the symptoms
whether or not it can be treated.

Sometimes, there is damage and you can't find the causative
organism, but you can at least localize the damage. And you treat
based upon localizing the damage because you might not be able to
cure the underlying process -

TI: What does "localize the damage" mean?

Kotler: Cryptosporidiosis affects the small intestine and is causing
malabsorption. Since we can't cure cryptosporidiosis, we try to
treat the malabsorption to minimize the symptoms and improve the
nutrition. There are people who have small intestinal damage that's
as bad as you'd see by cryptosporidiosis, but there's no bug.
The evaluation ends up saying, "You don't have crypto." Well, that's
not good enough. The evaluation should end up saying, "You have no
cryptosporidiosis, but you have damage to your small intestine that
gives malabsorption, just as if you did have crypto." The patient can
be treated nutritionally, just as if he had cryptosporidiosis because
the damage has been localized in the small intestine.

TI: So the idea is to correct for the malabsorption?

Kotler: If the damage is such that it prevents the proper digestion of
lactose and fat, the idea is to remove lactose and fat from your diet.
It's not to add lactose and fat just because they are great sources of
calories and you should at least absorb something - that doesn't
work. And it is certainly not enough to say, "Well, there's no
cryptosporidiosis. Good bye."

TI: You have said that you try to get people off of IV feeding. How do
you do that?

Kotler: By adjusting the diet. If somebody has intestinal damage and
can't deal with food given the regular way, the two possibilities to
get around the problem are to give food in a different way -
intravenously - or to give a different food.

To give a different food means to give medium chain triglyceride,
rather than long chain fats; less complex carbohydrates rather than
more complex carbohydrates; no lactose and use sugars that are
much easier to digest and absorb. And then see if this changed diet
is as good as feeding intravenously. We know that feeding
intravenously can improve nutrition.

Inflammation and HIV

TI: What behavioral things can people do to really extend their life?

Kotler: Oh, I would look at it the other way around. Patients should
avoid certain things - like being reinfected over and over again.

TI: Do we know for a fact that "reinfection" [with HIV] occurs?
Kotler: No, we don't know anything. We don't know the effect of
inflammation. But the guy who gets gonorrhea twenty times in the
course of a year-and-a-half and each time inflames his intestine,
which happens to have HIV in it, and the inflammation stimulates
the intestine and drives the T-cells into the intestine to fight the
inflammation where they get lost - I truly think that that sped the
disease along in the past. Do I know that? No.

TI: Is the inflammation of the intestines central to HIV progression?

Kotler: Well, this is my personal and speculative view of disease
progression:

Take it from the intestine and to a different, but similar group of
structures - the mucous membranes. They have facets that are
different than any place else in the body. They're an interface
between a very clean and pristine, internal environment and a filthy,
contaminated, external environment. Think about the rectum, the
vagina, especially the cervix. The mouth isn't so much better. It's a
very fine membrane separating an immune system from bugs of all
types.

The body, over millennia, has learned to react promptly to any type
of invasion of organisms. Membranes of bacteria or other organisms
are perhaps the strongest immune stimulators you could ever find.
Any break in the lining of a mucous membrane will tend to bring
those bugs in direct contact with the immune system. So the
inflammation would be prompt and strong. That wouldn't happen in
the kidney or the adrenal gland because there's no bugs around to
cause that rapid stimulation. But in the intestine, in the other
mucous membranes, they are there all the time.

So if anything like gonorrhea - or a cold - breaks the lining and
opens up its pores for permeability and schmutz gets in and the body
responds with a very strong inflammatory response, that
inflammatory response will, at the same time, recruit lymphocytes
that activate each other. It becomes self-perpetuating. So the
inflammation reproduces the initial insult - weakening of the
barrier. As long as the inflammation is there, the barrier will
continue to be weakened. Stuff will continue to get in. The
inflammation will continue to go on. So having bugs around and a
weak barrier becomes like an amplifier.

Now, the normal immune system has shut-off mechanisms. For every
yin there's a yang. For everything that turns something on, there is
something that will turn it off again. And early in the disease, this
may happen - the immune system is intact enough so that it will
limit [its reaction] and localize it and shut it off. There may come a
point during the weakening of the immune system where the turnoff
switch is missing, and then there's nothing to hold it back.
Think of it. You salivate because you get some stimulus. Unless there
was something to shut that off, once you started salivating, you
would just continue to salivate until you dehydrated yourself and
died. You need the shut-off valve to make you stop salivating.

