AIDS Treatment News
February 7, 1997

Retroviruses Conference Overview:
Consolidating the Advances

The meeting had its problems as well. Most people with HIV who wanted to attend were barred from this meeting (see article below). And some areas, such as nutrition, were largely absent. The rejected abstracts may be as important a story as any other from this meeting, but it is hard to learn about them because no list is available. This Conference reflected one particular group's vision of scientific quality and prestige.

• New HIV treatments have greatly reduced deaths, illnesses, and hospitalizations, when they are available. They can partly or completely pay for themselves by reducing other medical costs -- which is important to know for getting reimbursement and therefore treatment access. But cost savings do not automatically translate into institutional motivation to do the right thing, since different medical expenses often come from different budgets. Therefore, advocacy is necessary.
  
• The AIDS medical community is clearly moving toward the view that when antiretroviral treatment is used, the goal should be complete suppression of HIV (plasma viral load below the limit of detection of the test used). Unless viral replication is essentially shut off, by continuous use of antiretroviral drug combinations, the patient's HIV will evolve to become resistant to the drugs. But if viral load is kept undetectable by continuous use of the drugs, then resistance develops very slowly or not at all.
  
• When to start antiretroviral therapy has been a more difficult question, but a practical consensus does seem to be building around starting "when the patient is ready." In other words, there are biological reasons to start anti-HIV treatment as early as possible; but if a person is not ready to follow the regimen, the drugs will do more harm than good because that patient will be likely to develop resistant virus, and lose most of the benefit of some important drugs forever. The resistant viruses can also be transmitted to others.
  
• There is no case yet where an established HIV infection has been eradicated by treatment. Mathematical calculations based on patient data suggest that if all viral replication could be stopped, in all body compartments known to harbor the HIV, the virus might be eliminated from the body eventually by normal cell turnover -- but this would be expected to take at least two and a half years of complete viral suppression, based on known compartments, and it could take much longer if HIV is also present in other cells where it is not now known to be. The mathematical models have been revised since the last major conference in Vancouver, and it is now realized that viral eradication, if possible at all with drugs now available, will take longer than had been thought. As a result, researchers have decided to wait before encouraging any volunteer in their trials to stop drugs in order to test whether eradication has occurred.
  
• Much new data was presented on combinations of existing drugs. One especially important finding was that a combination of indinavir (Crixivan(R)), AZT, and 3TC reduced viral load to below the limit of detection (500 copies) at week 24 in 65% of patients who had advanced AIDS and much prior experience with AZT. When they began the study, these volunteers had a median CD4 count of 15, a median viral load of 89,500 copies, and all had used AZT for at least six months previously. (By contrast, only 2% of those randomly assigned to indinavir alone, and no one assigned to AZT plus 3TC, had viral load reduced to under 500 copies.) This study contributes to the critical task of finding effective treatment for the most difficult patients -- those with advanced disease and much prior antiretroviral therapy.
  
• Information was also released on new drugs, on which little or nothing has been published before. One important example is ABT-378, a "second generation" protease inhibitor from Abbott. Another potential treatment to watch is pentafuside (T-20), a synthetic peptide which prevents HIV from entering cells.
  
• Basic science involving HIV also had its most successful year in 1996. A particularly important area concerned understanding of "co-receptors" -- molecules in addition to CD4 which HIV uses when it enters cells. These discoveries have not produced new treatments yet, but they are likely to, because there are various processes which occur, and molecules which are formed, only when HIV interacts with cells. These can be targets for development of new classes of drugs.
  
• Progress continues in the prevention and treatment of opportunistic infections and other conditions. For example, a study by the U.S. AIDS Clinical Trials Group (ACTG) has found that pneumocystis prophylaxis with Bactrim (Septra) can be tolerated by more patients if the dose is increased gradually at first, instead of being started suddenly. (This result was released in December 1996 at a meeting of the ACTG, but was presented to a larger audience at the Retroviruses conference.) And for CMV, information was presented on new drugs, including 1263GW94, lobucavir, and valganciclovir.
  

AIDS Treatment News will publish more detailed reports in separate articles on these and other results.

