AIDS TREATMENT NEWS Issue #178, July 9, 1993 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Berlin Treatment Leads: Topotecan; Hydroxyurea Berlin: Long-Term Survival Studies Suggest New Treatment Strategies Amino Acids, Herbs, Other Supplements: FDA Proposes New Regulations, Public Comment Until August 17 Peptide T Unavailable in Buyers' Clubs Political Funeral in Washington, D.C., Disrupted by Police AIDS: An Expanding Tragedy -- National Commission On AIDS Final Report ***** Berlin Treatment Leads by John S. James The following are two of a number of treatment leads presented at the IX International Conference on AIDS, held in Berlin on June 6-11, 1993. ** Topotecan Topotecan is a chemical now being tested in patients by SmithKline Beecham as a potential cancer treatment. Its possible use against AIDS was first proposed by researchers at Harvard Medical School, in a paper published in the March, 1993, Proceedings of the National Academy of Sciences, USA. This paper reported laboratory studies showing that topotecan inhibits HIV in chronically as well as acutely infected cells (which AZT, ddI, etc. do not do), and that it is effective at a concentration 200 times lower than that which has been tolerated by cancer patients -- suggesting that as an AIDS treatment the drug may have a large therapeutic range (between effective and toxic doses). The anti-HIV activity of topotecan was found by a screening test which looked for inhibitors of the "long terminal repeat" (LTR) of HIV, which is important in activation of the virus. The same test also found that curcumin, the ingredient which gives curry its yellow color, has the same kind of anti-HIV activity (see AIDS TREATMENT NEWS #176, June 4, 1993, for background on curcumin, which also is effective against HIV in chronically as well as acutely infected cells). The laboratory tests found that topotecan is more powerful than curcumin as an inhibitor of HIV. But topotecan also has a disadvantage in that so far it is only available in an intravenous form (although an oral form may be developed). And there is no way to obtain topotecan at this time, whereas curcumin is readily available. This is why there has been more public interest in curcumin than in topotecan. The Berlin talk, by Boston AIDS researcher Clyde Crumpacker, M.D., who is one of the authors of the PNAS report, gave additional details that were not in the paper. In laboratory studies with cells acutely infected by HIV, topotecan worked about as well as AZT, and better than ddI. But it also worked well in chronically infected cells, where very little effect was found with AZT, and none with ddI. And topotecan was also effective against an HIV isolate highly resistant to AZT (with three different mutations for AZT resistance), giving 50 percent inhibition at about 0.08 micromolar concentration. The research team is now trying to develop topotecan- resistant virus, in order to learn more about the mechanism of action of topotecan, which is largely unknown. But so far they have not identified any significant resistance. The Berlin talk, on June 8, was to a large and attentive audience. Since then there has been considerable professional interest in getting topotecan tested as an HIV treatment (it has not yet been tested in people with HIV). We will follow this effort as it develops. [Incidentally, during the question period Dr. Crumpacker was asked if he and his colleagues would continue looking at curcumin. He answered that, "Curcumin is not as active as topotecan on a microgram per microgram basis, but it is found as a normal food product, and many parts of the world consume this. We are pursuing curcumin, but how it would be developed in a clinical trial is unclear yet." The problem, apparently, is the old one of natural treatments not being tested because they are low cost and no company has a monopoly on them.] ** Hydroxyurea Hydroxyurea is a readily available drug that has been in use for three decades in treating certain kinds of leukemia and other cancers; it may also be promising for treatment of sickle cell disease. The exact mechanism of action has been unknown. It has been known that hydroxyurea immediately inhibits DNA synthesis without inhibiting the synthesis of RNA or protein, but until recently it was not known how it did this. On June 8, Robert Gallo, M.D., presented laboratory work, by researchers at the U.S. National Cancer Institute and elsewhere, which seems to explain the mechanism of action of this drug.(1) This new work, not presented before, also suggests that hydroxyurea might be useful as a new kind of anti-HIV agent. Dr. Gallo suggested the approach of targeting not the virus, but the cell -- "cell gene products which the virus needs and the cell could afford to lose a little bit of without undue toxicity." Viruses must live in cells, and they need many cellular chemicals to complete their life cycle; HIV may need more than most viruses. The advantage of targeting the cell, Dr. Gallo explained, is (1) that it opens a whole new avenue for treatment development, and (2) cells mutate far less rapidly than HIV does, so resistance to these drugs is unlikely to develop. In 1986, Gallo, Zagury, and others showed that while HIV could enter the resting T-helper cell, it could not complete its life cycle unless the cell was activated.