Treatment Issues, Vol 9, No. 2 - February 1995 Gay Men's Health Crisis, New York ---------------------------------------------- Reports from the National Retrovirus Conference by Dave Gilden, David Gold, and Gabriel Torres, M.D. In this issue we present some of the highlights of the Second National Conference on Human Retroviruses and Related Infections, held in Washington, D.C. on January 29 to February 2. The conference is well on its way to establishing itself as the major conference for presenting new research on HIV and AIDS. Next month's Treatment Issues will include a more detailed report on the Conference, including such issues as drug resistance, the treatment and prevention of opportunistic infections and clinical trial design. Viral Dynamics Viral dynamics -- the rate of HIV particle production and clearance within the body -- was a key issue dominating the Second National Conference on Human Retroviruses and Related Infections. Two leading AIDS researchers, David Ho, M.D., from the Aaron Diamond AIDS Research Center in New York and George Shaw, M.D., from the University of Alabama started off the proceedings with oral presentations on this topic. Their findings -- that production of HIV virions and CD4 cells both can exceed a billion per day -- indicate the massive struggle occurring during HIV infection. Those findings also indicate the difficulties involved in relying on antiviral drugs to eliminate the virus, especially given the number of mutant, drug-resistant variants that viral production of this magnitude makes possible. Dr. Ho reported on twenty patients with high viral loads (over one million copies of HIV RNA per milliliter of plasma) who received Abbott Laboratories' protease inhibitor. This compounded lowered study participants' plasma HIV levels by 98 percent within two weeks. The virus's exponential rate of decline indicated that the half-life of virus particles was on average approximately 2.1 days. This means that one-half of the HIV in an infected person is renewed every two days, for a daily production of 680 million HIV particles per day. This rate of renewal appears relatively constant throughout all stages of chronic HIV infection. This is a conservative estimate of viral turnover, since all virus production is not shut off by the Abbott drug. Residual virus may be due to inadequate drug penetration of tissues, drug-resistant virus, long-lived virus-producing cells and gradual activation of latently infected cells. Using a similar model, Dr. Ho calculated the rate of CD4 production and clearance based on the CD4 responses to the Abbott drug. He estimated that each day anywhere from 35 to 53 million new CD4 cells appear in the blood. Given that the lymph system contains nearly 50 times more CD4 cells than the blood, approximately 1.8 billion CD4 cells are produced in the human body per day during HIV infection. Dr. Ho's group inferred from these figures that even in persons with low CD4 counts, the loss of CD4 cells is not due to lack of production, but rather to excess destruction. He concluded from these experiments that the continuous high viral replication is the engine driving the pathogenesis of AIDS. In experiments by Dr. Shaw's group, patients were treated with the Merck or Abbott protease inhibitor, and similar viral and CD4 kinetics were seen. The Shaw team also used nevirapine, an antiretroviral agent that leads to the rapid emergence of resistant HIV. The researchers noted the appearance of mutant, nevirapine-resistant virus within two weeks. In the Ho and Shaw studies, resistance to both the Abbott and Merck protease inhibitor were observed, although some patients still had sensitive virus after six months of therapy. Also, cases of marked, although usually short-lived, CD4 increases were seen, with one patient who received the Abbott compound going from a CD4 count of 68 to 680. The implication of both of these studies is that aggressive treatment with a combination of more than one drug should be started as early as possible. Keeping HIV levels and replication at a minimum would delay the emergence of resistance to particular therapies. Dr. Ho plans to conduct a study of aggressive combination therapy, including protease inhibitors, for people experiencing initial, acute HIV infection. His goal is to assess whether lowering viral load as early as possible may alter the course of, or even eradicate, HIV infection. Protease Inhibitors ABT-538: Abbott's compound, ABT-538, continues to appear the most potent protease inhibitor now being tested in HIV- positive individuals. Dr. Martin Markowitz from the Aaron Diamond Research Center in New York presented phase I data on ABT-538. At week four, viral load reductions had decreased by an average of two logs (99 percent), and by week twelve, HIV levels were still an average of 70 percent below baseline. CD4 counts were 75 to 95 percent above baseline at week twelve in the higher doses. The maximum antiviral effect occurs within weeks of beginning therapy. It was not clear from the data how long viral load reductions are maintained on ABT-538. Australian researcher David Cooper presented additional data from a 21-patient study of ABT-538. As reported in Treatment Issues last month, two patients in this study had short-term remissions in Kaposi's Sarcoma lesions after beginning ABT- 538. Other reported clinical improvements included: regression in oral hairy leukoplakia (two patients) and weight gain of over fifteen pounds (two patients). One patient had remission of thrombocytopenia (low platelet count), and one patient experienced a clearance of cryptosporidiosis. The current formulation of ABT-538 is a cherry syrup which, company officials admit, "tastes terrible." Reported side effects include headaches, diarrhea and a cluster of symptoms including lightheadedness and fatigue, which were most common at the higher doses. According to researchers, some patients on the highest doses of ABT-538 "felt real lousy" for the first week. In a meeting with community activists, Abbott officials described two placebo-controlled trials of ABT-538 that will begin enrolling within a month. One study will enroll 250 AZT-naive patients and will measure surrogate markers (viral load and CD4 cells). The other will look for clinical benefits (differences in progression or survival) in 700 patients with less than 100 CD4 cells. In this trial patients will be allowed to take the standard of care (i.e., whatever nucleoside analog therapy they wish). The dose will be 600 mg twice a day. Abbott researchers hope to file for FDA approval of ABT-538 within four months after beginning these studies. Another study, of 900 AZT-experienced, asymptomatic people, will begin at a later date. Abbott is also doing a dose escalating study using 700 mg twice a day at Duke Medical Center in North Carolina. Some suggest that drug interactions may be a problem with ABT-538 (particularly with rifabutin and fluconazole). Saquinavir: Stanford University researchers reported preliminary data from a phase I/II study of 40 people treated with higher doses of saquinavir (3,600 and 7,200 mg per day). The findings indicated greater reductions in HIV levels and increases in CD4 levels than the 1,800 mg dose being used in phase III studies of the drug. Even at the higher doses, saquinavir was reasonably well tolerated and there was a direct relationship between blood level of saquinavir attained and greater reductions in HIV levels. The anti-HIV effect is still probably less potent than the Abbott protease inhibitor, though. Interestingly, the Stanford researchers noted that resistance to saquinavir seemed to develop at a point after HIV RNA levels had already started to rebound. Roche representatives claim that they are confident that the 1,800 mg dose of saquinavir taken in combination with nucleosides analogs will provide a "meaningful antiviral effect." The company plans to file for FDA approval of the drug by December of 1995. AG-1343: Agouron researchers presented early phase I data on AG-1343 in HIV-negative volunteers. The results showed that the drug was extremely well absorbed and well tolerated. In a meeting with activists, company officials outlined plans for a phase I study including 25 HIV-positive people in London. In