Software Vault: The Gold Collection/Software Vault - The Gold Collection (American Databankers) (1993).ISO/cdr13/atn168.zip/ATN168.TXT

Text File | 1993-06-06 | 51KB | 1,060 lines

Subject: AIDS TREATMENT NEWS #168
Date: Feb  5 1993 (1058 lines)

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J O H N   J A M E S  writes  on  A I D S
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Copyright 1993 by John S. James;
permission granted for non-commercial use.

AIDS TREATMENT NEWS Issue #168, February 5, 1993
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:  [items are separated by "*****" for this display]

Sulfadiazine Shortage:  Buyers' Club Has Drug
TP-5:  Thymus Hormone Trial Suggests Benefit
Clinton:  Setting New Directions on AIDS
Political Action Proposal:  Cultural Change for Grassroots
   Electronic Democracy
New CDC Definition Now in Effect, But Confidentiality
   Questions Remain
CMV Experimental Treatment Overview, Part II
Announcements



***** Sulfadiazine Shortage:  Buyers' Club Has Drug

by John S. James

     Due to a production shutdown at the only U. S. manufacturer,
a critical shortage of the drug sulfadiazine has developed in New
York, Boston, and many other parts of the U. S. Sulfadiazine is
part of the first-line treatment for toxoplasmosis, and a
shortage could become life-threatening to patients.  The U. S.
Centers for Disease Control (CDC) has obtained a small supply
(enough for fewer than 70 patients), and is rationing it for
emergency use, especially for infants with congenital
toxoplasmosis.  The CDC is seeking FDA permission to import more
from Canada; but even when it obtains an adequate emergency
supply, release of the drug will require considerable paperwork
for each patient, which is usually impossible for public clinics.
It could take up to a year for regular commercial supplies to be
re-established.

     The good news is that the shortage is only in the U. S. ;
elsewhere, the same drug is plentiful and inexpensive.  The
products available abroad have not been explicitly approved by
the FDA for U. S. sale, and there is no available procedure to
give emergency permission for their importation.

     Physicians and patients should know that sulfadiazine from
Europe is available through the PWA Health Group, a New York
"buyers' club" which has helped people import personal-use
quantities of AIDS medications not available in the U. S. The
organization will ship the drug.  It requires a prescription, and
the use of its own order form.  For more information, call the
PWA Health Group at 212/255-0520.

Trying to Fix the Problem

     Similar shortages have recently occurred with other critical
drugs:  streptomycin for multi-drug-resistant tuberculosis, and
nitroglycerine tablets for certain heart conditions.  On January
12 the New York Times quoted FDA Commissioner David Kessler as
saying that all three problems had been solved. But on January 29
and February 1 AIDS TREATMENT NEWS found that the CDC believed
that it had submitted all necessary documents and was waiting for
FDA action, while the FDA believed that it needed more documents
from the CDC before it could process the application.  Each
agency appears to be waiting for the other.

     The mechanism the agencies are using to allow the CDC to
obtain more supplies for its emergency program (which distributes
the drug free) is the "treatment IND," an FDA procedure intended
to allow early access to experimental drugs; it is being used
here for a drug approved for 40 years, simply because no other
mechanism is available.  The problem is that this procedure will
only provide the drug on a patient-by-patient basis, with
considerable paperwork each time.  Many physicians, especially
those not familiar with AIDS or those practicing in understaffed
public clinics for underserved populations, will not use this
method for getting sulfadiazine specially shipped from the CDC,
and instead will prescribe other drugs which are less desirable.
The PWA Health Group is trying to find a way for the CDC to
release bulk supplies of the dg directly to hospitals andlinics.

Comment

     The obvious solution would be for the FDA commissioner to
give emergency permission to allow the usual commercial
distributors of the drug to import sulfadiazine which has been
approved for sale in certain countries known by the FDA to have
adequate quality standards.  We do not know what regulations or
laws, if any, would need to be changed to permit the FDA to do
this.  But similar shortages have already occurred with several
drugs, and the problem potentially threatens patients with many
different diseases -- important reasons to make the changes
required to respond effectively to present and future shortages
as they happen.

***** TP-5:  Thymus Hormone Trial Suggests Benefit

by Dave Gilden

     Evidence that the thymus gland suffers extensive damage
during HIV infection has led to research on using thymus hormone
replacement therapy as a means to counteract the damage.  Thymus
hormones are proteins that affect the development of immune
system T-cells in the thymus gland. They also enhance immune
function in mature T-cells in the blood and lymph.  While their
exact role in AIDS therapy is unclear, various experiments
suggest that injecting thymus hormones can increase the numbers
of the various T-cell subpopulations.  By enhancing the activity
of the immune system's killer cells, they may increase these
cells' ability to seek out and destroy cells infected by HIV.

     Three injectable thymus hormone derivatives are now in
formal trials as AIDS therapies -- TP-5 (thymopentin), THF-g2
(thymic humoral factor) and thymosin-alpha1.  No toxic effects
have been noted for any of them.

     Despite years of interest in using thymus hormones for AIDS,
hard data has been lacking.  Now, investigators claim they have
data showing that injecting TP-5 three times a week confers some
protection against progression of HIV disease.