Retroviruses Conference:
Where to Get Information

One of the best in-depth sources of information about the Conference is the Web reporting of Healthcare Communications Group, http://www.healthcg.com. Each night a team of leading AIDS physicians and treatment writers summarized major presentations from the day before, creating extensive reports which healthcare professionals can use for CME (continuing medical education) credit. The writing is aimed at physicians, and is often difficult for those without some background in AIDS treatments. This reporting was published despite strong opposition of the Conference organizers (the Steering Committee of the Scientific Program Committee).

For excellent reviews of treatment developments, at a less technical reading level, see the Project Inform site, http://www.projinf.org/RetrConf.

Other useful sites, all of which have different material, are:

The American Medical Association, http://www.ama- assn.org/special/hiv/retrocon.htm. This has links to the Healthcare Communications Group site and to the official Conference site (see below). It also has relevant news releases, and essays by experts.

The Body ("an AIDS and HIV resource"), http://www.thebody.com/retro197/retro197.html, includes reports on the Conference by Andrew Pavia, M.D., and Ramon (Gabriel) Torres, M.D. Also, it allows you to ask them questions electronically; the questions and answers are then posted for public access.

The International Association of Physicians in AIDS Care has a series of reports from the Conference which were written for its journal. Its site is at http://iapac.org/conferences/aidscan3/preliminary.html.

The National AIDS Treatment Advocacy Project, http://www.aidsnyc.org/natap, has reports focusing on protease inhibitors.

The official site of the Retroviruses conference, www.retroconference.org, includes only about a third of the talks which were given. It does have many of the slides shown in those talks, the only place the slides are generally available. The talks themselves are in audio, not in text; one can select a slide and hear the part of the talk which goes with it. The published abstracts of the talks are also available on a different page of this site, with a search function to find all abstracts which contain a certain word (e.g. the name of a drug). Unfortunately, the address of the abstracts page has been changed from time to time, apparently to prevent other sites from linking directly to the abstracts (and bypassing the Conference's home page and survey); this means that a "bookmark" (for easily getting back directly to the abstracts later) may not be reliable; it is better to bookmark www.retroconference.org, and go through the introductory pages and survey each time. Also, one is likely to encounter technical problems before successfully using the audio and slides.

Immunet (http://www.immunet.org) is preparing a page to link to all of the sites reporting on the Retroviruses conference; it should be ready within a week.

Low Vitamin B-12 Blood
Levels Associated with Faster
Progression to AIDS

The study did NOT find evidence that additional vitamin B-12 serum levels (beyond that necessary to avoid a deficiency) were associated with additional benefit.

The analysis was done retrospectively, by analyzing stored serum samples after a followup period of about nine years. Therefore, it is impossible to know whether the low levels caused the faster disease progression, or occurred as a result of it; a randomized trial would be needed to be sure that correcting an abnormally low level will improve a patient's prognosis. But the researchers suspect that the low levels were causing disease progression, not vice versa, for various reasons -- including the fact that the relationship was found even in the healthiest patients at least three years before development of AIDS, who presumably would have been least likely to have low blood levels as a result of the disease.

In contrast to vitamin B-12, serum levels of vitamin B-6, or of folate, were not found to correlate with disease progression in this study.

The almost two-fold increase in progression to AIDS in those with low B-12 levels was found "after adjusting for HIV-1- related symptoms, CD4+ cell count, age, serum albumin, use of antiretroviral therapy before AIDS, serum folate concentration, and frequency of alcohol consumption . . . Therefore, serum vitamin B-12 concentrations seem to be an early and independent marker of HIV-1 disease progression."

Note: An earlier study by the same Johns Hopkins group,³ which found greater survival associated with vitamin B-6 and several other micronutrients, was different because it estimated nutrient intake based on food questionnaires. It did not measure blood levels. (See AIDS Treatment News issue #214, January 6, 1995).

References:

1. Tang AM, Graham NMH, Chandra RK, and Saah AJ. Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression. JOURNAL OF NUTRITION. February 1997; volume 127, pages 345- 351.
   
2. Tang AM, Graham NMH, Semba RD, Chandra RK, and Saah AJ. The role of serum micronutrient levels in HIV-1 disease progression. XI International Conference on AIDS, Vancouver, July 7-12 [abstract #Mo.C.320].
   