(2) Others showed that in resting T-cells, little HIV DNA was created, and almost all of that was incomplete. At the International Conference on AIDS in Florence two years ago, Gallo suggested that this might be because of inadequate supply of the four building blocks of DNA. These are found at low levels in resting T-cells, but at much higher levels in activated T- cells, because those cells need to make DNA since they are about to reproduce. The great majority of T-cells are resting. Due to work at the NCI and elsewhere, it has been learned that hydroxyurea inhibits an enzyme which is necessary for one step in the process of preparing the building blocks of DNA. Apparently it does this by quenching a free radical which that enzyme produces. In the laboratory, activated cells were converted to resting status, blocking the synthesis of HIV DNA. But a negative result came from a laboratory study, reported at the 1992 International Conference on AIDS, which suggested that hydroxyurea would not be useful as a treatment.(3) In this study, "The concentrations used [to inhibit HIV in the laboratory] make it an impractical drug for anything other than ex vivo studies." If this is correct, attempts to use the drug for HIV would give only its side effects but no benefit. All the information available should be reviewed by qualified professionals who can evaluate the contradictory reports. But clearly there is enough need for new treatments today that an otherwise-promising lead should not be dismissed because of one negative report, without further investigation. How does this translate into a practical treatment possibility? Hydroxyurea is a drug that must be used with care, because it can cause bone-marrow suppression. The Physician's Desk Reference advises that blood tests for hemoglobin, total leukocyte counts, and platelet counts, should be performed at least weekly while the drug is used. But hydroxyurea is commonly used with chemotherapy and/or radiation, so it can be tolerated with these treatments, which also can cause bone-marrow suppression. The risk for persons with HIV -- especially if they are using other drugs which can suppress bone marrow, such as AZT -- is unknown. It is also possible that lower doses than used for leukemia might be enough for HIV treatment. Probably the first HIV trials will start with low doses and very careful monitoring of blood tests for side effects, and use a test for viral activity (such as the ICD p24 antigen test, for those who are positive on this test) as an indicator to show which dose is effective. (Even this indicator might be slow to respond, however, since the drug may only shut off viral reproduction, not other activity of the virus which already exists. Perhaps some other test would be more appropriate.) AIDS TREATMENT NEWS would be interested in hearing from anyone who has information about possible AIDS-related uses of hydroxyurea. References 1. Gallo RC. Perspectives for the future control of HIV. International Conference on AIDS, Berlin, June 6P11, 1993 [talk OP-01-1]. (Note: there is no information about hydroxyurea in the published abstract. An audiotape, tape #27, is available from Intrec, in Utrecht, The Netherlands, fax number 31-30-340334.) 2. Zagury D, Bernard J, Leonard R. and others. Long-term cultures of HTLV-III--infected T cells: a model of cytopathology of T-cell depletion in AIDS. SCIENCE. February 21, 1986; volume 231, number 4740, pages 850-850. 3. Meyerhans A, Vartanian JP, Hultgren C, Eriksson S, and Wain-Hobson S. The intracellular nucleotide pool affects HIV replication. International Conference on AIDS, Amsterdam, July 19-24, 1993 [abstract #PoA 2118]. 4. Kiernan R, Doherty RR, and McPhee D. Production of HIV-1 protein but not infectious virus in G1 arrested MT-2 cells. International Conference on AIDS, Florence, June 16-21, 1992 [abstract #M.A.1053]. 5. Getman DP, DeCrescenzo GA, Heintz RM, and others. Discovery of a novel class of potent HIV-1 protease inhibitors containing the (r)-(hydroxyethyl)urea isostere. J. MED.CHEM. January 22, 1993, volume 36, number 2, pages 288- 291. ***** Berlin: Long-Term Survival Studies Suggest New Treatment Strategies by Dave Gilden Many of those attending the IX International Conference on AIDS in Berlin went away disappointed at the lack of AIDS treatment breakthroughs. Disappointing reports such as the Concorde study of early intervention with AZT, and the apparent failure of the Hoffmann-la Roche tat inhibitor, suggested that, at least superficially, science was going backwards. Yet the distressing state of treatment research masked considerable advances in understanding disease mechanisms ("pathogenesis") in AIDS. Much of that progress came from studying the natural success stories: so-called long-term survivors who remain comparatively healthy despite many years of living with HIV. In a conference last February at the National Institute of Allergy and Infectious Diseases, researchers categorized three types of long-term survival. First are people who maintain stable levels of T-helper cells for seven or more years following infection with HIV. Within this group is locked the mystery of successful resistance to HIV. Elucidating the reasons for this success would probably yield an effective way to manage HIV infection. It is worth noting that chimpanzees belong to this group -- they become infected with HIV but do not exhibit symptoms. In the second category of survival are people who stay clinically healthy although the T-helper cell population in their peripheral blood, at least, has deteriorated significantly. This group presents a dual mystery: How can the immune system still function without T-cells to orchestrate it, and why does the HIV infection itself stabilize after it first escapes immune system control? A very few people are even able to recover somewhat, with their T-cell counts bouncing upwards again. Finally there is a group whose members are not technically survivors because they never became infected with HIV at all. These are people whose personal histories indicate extensive exposures to the virus, through unsafe sex, contaminated syringes, or blood transfusions, but who show no sign that they are carrying HIV at present. The key to effective vaccines may lie within in this group's natural resistance. The Berlin Conference included extended discussions of the basis for long-term survival. One obvious factor in survival is the virulence of an individual's predominant strain of HIV. But HIV's ability to evolve into more virulent forms after infection is of secondary importance if that infection is under control, since mutations cannot develop if the virus is not reproducing. Participants at the Conference suggested that differences in personal immune function, genetics and psychology all influence how a person successfully counters HIV. Immune Response In a major address to the Conference, Jay Levy described his experience working with healthy non-progressors.(1) Levy's main finding concerns cytotoxic lymphocytes, certain blood cells whose usual job is to search out and kill cells infected with viruses. Levy has found a certain subpopulation that instead of killing its HIV-containing targets, secretes a still unidentified chemical that suppresses new virus production, leaving the HIV inside the cells locked in a latent phase. In long-term survivors, these cells' activities strongly persist well after they have declined in most HIV- infected individuals. Identification and synthesis of this chemical, which exists naturally in only tiny amounts, could lead to a potent therapy for controlling HIV. (Dr. Levy first reported the existence of this chemical in 1986,(2) but certain details were reported in Berlin for the first time.) Posters by Landay and others(3) and Ennen and others(4) on African green monkeys supported Levy's observations about a soluble HIV-suppressing factor produced by a particular sort of cytotoxic lymphocyte. Several talks at a session on "markers of non-progression" stressed the importance of other types of cytotoxic lymphocytes for long-term survival.(5,6,7) The work of Mario Clerici and Gene Shearer helps explain what happens to cause cytotoxic lymphocytes' decline. There is a partial tradeoff between the cytotoxic lymphocyte arm of the immune system, which is stimulated by a particular T-helper cell subset known as Th-1, and the antibody-producing arm, stimulated by Th-2 helper T-cells. Other concomitant infections or just increasing levels of HIV may cause the immune system to emphasize antibody production at the expense of the cytotoxic lymphocyte arm. Antibodies are good for fighting bacteria and free viruses, but for HIV their effectiveness is questionable. The rapidly mutating HIV replicating within cells is not much affected by antibodies, and its mutant progeny can escape antibody control even when released and floating free in the plasma between cells. A poster by Zvi Bentwich and others(8) described antibody activation processes in Africans with HIV. In another poster,(9) Bentwich and his colleagues described detecting cellular immune defenses against HIV in antibody-negative sexual partners and children of Africans with HIV. Several other presentations at the Conference also supported the particular importance of the cellular (as opposed to the antibody) immune response, in blocking initial infection in people with probable multiple exposures to HIV. Among these were Shearer, Clerici and others on gay men,(10) Clerici and others(11) on macaque monkeys and Weiss and others(12) on IV drug users. In all these cases, people or monkeys consistently tested negative on the standard HIV antibody test, and usually also in direct tests for the presence of virus. Yet an immune response did exist on cytotoxic lymphocyte level, indicating past exposure to and successful containment or elimination of HIV. These observations indicate that a treatment to prevent AIDS could be fashioned from immune modulators that switched or held the immune response to the Th-1, cytotoxic lymphocyte mode. One suggestion has been to create a chemical or antibody that attacks IL-10, a natural messenger molecule in the body that promotes antibody production while curtailing the activity of cytotoxic lymphocytes. Another possibility is the administration of IL-12. IL-12 enhances the activity of Th-1 cells and has been found to be low in people with HIV.(13) It is difficult to predict the ultimate consequences of playing with the internal balance of the immune cells' messenger system, which has a wide spectrum of effects. Blocking IL-10 is problematic if antibodies are needed to combat a bacterial co-infection, for example. In addition, Robert Yarchoan, Samuel Broder and others in a presentation at the conference proposed using IL-10 as an anti-HIV therapy because it inhibits the virus' replication in monocytes and macrophages.