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[Electronic distribution for GENA/aegis by GENA/aegis_World_HQ * 714.248.2836] Volume 8 no. 9 Gay Men's Health Crisis: Treatment Issues ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ > David Ho on HIV Treatment Strategies and Research > Anti-HIV Therapies at Yokohama > Immunosuppressive Therapy for HIV Infection > OI Update from Yokohama >> Cytomegalovirus Infection >> Pneumocystis Carinii Pneumonia >> Mycobacterium Avium Complex >> Tuberculosis > Kaposi's Sarcoma Reports at Yokohama > New York AIDS Trial Sites Cancelled > FDA Reaffirms Support for Accelerated Approval > Cryptosporidia and the Water Supply > Treatment Briefs >> d4T Trial for Newly Infected >> Viral Strain and Long-Term Survivors >> Shameful Wait for HIV Testing in NYC >> Hospital Water May be MAC Risk >> Report on Clinical AIDS Research at NIH >> GMHC Treatment Fact Sheets ============================ David Ho on HIV Treatment Strategies and Research >> David Ho, M.D., is the Director of The Aaron Diamond AIDS Research Center in New York City. Dr. Ho is one of the most respected HIV researchers in the world. In just three and one half years he has built the Aaron Diamond Center into a world-class AIDS research center employing over 60 full time staff. David Gold and Dave Gilden of Treatment Issues spoke with Dr. Ho in his office about the therapeutic implications of his work on the behavior of the human immunodeficiency virus. Protease Inhibitors.<< Treatment Issues (TI): Given the substantial interest in HIV protease inhibitors, where do you think we are in the development of this class of compounds? David Ho: It is nice to have so many compounds from different companies in clinical development. They all target the active sites of the protease. Many of them are really pretty potent against HIV in vitro [in the test tube] and there are several that are showing different levels of in vivo [in the body] efficacy. The thing that encourages me the most is the fact that we have inhibitors with different structures that bind differently to the active site, meaning that we might be able to combine some of these. And the in vitro observation so far is that you could have differences in the patterns of resistance, so that combining them might begin to make some sense. So I am encouraged by the number of inhibitors that are pretty potent, and the fact that the virus cannot make one mutation and resist all of them. At this point, looking at about ten inhibitors, there are at least two major patterns of resistance, and more likely three patterns. TI: Researchers from Merck report that they have seen one patient who is resistant to all the protease inhibitors. Does this surprise you? David Ho: When you are dealing with many different strains of HIV, given a particular background, and particular set of mutations, you can find viruses that become more and more resistant. But most of them do follow the patterns. Resistance to all compounds may occur in a particular case. But that may not be a general rule. TI: Your lab is overseeing a clinical trial of the Abbott protease inhibitor. Can you tell us about it? David Ho: We are doing a Phase I study of the compound in about two dozen patients and we are many months into it now. We would like to present our data on safety and antiviral efficacy at the ICAAC [Interscience Conference on Antimicrobial Agents and Chemotherapy] meeting. At this point, I have been instructed not to comment on the study. You could sort of guess that if we are eager to present at the October meeting as a late breaker report, we have some meaningful data, which would be of interest to the field. Using Viral Load Measurements TI: What standards should be used for determining whether the FDA should approve the protease inhibitors? David Ho: It depends on your philosophy about this disease. My view is that we are dealing with a viral infection, a viral disease. I believe less in the autoimmune mechanism and such indirect pathways for pathogenesis. So for me, a very potent antiviral effect in vivo goes a long way. But that doesn't promise clinical benefit if the in vivo effect lasts only for a short period. So in the long run, we certainly need clinical endpoints to support the initial antiviral observations. TI: If a drug is relatively safe and has reasonable antiviral activity, should it be considered for accelerated approval? David Ho: Demonstrating the antiviral's effect is a very encouraging piece of data. I have mixed feelings about whether the approval should be made on that basis alone. I think there is not enough data to make a very conclusive statement on that issue [but] as we go through some of these, we may get better answers to that question. TI: When will we be able to know whether and what kind of virus load changes are really significant? David Ho: Over the years, many compounds were touted as antivirals, but when you