AIDS Treatment News
by John S. James
The important 3rd International Congress on Drug Therapy in
HIV Infection took place in Birmingham, UK, November 3-7; we
could not attend and are still gathering information as we go
to press November 12. There was much interest in studies
relevant to the complete suppression of HIV replication by
A small but widely discussed study at the University of Amsterdam found that antiviral treatment which reduced viral load to undetectable levels in the blood, also reduced viral load to undetectable levels in lymph tissue. This was found in six out of six patients in a substudy of a larger trial. The lymph tissue was taken by a biopsy of the tonsils (which is much less invasive than the conventional procedure of removing a lymph node), before starting treatment and again after six months of treatment.
Researchers at the University of Minnesota developed the methodology to measure HIV in lymph tissue from tonsils; see recent paper by Haase AT, Henry K, Zupancic M and others, "Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue," SCIENCE, November 8, 1996, pages 985-989.
Undetectable HIV viral load in the lymph nodes does NOT mean that the virus has been eradicated -- only that it is not actively reproducing. This viral load test only looks for viral particles; it does not detect the viral DNA that is still in the patients' cells -- ready to start up the infection again if the drugs are stopped. No one knows whether or not all these cells will eventually be eliminated by the body, if replication can be stopped for long enough.
While the growth of the virus is being completely suppressed, drug resistance apparently does not develop. The virus develops resistance when it is able to reproduce to some degree in the presence of the drugs, since then the viral variants which happen to be resistant to those drugs have a selective advantage, and can replace the more susceptible virus.
These results are not surprising, as there have long been indications that if viral replication is being suppressed in the blood by antiretroviral drugs, it is also suppressed in the lymph nodes (where there is much more HIV than in the blood, and where the virus is more important in the development of disease). And no one would expect the drug resistance of the virus to increase if the virus is not reproducing. But it is important to get direct evidence, since these questions are central to the interpretation of viral load tests and the management of therapy.
Note: The drug combination used in this University of Amsterdam study was ritonavir, AZT, and 3TC, in volunteers who had not used any antiretroviral before. However, there is nothing special about this particular combination; all evidence suggests that what is important is reducing the viral replication essentially to zero and keeping it there, using whatever drugs can do so for a particular patient. Similar suppression of replication has also been achieved with other combinations using a different protease inhibitor -- or even no protease inhibitor at all.
The main problem now is that some patients are more difficult to treat -- especially those with more advanced HIV disease, those who have already developed resistance to existing antiretrovirals, and those who cannot tolerate the drugs. This is why the problem of HIV treatment is not solved, despite the good results in some people. We need continuing development of better drugs -- with stronger and more durable antiviral effects, and/or less toxicity, and/or different resistance profiles than existing treatments, and/or drugs which may not be superior on the average but do work for some people when others treatments do not. And then of course there are still the economic barriers of getting effective treatments to those who need them.
More work is also needed on measurement of HIV in lymph tissue, since the most sensitive tests are quite difficult to do at this time.
There has long been an ongoing debate about the importance of aiming specifically for complete suppression of viral replication, vs. being willing to compromise on partial suppression due to practical concerns of toxicity, cost, and onerous compliance with regimens of three drugs or more. Professional opinion now seems to be moving more strongly toward the importance of complete suppression whenever antiviral therapy is used, because of the danger that otherwise the patients' virus will develop resistance to the drugs one by one, and each drug in turn will be lost for that person. This probably means that when therapy is begun, it will usually be with three or more drugs started together (instead of starting with one or two, then adding other drugs when the first ones fail); those who have already used antivirals will need to start or add combinations of at least two new drugs they have not seen before. What counts is keeping the viral load essentially at zero, whatever treatment that requires, because otherwise the virus will eventually escape the control of the drugs.