the study, patients will be randomized to 100 and 300 mg three times per day for four weeks. If all goes well, a phase II study will begin in the US shortly thereafter. Agouron's data was considered reasonably impressive, but activists are concerned that the company is moving too cautiously and that the company has not outlined studies to determine the optimum dose of AG-1343. Agouron is also working on developing protease inhibitors for CMV, hepatitis C and rhinovirus (the common cold). Resistance to Protease Inhibitors Dr. Markowitz also presented work by Aaron Diamond researchers on resistance to protease inhibitors. The test tube studies suggest HIV can develop cross-resistance to the Abbott, Agouron, Roche and Merck compounds with long term use. But the resistant HIV is still susceptible to the Upjohn's protease inhibitors and a novel compound from Searle. While this study provides some more sobering news about drug resistance, it should encourage drug companies to focus more effort on developing protease inhibitors which require unique viral mutations to create resistance. New Data Provides a Second Look at 3TC Previous studies: The December, 1994 edition of Treatment Issues reported extensively on antiviral therapy with 3TC and AZT. We noted that this two-drug combination did seem to produce a "comparatively robust" effect, with HIV levels in blood plasma falling off dramatically and CD4 counts rising significantly. But questions remained as to how long-lasting and profound this response was. The conclusion that benefits from 3TC/AZT still existed a year after therapy began or that adding 3TC to preexisting AZT monotherapy preserved the latter's effect turned out to be based on meager information. Newly presented studies: At the Washington retrovirus conference, US researchers presented new data from two large studies conducted in North America. Joseph Eron, M.D., of the University of North Carolina-Chapel Hill reported on a trial of 364 persons without prior experience on AZT (oral presentation no. LB34). The group was divided into four arms: 93 were on AZT alone, 85 were on 3TC alone, and 186 received AZT/3TC combination therapy with two different doses of 3TC (150 and 300 mg twice daily). The median initial CD4 count was 351. At week four, both combination therapies had triggered a 98 percent reduction in plasma HIV levels whereas AZT alone decreased virus levels by 70 percent and 3TC alone resulted in a 95 percent drop. By week 24, virus levels in the monotherapy groups had climbed back considerably toward their original values. The combination therapy groups, in contrast, retained an 84 to 90 percent viral load decrease. The pattern was similar as far as CD4 counts go, although there was a time lag between changes in HIV levels and CD4 cell numbers in the blood. By week 24, the AZT and 3TC monotherapy groups had fallen on average almost back to their initial CD4 count while the combination therapy groups were still above baseline: People on AZT plus high dose 3TC had an average CD4 count of 58 over baseline (at week eight they averaged 66 over baseline) and the low dose 3TC combination group had an average CD4 count gain of 37 at week 24 (compared to 70 over baseline at week eight). This 40 to 60 cell superiority may be modest in the overall scheme of things (especially compared to some of the first data coming out of protease inhibitor trials), but it seemed to persist out to one year. As Dr. Eron pointed out, though, no firm conclusion can yet be drawn beyond six months because information on study participants after that point is still largely lacking. The second trial (oral presentation LB35) involved 254 people with an average of two years' prior experience on AZT and a median CD4 count of 211. The trial compared AZT plus 3TC therapy to AZT plus ddC. The results, described by John Bartlett, M.D., of Duke University, were much more disappointing in this population, which had more advanced disease than the first trial. Despite some initial superiority, AZT plus 3TC performed little better than the more traditional AZT/ddC combination. Decreases from baseline virus load were nearly the same by week 24 (and were almost below the sensitivity of the PCR assay). CD4 cell count differences were marginal: Up 32 for the low dose 3TC combination, up fifteen for the high dose 3TC combination and down fifteen for AZT/ddC. All these CD4 values were reduced somewhat from their peak values early in the trial. Analysis: The data comparing AZT/3TC and AZT/ddC in AZT- experienced individuals is particularly puzzling in that there are strong theoretical reasons, based on laboratory experiments (oral presentation no. LB33), to think that the AZT/3TC combination should represent a therapeutic breakthrough. In persons treated with 3TC, HIV becomes resistant to the drug within a matter of weeks, through a single amino acid change in the reverse transcriptase enzyme. This single mutation appears to reverse other changes in the enzyme that enable it to resist the effect of AZT. In the laboratory, it is impossible for HIV to be resistant to both drugs at the same time. Yet, giving 3TC to people on long-term AZT proved little better than adding ddC to the regimen. In the first study, 3TC alone actually performed at least as well as AZT alone even though developing resistance to AZT seems to be a longer, more drawn-out genetic process than for 3TC. High- level resistance to AZT takes months to develop and requires several genetic mutations. It would be interesting to further test combination nucleoside analog therapies such as AZT /ddC against AZT/3TC, especially in AZT-naive persons, to check if the latter combination really possesses any special magic. But theory aside, the final proof is whether combinations including AZT and 3TC provide added clinical benefit (i.e., fewer opportunistic infections) than other combinations. A one-year trial looking at these issues is now starting up in Europe. It includes 1,200 people with CD4 counts of 50 to 250, and will compare the clinical effect of remaining on current treatment (either AZT or AZT/ddI or AZT/ddC) to current treatment plus 3TC or current treatment plus 3TC and loviride (an experimental compound under development by Janssen Pharmaceuticals that blocks reverse transcriptase but is not a nucleoside analog). The problem here is that the "current treatment" rubric obscures the differences between the various regimens that do not include 3TC. Also, adding loviride, a second drug of uncertain effect throws a wild card into the proceedings. In the meantime, the 3TC expanded access program (call 800/248-9757 to register ), continues to enroll patients at the rate of 2,000 per month. Since the studies showed no additional benefit to the 300 mg dose, all patients will be given the 150 mg dose. Glaxo plans to file for FDA approval of 3TC by June of this year. Other Reports Acyclovir for HIV: While a number of studies have suggested a survival benefit from continual acyclovir (Zovirax) therapy in HIV-positive individuals, two studies presented at the conference, a placebo-controlled ACTG study (oral presentation 383) and an observational study conducted by Johns Hopkins University (oral presentation no. 382), failed to find such a benefit. A more detailed analysis of the acyclovir results will appear in the March Treatment Issues. Flu vaccinations and HIV: A number of poster presentations reported that influenza or pneumoccocus vaccines can temporarily increase the levels of HIV in HIV-positive individuals. Researchers from the University of Nebraska said that pneumoccocus vaccines resulted in a rapid, and in some cases profound increase in viral burden (poster 240). A consortium of medical centers in San Francisco reported that "a substantial, yet transient increase" in HIV RNA was observed in 78 percent of 30 HIV-positive individuals who were given influenza vaccines and then closely monitored for changes in viral load (poster 151). It is still unclear whether these transient increases in HIV levels have any clinical meaning at all. Moreover, the possible risks from vaccination have to be weighed against the serious dangers that influenza or pneumonia may cause in HIV-infected individuals. Saliva's anti-HIV protein: Researchers from the