(14) Posters by Bentwich(15) and Howard Urnovitz(16) (and, from a somewhat different perspective, a major address on cofactors by Luc Montagnier(17)) indicate that an alternative way to delay disease progression is to actively avoid contracting co-infections and aggressively treating those that do occur. Comments by many long-term survivors about ways they have improved their general state of health fit into this perspective. Certainly a study comparing the overall health status of slow progressors versus others with AIDS, and analyzing the role played by such differences, would be a very valuable addition to both community and scientific knowledge on how to delay the onset of the disease. Genetic Differences In San Francisco, the City Clinic Cohort was already functioning before the AIDS epidemic as a Hepatitis B study. Since then it has been tracking men with HIV and AIDS. The study has built up a unique collection of blood samples documenting the transmission of HIV and the course of disease since the late seventies. Eight percent of the 593 men from the group with well-defined dates of HIV infection are considered "healthy long-term positives" -- they have T- helper cell counts over 500 despite being HIV-positive for ten years or more. In analyzing this group, Susan Buchbinder found specific genetic differences that distinguished the non- progressors.(18) These differences involved the "major histocompatibility complex" (MHC), a group of genes that determines certain cell surface molecules. The MHC molecules present foreign proteins extracted from invading microbes (or from cancerous cells) to T-helper cells and cytotoxic lymphocytes in order to activate immune defenses. Immune system stimulation depends on the particular shape of the MHC-foreign protein complex, which must look like a foreign, or "non-self," protein to immune cells. Since HIV's gp120 outer coat protein resembles part of the natural T- helper cell receptor, establishing a healthy immune response to HIV may be particularly difficult. People with MHC molecules structured in certain ways may pick pieces of HIV protein that are more noticeable to the immune system, or the molecules may present the protein in a more conspicuous way. And it is an individual's particular MHC genes that the determine the shape of these molecules. One poster by Kaslow and others(19) related rapid disease progression to certain MHC genes that seemed to result in high levels of a certain class of antibodies (IgA). MHC genetic differences may well confer protection by the precise type of immune response they promote in the presence of HIV. Thus the observations about MHC variations fit in with the Th-1/Th-2 (cytotoxic lymphocyte versus antibody) conflict mentioned above. (Costagliola and others(20) also found a striking detrimental effect in hemophiliac patients from a certain MHC gene.) Support for the idea that particular MHC genes have a major protective effect came from several other studies presented in Berlin besides Buchbinder's. Dean Mann, of the National Cancer Institute, described similar findings in a group of 122 men who have been followed since 1983.(21) One type of gene seemed to result in slower progression early in the course of the disease, while later on, certain genes of another class were associated with greater protection against AIDS. Still others seemed linked with more rapid progression later on. A study of a San Francisco woman(22) found similar MHC genetic advantages similar to the Mann and Buchbinder studies. The woman received an HIV-contaminated transfusion in 1981 but remains healthy and with no culturable HIV in her blood (although she produces HIV antibodies). An investigation of consistently HIV-negative female prostitutes in Nairobi(23) as well as a report from a heterosexual partners study in California(24) found an association between MHC genes and protection from HIV transmission in people frequently exposed to the virus. People tend to despair when the mention of genetic advantages comes up because knowledge of such advantages seems to offer no help to those not so endowed. But use of genetic markers may help to determine who has need of early treatment and what sort of treatment to offer. MHC-based treatments are still in the realm of speculation, but might include cytotoxic lymphocyte stimulators or specific chemicals that bind to MHC molecule-HIV fragment complexes to make them mimic the complexes created by people with the more protective genes. Insights into the effect of MHC molecule shape may also contribute to the design of more potent therapeutic and prophylactic vaccines. Psychology Personal lifestyle is one aspect that is open to individual alteration in an effort to slow progression to AIDS. For example, Susan Caumartin and colleagues at the University of Michigan presented a poster(25) that found a close linkage between social affiliations and survival time at every level of health. Among the indices of social participation used by the researchers, the one measuring how actively respondents tried to help other gay men through the epidemic especially stood out. Social participation also appeared indicative of a group of other personality traits (optimism, social integration, lack of denial, health vigilance) that are considered to prolong survival. In another commentary Robert Remien, Ph.D., described a group of 53 long-term survivors of AIDS (three to nine years since diagnosis) that he and his colleagues had observed in New York.