Extending and applying these principles to the treatment of
many different patients in different situations, given the
limitations of the drugs available and the practical
limitations imposed by the difficulties of therapy, will be a
central challenge in AIDS medicine for the next several
Federal Team Developing
by John S. James
The Office of AIDS Research (OAR) of the U.S. National
Institutes of Health has selected a panel "to make
recommendations regarding initiation of treatment;
suppression of HIV replication; minimizing or preventing
emergence of drug-resistant HIV variants; prolonging
effectiveness of therapy; and addressing the public health
consequences of transmission of multi-drug resistant
"The panel's activities will involve a series of meetings and analysis of the most recent available data. The panel is expected to work over the next several months to develop these recommendations, which will help health care practitioners and HIV-infected individuals make informed decisions about treatment options. It is also anticipated that the recommendations of this panel will assist public and private health care payers in providing reimbursement for essential care for HIV-infected patients."
The "NIH Panel to Define Principles of Therapy of HIV Infection" has 24 members and is chaired by Charles Carpenter, M.D., of Providence, Rhode Island; its executive secretary is Mark Feinberg, M.D., Ph.D., of OAR. There are two community representatives: Dawn Averitt, of Women's Information Service & Exchange (WISE) of Atlanta, and Mark Harrington of Treatment Action Group (TAG) of New York. Three panelists are from Europe and Australia, with most of the U.S. members from the East Coast.
The panel's first meeting is November 13 and 14 in Washington, during which the panelists will hear more than 30 presentations on the current state of scientific knowledge, focusing mainly on recent information learned too late for presentation at the Vancouver international conference in July.
The meeting occurs after this issue of AIDS Treatment News
goes to press, and OAR does not plan to issue a report of
this particular meeting (clearly there will be a report from
the panel eventually). But the list of presentations (from
the draft agenda released by OAR) gives an excellent overview
of the state of the science today, of some of the issues
considered most relevant to designing the best possible
treatments for HIV disease. The titles are listed
chronologically from a November 11 draft agenda, but because
of lack of space we did not include the names and
affiliations of the presenters.
Wednesday November 13, 1996:
Session I: Virus and T Cell Population Dynamics in HIV Infection
Session II: The Relationship Between HIV Replication and Disease Progression
Section III: Relationship between Therapy-Induced Decreases in HIV-1 Replication and Protection from Disease Progression
Thursday November 14, 1996:
Session IV: Therapy-Induced Changes in CD4 T Cell Levels and Recovery of Immunologic Function
Session V: Strategies to Delay or Prevent Antiviral Drug Resistance
Session VI: Protease Inhibitors Resistance and Cross Resistance
Session VII: Combination Antiviral Therapy of Established HIV-1 Infection
1592: Two Studies Recruiting
1592U89, usually called 1592, is an experimental nucleoside
analog drug (in the same class as AZT) with much community
interest, for several reasons. First, research has shown that
under some conditions at least, it can produce a 2-log (100
fold) viral reduction with just one drug. Also, it has good
penetration of the blood-brain barrier, suggesting potential
use for treating AIDS-related dementia. And a third reason
for the intense interest is that 1592 is a new possible
treatment for persons who do not have other options.
[Note: On November 12 THE WALL STREET JOURNAL published a major article on 1592, "Why Isn't Glaxo's New AIDS Drug Ready Yet," by Michael Waldholz, page B1; it asks why 1592 has been in research much longer than other new AIDS drugs but is not expected to be marketed until almost two years from now, and is not being made available through expanded access for those with no other treatment options. Activists suspect that the drug is being delayed to avoid competing with AZT and 3TC; Glaxo says it did not know until about a year ago how much more powerful this drug is than others. It is remarkable how Glaxo's arguments against expanded access resurrect those that were used years ago against other AIDS drugs, and long ago abandoned.]
Glaxo Wellcome is now running two preliminary trials of 1592:
This trial will test the antiretroviral activity of 1592 in 40 persons nationally who are already using certain approved nucleoside analog drugs. Forty persons will be enrolled in this study, and all will receive the same dose of 1592 (300 mg orally twice a day), in combination with other nucleoside analogs. There is no placebo. In order to enter this study, volunteers must be at least 13 years old, must have a CD4 count of at least 100, and must have a viral load of at least 30,000.
But there are complex entry criteria based on pre-existing antiretroviral therapy; for example, anyone who has used a protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor (e.g. nevirapine) is ineligible. In order to enter this study, a person must fit in at least one of the four following categories:
Anyone who has had other antiretroviral treatments is not eligible for this trial.