3. Tang AM, Graham NMH, and Saah AJ. The effect of micronutrient intake on survival in HIV-1 infection. Tenth International Conference on AIDS, Yokohama, August 7-12, 1996 [abstract PB0894].

GS 840 (Adefovir Dipivoxil):
Broad-Spectrum Antiviral Trial,
CD4 Count Under 100

Volunteers need to have a CD4 count less than or equal to 100, and be in reasonably good health ("not require considerable assistance and frequent medical care"). They can be using almost any medication, except for permanent or maintenance use of CMV treatments such as ganciclovir or foscarnet.

GS 840 is an oral prodrug of PMEA, meaning that it is changed into PMEA in the body. PMEA itself has long been studied as an antiviral, but is less practical as a drug because it must be given by injection. In this study, participants will continue their regular antiviral treatments, and add GS 840 (120 mg) or placebo once a day; the nutrient L-carnitine will also be given (to both the drug and placebo groups), at the request of the FDA, since GS 840 has been found to lower L- carnitine levels in the body.

GS 840 is known to be active against CMV, hepatitis B, HHV6 (human herpes virus 6), and Epstein-Barr virus. It has shown modest activity against HIV, with about a 0.6 log decrease in viral load. Resistance seems to be slow to develop, and the drug is active against many viruses which have become resistant to other drugs. Unlike most available HIV treatments, it is believed to be active against HIV in macrophages as well as lymphocytes.

The informed consent for this trial lists its five purposes:

• To find out if the investigational drug bis-POM PMEA [GS 840] is safe to give to people infected with HIV who have a low CD4+ cell count.
  
• To find out if bis-POM PMEA helps to slow the growth of HIV.
  
• To find out if bis-POM PMEA helps people infected with HIV to live longer.
  
• To find out if bis-POM PMEA helps to prevent people who are infected with CMV from developing CMV disease.
  
• To find out if a special test that looks at how much CMV is in your blood helps to predict which people infected with CMV may develop CMV disease.
  

Bis-POM PMEA has been studied in more than 200 HIV-infected subjects who had a CD4+ cell count of 100 or more. Most of these subjects were not taking other drugs to treat HIV infection and were able to tolerate taking bis-POM PMEA.

Because much is unknown about how this drug will interact with treatments the volunteers are already using, the first 400 persons in this trial will be entered into a special safety-and-virology cohort and receive intensive followup. Also, the first 400 must be CMV positive by a blood test; later volunteers can be either CMV positive or negative.

For more information about this study, including participating physicians and clinics in your area, call the AIDS Clinical Trials Information Service, 800-TRIALS-A, between the hours of 9 a.m. to 7 p.m. Eastern time, Monday through Friday; ask for information about trials of GS 840 (or adefovir dipivoxil). Or call Gilead Sciences Medical Information, 800-GILEAD-5 (press 3), from 8:30 a.m. to 5:00 p.m. Pacific time.

Opportunistic Infections:
Major Report Available

The opportunistic infections addressed are:

Viral Infections:

Herpes simplex virus I and II (HSV-1, HSV-2)

Varicella zoster virus (VZV)

Cytomegalovirus (CMV) retinitis

CMV neurological diseases

Progressive multifocal leukoencephalopathy (PML)

Bacterial Infections:

Mycobacterium Avium complex (MAC)

Fungal Infections:

Histoplasmosis, blastomycosis, coccidioidomycosis, aspergillosis, and candidiasis

Cryptococcal meningitis

Protozoal Infections:

Cryptosporidiosis

Microsporidiosis

Pneumocystis Carinii pneumonia (PCP)

Toxoplasmosis

Acyclovir-Resistant Herpes:
Expanded Access Available
for Cidofovir Gel (FORVADE(TM))

To be eligible for this program, patients must have mucocutaneous herpes simplex infection unresponsive to at least a ten-day course of treatment with acyclovir. They must be over 13 years of age, and must not concomitantly use drugs with anti-herpes activity, or use other topical medications for the lesion. There are some other inclusion/exclusion criteria.

For more information about this program, patients should have their physician call Gilead Sciences Medical Information, 800-GILEAD-5 (press 3), from 8:30 a.m. to 5:00 p.m. Pacific time.