(26) Remien found that resilience in the face of adversity was typical of his group. Even up to the time of death, Remien's long-term survivors maintained a high level of enjoyment in life and minimal psychological distress. Reflecting the importance of social connectiveness, Remien noted that the greatest difficulty the group's members faced was watching many of their friends die. Remien listed the following as distinctive characteristics of long-term survival: Realistically acknowledging life's challenges and grieving the losses, reframing one's view of situations so as to keep up a positive attitude, maintaining goals and an active life, recognizing the value of social supports, developing a good doctor-patient relationship, and seeking an active role in managing one's own medical care. Remien's remarks were seconded by F. Bofinger in a poster.(27) In an unabstracted speech during a "roundtable" session on long-term survival, Rafael Pagn of Puerto Rico described additional personality factors that contribute to staying healthy. He thought the "will to live" is central to survival and recounted how he helps build self-esteem and the ability to carry on a satisfying sex life after testing positive. Dr. Pagn's clinic (the Community Network for Clinical Research on AIDS) is the only gay-oriented and the only HIV- specialized health facility on the island. Note, though, that one poster from the Multicenter AIDS Cohort Study in the U.S. found that psychological depression at the beginning of the study did not correlate with faster progression to AIDS or death.(28) A Dutch study also found no effect on survival time from coping ability at the beginning of the study,(29) nor was there any noticeable effect from unsafe sex or intravenous drug use, two other commonly supposed disease accelerators. Intravenous drug use also was rejected as a detrimental factor by an American study(30) conducted by 17 American community-based research agencies that are part of the Community Program for Clinical Research on AIDS (CPCRA). To explain the relationship between psychological factors and health, one might have to resort to the field of psychoneuroimmunology and the poorly defined relationship between mental processes and the immune system. But a large part of the explanation might be much more straightforward: People with more "resilience" -- including greater connection to the outside social world and a more acute awareness of the nature of AIDS (as opposed to coping mechanisms based on denial) -- may simply be more able to seek out and demand better medical care. Their greater health consciousness may also cause them to reform their daily habits in positive ways, such as improving their diet. To cite a specific example, John Mordaunt, one of the speakers at the conference's final plenary session, is a long-term survivor and ex-heroin addict now on methadone maintenance. Mordaunt points out that obtaining clean syringes and clean drugs by itself strongly protects addicts' health. As noted above, absence of concomitant infections seems definitely connected to the quality of the immune response against HIV. The extent to which health-promoting behavior (or "health vigilance") acts as the bridge between the various elements associated with prolonged survival could not be settled at the Ninth International Conference on AIDS. Robert Remien notes that the biologists and the psychologists studying survival are still in "different camps." Although the Berlin conference did nothing to bring the different disciplines together, it did at last provide an occasion to survey what various fields can now say about resistance to HIV and AIDS. Further investigation is needed to confirm and expand previous observations, and some grand, unifying theory is required to apply the lessons of survival to the development of therapies. One meeting in Berlin attempted to initiate a network of long-term survivors and researchers to coordinate more study of survival factors. Aldyn McKean of ACT UP/New York, who gave a keynote address to the Conference on the importance of studying long-term survival, is coordinating this embryonic association. Those interested in furthering research into the sources of long-term survival can reach him at 212/674-2545. References 1. Levy, JA. HIV pathogenesis and long-term survival. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PS-05-2]. 2. Walker CM, Moody DJ, Stites DP, and Levy JA. CD8+ Lymphocytes Can Control HIV Infection In Vitro By Suppressing Virus Replication. Science. December 19, 1986; volume 234, number 4783, pages 1563-1566. 3. Landay AL, Mackewicz C, and Levy, JA. Activated CD28+ CD8+ T cell phenotype correlates with anti-HIV suppressing activity and asymptomatic clinical status. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO- A14-0284]. 4. Ennen J, Findeklee K, Werner SG, Norley ME, and Kurth R. CD8+ T-lymphocytes of African green monkeys efficiently suppress SIVagm replication. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-A09-5]. 5. Klein MR, Bende RJ, van Baalen CA, Keet IPM, Eeftinck Schattenkerk JKM, and Miedema, F. Persistent high gagCTLp frequency and low viral load in long-term asymptomatic HIV infection. International Conference on AIDS, Berlin, June 6P 11, 1993 [abstract #WS-B03-3]. 6. Rivire Y, McChesney M, Porrot F, Tanneau F, Buseyne F, Regnult A., and others. Role of HIV specific cytotoxic effector cells in disease progression. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS- B03-4]. 7. Reiter WM, Vorce DE, Cimoch PJ, Keller RH, Berger DS, and Ping AC. Cytotoxic CD8+ lymphocyte response to HIV-1 infection correlated with longitudinal analysis of CD4+ lymphocyte percentage. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-B03-5.]. 8. Bentwich Z, Burstein R, Weisman Z, Kamminsky M, and Kalinkovich S. Th2 activation and pathogenesis of African AIDS. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-A19-0392]. 9. Bentwich Z, Jehuda-Cohen T, Bar-Yehuda S, Miltchan R, Kamminsky M, and Vansover A. HIV specific immunity in seronegative individuals. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-A22-0490]. 10. Shearer GM, Clerici M, Berzofsky JA, Pahwa S, Chess L, and Lederman S. HIV exposure in long-term non-seroconverting homosexual men at risk for HIV infection. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS- A09-4]. 11. Clerici M, Axberg I, Polacino-Firpo P, Kuller L, Morton W, Benveniste R., and others. SIV-specific cellular immunity in seronegative macaques exposed to siv/Mne. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS- A15-3]. 12. Weiss SH, Clerici M, Hewlett I, Mayur RK, Berzofsky JA, and Shearer GM. Evidence of immunologic and virologic responses to HIV exposure among a high risk but long-term HIV antibody seronegative (HIV-) cohort of injection drug users (IDU). International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-A15-5]. 13. Chehimi J, Trinchieri G, Frank I, Aste M, Sennelier J, and Starr SE. IL-12 deficiency in HIV-infected patients. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-A08-4]. 14. Saville Mw, Tosato G, Taga k, Foli A, Broder S, and Yarchoan R. Interleukin-10 (IL-10) is a potent inhibitor of HIV replication in monocyte/macrophages (M/M). International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS- A08-1]. 15. Bentwich Z, Burstein R, Weisman Z, Kamminsky M, and Kalinkovich S. Th2 activation and pathogenesis of African AIDS. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-A19-0392]. 16. Urnovitz HB, Sturge J, Gottfried TD, and Robison DJ. Western blot confirmation of urine HIV-1 envelope antibodies from EIA seronegative subjects. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-A31-0733] 17. Montagnier L. HIV, cofactors and AIDS. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #OP-03- 1]. 18. Buchbinder S, Mann D, Louie L, Villinger F, Katz M, Holmberg S., and others. Healthy long-term positives (HLPs): genetic cofactors for delayed HIV disease progression. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-B03-2) 19. Kaslow R, Rinaldo C, Friedman H, Kuo V, Visscher B, and Phair J. Association of high serum IgA with HLA-A1, Cw7, B8 in men with rapidly progressing HIV infection. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO- A23-0507) 20. Sahmoud T, Laurian Y, Cazengel C, Sultan Y, Gautreau C, and Costagliola D. HLA-B35 and progression to AIDS in haemophiliac patients. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-C04-2672]. 21. Mann D, Carrington M, O'Donnell M, Yeager M, Harding A, and Goedert J. Selected HLA class I and II alleles are associated with relative rates of disease progression in HIV- 1 infection. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-A07-6]. 22. Schwartz D, Sharma U, Farzedegan H, and Viscidi R. Immune response without HIV in the blood of a long term survivor. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-A21-6]. 23. Plummer Fa, Fowke K, Nagelkerke Njd, Simonsen Jn, Bwayo J, and Ngugi E. Evidence of resistance to HIV among continuously exposed prostitutes in Nairobi, Kenya. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-A07-3]. 24. Louie Lg, Just J, Padian N, and King M-C. HLA genotype and risk of heterosexual HIV transmission. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO- B02-0935]. 25. Caumartin Sm, Joseph Jg, and Gillespie B. The relationship between social participation and aids survival in the Chicago Macs/ccs cohort. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-D20-4008]. 26. Remien R, Rabkin J, Katoff L, and Wagner, G. Medical and psychological characteristics of extended longterm survival with aids: a follow-up study. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-D15-3]. 27. Bofinger F, Marguth U, Pankofer R, Seidl O, and Ermann M. Psychological aspects of longterm-surviving with AIDS. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-D20-3961]. 28. Lyketsos Cg, Hoover Dr, Guccione M, Senterfit W, Dew M, and Wesch J. Depression does not predict CD4 decline or future HIV outcomes in the Multicenter Aids Cohort Study (MACS). International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-B02-0930) 29. Keet Ipm, Krol A, Klein M, Veugelers P, Goudsmit J, Miedema F, and Coutinho RA. Characteristics of long term survival early and late in HIV infection. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS- C03-3]. 30. Brown LS, Neaton J, Wentworth O, and Sherer R. A national, multi-site HIV disease progression and survival study in injection drug users (idus) and non-IDUs. International Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-C03-4]. ***** Amino Acids, Herbs, Other Supplements: FDA Proposes New Regulations, Public Comment Until August 17 by John S. James The FDA is planning major changes in how it regulates dietary supplements. The most drastic proposal concerns free-form amino acids, which the FDA wants to make prescription drugs. In a second category, herbs, the FDA is exploring approaches to regulation to assure safety of herbal products. Vitamins and essential minerals may have the least regulatory changes (although one proposal would declare only the recommended daily allowances (RDAs) as safe, unless manufacturers or others proved safety of higher doses to the FDA's satisfaction). In the fourth category, "other" supplements (including fish and plant oils, other lipids, dietary fiber, and miscellaneous, sometimes dangerous substances such as germanium), the FDA is asking for public comment on approaches to regulating safety. These proposals were published in the Federal Register, Friday, June 18, 1993, pages 33690 through 33700. [Note: Three other sets of proposals on dietary supplements follow in that issue, on pages 33700 through 33751. These mainly concern industry, however, because they propose to regulate requirements for making a health claim for a dietary supplement, how the labels on the bottles must look, and the exact definition of claims such as "less", "reduced", "fewer", or "no added sugar."] The FDA is legally required to prepare new rules for regulation of dietary supplements by the end of 1993. To be considered in this rulemaking, public comments must be in writing and received by August 17 at: Dockets Management Branch (HFA-305) Food and Drug Administration, rm. 1-23 12420 Parklawn Drive Rockville, MD 20857. Comments should be identified with docket number 93N-0178. Two copies of any comments are to be submitted, except that individuals may submit one copy. Comments received are open to public inspection in the Dockets Management Branch between 9 a.m. and 4 p.m. Monday through Friday. Comment We are most concerned with the proposal to take amino acids off the market. The AIDS community has barely begun to explore amino acids so far (except for NAC, which is a close relative of an amino acid, and lysine, which is widely used as an "underground" herpes treatment). These food substances have been proposed for a great many medical purposes. We fear that AIDS-related uses will never be explored, at least not in the foreseeable future, if these potential natural therapies are taken away from patients and physicians and turned into pharmaceutical-company monopolies. Our concern with other aspects of the proposal is that it is not specific, and yet the FDA is under pressure to make new rules by December of this year. As a result, it is hard for the public to engage meaningfully with these proposals -- which also are complex, technical, and related to a vast array of legal, medical, and policy issues. Therefore, the final rules are likely to come out with little real public input. The public must trust the FDA to respect its demand for maximum possible access and choice consistent with safety -- and must be ready to fight the Agency in the courts and in Congress if this trust is abused. ***** Peptide T Unavailable in Buyers' Clubs by John S. James An estimated 3,000 people have been cut off from access to peptide T, as buyers' clubs across the U.S. have been unable to get supplies. Peptide T, which has been in development for many years (AIDS TREATMENT NEWS first covered it in issue #22, January 16, 1987; it had already been tested in humans at that time) is not formally approved, but is used to treat AIDS-related neurological problems, especially painful neuropathy and cognitive disorders. Peptide T is believed to be entirely safe. The immediate cause of the cutoff is that the European supplier decided not to sell it any more to the U.S. buyers' clubs. The drug may be available through other sources, but none has yet been found. Peptide T access was also cut off a year and a half ago, as covered in AIDS TREATMENT NEWS #119, January 18, 1991. That instance was precipitated by the beginning of a new round of clinical trials, which brought peptide T under a different legal framework and under a different bureaucracy within the FDA. We do not know why the recent problem occurred. It may have been because of fear of the FDA, but without any specific action by the FDA. On May 25th of this year, AIDS TREATMENT NEWS was called by a New York law firm representing an unidentified European pharmaceutical company which had new- drug applications before the FDA. The company was worried that, either because of the new presidential administration or otherwise, the FDA might have changed its attitude toward buyers' clubs, and might retaliate against the company for its former sales to them. We do not know if this call was relevant to peptide T, or concerned other drugs. Note: ACT UP/Golden Gate mentioned the peptide T supply problem in its July 1993 newsletter, Treatment Agenda, in the context of a survey designed and conducted by