The trial is being run in eight cities; we list the state, city, study coordinator, institution, and phone number at each site. For more information, call the contact person listed:
This is a 90-patient phase III study for persons with HIV- associated dementia. Volunteers will be able to continue their current antiretroviral treatment in most cases, and will be randomized to receive 1592 or placebo for 12 weeks. After the 12 weeks, all participants will receive 1592 for 40 weeks. The dose of 1592 used in this study is 600 mg twice a day.
To be eligible, persons must be between 18 and 65 years old, and must have been stable on their current antiretroviral treatment for at least six weeks. There are a number of exclusion conditions, especially for certain abnormal laboratory tests, or for certain unrelated illnesses.
For more information, call the contact person at a site which you could attend:
by Denny Smith
In less than one year, the options for managing HIV have more
than doubled. The number of drugs approved to treat HIV
infection has risen to nine, with two others now available to
qualifying persons under expanded-access programs. We
prepared this quick guide to help people orient themselves to
the various drugs and their different names; these brief
descriptions could not possibly be complete, and people with
HIV must work with their physicians to be aware of the
different possible side effects, and the other instructions
which are essential for using these treatments correctly.
Generally no anti-HIV drug should be used alone, given the ease with which HIV develops resistance. Some drug combinations have been proven more effective--or have fewer side effects--than others. But much is still unknown about combination therapy, and most people must experiment intelligently with different combinations to see what will keep both their viral load and treatment-related toxicities as low as possible.
Most clinicians we know are now making treatment recommendations based on drug tolerance and viral load, rather than CD4 cell counts. The CD4 count is now used largely for deciding when to use prophylaxis therapies to prevent opportunistic infections.
We have listed the reverse transcriptase inhibitors first,
followed by the protease inhibitors, followed by hydroxyurea,
which was originally developed as an oncology drug, but which
may work in a unique manner against HIV. Important note: The
side effects described for each entry below are only the most
common or important ones. Physicians and patients should
always be prepared for other toxicities, which are described
at length in the product inserts available at any pharmacy.
Reverse Transcriptase Inhibitors
These drugs work by inhibiting an enzyme -- reverse transcriptase -- which the virus needs to replicate.
Non-Nucleoside Reverse Transcriptase Inhibitors
These drugs target a different enzyme of the virus -- the HIV protease -- which is essential for HIV to make working copies of itself. More than with most drugs, it is very important not to miss doses of the protease inhibitors.
Medical Marijuana Wins
by John S. James
By 55.7% to 44.3%, California voters passed Proposition 215
to allow medical use of marijuana. Arizona voters passed
Proposition 200 by a much larger margin, 65.3% to 34.7%. The
Arizona measure is broader than California's; in addition to
allowing medical marijuana, it may lead to release of persons
already in prison for certain nonviolent offenses. It is much
less well known than the California initiative, because
supporters in Arizona did not want outside help, due to
sensitivity of Arizona voters to interference in their
Californians for Medical Rights, the official sponsor of the 'Yes on 215' campaign, is preparing a brochure for patients and doctors "who need to know what Proposition 215 means to them. By the same token, we will help to inform people who are NOT sick as to why Propositions 215 will not apply to them. We don't want anyone to get the wrong idea about this new law, and end up putting themselves at risk unnecessarily." To leave your name and address to receive a copy of the free brochure, call the Proposition 215 Patient Information Hotline, 1-888-YES-4-215 (toll free).
No county in California had less than 40% of voters
supporting the medical marijuana measure, according to a
voter survey of over 2,000 voters published the day after the
election (we do not have the final official figures, which
would include absentee ballots and may differ somewhat from
the survey). The highest support was in San Francisco, with
78% of voters interviewed. Los Angeles supported Proposition
215 by 56%. See the SAN FRANCISCO EXAMINER, November 6, page
A-24, for a vote breakdown for all counties, and statewide by
demographics, political beliefs, etc.
Despite exaggerated statements from both sides suggesting that California marijuana laws are now unenforceable, we suspect that the main immediate effect of Proposition 215 will be to create a limited legal defense in court. A state proposition cannot overrule Federal laws against marijuana for medical or other use. It will be necessary to build a national campaign to change Federal laws.