National Institute of Dental Research said they have identified a protein in saliva that inhibits HIV (poster 165). The test- tube studies suggest that the protein, called SLPI (secretory leukocyte protease inhibitor), attaches to white blood cells and prevents HIV from infecting those cells. Amgen, a California based biotech company, is studying whether SLPI has application as an anti-HIV treatment or as a viricidal adjunct to safer sex. Good news for gym queens: An observational study at the Naval Medical Center in San Diego suggested that HIV-positive individuals whose workouts consisted primarily of weight- lifting lost fewer CD4 cells over a 24 month period than those whose exercise came mostly from running (poster 544). HIV Integrase: A New Therapeutic Target by Vincent Pieribone, Ph.D. The surging interest in new viral targets has brought about the first scientific meeting dedicated exclusively to the HIV enzyme integrase (January 19 to 20 at the National Institutes of Health in Bethesda, MD). What is Integrase? HIV integrase is the virus's third enzyme (the other two are reverse transcriptase and protease). HIV uses integrase to incorporate its genes into a host cell's DNA. (The DNA form of the viral genes is produced by reverse transcriptase.) Inhibition of HIV integrase is an attractive therapeutic strategy since it would potentially protect healthy cells from infection thereby helping to bolster the immune system. Promising Reports At the conference, several laboratories presented ongoing work that may lead to agents that could block integrase's action. Notably, workers at the National Institute of Diabetes and Digestive and Kidney Diseases have determined the three dimensional structure of the central catalytic region of the enzyme. By knowing the structure of the enzyme's active site, scientists can begin to "design" compounds that bind to and possibly inhibit the enzyme. This "rational" approach proved successful in producing inhibitors of HIV protease. Sometimes merely knowing the structure of the enzyme reveals a similarity of other related enzymes for which cross- specific inhibitors may already exist. Researchers have found that integrase resembles the structure of cellular RNAase H and another DNA binding protein termed mu-transposase. Dr. Stephen Goff of Columbia University has used a novel molecular biologic technique to identify a host protein that binds to integrase and dramatically enhances its activity. Working with HIV integrase, the protein seems to help the viral genes to join properly with cellular DNA. In screening the National Cancer Institute's drug library, Dr. Yves Pommier's laboratory has discovered three classes of compounds that are effective at blocking HIV integrase. These include DNA binding molecules, polyhydroxylated aromatic compounds and various nucleotides. Polyhydroxylated aromatic compounds naturally occur in a variety of plants. One active form is found in nectar from flowers and is used by bees to improve their hives. Some synthetic derivatives are ten times more potent at blocking integrase and have exhibited some anti-HIV activity in an NCI in vitro screening test. Another promising lead reported at the meeting was a short inhibitory peptide that was extracted from a synthetic "combinatorial peptide library." These libraries consist of millions of different peptides with known sequences. By systematically testing mixtures with progressively fewer numbers of different peptides, one can identify the exact sequence of a peptide (or peptides) that has inhibitory activity. Using a collection of compounds synthesized by Houghten Pharmaceuticals in San Diego, Dr. Ronald Plasterk's group from the Netherlands Cancer Institute found several lead peptides that inhibit HIV integrase. While these peptides are too large to be clinically relevant, they do provide structural constraints that chemists can use to create second generation molecules with more therapeutic potential. Finally, the French company Rh™ne-Poulenc Rorer has been screening their large chemical collection and have identified several lead compounds. Probably the most exciting outcome of the conference was the fact that so many large pharmaceutical companies attended the meeting. This indicates a growing interest on their part in developing compounds active against integrase. Potential Drawbacks Integrase as a therapeutic target does have several possible pitfalls. While HIV reverse transcriptase and protease are required to act for a significant period of time during the viral life-cycle, integrase acts for only one brief step during infection of the cell. This reduces the chances that a drug will interfere with integration. Conversely, however, the intracellular levels of integrase may be extremely small, and this scarcity works in favor of an integrase inhibitor. Also, interfering with the integration step would not affect the yield of viable virus from infected cells. Since HIV seems to produce a great deal of mutations throughout its genes, inhibition of existing HIV integrase may merely cause the rise of drug-resistant mutant versions. The hope is that a combination of therapies targeting different enzymes, including integrase, will convey lasting benefit to the infected person by reducing HIV's replication rate, and therefore the emergence of mutant strains. Another Look at IL-2 Therapy for HIV by Craig Sterritt Over the past dozen years, a major effort has been under way to develop the natural immune system stimulant IL-2 (interleukin-2) as a therapeutic weapon against HIV. IL-2 induces the multiplication of CD4 (T-helper) cells in the test tube. If the same effect can be achieved in the human body, CD4 cells destroyed by HIV could be replaced, and the immune system perhaps reconstituted. There is also a substantial body of evidence suggesting that HIV is controlled in the body during the early period of infection by a strong response by the cell-mediated arm of the immune system (chiefly suppressor and cytotoxic CD8 T- cells activated by IL-2 released by CD4 cells). The cells involved in this response gradually lose their ability to effectively respond to HIV and other pathogens, possibly owing to a decline in IL-2 production by CD4 cells. Intermittent Continuous IL-2 IL-2 trials in the past found that the molecule's positive influence on CD4 cell numbers disappeared after a few weeks of continuous infusion therapy. Cells seemed to become refractory to IL-2 after chronic exposure to the compound. But an as yet unpublished study of IL-2 conducted by Joseph Kovacs, M.D., and H. Clifford Lane, M.D., at the Laboratory of Immunoregulation (part of the NIH's National Institute of Allergy and Infectious Diseases -- NIAID) for the first time observed substantial and prolonged IL-2-induced CD4 cell increases. The NIAID trial employed a unique cyclical dosing regimen rather than administering IL-2 on a steady weekly schedule as previous trials have. Every eight weeks, study participants received a five-day continuous IL-2 infusion of six to eighteen million international units (IU) per day. This regimen of intermittent continuous infusion lasted for eleven to 25 months. In the course of the study, sustained CD4 cell rises of greater than 50 percent were seen in six out of ten patients who started with over 200 CD4 cells per cubic millimeter of blood and were on stable antiretroviral therapy. Three patients experienced three- to four-fold increases in CD4 counts over the course of the trial. In addition, Dr. Lane now reports that three initial responders whom he has followed for nearly three years have been able to maintain CD4 counts in the high normal range of greater that 1,000 by receiving "booster" five-day infusions whenever their CD4s drop below 1,000 (every seven to twelve months). (It should be emphasized that these patients who remained on therapy are the IL-2 "success stories." They do not necessarily represent the average patient's experience with IL-2.) A new, larger trial is following 60 participants with CD4 counts greater than 200. The trial is comparing intermittent continuous IL-2 (18 million IU/day for five days every eight weeks) combined with antiretroviral drug therapy to antiretroviral therapy alone. The trial is still underway and results are not yet