     "In my mind, there is very strong evidence that the drug
prevents progression to AIDS-related conditions," said Marcus
Conant, M. D., a San Francisco AIDS physician and researcher.

     The latest TP-5 study, conducted by Dr. Conant and others,
compared the drug against a placebo for 48 weeks in 354
asymptomatic HIV-positive persons.  This study was double blind
-- no one knew who was getting TP-5 and who the placebo.  All the
study participants took AZT, and they started out with T-helper
cell counts of between 200 and 500.

     A close review of the data by AIDS TREATMENT NEWS verified
that something useful does seem to be happening:  For those study
volunteers who had been on AZT for longer than six months,
protection against early symptoms of HIV infection was apparent,
though hard to quantify exactly.  In this 235- person subgroup,
14 volunteers on placebo developed symptoms versus only four of
those on TP-5.

     But major questions persist as to the extent of TP-5's
beneficial action.  An attempt by Johnson & Johnson, TP-5's
sponsor, to accelerate FDA approval of the substance was rebuffed
when the company sat down with agency officials in December.

     The corporate push began when the study was terminated four
months early by an independent, ad hoc Data and Safety Monitoring
Board (DSMB) reviewing the interim figures.  Early termination by
a DSMB usually occurs because a study has already yielded
decisive results.  The DSMB's decision on TP-5 sparked loose talk
of an impending step forward in AIDS care, similar to the
introduction of AZT for early HIV infection.

     But no dramatic statistical observations underlie the DSMB's
reasoning.  The board simply noted that the TP-5 trial was
dragging on for no reason.  It would take another four months to
collect the final five percent of the data without any chance
that the study's conclusions could be significantly altered.

     The DSMB noted that the data could be considered unreliable
in several respects:

     % The drop-out rate was rather high, 20 percent in both the
     placebo and treatment arms.  High drop-out rates distort
     study findings because the volunteers who are doing poorly
     or who suffer adverse effects from the experimental drug are
     most likely to be the ones who quit.  One of the FDA's
     requests to Johnson & Johnson was to perform an "intent to
     treat analysis" on the data.  Using this statistical method,
     the company will have to include the drop outs' experience
     over the 48 weeks as if they actually continued with the
     study.  We will then have a better picture of how well TP-5
     would perform under real conditions, in which patients
     frequently fail to follow prescribed treatments.

     % The clinical symptoms used to judge progression of HIV
     disease were limited and subjective.  The criteria required
     two of the following:  10 percent weight loss, temperature
     of 38!C for five consecutive days or any 10 days out of any
     30, unexplained diarrhea for seven out of any 30 days, just
     one episode of oral candidiasis, a single localized eruption
     of herpes zoster, or oral hairy leukoplakia.  Confirmation
     of symptoms was by clinical examination and patient report
     only; it is possible that some signs of immune decline were
     misdiagnosed or missed entirely.  And other disease episodes
     not on the trial's list would not be counted, even if they
     were severe.

     % There was also a T-helper cell criterion for progression
     of HIV disease -- to be counted as progressing, an
     individual's count had to drop below 200.  However, there
     was no difference at all in T-helper cell trends between the
     study arms.  Even in those with more than six months' use of
     AZT, T-helper cell counts held steady on average throughout
     the 48 weeks, no matter whether volunteers were on TP-5 or
     not.  Such a finding is at odds with the previous study of
     TP-5 as an AIDS therapy (published in AIDS, November 1992,
     pages 1335-1339).  That small study did find indications of
     T-helper cell protection using TP-5, but its volunteers did
     not use AZT or any other antiviral medication.  It may be
     that the effect of AZT in the current trial overwhelmed and
     hid any direct support TP-5 gives to T-helper cells.

     When looking at a summary of the symptoms volunteers
developed, we were struck by how much TP-5's observed benefit
depends on differences in the rate of occurrence of thrush and
oral hairy leukoplakia.  This limited difference has led to some
criticism in the AIDS activist community that TP-5 merely
represents an unnecessary alternative to simpler treatments for
these two diseases of the mouth.  But there is no reason to
believe that TP-5 has any direct activity against these
conditions; therefore, if it reduced their incidence, it probably
did so by strengthening the immune system, implying that the drug
did work as intended.  TP-5 seemed to make the biggest difference
for people who had used AZT for more than six months.

     Howard Grossman, M. D., a New York City physician who
participated in the TP-5 trial, commented, "Even if TP-5 only
does a little, everybody with HIV will be on it if the price is
low."  (Pricing is an issue because the effective dose of TP-5
costs about $100 per week in Italy, where the substance is
legally sold.)

     According to Robert Kniffen, a Johnson & Johnson
spokesperson, the company is now putting together an expanded
access program (which will probably be free for those eligible).
Dr. Grossman noted that there really is no reason why anyone
eligible shouldn't participate since TP-5 has no record of
adverse side effects.

     While the expanded access program is in operation, a
confirmatory study involving up to 1,000 people taking
antiretroviral therapy together with TP-5 or a placebo will be
carried out.  Two years will go by before TP-5 can be approved.

     Robert Kniffen summarized TP-5's current status in this
manner:  "Details of the confirmatory study and an interim
expanded access program are being worked out in consultation with
the FDA and the principal investigators.  The status of the drug
reflects the study data, which are unclear.  The trick is to get
clear-cut, definitive data."