The biggest ultimate impact of these votes may be to open doors to rational discussion about the war on drugs. And here it is clear that the country desperately needs other policy options besides prohibition or official indifference. This writer has strongly supported Proposition 215, but would never want to see massive television and billboard promotion of marijuana. Today with tobacco, companies sanctimoniously agree to help keep it from children, while knowing full well that their future centrally depends on getting children and teenagers to smoke, since few smokers begin as adults -- leading to highly sophisticated, lavishly financed corporate promotions to children, cleverly designed to stay mostly under the radar of civil society.
We need a new category between legal and illegal, for activities where adults are clearly allowed to make their own decisions, but where public policy is not neutral, discouraging an activity by other means than by making it a crime (such as by prohibiting routine or large-scale promotion). The Supreme Court has made such policies difficult, by defining advertising as Constitutionally-protected "speech" -- making it hard to regulate promotion of products such as alcohol, tobacco, or marijuana, without first making them a crime and invoking all the deadly baggage of prohibition, for no public purpose.
The Proposition 215 demographic breakdowns in the EXAMINER survey are fascinating. Sex made little difference, with females slightly more supportive of medical marijuana. There were big differences by race, with Black most supportive of proposition 215, Asian least supportive, and White in the middle. By age, support was lowest among voters over 60. Voters who currently were paid full-time workers were considerably more supportive than those who were not.
But what may be most important was the breakdown by whether the voter has children under 18. There was almost no difference in support -- only a 2% difference, and the survey had a margin of error of 3%. We would have thought that the basis of opposition to this proposition would have been parents worried that their children could get in trouble with drugs. But that is not what happened.
What, then, IS the basis of the opposition to medical
marijuana, or to this particular initiative? Polls have
repeatedly shown strong support for the right to use
marijuana for legitimate medical needs; in view of this
consistent support, the 55.7% vote in California seems
disappointing. Supporters should ask the 44.3% who voted
against Proposition 215 what was on their minds. Addressing
their objections will be an important part of making this
initiative work well enough to be an effective national
FDA Internet Regulation?
On October 16 and 17 the FDA held a public meeting, "FDA and
the Internet: Advertising and Promotion of Medical Products,"
near Washington D.C.; several hundred people attended, mostly
from industry (apparently there were no more than two AIDS
community or activist representatives). This meeting has been
widely reported in the press, but these articles did not tell
their readers that anyone can submit written comments until
Background about the meeting was published in the Federal Register, September 16, volume 61, number 180, pages 48707- 48710. That Federal Register notice included the following summary:
"The Food and Drug Administration (FDA) is announcing a public meeting to discuss issues related to the promotion of FDA-regulated medical products on the Internet. FDA is seeking participation in the public meeting and written comments from all interested parties, including, but not limited to, consumers, patient groups, information vendors, manufacturers of FDA-regulated medical products, and health care professionals. This meeting and the written comments are intended to help guide FDA in making policy decisions on the promotion of biologics, human and animal drugs, and medical devices on the Internet and the World Wide Web (the Web)."
The meeting was divided into five discussion groups: Investigational product information; Chatrooms and newsgroups; Additional regulatory issues; Website links; and International issues.
A complete transcript of the two-day meeting is available on
the FDA Web page, http://www.fda.gov.
How to Submit Comments
"Submit written comments on the questions to the Dockets Management Branch (DMB) (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. After the meeting, a transcript will be available at DMB (address above) between 9 a.m. and 4 p.m., Monday through Friday."
We suggest that persons preparing comments examine the
meeting transcript, available either worldwide through the
Web or at the FDA's Rockville office, or at least read the
Federal Register announcement of the meeting, which includes
the FDA's specific questions for each discussion group.