Protease Inhibitor Failures:
Call for Information

"We are collecting stories from people who have failed protease inhibitors, or who have had unusual responses to the drugs. 'Unusual responses' would include the following:

• "People whose viral loads did not change after starting combination therapy. This includes people who eventually saw decreases, but only after more than two months on therapy.
  
• "People whose viral loads decreased in response to treatment, but who experienced a rebound in viral load within the first six months of therapy.
  
• "People whose viral loads INCREASED when they started therapy.
  
• "People whose viral loads remained high but whose T-cell counts seemed to increase anyway.

"Users who wish to report serious side effects are also welcome to report their experiences, although this is not a focus of this project.

"For more information, contact Rick Loftus, 415/695-3818, Rick_Loftus@quickmail.ucsf.edu."

The Web address for this project is: http://www.netcom.com/~protease.

Non-Approved Liver Treatments:
Call for Information

If you have information, contact Denny Smith, AIDS Treatment News, P.O. Box 411256, San Francisco, CA 94141, or fax to 415/255-4659, or email to aidsnews@aidsnews.org. Or call 800/TREAT-1-2, and leave the number and time best to reach you.

Retroviruses Conference
Excludes People with AIDS,
Researchers, Physicians

Apparently the security was hired to deal with several individuals who often disrupt AIDS meetings in San Francisco, where security at AIDS forums is now routine; the guards knew some of those people by name, and presumably were chosen because they knew their faces and tactics. But none of them showed up in Washington. No one came to disrupt the Retroviruses conference, so the expensive security only stopped people with HIV seeking medical and scientific information. (For background on the San Francisco disruptions, see AIDS Treatment News issue # 244, April 5, 1996.)

The official waiting list of researchers and physicians who also were denied attendance was approximately 500, but it is clear that many more people wanted to attend but were unable to. Some of the nation's leading AIDS research physicians -- as well as the Chair of the Presidential Advisory Council on HIV and AIDS -- were among those who tried to go but could not get in. Some applicants never heard back after they faxed their initial application -- and unless they called within about two days of the official opening date and learned that there was no record of their application, and that they had to send the paperwork again, it was usually too late.

One of the many press restrictions was that faxed newsletters reporting from the Conference with pharmaceutical-company support were prohibited. The International Association of Physicians in AIDS Care -- threatened with having its writers and staff banned from future conferences -- in the last week had to cancel its plans for daily reporting to its member physicians, at considerable cost to the organization. This affected many physicians, whose patients ask about treatments that are in the news; without daily medical reports from an ongoing conference, it can be hard to get in-depth information quickly.

The annual Retroviruses conference was started at the request of Federal agencies (the National Institutes of Health, and the Centers for Disease Control and Prevention), and has in fact become the U.S. national AIDS conference. As far as we can tell, all decisions regarding arrangements for this year's meeting were made by a four-person Steering Committee (which is within the Scientific Program Committee): Douglas Richman, M.D., chair; Constance Benson, M.D., vice chair; Chip Schooley, M.D., last year's chair; and Melissa Sordyl, M.B.A., executive director of the IDSA (Infectious Diseases Society of America). The rationale for limiting attendance was stated by Dr. Richman as the first words of the Conference:

"Before we start the program, I'd like to make a few remarks about the principles of this meeting. The Program Committee, in the design of this meeting, (wanted) to have a forum put together by basic and clinical investigators for basic and clinical investigators to present and exchange information, and with that objective in mind, the program committee confirmed -- by a very large proportion of the participants over the last three years -- (that they agreed) to keep it a meeting of this size and not expand it. . . The cost of that has been a (meeting) limited in size, and with some frustration, obviously, to some people, but there's always a trade-off between having a meeting of unlimited size with all of the circus-related activities that we've come to experience with some of the larger meetings, and something of this size. . . "

The four-person steering committee and others met privately on January 24, and is rumored to be inclined to enlarge the Conference by 1,000 to 1,500 additional people next year, although no official decision has been made.

At least four organizations or coalitions have started, or are considering, legal action to prevent a repeat next year of what happened at this Conference. Federal laws regarding disabilities, and regulations on closed meetings and dissemination of publicly-funded research, are being explored.