Another Thymus Derivative

     Trials of other thymus hormone derivatives will also need to
show clear data on clinical improvement or viral load, since
these substances' effect on T-helper cell counts may not reflect
their total activity.  At Stanford University, Thomas Merigan, M.
D., is conducting a federally-sponsored (ACTG) trial combining
thymosin-alpha1 (a thymus hormone derivative), IL-2 (a substance
used by the body to stimulate T-cell growth), and the anti-viral
drug AZT.  Dr. Merigan will use his quantitative polymerase chain
reaction (PCR) technique to detect changes in volunteers' HIV
levels.

     Thymosin-alpha1 attracted Dr. Merigan's interest because one
preliminary trial in people with chronic hepatitis B provided
evidence that thymosin cleared that virus from the body.

     "Both thymosin and IL-2 affect lymphocyte maturation, but
thymosin works at an earlier point, so it may potentiate IL- 2's
action," Dr. Merigan explained.

     Dr. Merigan's study raises the possibility that thymus
hormone derivatives may work better in combination with other
immune modulators.


***** Clinton:  Setting New Directions on AIDS

by Keith Griffith

     What are influential voices in the AIDS community expecting
from the Clinton Administration?  To help answer this question,
AIDS TREATMENT NEWS spoke with a diverse segment of the national
AIDS leadership -- from a Nobel prize-winning scientist to one of
the most outspoken activists in the United States, from insiders
in the Clinton transition team to front-line physicians.
Everyone agreed that a Clinton Administration would be more
responsive than its predecessors; for some, this was more an
indictment of the Reagan/Bush years rather than an endorsement of
Bill Clinton. Melanie Thompson, M. D., principal investigator for
AIDS Research Consortium of Atlanta, echoed many others
interviewed when she said, "Not only is this a significant
opportunity, I think it is the only opportunity we have really
had in the twelve years of this epidemic."

Campaign Themes

     During the campaign the Clinton team issued a lengthy
position paper entitled, "Bill Clinton on AIDS.  " Less than a
week before the November election, the candidate delivered a
speech to a group in Jersey City, New Jersey, on the subject.
Both of these publicly delivered documents are at the centerpiece
of any discussion about what the new administration is expected
to deliver.  Among policy moves we may see from Clinton:

     (1) "Loud, clear, and consistent" leadership on all AIDS
     issues.  To carry this out, the president will appoint one
     person, an AIDS czar as he phrased it, "to oversee and
     coordinate all federal efforts related to this issue, a
     person with my ear, my attention and my support, with the
     power to cut through red tape and the mandate to get results
     as quickly as possible."

     (2) He will appoint a "high-level AIDS task force in the
     White House to coordinate a federal 'Manhattan Project,'"
     (referring to the intense scientific/technological project
     which developed the atomic bomb).

     (3) "Increase funding both for AIDS-specific and general
     biomedical research."  Furthermore, he stated, "I will not
     tolerate a business-as-usual attitude towards AIDS
     research." He called for an expansion of clinical trials
     including community-based trials and for the National
     Institutes of Health infrastructure to "be reorganized to
     streamline its AIDS research efforts, and to increase
     planning, efficiency, and communication."

     (4) Finally, the campaign promised a whole series of changes
     in the delivery of health care which will directly impact
     people living with HIV.  This included guaranteed access to
     prescription drugs and improved access to experimental
     therapies.

Transition Plans

     To outline the often-mysterious transition process before
Clinton's inauguration, AIDS TREATMENT NEWS spoke with Steve
Morin, Ph.D., long-time assistant to Congresswoman Nancy Pelosi
(Democrat, San Francisco) and one of the handful of people on
Capitol Hill working full time on AIDS.  During the transition,
Dr. Morin was assigned to the Health and Human Services
Transition Cluster Group.  While AIDS was not the focus of the
group, it was a top priority.  Morin offered this explanation of
what his group was charged to do regarding AIDS:  "First, we had
to identify issues that would require high-level attention in the
rst 90 to 180 days of the inistration.  There are a number of
policy issues that need to be reversed from the Reagan/Bush
years.  Then there were emerging controversies which needed to be
identified along with options available in dealing with them.
All of this was followed up with other groups on the transition
team such as the personnel department in selecting people for
posts or the budget group in revising numbers that will replace
the 1994 Bush budget."

     Morin told AIDS TREATMENT NEWS that this work was some of
the most satisfying he has experienced in public service.  "There
is a level of commitment in these people that would have been
unthinkable under Reagan or Bush.  This administration is
determined to address AIDS as promised."

The AIDS "Czar"

     The administration is now referring to this new position as
the Special Assistant to the President for AIDS.  Transition
member Steve Morin confirmed for AIDS TREATMENT NEWS that a
decision has been reached to keep this position in the White
House.  Morin says that the job description is under review. The
key issue right now in administration discussions is over whether
the Special Assistant will be primarily a policy position or more
a public spokesperson.  Dr. Thompson believes, as do many in the
community, that this job must not be reduced to "a public
relations figure, a mere figurehead. The choice for this position
will reflect the kind of direction Clinton intends to offer in
this epidemic."