available. Two separate informed sources, however, have told Treatment Issues that CD4 responses similar to those in the first trial are occurring. One source also reported that several participants who received between three and six infusions in the ongoing study have had CD4 counts of over 1,000 for as long as seven to eleven months since their last infusions. As in the follow-up of the first trial, these participants will receive additional five-day courses of IL-2 whenever their CD4 counts drop below 1,000. The source added that CD4 increases in many individual cases are detectable only after several infusions. Rather than diminishing over time, the increase observed after infusion tends to become greater with additional courses of IL-2. Advanced Disease and Viral Load Results from experiments using the same IL-2 regimen in patients with lower baseline CD4 counts have been less encouraging. Earlier IL-2 studies had indicated that treatment benefits were less likely to be seen in patients with AIDS or with low numbers of circulating CD4's, and the NIAID data confirmed these findings. Only two of six patients with baseline CD4 counts of 100 to 200 have demonstrated significant CD4 increases (greater than 50 percent) while none of the six patients with CD4 counts lower than 100 had such increases. The majority of study participants with low CD4 cell counts also had significant, lasting rises in their HIV levels in the blood (as measured by p24 antigen and viral RNA assays). In contrast, the participants in the higher T-cell group had transient increases in HIV RNA just after IL-2 infusion (up to six-fold). Their HIV levels returned to their original point before the next infusion. Those higher CD4 cell participants who added an additional antiretroviral drug during the study had reduced increases in viral load and improved CD4 responses. There has always been a grave concern that IL-2 stimulates HIV along with T-cells. The virus reproduces in infected, activated CD4 cells, and HIV-free activated CD4 cells are especially vulnerable to becoming infected. The NIAID observations suggest that IL-2 boosts both CD4 counts and viral levels, and that IL-2's treatment effect may be determined by a tradeoff between the ability of IL-2 to stimulate CD4 cells and the ability of increased amounts of HIV to destroy CD4 cells. In addition, NIAID director Anthony Fauci, M.D., has suggested that IL-2 stimulates "CD8 suppressor cells" which block HIV replication within infected cells. These suppressor cells are lost in advanced disease, and this may help explain the different responses to IL-2 in the high and low CD4 cell groups. Immune Function Researchers have presumed that a boost in CD4 cells is a good sign. There is, however, no way of knowing at this time if an IL-2-induced CD4 count of 1,000 is as good -- or anywhere near as good -- as a naturally occurring CD4 count of 1,000. We cannot assume that IL-2-induced CD4 increases will translate into any clinical benefit, such as delayed disease progression or prolonged survival. The NIAID trials unfortunately have not observed the qualitative immune improvements seen in previous IL-2 trials with various regimens. Such markers include increased natural killer (NK) and lymphokine activated killer (LAK) cell function. Indication of heightened cell-mediated immunity -- greater CD8 and cytotoxic lymphocyte (CTL) numbers and activity and a more intense reaction to delayed-type hypersensitivity (DTH) skin tests -- also were lacking. Some of the cell-mediated immunity tests (CTL, DTH) were not carried out during the NIAID trials while others (CD8 numbers) remained unchanged in trial participants. In a telephone interview, Dr. Lane reported that during lab tests, T-cell replication upon exposure to certain test proteins increased in some patients, and this improvement may correlate with the observed increase in IL-2 receptors on cell membranes. No patients whose CD4 cells were unresponsive in these proliferation tests prior to IL-2 became responsive following IL-2 therapy, though. Dr. Lane could only speculate as to why indices of NK and LAK cell activity were unchanged by IL-2, which ordinarily stimulates such cell populations. The absence of information about CTL and CD8 activity is particularly worrisome given that this might be the immune system's strongest anti-HIV response. Clinical Symptoms Dr. Lane and Dr. Gwen Fyfe (of Chiron Corporation, the manufacturers of Proleukin brand IL-2) expressed concern that once IL-2 therapy is begun, CD4 count and slope (the rate at which CD4 counts are going down) no longer have any value as a prognostic marker or as a tool for making treatment and prophylaxis decisions. One patient in the NIAID trials (who received IL-2 but was not considered a responder) subsequently developed Pneumocystis carinii pneumonia (PCP) with a relatively high CD4 count of about 400 as well as an extremely high viral burden. In addition, two HIV-positive patients in the Washington, D.C. area developed PCP with CD4 counts over 300 after receiving intermittent continuous IL-2 from their private doctors. (See below for other cautions about community use of IL-2.) IL-2 may either boost or preserve CD4 numbers without necessarily making those cells competent. Alternatively, IL-2 may simply cause a "retrafficking" of CD4 cells, in which cells enter the blood from the lymph system, where 95 percent of them are concentrated. Dr. Lane is currently examining lymph node and tonsil biopsies before and after IL-2 therapy to ascertain to what extent IL-2 induces CD4 cell increases there as well as in the blood. More exacting methods will probably be necessary to accurately determine the retrafficking phenomenon's extent. Safety and Toxicity The original IL-2 dose for these studies was 18 million IU per day, but the majority of patients required dose reductions to either twelve or six million IU, primarily because of the debilitating side-effects that historically have accompanied high-dose IL-2 therapy. These include fever, severe flu-like symptoms, capillary leakage, lung congestion and swelling, liver, kidney and gall bladder disorders, neutropenia (low neutrophils, a type of white blood cell), thrombocytopenia (low platelets), glucose intolerance and irritating dermatologic problems such as psoriasis flare-ups. Some participants have dropped out of the NIAID trials due to the severity of the symptoms. But most found that the side- effects, though very unpleasant, were at least temporary under the intermittent regimen. One participant in the ongoing trial noted that a recovery period of two to three days following the five-day infusion in most cases restored completely normal daily functioning. Community Use of IL-2 There are various reports that people with HIV and their doctors are obtaining commercial IL-2 (brand name: Proleukin), which is approved for the treatment of renal cell carcinoma, and trying to mimic the NIAID protocol. All of the findings discussed here are preliminary, and there is no indication as yet that IL-2 can yield any clinical benefit to people with HIV. Some community sources also are attempting to administer IL-2 by injecting it under the skin rather than infusing it into a vein. This technique is particularly problematic (see below). Drs. Lane and Fyfe are wary that patients most likely to seek out an unapproved AIDS therapy, especially a toxic one like IL-2, are those who are failing currently available treatment options and consider themselves to have a poor prognosis. According to the data from the NIAID and earlier trials, such persons are the least likely to reap any immunologic benefit from IL-2 therapy. The NIAID studies further imply that IL-2 can accelerate disease progression in patients with CD4 counts below 200 by substantially increasing HIV levels. Dr. Kovacs has hastened to add on several occasions that the HIV-promoting nature of IL-2 is probably worst among patients in whom HIV has developed resistance to the antiretroviral drugs they are taking. It is possible that drug-resistance in the lower CD4 cell groups, besides higher viral burdens to begin with, contributed to the sustained increases in viral levels. The current consensus among investigators is that if there is any recipe for success with