Comment: Access to Information

We believe that activists should avoid a negative focus on this particular meeting, by looking beyond it to the larger problems of medical information dissemination in an epidemic (including the Retroviruses conference). The system is not working. A current example concerns CPCRA 006, a study comparing daily vs. three times a week pneumocystis prophylaxis. This study, the largest controlled trial ever in AIDS, was surprisingly rejected from presentation as a "late breaker" at the Retroviruses conference. As a result, it was blacked out of all public and most private conversation at the Conference, where experts lectured on pneumocystis and its prophylaxis without mentioning the new information. Because of a U.S. Division of AIDS policy against releasing summaries before peer review, the results of CPCRA 006 might not be published until the ICAAC conference, September 28 - October 1 in Toronto. (Conferences such as ICAAC, or the Retroviruses meeting, are minimally peer reviewed in that presentations, submitted as abstracts, can be rejected. Journal peer review is usually more extensive, because the entire article is submitted and the reviewers can ask for changes, instead of only being able to accept or reject.)

Unfortunately it has become almost routine for information of medical and public-health importance, obtained with public funds, to be kept secret from the public and from most physicians. (Another major example is the International AIDS Society treatment standards, delayed for months before their release on July 10, 1996 when they were already largely obsolete.) This semi-secrecy, ostensibly to keep publication standards high and avoid misleading the public, really serves to increase the sales and prestige of scientific and medical journals by putting them at the center of national publicity when important news breaks; otherwise, there would be little objection to releasing the information during or after review, but before publication of record. Researchers cannot take the lead in correcting these abuses, because they fear retaliation when their own work is considered for publication.

But activists could blow the whistle. It is usually easy to confirm the existence of withheld information, given a detailed tip, even an anonymous one -- and usually dozens of people, sometimes hundreds, know enough to provide the tip. If there were a high-profile organization addressing this problem, anyone who knew about wrongful or questionable withholding of information important for public health would know whom they could write or call, at no risk to themselves. (For an example which already happened, note the recent press leak of the two-thirds drop in AIDS deaths in British Columbia during the last two and a half years; see "1997 Outlook," AIDS Treatment News #263, January 17, 1997. This information, important worldwide for treatment reimbursement and access to care, could otherwise have languished indefinitely awaiting publication -- although it is hard to see how peer review could much improve a simple report of a two-thirds drop in death rates.)

Another approach would be to investigate whether the current system of "information purgatory" -- major medical and scientific advances produced with public funds but withheld from the public for months -- provides unfair advantages to companies and investors with the right connections, creating a trade in private favors. Does this help to explain why a clearly dysfunctional system has been so resistant to change?

But the first steps should not be confrontational, but rather to work with researchers, physicians, publishers, and others concerned about medical care and effective information dissemination, to devise a system which better serves the public interest. A mechanism of rapid peer review followed by Internet or online-journal publication (to avoid the weeks or months of wait for physical page space) -- and which would count as peer-reviewed "publication" in Medline and elsewhere -- would be a major step forward. Meanwhile, activists can support researchers who want to release their findings more quickly, but are not in a position to advocate for a more rational system.

For More Information

Also see "Strange Bedfellows Damage CDC and NIH Credibility," a strongly worded editorial in the February 3 issue of AIDSWEEKLY PLUS, an AIDS newsletter published since 1985, which was denied access to report on the Retroviruses conference.

For an information packet -- or to connect with other people who want to work on these issues -- contact either: Gary Rose, AIDS Action Council, 202/986-1300 x3026 or fax 202/986- 1345; or the Linda Grinberg Foundation, 310/471-4108 or fax 310/471-4565.

Note: Before publishing this article, we faxed a draft to the Steering Committee, asking for their comments about any facts in dispute, or other changes they might suggest. The Committee replied that "there are several inaccuracies in your story, particularly related to access to information, security, policy decisions related to the Conference, fax newsletters, registration for the Conference, and distribution/publication of new information in late breaker abstracts not accepted for presentation." The reply did not specify which of our statements were considered inaccurate, nor did it suggest any corrections or changes that we could make to meet their approval. We may publish a longer statement from the Steering Committee in the future.

Copyright 1997 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.