     President Clinton pledged to appoint an AIDS czar who would
oversee all components of AIDS, not a scientist who would dole
out research grants.  This person will probably spend at least as
much time dealing with prevention campaigns and other pieces of
the AIDS agenda as with research.  Dr. Morin sees the Special
Assistant as someone who will facilitate cutting across
government agencies, for instance getting Immigration and
Naturalization talking with Health and Human Services.  He says
that "this doesn't mean this person is in charge of running all
AIDS programs in every branch of government.  It is a problem-
solving, leadership position."

     One additional appointment that should be announced by mid-
February is the position of Assistant Secretary for Health and
Human Services (HHS).  Candidates were being interviewed as we
went to press.  Morin believes that ultimately the person chosen
for this post will coordinate many critical AIDS programs at HHS.

Funding Levels

     According to an article in Nature (No. 356, April 16, 1992,
page 555), the federal government spends $70 billion annually on
science and technology, weighted heavily toward military research
and development.  The President agreed during the campaign that
this country's investment in research and development needed to
shift more towards civilian needs, including AIDS research.
Activists, taking their cue from the administration, are taking a
new approach to funding issues. AIDS activists have begun
demanding major increases in all biomedical research at NIH, with
a special recognition of extra funding needs for all life-
threatening diseases.  For the 1994 fiscal year activists and
lobbyists are calling upon Clinton to double the entire NIH
budget, including a sizable increase for AIDS.  The Clinton
administration will not release details of possible changes in
the 1994 budget until the State of the Union address in mid-
February.

     We asked Terry Beswick, AIDS Research Policy Analyst for the
Human Rights Campaign Fund and one of only three people in
Washington paid to lobby for research money on behalf of the AIDS
community, what to expect from Congress.  "Budget issues are
going to get worse.  Over the last two years, we saw
congressional funding for NIH drop below what even Bush
requested."  Beswick believes that Congress is going to be a
major obstacle not only in funding, but also in other AIDS
issues.  "Congress has long been our obstacle.  They have moved
far too slowly, and leadership hasn't come unless they were
dragged into it by sheer necessity."  Beswick added, "What we
need now is a groundswell of support for our position that there
even is a problem."

     Larry Kramer, one of the founders of AIDS street activism,
believes that what is most needed is not just more money, but a
greater willingness to take risks:  "To be gutsy doesn't cost a
lot of money.  Far from it.  But just to do things in ways that
haven't been done before tends to scare everybody."

[Part 2 of this article will examine ideas for improving the
organization of AIDS biomedical research.]


***** Political Action Proposal:  Cultural Change for
      Grassroots Electronic Democracy

by John S. James

     AIDS activist organizations could make a major contribution
to correcting a serious political weakness which is hurting the
fight against AIDS in federal, state, and local issues.

     The problem can best be illustrated with a non-AIDS issue in
the headlines last week:  whether openly gay soldiers should be
allowed in the U. S. military.  Opinion polls consistently showed
that the public was about equally divided on that issue, yet
phone calls to congressional offices were as much as 100 to one
against; this is why Congress has been hostile to the gay
soldier.  Clearly one side was far better than the other in
getting its supporters to contact their representatives.  It is
striking that the gay community, so excellent in getting to the
polls to vote in elections, is so poor in calling their
representatives when necessary.

     Since last year's presidential campaign and election, U. S.
political observers have noted an accelerating move toward a kind
of electronic plebiscite -- with talk-show formats which bypass
reporters, and instant "voting" through phone calls and other
means, becoming more important.  In this fast-moving forum,
issues may come and go in days, leaving lasting traces behind
them even as they are replaced by new issues.  This kind of
direct democracy is not necessarily good or necessarily bad.  But
both the gay and AIDS communities have had a serious cultural
weakness in this political forum -- the widespread reluctance of
people to contact representatives and other officials to make
their desires known.

     We believe that political success will increasingly require
all of the following:

     (1) Being right on the merits of the issues.  This includes
     integrating one's efforts with the public interest, so that
     one is genuinely pulling for the public interest, not only
     for one's own;

     (2) Successfully explaining and communicating the issues --
     including through coalitions with other groups which agree;
     and

     (3) Getting out the vote -- both at the ballot box (which is
     still the most important), and through phone calls and other
     contact with officials, as electronic plebiscites develop.

     Why are people reluctant to pick up the phone and tell their
public officials what they want?  There are several reasons:

     (1) In some localities such as San Francisco, many
     politicians already agree with the AIDS community on most
     issues, so people think calling is unnecessary.  That is a
     mistake; their representatives need to count the calls which
     support them, not only those on the other side.  The same
     logic applies in reverse when representatives seem
     unalterably opposed.

     (2) People feel they do not know enough to speak publicly on
     the issues.  But their representatives need their vote --
     yes or no on a current question -- not a speech or analysis
     for the busy telephone receptionist.  You need only state
     your position clearly enough so that the receptionist does
     not accidentally count you on the wrong side.

     (3) The gay community has a history of needing to be
     inconspicuous or secretive.  This style persists even when
     not necessary.

What to Do

     Before writing this article, we asked several gay friends
and associates if they had called the White House public-comment
line (202/456-1111) or called or faxed any of their
representatives about the gay-military issue.  The results were
interesting.  No one had called; some were uncomfortable with the
thought of doing so.  We believe we would have had to ask many
more before finding anyone who had made any call on this issue.