IL-2, it includes higher baseline CD4 counts, lower baseline HIV levels, and the presence of a strong antiretroviral drug effect during IL-2 therapy. It is hoped that future analyses of ongoing and upcoming trials will be able to determine the specific factors that determine an individual's response to IL-2 therapy -- such as CD4 count, percentage, HIV characteristics and virus level. Persons with HIV who insist on trying IL-2 should have their doctors procure information on contraindications, safety and viral monitoring from investigators involved in ongoing IL-2 trials (See box). Future Directions Dr. Lane stated that his lab's first goal, to discover if IL- 2 can be used to sustain significant CD4 increases, has been accomplished in a preliminary fashion. The larger, randomized trial described above is pursuing more detailed data along these lines. A second goal is to see if the same effects can be accomplished in patients with more advanced HIV disease when IL-2 is administered in conjunction with a potent, new antiretroviral drug -- namely, the Merck protease inhibitor. Preliminary studies of the Merck drug indicate that unlike the nucleoside analogs, it may have a very strong antiviral effect in later-stage HIV infection. As a brand-new drug, HIV resistance to the compound is not an immediate problem either. Dr. Lane believes that by strongly suppressing viral replication during IL-2 therapy, CD4 responses may be much more pronounced in late-stage patients. A small trial in persons with CD4 counts lower than 100 is currently enrolled, and Dr. Lane is hopeful that this approach can be expanded in a larger follow-up study. Another goal is to discover ways to achieve the same CD4 effects without the onerous, risky and expensive five-day infusions every eight weeks. As mentioned above, it is possible that following an initial phase of three to six infusion cycles, individuals may be able to maintain normal to above normal CD4 counts with less frequent dosing -- possibly only once or twice a year. Another possibility is to reduce the infusion period to three or four days rather than five -- this will be the subject of a Chiron-sponsored trial. In a very different approach, investigators are examining the efficacy of IL-2 injected subcutaneously (under the skin). An efficacious subcutaneous regimen is a major goal of Chiron. A company study is evaluating a two-week on/two-week off treatment cycle in which twelve million international units are injected once daily for five days in each "on" week. This study is still underway, but already many participants have had their daily doses reduced to nine or six million IU. Sources told Treatment Issues that the regimen is not meeting with profound success, possibly due to either the brevity of the treatment intervals or the lack of continuous exposure to IL-2. NIAID investigators have also found discouraging results with once daily injections of IL-2. They are now seeking to determine if IL-2 blood levels and CD4 rises comparable to those obtained in the intermittent IL-2 infusion trial can be achieved with two to three subcutaneous injections daily for five days every eight weeks. Another study, conducted by Applied Immune Sciences in California, has yielded data on the effects of twice daily subcutaneous injections for five days every four weeks (with and without concomitant infusion of proliferated CD8 cells taken from the patient). Injected doses of two or four million IU per square meter of body surface per day each caused a 1.4-fold mean CD4 cell increase for the duration of the trial (over nine months). The CD8 infusions gave no extra benefit. A third goal is to reduce the severity of side-effects associated with higher doses of IL-2. Some suggest that most of the toxic effects of IL-2 therapy are caused by elevated levels of tumor necrosis factor (TNF), an immune system modulator released by cells in response to IL-2, which is also known to increase HIV replication. There are plans to explore intermittent continuous IL-2 in conjunction with such TNF inhibitors as pentoxifylline (PTX), thalidomide and the Centocor anti-TNF monoclonal antibody (MAb). Drs. Lane and Fyfe say PTX and the Centocor MAb will probably be studied in NIAID-sponsored trials, while the thalidomide/IL-2 trial is under consideration by Chiron and investigators in the United Kingdom. Findings from studies of PTX alone, as well as reports from a few patients who have received PTX in conjunction with IL-2, indicate that PTX is not that effective in decreasing TNF levels. Thalidomide and the Centocor MAb (besides newer TNF-inhibitors under development) are now more promising candidates. Conclusion Despite the remaining unknowns, there is considerable excitement among IL-2 researchers over the intermittent continuous IL-2 findings. NIAID's Division of AIDS has just commenced working on a comprehensive, long-term development plan for IL-2 in collaboration with Chiron. The plan's purpose is to delineate the fastest and most accurate way to determine if IL-2 should be taken into large-scale efficacy trials and then to envision how to conduct such trials. A logical next step will be to couple long-term follow-up of patients in current and upcoming IL-2 trials with in-depth analyses of IL-2's biologic effects. There is an immediate need to determine what IL-2's exact effects upon the immune system are and whether those effects are likely to slow the progression of HIV disease. A precise evaluation of the amount of real T-cell proliferation that occurs compared to the amount of T-cell retrafficking is of particular importance. Another objective is a broad determination of the specific types and usefulness of all the immune cells influenced by IL-2 therapy. IL-2-induced CD4 increases ultimately will need to be correlated with explicit improvements in immune function for the therapy to proceed into large, expensive efficacy phase III trials. Improvements in immune function will then need correlation with clear health and survival benefits in order for IL-2 to be validated and approved as a treatment for HIV infection. Issues to Consider Before Starting IL-2 IL-2 therapy is not approved for HIV disease. But because it is approved for other conditions, a number of doctors around the country are currently offering IL-2 to HIV-positive patients. Some of these doctors are giving patients injected IL-2, while others are offering infusions of IL-2 similar to those used in the NIH trials. Both doctors and patients should consider the following issues before initiating IL-2 treatment: 1. IL-2 therapy can be very toxic, particularly in high doses (3-18 million IU/day). It can cause severe flu-like symptoms that will interfere with normal daily functioning. During IL- 2 infusions, you should have someone with you in the event that respiratory or other complications arise. Liver and kidney function and blood pressure should be monitored during therapy. Individuals with heart problems or active opportunistic infections should not experiment with IL-2. 2. IL-2 therapy has been shown to increase levels of HIV. These levels often go back to baseline in a matter of days or weeks. Nevertheless, all patients given IL-2 must remain on antiretroviral therapy. Antiviral therapy should include at least one new agent to which your virus is not resistant. New antiviral drugs should not be started at the same time as IL- 2 since it may be impossible to distinguish between side effects from IL-2 and the new drug. 3. HIV levels must be monitored closely in all patients given IL-2. New methods of measuring HIV RNA in the blood, such as PCR or branched DNA tests, should be used both before starting therapy, to establish a baseline level, and several weeks after each infusion. These new HIV tests cost more than $200 a piece. Increasing virus levels are a warning that IL-2 therapy is failing or is counterproductive. 4. It is not clear whether the large increases in CD4 counts often seen with IL-2 therapy have biological significance or translate into any benefit to patients. 5. IL-2 does not appear to increase CD4 cells in patients with low CD4 counts (less than 100). In fact, these patients are far more likely to get an increase in HIV levels from IL- 2. Studies completed so far do suggest that patients with over 200 CD4 cells have a good chance of receiving a CD4 boost from IL-2 therapy. 