TI: So you want to avoid getting any additional bugs that survive.
Which raises the common question, should people not be drinking
water in major urban areas, such as New York City?

Kotler: I'm not sure that bottled waters are better. I recommend a
good filter that gets changed often. You usually won't see chronic
cryptosporidiosis unless the CD4 cells fall below 200.

Boiling is okay [but] difficult to do, to make big boiled water tanks. I
suspect that most bottled water is free of contamination. But it is
insufficient if you wash your lettuce or make your ice from tap
water.

TI: What about salad bars and fresh vegetables?

Kotler: Stay away, unless you're going to clean them with a water
source that's okay.

There's a lot of stuff written. And it's best coming from dietitians.
Your cutting board shouldn't be wood, so that stuff gets caught in it.
If you're cutting raw meat, use different cutting boards for other
foods.

Therapies for HIV-Wasting

TI: What role do anabolic hormones, like testosterone and
oxandrolone [a synthetic testosterone-like steroid with reduced
masculininzing effects], have in therapy?

Kotler: It seems clear that anabolic agents, under certain
circumstances, can allow people to build back their protein and
muscle stores, and in doing so, feel a whole lot better. Low
testosterone levels have to be looked at as a natural response to
chronic inflammation.

Anabolic steroids shunt the amino acids back to the muscles to make
them grow. The body can't be asked to do two things at once - to
give up its protein [to support the inflammatory response] and at the
same time make bigger pecs. Now, it may not be so important any
more, since God's Love We Deliver [a New York City meal delivery
group] can give you all the amino acids you need. But the body's
metabolic machinery was set up in a different millennium [when
protein and energy sources were scarce].

TI: What about exercise?

Kotler: Absolutely. You can perhaps maximize the effect of an
anabolic steroid by using resistance-training exercise. On the other
hand, you might be able to get pretty far without using any anabolics
at all and just using resistance-training exercise.

TI: And what role can recombinant human growth hormone play?

Kotler: That's another anabolic. I think in both cases, the more you
use, the better response you get, and that you're going to have to
supply the energy and the nutrients along with it to have them work.
Then after that, I don't know.

TI: Can women use anabolic steroids?

Kotler: There's only one that's ever been recommended in women
because the others appear to have too much androgen activity, but
I'm not really sure. Estrogen and progesterone do not seem to act as
anabolic steroids in women. It's really unclear what is an analogous
anabolic agent for women.

In fact, it may go back to a chemical that was bandied around in
AIDS circles years ago and then pretty much neglected recently -
that's DHEA [dehydroepiandrosterone]. DHEA is a precursor to the
anabolics and it may be that one of the reasons the anabolic levels
fall is because DHEA metabolism is diverted to something else
rather than anabolics. Perhaps, if you're given DHEA, you can
overcome that.

The people who did DHEA studies did nothing to see if it had an
anabolic effect. Although some people taking DHEA looked pretty
good, it was all being looked at as an antiretroviral agent or an
immune modulator. It didn't really show very much that way, but it's
conceivable that it is an anabolic agent. And it might well be that
early on, that might be the best one to use, but no one studied it that
way.

Reducing the Inflammatory Response

TI: Let's talk more about inflammation. Is there anything that
patients could do to cut down on inflammation in a beneficial way?
Kotler: You can cut down on inflammation with an anti-inflammatory
agent - we're doing a study right now with aspirin. The rationale is
that several of the inflammatory signals directly stimulate HIV.
Tumor necrosis factor [TNF] and interleukin-1 [IL-1], which are the
messengers of the inflammatory response, happen to activate HIV.
A number of compounds, like aspirin and thalidomide, inhibit
inflammatory signals. There are many anti-inflammatories, some
may be perfect, some awful. There's a difference between the
aspirin-type and the Motrin-type agents.

Another consequence of inflammation is what's called "oxidative
stress," which uses up the body's naturally available antioxidants.
There are people who are using antioxidants in an attempt to
compensate for that loss.