     We suggest that people experiment, as appropriate issues
arise, with asking others to make calls (or write letters) in
support of the fight against AIDS.  Try doing it only when it
feels right.  If it doesn't feel right, explore why.

     The White House comment line (number above) may be a good
one to start with to help people overcome old habits of
reluctance to pick up the phone and make a political call. (The
only drawback at this time is that so many people are calling
that the number is usually busy.  Still, it is important to try,
because, statistically, the calls that are completed will
represent the ones attempted.)  There is usually no problem
getting through to the local or Washington offices of your
congressional representatives.  Any member of Congress can be
reached through the Capitol switchboard (202/224-3121), and each
also has an individual number in Washington, as well as a local
office number in their home district.  On federal issues, calls
to your three representatives in Congress are usually the most
important political calls you can make.

     AIDS activist organizations should consider the project of
training a cadre to not only make the calls themselves, but also
to gently confront others they know and get them to start doing
so.  It might help to print business cards with the numbers most
likely to be needed for local and national issues; people can
carry the cards so they can call any time. Budget issues (local,
state, and federal) will be especially important to address in
this way over the coming months and years.  But organize first;
don't wait for an issue to come along, because when it does,
there may be only a few days to respond.

     The goal is to spark a widespread cultural change in the
AIDS and gay communities, so that most people will call or
otherwise contact their representatives several times a year or
more, for the rest of their lives, as important issues arise.
Cultural changes are always difficult, but this one is feasible,
since the communities are already political, already very good at
voting, and already phone and fax oriented (and note the "phone
zap" already in activist use).

     Some have said that the AIDS community could never turn out
political calls and letters as well as the religious right, with
its television and radio networks, and its ideology of people
doing what they are told in sending contributions of both money
and political influence.  We do not need to do equally well, but
we need to do much better than we have until now.  And
potentially the AIDS community could respond powerfully indeed.
Almost three years ago, a nationwide survey by the Boston Globe
(July 17, 1990) found that one American in five personally knew
somebody who had AIDS or was HIV positive; undoubtedly many more
do today.  While AIDS does not have its own television networks
to turn out mass responses for an instant issue, we can mobilize
in a decentralized way instead, if enough people independently
follow the news and spread the word to others when important.

     A few organizations and committed individuals could help
spark a community change to eliminate the greatest political
weakness we now have, and help greatly to mobilize the U. S. and
the world against AIDS.


***** New CDC Definition Now in Effect, But Confidentiality
      Questions Remain

By Nancy Solomon

     The new U. S. Centers for Disease Control (CDC) criteria for
an AIDS diagnosis -- which now add pulmonary tuberculosis,
recurrent bacterial pneumonia and invasive cervical cancer to the
previous list of 23 opportunistic infections needed for an
official diagnosis -- took effect January 1.  The new criteria
also include anyone with less than 200 T-helper cells.

     The CDC definition is important because it affects whether
someone with HIV is eligible for social services and also because
it alerts doctors to test for HIV when someone has a condition on
the official list.  While most government and non-government
agencies use the CDC definition to determine whether or not they
provide services, the Social Security Administration will not
change its requirement that an applicant for disability benefits
must show actual physical disability.

     Activists had pushed for the change because the former list
excluded many of the opportunistic infections common among women,
injection drug users and poor people.  The changes represent a
compromise between the activists and the CDC.

     The new definition is expected to double the number of AIDS
cases in the United States.  But several thorny legal and
political issues have made the long sought changes more of a
mixed blessing.  The new criteria are expected to send some state
public health officials rummaging through patient records to
boost their caseload statistics so that their states can receive
more federal funds.  This pr, legal advocates say, willdermine
patient confidentiality, leading to fewer people seeking testing
and an eroding of HIV confidentiality standards.

     "Despite extensive advocacy directed at the CDC requesting a
bar on name-based lab reporting of low (T-helper cell) counts, we
find that we are forced to fight this battle on a state-by-state
basis," says a memorandum from the AIDS Legal Referral Panel in
San Francisco.

     Legal advocates are asking that activists fight name-based
reporting of T-helper cell counts at the local level.

     The new definition also raises questions about access to T-
helper cell testing, which can cost $100-$200, beyond the means
of most people without health insurance.  Lack of access to
testing will continue to perpetuate undercounting of the epidemic
and lack of HIV services among women, people of color, and the
poor.  Legal advocates also ask that activists pressure local
government agencies to provide anonymous T- helper cell testing
to all who need it.

     For a copy of the new definition, contact the CDC National
AIDS Clearinghouse, 800/458-5231; or for more information about
the legal and political impact, call the AIDS Legal Referral
Panel, 415/291-5454.


***** CMV Experimental Treatment Overview, Part II

by Giacomo Palazzolo

     Note:  Part I of this article, published in AIDS TREATMENT
     NEWS #167 (January 15, 1993), looked at ganciclovir in
     combination with G-CSF or GM-CSF, at ganciclovir eye
     implants, and at oral ganciclovir.