ACT UP/Golden Gate on the effects of d4T. D4T can cause peripheral neuropathy in some patients. ACT UP/Golden Gate has heard a number of reports of peptide T providing relief from the pain, but not the numbness, associated with neuropathy apparently caused by d4T. The organization also heard at least two reports of peptide T failing to provide relief in this situation; it is not known if these people had a different kind of neuropathy, however. ACT UP and others are continuing to investigate the latest peptide T cutoff. For a copy of the newsletter, mail a request for the July Treatment Agenda, together with a self-addressed stamped envelope, to: ACT UP/Golden Gate, 519 Castro Street, Box #M- 93, San Francisco, CA 94114. What You Can Do It looks as though peptide T will not be available for some time, as the underground has yet to find other secure sources. In the meantime, the PWA Health Group, a New York buyers' club, is collecting names and numbers of people with AIDS, their doctors, and others concerned, in order to prepare for a concerted community campaign to secure equitable access through some form of expanded access program. For more information, or if you can help, call the PWA Health Group at 212/255-0520. ***** Political Funeral in Washington, DC, Disrupted by Police by John S. James A July 2 political funeral for AIDS activist Tim Bailey, who had asked in his will to have his body carried from the Capitol to the White House, was disrupted by police, despite extensive legal preparation and, according to funeral organizers, all necessary paperwork. After hours of delays, as police from three jurisdictions tried one reason after another to halt the 1 p.m. march, each time retreating on advice of their legal department, police gave permission, then revoked it on the grounds that it was rush hour. The march was called off and a memorial service was held near the Capitol. Bailey's brother and executor, Randy Bailey, who is not an AIDS activist, was injured by police and hospitalized. The events were filmed by several television stations, and covered in articles and photos published in The Washington Post, The Washington Times, The New York Times, Newsday, and the New York Daily News. Tim Bailey, a member of The Marys, an affinity group of ACT UP/New York, helped organize the major AIDS protest against then-president Bush in Kennepunkport, Maine, in 1991. He also contributed to demonstrations in the New York studios of CBS Evening News with Dan Rather, and the McNeil/Lehrer News Hour, while nationwide news was being broadcast, during the Day of Desperation protests in 1991. In 1976 he moved to New York from Youngstown, Ohio, to become a specialist in clothing design and merchandising. Legal assistance is needed for the defense of Randy Bailey, and of Jim Aquino, another funeral organizer who had himself arrested so that Randy would not be alone in jail. Anyone who might help could call Eric Sawyer at 212/864-5672, or Barbara Hughes at 212/533-2272. Comment The larger issue in this case is the national attitudes toward AIDS illustrated by the police behavior here -- attitudes which sabotage AIDS prevention programs and also treatment development, greatly contributing to the death toll and the overall extent of the epidemic. With anything like a sound national approach to the disease, what happened July 2 would have been unthinkable. ***** AIDS: An Expanding Tragedy -- National Commission On AIDS Final Report The National Commission on AIDS, whose authorization expired in September 1993, issued its final report, with two major recommendations: that leaders at all levels must speak out about AIDS to their constituencies, and that we must develop a clear, well-articulated national plan for confronting AIDS. The report includes 15 pages of summary and recommendations, and over 100 pages of reference material, including an indexed guide to the reports of the Commission, cumulative recommendations of the Commission, and lists of its hearings and witnesses. In its four years of existence, the Commission has heard from over 1,000 people on all aspects of the epidemic, creating a permanent, public record which will assist future AIDS-control efforts. "Our reports to date, particularly America Living with AIDS, spell out the particulars. Clearly our work is unfinished. Although the Commission has listened diligently, considered carefully, and kept the problem of AIDS before the public, most of our recommendations remain to be implemented. But it is time for AIDS to be swept into the mainstream of America's national agenda. To continue to treat HIV/AIDS as a marginal problem gravely threatens our nation's future. Without action on our nation's unfinished business on AIDS, we will have a continually expanding tragedy. We call on America to get on with the job. What should be done is not complicated. But it requires leadership, a plan, and the national resolve to implement it." For copies of this or other reports of the National Commission on AIDS, call the CDC National AIDS Clearinghouse, 800/458-5231. AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number 415/255-4659 fax Editor and Publisher: John S. James Medical Reporters: Jason Heyman John S. James Nancy Solomon Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. 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.