It may be that the body's oxidative balance relates directly to how
HIV grows, so that people who take salicylate [aspirin] or
antioxidant therapies - vitamin E or C - may inhibit the virus to
some extent.

TI: What is your present research with anti-inflammatory therapies?

Kotler: Our anti-inflammatory agent study originally was related to
inflammation and HIV expression in the gut. We found that aspirin-
like anti-inflammatories seemed to dampen both the inflammation
and its symptoms and decrease the expression of HIV viral proteins
in the GI tract.

I was unable to get further funding to study this in the gut and
instead got funding to do the systemic study of aspirin in a group of
HIV-infected people. That's being done at Community Research
Initiative on AIDS [CRIA] in New York.

TI: When do you expect to have some data from the aspirin study?

Kotler: Don't know. The techniques we were using were insufficient
to show the changes that we were looking for. We are now using a
much more sensitive assay to measure viral load (the branched chain
DNA), but only a few people have started the study and we want at
least 50. We've already screened 35. With a more sensitive assay we
probably would have needed 25 or 35 in the study. Once the study
accrues, it's only a two-month study.

It's very difficult to get funding for an aspirin study. There's no
patent at the end of the road. Nobody's going to make a lot of money,
so the research money is limited.

TI: The dose being used is equivalent to how many aspirin per day?

Kotler: Twelve, like the arthritis dose. It's big-time aspirin as a
drug, leading to [high] blood levels, not aspirin as a headache remedy.

TI: What do you think aspirin does, specifically? What's its mode of
action?

Kotler: A recent paper in Science says it inhibits a cellular activity
promoter - NFkappaB - that is turned on by TNF and other signals.
It also may be a free radical scavenger and act as an antioxidant.
Certain salicylates do that. But in fact, I really don't know how it
might work. People have been using aspirin for hundreds of years,
and the mechanism of action was worked out, I believe, in the early
seventies.

Reforming Research

TI: Let's talk about antiretroviral therapy. What do you tell your
patients?

Kotler: My own feeling is that people should be on therapy early, that
if they're willing, an antiviral therapy can be part of that, and that
consideration of a combination therapy should come up early rather
than late.

TI: What other therapy would be part of the combination, if not an
antiviral?

Kotler: Besides behavior modification, good diet, and lots of sleep
and stress reduction, I often use NAC [n-acetyl cysteine, a precursor
to the cellular antioxidant molecule glutathione] and moderate doses
of vitamins and minerals, including the antioxidants. There's a little
bit too much "either/or" in AIDS treatment these days. You know
people are put on AZT and just kept on it until they turn terrible and
their doctors are virtually forced to change therapy out of
embarrassment and shame.

TI: Where should we be putting our AIDS research dollars?

Kotler: Alternate hypotheses for pathogenesis. The hypotheses of the
effects of inflammation. The effects of oxidative stress. They're
here. There are drugs on the shelf that can be used right now if we
knew they were good. These therapies took the back seat to the
antiretrovirals. So a huge amount of data was, and still is, being
generated about antiretrovirals in ways that're unbelievably
confusing.

We've been let down. After all this time, what's the proper dose of
AZT? What's the blood level you really need? Do you really need a
blood level or do you need a level in CD4 lymphocytes? If so, what is
that level? Basic answers aren't known.

TI: Why is it so hard to get studies funded?

Kotler: They're expensive. Somebody has to lay out the money for
them. And the people who were making the decisions, came down
hard on the side of the chemotherapeutic agent and antiretroviral
agents, seeking the precise molecule to take out HIV altogether and
bring about a cure.

They're still looking at new single agents that will hold HIV off
altogether, indefinitely. And every new drug that comes out, it
seems like it's being looked at in exactly the same way.
Can you imagine a baseball game where the home team is down three
to two in the sixth inning, and everybody tries to hit a home run, but
they all strike out? Nobody tries to get to first base. That's my view
of AIDS drug development. Everybody is looking for a $2-billion a
year drug and nobody is looking for things that might just help.

TI: Whose responsibility is it to change that - private industry or
government?

Kotler: I don't know. Probably the patients. You've been pushing
things along pretty well up to now. If there's a change, you're
probably going to have to be the ones to force the change. I wouldn't
leave it to the people who are now in charge because they benefit
from the status quo. From their point of view, things might be going
okay. But from a different point of view, things are not going so well
at all.