6. IL-2 infusions are extremely expensive around $2,000 per four or five day cycle. These cycles are repeated every eight weeks. Patient advocates at Chiron, the manufacturer of IL-2, can talk to your insurance company about the cost of the actual drug and will provide it free of charge if your insurer will not pay. This does not include the cost of infusions, which are the most expensive part of IL-2 treatment. 7. If you use IL-2, you may be excluded for clinical trials of new therapies. 8. ACTG 248, a trial of low dose, injected IL-2, will soon begin enrolling individuals with CD4 counts of over 300 at several sites across the country (including New York). Patients will receive IL-2 therapy for at least six months. All necessary blood work and medical monitoring will be included at no cost. For more information, call 800/TRIALS-A. There will be a forum on IL-2 therapy for HIV on March 20, 1995 at 8p.m., at St. Vincent's Hospital, Cronin Building, tenth floor auditorium, Seventh Avenue and Eleventh Street, New York City. Larry Kramer on the Politics of AIDS Research Larry Kramer co-founded GMHC and founded ACT UP. In 1986, Kramer began publicly pressuring GMHC to start a treatment newsletter and hire Dr. Barry Gingell, a noted physician and PWA, as editor. Shortly thereafter, in 1987, Treatment Issues began publication with Barry Gingell as its first editor. Since that time, Kramer's AIDS activism has focused primarily on AIDS research and, as he describes it, "the fight for a cure." He maintains a wide network of contacts among AIDS researchers, physicians, activists, government officials and those in the media and has not hesitated to attack, often in bitter and personal terms, individuals and organizations (including GMHC) with whom he may disagree. Larry Kramer is described in The Gay 100: A Ranking of the Most Influential Gay Men and Lesbians, Past and Present (Citadel Press, 1995) as, "Rude, opinionated, inconvenient, invaluable, and irreplaceable, he is the most influential gay man in America today. The organizations he helped found have become some of the most important institutions in contemporary gay America's struggle to survive. If the community does in fact survive, it will owe that survival in no little degree to Larry Kramer." Dave Gilden and David Gold of Treatment Issues spoke with Larry Kramer in his Manhattan apartment and got his views on the politics of AIDS research. Overall AIDS Research TI: Where do you think we are in terms of the AIDS research effort? KRAMER: It's hard to know because there's no one in charge and it seems to be worse under Clinton. He has been grotesquely and tragically useless on AIDS. In terms of AIDS research, we were actually better off under Bush. Everything seems more fractured and splintered. There's less communication than ever. The Office of AIDS Research [OAR] has been an enormous disappointment. It's split whatever NIH effort was going on into different camps that don't seem to get along well. Fauci, Gallo, Paul and Broder -- nobody talks to anybody else. The most interesting research is being done outside of the government at places like the Aaron Diamond Center, the Salk Institute, Dr. Cecil Fox's Molecular Histology Lab, and at various drug companies. All this has little to do with government. So one wonders what we get from the $13 billion a year that goes to the NIH. Did you know there's never been a cure for any major illness that has come out of the NIH? TI: What about William Paul [Director of the OAR]? KRAMER: Bill Paul is a nice man and a smart scientist, but he has no sense of urgency. He is a wimp. This would not have happened but for the lessening of ACT UP's energy. TI: But before the OAR reforms no one at NIH was looking at how AIDS research dollars were being spent. KRAMER: The OAR changes killed our only friend down there -- Tony Fauci [Director of NIAID, the NIH institute with the largest AIDS research program]. He invited us in. It was a courageous and generous act that allowed the activist community to get what power it does have. TI: What about the Director of NIH, Harold Varmus? KRAMER: Harold Varmus, like William Paul, has been an enormous disappointment. He is not interested in AIDS and does not appear capable of making everybody sit down at the same table and talk -- of being the general. TI: What are your current thoughts on Tony Fauci? KRAMER: Well, your publication has been harsh on Tony, and there are things to be harsh about. But emasculating Tony, which is what has happened because of the OAR reforms, resulted in us getting something worse. When we got rid of Dan Hoth [former assistant to Fauci and director of the Division of AIDS -- DAIDS] what did we get? Jack Killen [current Director of DAIDS]. TI: But Tony Fauci's job is to attract quality people to NIAID and oversee operations such as the ACTG [AIDS Clinical Trials Group], which is a mess. KRAMER: Tony hasn't been a very good administrator, but he's a brilliant scientist. And it's hard to get anybody to work for the NIH because the salaries are so low and because the place is such a cesspool of mediocrity. Why has Tony become the lightning rod of all the anger? Why did nobody go after Sam Broder [the outgoing Director of the National Cancer Institute -- NCI]. Or Varmus? The same thing happened here in New York. We spent so much energy going after Ed Koch and never went after Cuomo, D'Amato or Moynihan. These people, in some instances, were more important than Ed Koch. TI: What about Robert Gallo's work? KRAMER: Some very important work has come out of Gallo's laboratory at the NCI and we need him to continue. Two of the most important people in AIDS research, Bob Gallo and David Baltimore, have been crucified by Congressman John Dingel for exceedingly petty reasons. We've lost two of the smartest brains in AIDS research because some idiot Congressperson who doesn't know anything about humanity has killed them. David Baltimore should have been in charge of all AIDS research in this country. TI: What about the AIDS Drug Development Task Force that was announced with great fanfare last year? KRAMER: It meets once every three months, which is shocking. A number of members would like it to meet every month. They've asked Kessler [FDA Commissioner David Kessler] to meet every month and he has refused. So I called David and he said there simply isn't enough stuff to push through for a monthly meeting, which is kind of scary. Secondly, he wants to get the Abbott protease [inhibitor] out fast and doesn't want to upset the apple cart. So let's see what he does with the Abbott compound. If the members themselves can't get the damn committee to meet every month, how can I do it? [But] Kessler is the least of our problems at this point. Approving AIDS Drugs TI: So you think the protease inhibitors are ready for accelerated approval? KRAMER: Absolutely. Why aren't we fighting for the Abbott protease the way we fought to get aerosolized pentamidine approved? We fought so hard in the early days of ACT UP to get a bunch of lousy drugs released. Now, when there are decent drugs on the horizon, nobody is fighting for access. You're talking to someone who could make a good case that we don't need an NIH, an FDA or an ACTG. We know more about AZT and how it works from patients taking it than we have learned from a billion dollars' worth of trials. This is what makes me so angry with groups like TAG [Treatment Activist Group], which are advocating a return to a rigid system of drug approval that we spent so much time dismantling. TI: Some would suggest that we don't know how to use these drugs or if they are beneficial. KRAMER: Well, large simple trials may not give you the answer. Chemotherapies for cancer have been in existence for 40 years and still haven't produced consistent results. Doctors can learn more about how to use a drug from personal experience on their patients than from clinical trials that may take ten years. TI: So, if a drug has anti-viral effect and a known toxicity profile it should be approved? KRAMER: Yes. TI: But just because a drug is safe, doesn't mean that it works. KRAMER: You'll find out soon enough. And "safe" is a very loaded