measured viral load, no real changes were observed. For example, soluble CD4, compound Q, oral interferon and, perhaps, hypericin all had no antiviral effect in vivo even though they were developed as antiviral agents. This kind of data suggests that a drug should probably be dropped or at least modified. But we now have some idea of the decreases one gets with compounds like AZT and ddI and other reverse transcriptase inhibitors, like nevirapine. And we have a pretty good idea from a couple of the protease inhibitors. With saquinavir [Roche's compound], by itself, and at doses tested, the antiviral effect is not dramatic. With the Merck compounds, the effect, at least short term, could be very dramatic. So you begin to get a feel for the magnitude of the antiviral effect in vivo. If we could correlate that with clinical endpoints, we would have learned quite a bit, which could be used in assessing future candidate drugs. TI: Are you referring to a trial to study whether a specific drop in viral load correlates with improvement in people's symptoms? David Ho: Well, a trial would be a more formal way, but I think we are getting the impression from these current studies that some compounds will be very useful. TI: A couple of studies presented in Yokohama looked back to see whether reductions in viral load were associated with clinical improvement. David Ho: Yes. The impression is that the antiviral benefit correlates with clinical data. The Walter Reed data[1] and the Coombs data[2] would be consistent with what we know about pathogenesis. The viral load and the biological properties of the virus all correlate with the disease progression. So, if we could bring viral load down to a level that we find in an asymptomatic individual, or better yet, the level in long- term survivors, we could conclude, based on the available evidence, that this would result in a significant clinical benefit. But that is putting a lot of different types of data together and making a link. TI: Some physicians are using viral load measurements [Roche's PCR or Chiron's branched DNA tests] to get some idea about treatment strategies for their patients. Do you have any advice for physicians or patients who are spending significant amounts of money for these tests? David Ho: I believe that viral load is a very useful parameter and that it is going to be the upcoming trend for clinical practice. These quantitative techniques have been available for several years in our labs, and I find them useful with the few patients that I see. We have a limited number of antivirals, but you could at least play with those using viral load as a guide. And the tests are becoming easier to do. They are pretty accurate. And now with these two companies [Roche and Chiron] making a major push, we hope the price will continue to drop so that it will be affordable. So I find these tests useful. TI: In what ways? David Ho: For example, if a patient starts on a new antiviral, fairly consistently we see a decrease in viral load. And if with time, say six months, three months, that creeps up or increases dramatically, assuming the patient is taking the drug, it says there is some evidence of virologic failure. You could think about adding or switching therapies. So I find it particularly useful, and have used that information to manipulate the antiviral agents, and try to keep it at a level that I am comfortable with. What I find is a lot of physicians in the New York area are using [the tests], yet they don't know what the values mean. Such as what does 25,000 [copies per ml] mean? Or 200,000 mean? The companies have not done a good job in educating the physicians who are likely to use this test. TI: What does it really mean if you have an HIV RNA level of 200,00? David Ho: Well, obviously, the lower the better. But let's say that it is on the order of 10,000 to 20,000. That is, relatively speaking, pretty low. Whereas if you begin to have levels of 100,000, that's pretty rampant viral replication, and I would do something to control that. Initiating Antiviral Therapy TI: What do you suggest to your patients about whether and when to begin antiretroviral therapy? David Ho: I use the numbers to guide me. CD4 to some extent, usually in conjunction with viral load data. So if a patient's viral titer is, say, below 10,000, sometimes below 5,000 - and that is generally in conjunction with a pretty decent CD4 cell count - I say, that in most cases, we would shoot for levels like this, and you are already there. We don't know how low we could go, and the assays are not particularly good at monitoring the low levels in a reliable way at the present - although a year from now that might be different. So we would go through that discussion and probably not think about initiating therapy. In addition to viral load levels, I also look at the CD4 trend. If a patient's CD4 count is 450 and if the viral load is pretty high, say 