Foscarnet

     Foscarnet (brand name Foscavir) was the second drug approved
for treating CMV retinitis in persons with AIDS.  In the U. S.,
government approval came only after much work by AIDS treatment
activists; in Europe, however the drug had long been used often
as first-line therapy.  Foscarnet is also active against other
herpes viruses, and to a limited degree against HIV.  It is
currently being tested in clinical trials as a treatment for CMV
colitis, acyclovir-resistant herpes simplex, and herpes zoster
infections.  Risks of foscarnet include kidney toxicity,
electrolyte abnormalities, anemia, and penile ulcerations.
Individuals taking foscarnet must be carefully monitored by an
HIV-knowledgeable physician for these side effects.

     One of the advantages of treatment with foscarnet is that
there seems to be a survival benefit greater than treatment with
ganciclovir.  This may be due to its antiviral activity against
HIV.  In one study of 234 people with CMV retinitis, average
survival was 12.6 months compared to an average survival time of
8.5 months for those treated with ganciclovir.  ("Mortality in
Patients with the Acquired Immunodeficiency Syndrome Treated with
Either Foscarnet or Ganciclovir for Cytomegalovirus Retinitis."
Studies of Ocular Complications of AIDS Research Group, in
collaboration with the AIDS Clinical Trials Group.  New England
Journal of Medicine, January 23, 1992, volume 326 number 4, pages
213- 220.)

     Currently, foscarnet is given intravenously.  An oral form
has been developed, and a single-dose pharmacokinetic study has
been completed in Europe.  A phase II trial in Europe is expected
to start this spring.

Combination Therapy with Foscarnet and Ganciclovir

     Ganciclovir- and foscarnet-resistant strains of CMV
eventually develop when these drugs are used, and disease
progression takes place.  Combination use of the two drugs is now
being tested to see if it can delay these problems.  AIDS
TREATMENT NEWS spoke with Mark Jacobson, M. D., Clinical
Professor of Medicine at the University of California in San
Francisco, who is conducting a phase I clinical trial of this
combination.  He told us that the study is for maintenance
therapy, after an initial occurrence of CMV retinitis has been
treated with an induction therapy of ganciclovir.  The 30
patients enrolled in this trial were randomized to maintenance
therapy with either daily alternating regimens of ganciclovir and
foscarnet, or concurrent therapy with both drugs.  According to
Dr. Jacobson, "the time to progression of CMV retinitis in the
interim analysis was similar in the two groups -- ganciclovir and
foscarnet combined vs. ganciclovir and foscarnet alternating.
Based on our data, and we are still following a number of these
patients, it looks like the alternating regimen may be better
than the combined one because there is not a big difference in
time to progression; therefore the simpler regimen with only one
infusion per day would require less infusion time than the
combination regimen."

     One German study presented at the VIII International
Conference on AIDS in Amsterdam reported on the treatment of
several patients with CMV retinitis who received both drugs (B.
Salzberger and others, abstract #PoB3253).

IVIG (Intravenous Immune Globulin)

     Gamma globulin is a blood product containing antibodies
pooled from various blood donors.  It gives the recipient a
passive immunity by increasing the amount of antibodies to CMV
(or other infections).  There are many different preparations of
IVIG, including some prepared specifically for CMV. Side effects
of IVIG rarely occur, although there may be pain at the infusion
site, headache, and malaise.

     Standard IVIG preparations, although not made for anti-CMV
use, may have varying amounts of anti-CMV antibodies, depending
on the donors of the blood used in each batch.  A representative
of Baxter Pharmaceuticals we spoke with said that a physician
could request a preparation of Gammagard (Baxter's brand of IVIG)
with higher than average concentration anti-CMV antibodies.

     A clinical trial is presently being conducted at Georgetown
University Medical Center comparing the efficacy of ganciclovir
plus IVIG to that of ganciclovir alone.  In this pilot study, 20
people with CMV retinitis were given IVIG five times during the
ganciclovir induction.  During maintenance therapy they received
IVIG weekly.  According to Princy Kumar, M. D., the treatment
"was extremely well tolerated.  Nobody had to be withdrawn
because of any complications related to the IVIG.  " The efficacy
data is still being analyzed and will probably be available early
in 1993.  While it is unknown whether or not IVIG can penetrate
the blood-retinal barrier (to reach the retina and the CMV
infection there), it penetrates into the cerebral-spinal fluid
well and this is an indication that it may also cross the blood-
retinal barrier.

CMVIg

     CMVIg [Cytomegalovirus Immune Globulin Intravenous (Human),
brand name Cytogam] is an IVIG preparation which is specially
made to contain high concentrations of antibodies against CMV. It
is manufactured by the state of Massachusetts, and is approved by
the FDA for use in the prevention of CMV disease in kidney
transplant patients.  Unfortunately, it was not studied in HIV-
infected individuals until recently, so it is only available off
label, by prescription, from the American Red Cross.

     CMVIg is currently being studied for preventing CMV disease
in persons with HIV.  A phase I safety study for HIV-infected
individuals with positive CMV blood cultures is being conducted
at the National Institutes of Health in Bethesda, Maryland.  The
dose used in this trial is 150 mg per kilogram of body weight
every two weeks or every four weeks.  This trial has enrolled
nine persons to date.  One volunteer may have developed CMV
colitis on the trial.  CMVIg is generally well tolerated, though
side effects include chills, muscle cramps, and fever.