word. Chemotherapy is not always safe. "Effective" is the better word. There are very few drugs that work across the board and do not have side effects in somebody. TI: But if a person is taking a bunch of drugs we may not know whether one drug is useful or not. KRAMER: Enough is known about the Abbott drug for it to be available right now, period. It is criminal to withhold that drug. We are in desperate straits and we need drugs out there faster. Researchers who we all respect think that the Abbott protease is good, including David Ho [director of the Aaron Diamond Center]. I would rather listen to David Ho than to the 25 mediocre doctors who are going to do an ACTG trial that will take four years. I have no faith in the drug delivery system in this country, as it presently stands. That includes the NIH, which is a cesspool of utter mediocrity, the ACTG which is $68 million down the toilet every year, and the FDA. There are cheaper and more efficient ways to collect data, such as using small quick trials and private physicians as data collection points. TI: But what if the effects of the Abbott protease inhibitor as a single agent are only for three to six months? KRAMER: Well, so that's three or six more months than most people have. It's probably not the cure but it's the next step, at a time when AZT isn't working on a lot of people. TI: Are you concerned about raising false hopes with the protease inhibitors? KRAMER: There's nothing wrong with hope that may not pan out. Hope keeps you alive. No hope, you slit your wrist. Both hope and panic can be useful and humane tools. Overhauling AIDS Research TI: Are things going to get worse, in terms of AIDS research, under the Republican-controlled Congress? KRAMER: I don't think it makes any difference who's in office -- who's the President or who's running Congress, Republican or Democrat. It's taken me fifteen years to come to this dreadful conclusion. What people don't understand is that you have to change the system, but the system doesn't change. It is run by civil service bureaucrats and laws on the books since 1776. No one ever bothers to change the system of how research is done, grants are funded or people are hired. TI: So how would you change the system? KRAMER: It will require a revolution and it's simply not going to happen. The more sensible question is, what can we do, that is possible, to make things go faster? Prevention education does not seem to work. Rates of HIV infection among young gay men continue to go up. That does not mean we should give up educating, but we must spend more time pressuring the system so that research moves faster. And if you want some suggestions I've got them. TI: Go right ahead. KRAMER: To begin with, the people who are important in AIDS research have to meet on a regular basis. The important ones in government, Fauci, Varmus, Paul, Kessler, Phil Lee [Assistant Secretary of Health], and Patsy Fleming [the new White House AIDS Coordinator] have to meet once a week and somebody has got to push them into establishing clear goals -- and meeting them. These people, believe it or not, do not speak to each other on a regular basis. Everybody has their own little fiefdom and that's grotesque. If I'm running a large corporation that's going to be any good, all my department heads would have to meet with me on a regular basis and show results. All these people report to Bill Clinton and Donna "Do- Nothing" Shalala. So, the apparatus is there. Hopefully, Patsy Fleming will somehow bring this about. But I'm told she feels she can't step into AIDS research. If that's true, and I hope it isn't, then Patsy Fleming is useless. Second, combinations of anti-viral drugs must be studied more quickly and aggressively. Third, why isn't anybody doing any major research on monkeys? This has been advocated by Dr. Cecil Fox. When it was put to Bill Paul and Tony Fauci both said, "Oh, yes, we're rushing to work on monkeys." Well, nothing has started on the monkeys. Why isn't combination therapy being studied on the monkeys? Or immune therapies like cyclosporine? It's just ludicrous. There's been a monkey model for this illness for how long? Why aren't GMHC and other groups providing pressure in this area? This is probably the biggest oversight going right now. Fourth, research on monkeys must be done by virologists, not by veterinarians. Evidently, part of the problem is that a lot of the monkey work is being controlled by veterinarians who do entirely different kinds of experiments than virologists. They do not understand AIDS the way a virologist does. Fifth, why isn't more work being done with infected babies? This is an ideal chance to use early intervention. How much earlier can an intervention be than in an infected baby? Here again is a population of patients that we're overlooking. Sixth, we need to get more drugs into the pipeline. Drug companies must be convinced to screen their chemical libraries. I'm grateful to David Ho for explaining this to me. The large companies, which have libraries with more than 100,000 compounds, should be screening their compounds against assays to study anti-HIV effect. This is one reason there are so few drugs in the pipeline. Why aren't we pressuring companies to do this? Some kind of apparatus has to be set up whereby companies are encouraged to do this, through tax credits or whatever. And, again, you come up against the terrible lack of somebody in charge who can convince the drug companies to do this work. Seventh, we need to make better use of data from the AIDS cohort studies. People who have data from the cohort studies, like those in San Francisco or at the New York Blood Center, have refused to share this data with other researchers. It is simply tragic that the New York Blood Center doesn't automatically provide these samples when a reputable scientist comes along and needs access to them. And no reason is given. These studies were funded by the government. What kind of attitude are we dealing with here? Eighth, we still don't know enough about pathogenesis of this illness -- how does the virus get into a person, step by step? What type of immune response do we need for a vaccine? Why aren't we making greater use of monkeys for this type of basic research? Ninth, it's wrong that the smartest researchers are forced to spend 30 to 40 percent of their time running after money. There's got to be some emergency mechanism set up so that the brightest scientists are allowed to have more free time to research. The dreadful thing about the current system is that it rewards the mediocre and punishes the smart. We're never going to get any kind of cure that way. Again, this is an area where private foundations should step in more. The Howard Hughes Institute, which has a gigantic amount of money, should take even more of a lead in this. Tenth, we've got to figure out how to attract promising researchers into AIDS. In this respect, the NIH can learn from the drug companies. Corporate people set goals, pay people a decent salary and give them decent benefits to achieve those goals. If those goals aren't reached, then they are out of a job. That's why the most exciting AIDS research is taking place outside of government. Now,these things are not impossible to do. The fact that they are not being done brings us back to the same problem -- nobody is in charge. There's no person with guts, persuasive powers, administrative skills and scientific knowledge who is in charge. Fauci, Varmus, Phil Lee, these are people who are not particularly strong at being leaders. TI: Who, in your mind, is this kind of leader? KRAMER: We tried Lowell Weicker, Lee Iacocca, Roy Vagelos and Admiral Watkins. The world is not short of these kinds of people. Major corporations around the world are run by them. These people are identifiable, and they're not controversial. Admiral Watkins did an amazing job on the AIDS Commission with a bunch of people who hated each other. So did the late David Rogers. Why is this useless President refusing to cast a net for someone like this? The Community Response TI: Why has the community been ineffective in the area of AIDS research? KRAMER: I have come to the terrible and sad realization that I don't know why people don't fight when their lives are threatened. We