From what we have heard after the meeting, it seems unlikely that the FDA will make major attempts to regulate the content of medical information on the Internet -- but there is no way to know for sure. We are concerned about a number of issues, for example:
AZT Twice-Daily Tablets
by John S. James
On October 25 the FDA approved a 300 mg AZT tablet, intended
for twice-daily dosing. (AZT is commonly taken as 200 mg
three times a day in the U.S.) The new dose is intended to be
more convenient by reducing the three daily doses to two --
hopefully improving patients' compliance with their
There are concerns that twice-daily dosing may not work as
well as giving the same amount of drug at more frequent
intervals, because of the greater variation in blood levels
throughout the day. These concerns are (1) that low trough
levels could allow viral resistance to develop faster, and
(2) that higher peak levels after each dose could increase
side effects. In defense of twice-daily dosing, Glaxo-Wellcome
notes that 250 mg twice daily is the standard AZT
dose in Europe, that most clinical trials using AZT today use
twice-daily dosing, and that no differences in safety or
efficacy was seen in a trial of 320 volunteers which compared
100 mg every four hours vs. 300 mg every 12 hours for 48
weeks (the trial was not powered to find differences in
efficacy, however, and it did not measure viral resistance).
Glaxo also notes that the new dose is only an option, since
the previous formulation remains available, and that trials
to measure the development of viral resistance are now in
progress or being planned.
by John S. James
The 4th Conference on Retroviruses and Opportunistic
Infections, January 22-26, 1997 at the Sheraton Washington
Hotel in Washington, DC, will probably be the most important
AIDS conference in the U.S. in 1997. The deadline for
"community based newsletters" (most AIDS-related newsletters)
to register as press is December 6. For "all other press,"
(newspaper and TV reporters, freelance writers on assignment,
etc.) the deadline is January 10, and applications will be
processed first come first served. Many industry publications
may not be allowed to register as press in either category.
There is no on-site registration.
The Community Liaison Subcommittee will review and approve the community press applications, and applicants will be notified in mid December. This Subcommittee is excellent, but only has a limited number of slots to approve.
The bottom line is that anyone who wants to attend this conference needs to start making arrangements as soon as possible. For more information, obtain the Press Registration packet from the Retrovirus Conference Secretariat, c/o Infections Diseases Society of America (IDSA), 703/299-0200, fax 703/299-0204.
Press rules include no photography, video recording, or formal interviews in session rooms or the poster hall, and no photography elsewhere except with prior approval. Audio recordings are allowed, but not for republication or rebroadcast.
For those not going, the published abstracts are scheduled to
be available on the Internet on January 22, at
http://www.idsociety.org. The printed abstract book will be
sent two weeks in advance to all registered press.
As we have noted in previous articles, some of the press rules for this conference are highly unusual and a major impediment to rapid, accurate reporting. For almost ten years we photographed poster presentations and occasional slides at AIDS conferences without ever being told not to. At the Vancouver conference we found that a good-quality video camera was exceptionally useful, both for recording posters and for recording key slides with the accompanying discussion. We have taken these pictures only to assure the accuracy of our own reporting, never for republication. Traditionally, only FLASH photography in oral sessions has been banned, for good reason. But at the retroviruses meeting the cameras will apparently be limited to interviews in the press room, damaging accurate technical reporting for no public benefit.
Another major press problem at the Retroviruses conference is the requirement that mainstream media register in advance. We do not know of any effective way to communicate this requirement to those who need to know. Enforcement will mean that press is turned away, as happened last year. The public has a legitimate interest in AIDS research, and is more likely to provide support if it can see the results.
The happenstance dynamics of one major and prestigious
conference must not be allowed to establish a general pattern
of dysfunctional impediments to the communication of AIDS
A course in Qigong (a traditional Chinese therapeutic
exercise) will be presented on public television in the San
Francisco area, starting Saturday December 7, 6:00 a.m. to
6:30 a.m. for four weeks. It will start again on January 4
and repeat for another four weeks.
This course is also available on videotape through the Immune Enhancement Project in San Francisco, 800/835-6555; all proceeds from the sale of this tape are contributed to serve people with HIV. The course grew out of a Qigong class which meets twice a week in San Francisco; for information about this class, call Emilio Gonzalez, 415/255-0265, or George Wedemeyer, 415/661-2080.
Other public broadcasting stations wanting to broadcast this series can contact Qigong for Health, through the Immune Enhancement Project at the 800 number above.