     Unfortunately this treatment is expensive, and because HIV
use of this preparation is off label, patients are unlikely to be
reimbursed by Medicaid or by their insurance companies. The cost
for 2.5 grams of this preparation is approximately $300 per vial,
so a person of average weight who used the same dose as in the
above trial would need to spend about $1000 per intravenous
infusion, not including the cost of administration.

MSL-109

     MSL-109 is a genetically engineered monoclonal antibody
against CMV. A small phase I/II of ganciclovir with MSL-109 is
being conducted at Massachusetts General Hospital.  The study
began in early 1990 and so far has enrolled seven individuals
with CMV retinitis.  There is still one more slot for someone
recently diagnosed with CMV retinitis who has done induction
therapy with either foscarnet or ganciclovir. MSL-109 seems well
tolerated, although it is unclear whether the combination is
effective at slowing the time to progression in CMV retinitis
patients.

TI-23

     TI-23 as another anti-CMV monoclonal antibody.  Results of a
small human trial at the University of Arizona were presented at
the 1991 International Conference on AIDS [abstract #W. B. 2291].
The researchers concluded that the treatment was well tolerated,
and that CMV retinitis progression data was favorable compared
with historical controls.  We do not have recent information.

HPMPC

     HPMPC is a broad spectrum antiviral active against many
herpes viruses, including CMV. It is presently in phase I/II
testing in San Francisco, and at the National Institute of Health
in Bethesda, Maryland.  The current trials are with HIV-infected
individuals who have no symptoms of CMV disease, but are at risk
for developing it because they have positive CMV urine cultures.
Gilead Sciences, the pharmaceutical company developing HPMPC,
announced on December 1, 1992, that preliminary data showed
evidence of anti-CMV activity in the phase I/II trial.  According
to Jay Lalezari, M. D., who is conducting the trial at Mt. Zion
Hospital in San Francisco, "HPMPC has shown unprecedented
efficacy in reducing titers of CMV in urine and semen.  Our only
concern is its potential for kidney toxicity.  We are currently
recruiting ten more individuals to study the role of probenecid,
a drug we believe will protect the kidneys from toxicity.
Assuming we have a therapeutic window [a dose which is effective
but not too toxic to use], we should have a treatment protocol
available by this summer."

     Persons interested in volunteering for this study can call
Dr. Jay Lalezari, Mt. Zion Hospital HIV Clinical Research,
415/476-6356.

[Note:  AIDS TREATMENT NEWS is preparing a longer article on
HPMPC, and on PMEA, a potential drug which is chemically related
to HPMPC but has both anti-CMV and anti-HIV effects.]

Acyclovir; BW256

     Acyclovir has very little effect against CMV, but some HIV-
infected individuals with low T-helper cells have tried to
prevent CMV disease with high-dose acyclovir.  A major clinical
trial at 19 centers in Europe and Australia for individuals at
risk for developing CMV disease has found that taking 800 mg of
acyclovir four times a day failed to stop progression to CMV
disease.  However, there appeared to be a survival benefit for
the group treated with acyclovir.  (There is some controversy
among physicians about this conclusion, since no one is sure how
the drug might be working.)

     According to Kenneth Mayer, M. D., Director of the Brown
University AIDS Program and Research Director of the Fenway
Community Health Center, the "acyclovir may be acting in several
ways that may preserve life.  Laboratory tests have shown that if
you add herpes simplex or CMV to cells which were previously
latently infected with HIV, the co-infected cells can be
activated and produce HIV.  "

     A new drug being developed by Burroughs-Wellcome, BW256, is
rapidly turned into acyclovir when metabolized by the body. Blood
levels of BW256 reach three to four times that of oral acyclovir,
making it a better candidate than acyclovir for CMV prophylaxis.
A phase I safety trial using this drug in HIV-infected
individuals with less than 150 T-helper cells is currently
underway at Johns Hopkins, and a protocol for an efficacy trial
is being developed.  At this time it is not certain whether the
possible anti-CMV efficacy or a possible survival benefit will be
studied.

Etoposide (VePesid or VP-16)

     Etoposide is an agent approved for use as a cancer
chemotherapy; it is currently being tested for treating AIDS-
associated Kaposi's Sarcoma (KS), and with other chemotherapies
for treating AIDS-associated non-Hodgkin's lymphoma.  Side
effects of this drug include severe bone marrow suppression,
nausea, vomiting and hair loss.  In the test tube this drug can
"turn off" the CMV virus by inhibiting an enzyme (topoisomerase-
2) found in the cells. Nobody knows what dose might be used to
achieve the drug level which showed anti-CMV effect in the test
tube studies.

     AIDS TREATMENT NEWS interviewed one person with AIDS who
tried, with his physician, to find an effective dose.  This
person had no CMV disease, but was at risk because of low T-
helper cell count and positive blood and urine cultures for CMV.
After taking etoposide, he lost all of his hair, and his
hematocrit level fell dangerously.  He felt very ill from the
toxic effects of the drug, and went off etoposide after about one
month.  In his case the blood culture and urine culture for CMV
remained positive.  Despite this one anecdotal case where the
treatment appears to have failed, this drug should be studied
further for possible use in treating CMV. Perhaps data collected
in the clinical trials of etoposide for KS and for lymphoma d be
analyzed to see if t is any anti- CMV effect in these patients,
who will be taking the drug anyway.