don't and we haven't. A few of us have died fighting. There's been an effort, but certainly not commensurate with the power and money that this community has at its disposal. I will obviously go to my death not knowing why. TI: You've criticized major AIDS service organizations such as GMHC and APLA [AIDS Project Los Angeles] for not devoting enough resources to treatment advocacy. KRAMER: I have, and I continue to do so. It is an abdication of these organizations' primary responsibility, which is to fight for the lives of their clients. The leaders of all of these organizations need to be more visible in the area of fighting for AIDS research. TI: But the core work of these organizations is to provide direct services to people with HIV, most of whom are in desperate need of such services. KRAMER: Why does it have to be either/or, direct services or fighting for a cure? GMHC and APLA get a lot of money. These organizations were not started just to be one thing! TI: But some suggest that it's easy for Larry Kramer, who lives on Fifth Avenue and East Hampton, to say we shouldn't spend so much money on direct services. KRAMER: I've never said that at all. I've said that you should spend more money and energy fighting the system and fighting for AIDS research. These organizations rarely seem to confront the system. TI: What about our organizations in Washington, such as AIDS Action Council? KRAMER: Who are they? AIDS Action Council has been like so many other AIDS organizations -- a waste of money. It has been run by people who are not very good and has achieved very little. It was set up initially by Paul Popham and myself to be a Washington presence separate from GMHC because in those days GMHC was looked upon as hogging everything and other AIDS organizations around the country resented it. So we attempted to set up an organization that would represent everybody. But it turned out to be mostly funded by GMHC -- and still is, as far as I know. The fact that GMHC continues to give money to it is something that I've never understood. GMHC would be better off funding its own Washington lobbyist. [Editor's note: Derek Hodel has recently been hired by GMHC in a newly created position, Director of Federal Affairs.] It's a never-ending pattern with our Washington organizations. We send people to DC to fight the system, they get invited to lots of lunches and become part of the system. TI: So how do you avoid that? KRAMER: You avoid it by asking for a return on your money. If GMHC is funding AIDS Action $200,000 a year, you say, "I want to know what I'm getting for my $200,000 a year." You set goals and demand results, like in any corporate environment. And quite frankly, if that were the case, you would have stopped funding AIDS Action long ago. TI: How do we get more government monies allocated for AIDS research? KRAMER: Everybody fights for more money, but the real issue is making sure the money is well spent. You can get more money for the ACTG, Bill Paul, and for an awful lot of inferior entities but it's not going to solve the problem. The problem is seeing that the money is spent wisely and given to smart people so that things move faster. Again I use the example of the monkeys. Do you know that because of the bureaucracy and red tape, it takes two years to requisition a monkey at the NIH? So it's irrelevant that the money is there. You can't get the monkey because of red tape. So AIDS Action, Patsy Fleming, the OAR, GMHC or APLA must all exert pressure to eliminate these delays. The "right wing" and the "religious right" never give up. They know that they are going to have to fight until the day they die. And there's no wavering. We give up very quickly. We must get a different mind-set on this, that you just simply cannot stop fighting. TI: So, what needs to be done? ACT UP is kind of burned out. KRAMER: I don't know whether what ACT UP does works anymore. You can make the system work by raising our voices and reaching increasing numbers of people. For a while ACT UP was able to do that. We're weak now because our voices are not heard. So organizations like GMHC, which have the money to mount campaigns and fund lobbyists, must be more aggressive. And other tactics have to come in. We should begin a series of protests against the media. The New York Times still does not have an AIDS reporter investigating this issue like they would a USAir crash. TI: The Wall Street Journal just transferred their AIDS reporter out of AIDS. KRAMER: That's appalling. The important media sources don't write about AIDS. McNeil/Lehrer and Nightline never do AIDS stories. I've long advocated nonspecific underground guerrilla activities. This is a war, a plague, and we're treating it as if it's not. On a community-response level, we are exceedingly passive and docile. I get particularly angry when we have resources that we don't use. By that I mean boards of directors. I have gone after GMHC in print any number of times because you have powerful people on your Board, people who have connections with powerful people. Why are these contacts not utilized? I was overwhelmed with anger when I recently discovered that the President of the Board of Harvard AIDS Institute is Maurice Templesman, who was Jackie Kennedy's friend. I called Max Essex [Director of the Harvard AIDS Institute] and asked if he ever requested Templesman to speak out or do a benefit. He said, "No, maybe I should ask him to do something." It's that kind of attitude. Scientists are wimps when it comes to politics. You have the same kind of important people on your Board. And you don't use them. The corporate world works because companies have powerful boards. No gay organization ever uses its board effectively. Treatment Decisions TI: How do you make your own treatment decisions? KRAMER: It's hard and it's not comfortable because doctors don't agree with each other. And that's very confusing for everyone. But people have access to more information than they think. It's vitally important that everybody who's HIV- positive take charge of his or her illness powerfully. And that is not impossible to do. It just requires a lot of work. It requires reading publications like your own excellent one, which I tell everybody to subscribe because you put out stuff that nobody else does. And reading John James' newsletter [AIDS Treatment News] and the stuff that comes from PWA groups, as well as talking to doctors and other patients who are plugged in. It's like researching a term paper and going to all the sources you possibly can and then making your own decision. I know it's not easy. It's not easy with any serious illness, particularly where there are different points of view. So you have to learn how to read your own blood work, ask your own questions and realize that your doctor, whoever he or she may be, is not going to be on top of your case with the thoroughness that is required. You have to see when things go up and down on the medicine you take, how you feel from it and what it does to your blood over a period of time. Find a doctor you feel comfortable with. Be assertive and tell your doctor everything. But it's not easy. TI: Tell us about your plans, aside from activism. KRAMER: Stephen Gendin recently said to me, "It's all your fault because you gave us such hope. You said there was cure." Well, I still believe there's a cure. And I've never lost hope. That helps keep me going. But I have this perennial conflict between being an activist and wanting to be an artist. And I'm embarked on a very long novel. I also have a lover for the first time in a long time and that's made me exceedingly happy. We bought a house in the country and I want to live there with him, write my book and play house. But I feel guilty that I'm not out there being what everybody wants me to be. Like most of us, I don't have that kind of energy anymore. I outlined ten things that would help the system go faster. Yes, it would be wonderful if there was a leader to appear who could push all these things. But, there are things we all can do. We have to keep pushing and pressuring a research system which moves far too slow. DISTRIBUTED BY GENA/aegis, your online global gateway to a world of people, information, and resources. 714.248.2836 * 8N1/Full Duplex * v.34