Hypericin

     Hypericin is a compound derived from the herb St. John's
wort, and in test tube studies shows activity against both HIV
and CMV. A synthetic form of hypericin has also been
manufactured.  There have been no clinical trials using hypericin
for CMV disease, and we have not heard of anyone trying it for
this purpose.  An early trial of hypericin as an HIV treatment is
underway.  [Note:  for more information about hypericin as an
experimental antiviral, see AIDS TREATMENT NEWS # 146, February
1992].

Notes:

(1) Other CMV drugs are in preclinical development.  We did not
include them in this article because they are not yet in human
use, and we have little information about them at this time.

(2) For background on CMV, see "CMV Infection," by Douglas
Dieterich, M. D., in PAACNOTES, October 1992.  This article
includes 34 literature references.  It only covers the FDA-
approved CMV treatments, ganciclovir and foscarnet.


***** Correction:  ddI vs. AZT

     In our last issue (#167), in the article, "ddI vs. AZT:  New
Results, No Press," the fourth paragraph on page two should have
read:

     "However, among 118 people with 8-16 weeks of prior AZT use,
one year progression rates were 11 percent for 500 mg of ddI, 17
percent for 750 mg, but 33 percent with AZT -- a statistically
significant advantage for ddI.  "

     The phrase '500 mg of ddI' erroneously appeared as '500 mg
of AZT'.

     The error was not the fault of the author, but was
introduced later during editing.


***** Announcements

** Therapeutic Vaccine Conference, New York, February 11-12

     About a dozen leading AIDS vaccine researchers will gather
on February 11-12 for The 2nd Annual Forum on HIV Vaccine and
Immune Therapies, cosponsored by the Gay Men's Health Crisis
(GMHC) and the Community Research Initiative on AIDS (CRIA).
Scheduled speakers include Robert Redfield, M. D., Fred
Valentine, M. D., Allan Goldstein, Ph.D., Ronald Desrosiers,
Ph.D., Martha Eibl, M. D., and Bernadine Healy, M. D.

     The conference will be at The Marriott Marquis Hotel,
Westside Ballroom, 45th and Broadway, New York City.

     For more information, call CRIA, 212/924-3934.


** Liposomal Daunorubicin for Advanced KS:  Limited Expanded
Access Program

     Liposomal daunorubicin, a treatment which may be a
significant advance over other chemotherapy for treatment of
Kaposi's sarcoma, is currently in phase III clinical trials, and
will also be offered without charge to patients with advanced KS
who are not eligible for the trials and who have failed other
chemotherapy, through designated physicians in New York, Los
Angeles, and San Francisco, and possibly also in Miami and
Chicago.  This program is limited because of short supplies of
the drug.

     Conventional daunorubicin is approved for treating leukemia,
but has severe toxicities and can damage the heart and other
organs.  In the liposomal form of the drug, the daunorubicin is
trapped in microscopic spheres composed of certain fats. In this
form, the drug is selectively absorbed by the abnormal cells in
the KS lesions, allowing high doses to be used with little
toxicity.  According to information released by Vestar, of 75
patients with advanced KS who had failed conventional therapy, 60
percent improved on liposomal daunorubicin, and most of the rest
remained stable; fewer than five percent of the patients got
worse.

     Liposomal daunorubicin (brand name DaunoXome() is also being
tested as a treatment for certain solid-tumor cancers not related
to HIV.

     The developer, Vestar, Inc., of San Dimas, California,
worked with ACT UP/Golden Gate in San Francisco, and with ACT
UP/New York, in setting up this program.  Andy Zysman, M. D., of
ACT UP/Golden Gate commented:  "It has been very gratifying for
us to be able to work so cooperatively with a company to achieve
our common goal:  namely, for patients to gain access to a new
drug as soon as its efficacy has been demonstrated in clinical
trials.  Vestar's role in this process has been a model for the
industry, and we're looking forward to weaving a close
partnership among physicians, patients, and the company.  The
limited drug supply remains a problem, and we hope that the
company can expand the program as the need becomes evident."

     For more information, contact the DaunoXome Study Center,
800/247-3303.


** Sarasota Clinic Seeks Medical Director

     The Comprehensive Care Clinic, Inc., in Sarasota, Florida,
is seeking a medical director.  Full-time responsibilities
include medical examinations, clinical drug trials, and ARNP
supervision.  Internal medicine, family practice, or infectious
disease specialist preferred.  Send resume to: Comprehensive Care
Clinic, 150 East Ave.  So., Sarasota, FL 34237, phone 813/366-
0461.



***** AIDS TREATMENT NEWS
      Published twice monthly

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Editor and Publisher:
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   John S. James
   Nancy Solomon
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AIDS TREATMENT NEWS reports on experimental and
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interview physicians, scientists, other health
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survivors have usually tried many different treatments,
and found combinations which work for them.  AIDS
Treatment News does not recommend particular
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ISSN # 1052-4207

Copyright 1993 by John S. James.  Permission granted for
noncommercial reproduction, provided that our address
and phone number are included if more than short
quotations are used.

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