100,000 copies, I would be more comfortable in initiating something like AZT to bring that down to a level more consistent with asymptomatic carriers of the virus. So I do use viral load measurements to help me make decisions. But in practice today, I am not sure how many people have access to viral load tests to guide them. TI: Let's say you personally were in a situation where you had been on AZT for six months to a year, and your viral load was going up again. Knowing everything that you know about the Roche or Merck protease inhibitors, would you try to get your hands on these drugs? David Ho: Yes, I would. I know less about saquinavir by itself. But I have seen data presented by various investigators who are studying the Merck compound to know that the antiviral benefit is substantial over a course of a few months. And it is something that I would consider very, very seriously. I have been impressed by the initial viral effect of the Merck protease inhibitors. TI: Do you think that the whole problem with new AIDS drugs is just viral resistance? David Ho: Yes. Viral resistance and the magnitude of it. Protease inhibitors are going to have resistance too. But the level of resistance is more in the order of ten-fold, twenty-, fifty-fold, not a thousand-fold. So that poses a particular problem. Some suggest that there are different patterns of resistance in the non-nucleoside reverse transcriptase inhibitors. Certainly, Upjohn and Boehringer Ingelheim believe they have inhibitors with different resistance patterns. Perhaps in the future they could be combined. TI: Could antivirals alone make HIV infection a chronic manageable infection or will we need some sort of immune therapy? David Ho: Antivirals could go a long way for many of the infected. I really can't say that for the patients who are very, very advanced, whose immune system may be depleted. But for a lot of the patients we have been looking at, if you show me someone with a two log [100-fold] drop in viral load, I will show you consistently a very nice CD4 response. In fact, if you see virus go down like that, you almost always see CD4 go up [correspondingly]. With AZT and with protease inhibitor, we know that the decline [in HIV] is very quick. Even in patients with 50 CD4 cells, there could be a doubling or tripling of CD4 levels, sometimes higher. We have seen cases, this is perhaps unusual, that go up to 350 to 400. If you look at the production rate of virus, even though the patient may have steady viral load for the period preceding the treatment, a lot of production is going on. And then with the treatment, viral production declines and a new equilibrium occurs. And looking at the rapid CD4 cell increases, you realize that the regenerative capacity is still pretty good. TI: Are these functional CD4s? David Ho: We don't know. But it is telling that when you do this and you think about regeneration of CD4, you shift the equilibrium to a different level. And what happens is that when you go through this calculation, you realize that the production rates are actually pretty high. That says you haven't totally wiped out the bone marrow storage or whatever is responsible for making these cells. And it makes me think - this is where my bias comes in - that we have to deal with the virus first. Long-Term Survivors TI: You gave a talk in Yokohama about long-term survivors that caused a lot of discussion. And you suggested there may be something in CD8 cells that suppresses the virus in some patients. Does this represent a change in thinking for you? David Ho: We looked closely at several different parameters in these long-term survivors. The virus in all of them is very well controlled. We went on to try to explain why that is and the conclusion we are left with today is that it is really not some sort of resistance of the host CD4 cell to infection, but rather a combination of immune responses to the virus and some evidence of attenuation of the virus. And the CD8 story is part of that. We found many more of the CD8 cells that are capable of suppressing virus replication. The mere finding of those CD8 cells was described by Jay Levy a long time ago. What we did was to quantify that response a little bit more, in greater detail, and show that numerically speaking, it takes a lot less CD8 cells for long-term survivors to see such inhibitory effect. At the same time, we also showed that the neutralizing antibody titers in long- term survivors are great. So that these individuals must be seeing the virus at least periodically. Maybe not fully infectious, aggressive forms, but at least seeing the viral antigen. So I think that information is useful to know as we design vaccine strategies and immunotherapeutic strategies. The CD8 story is very controversial. Jay Levy's contention is that they are not CTLs [cytotoxic lymphocytes]. Yet we know the CTLs in vitro could do exactly that. If you stimulate the CTLs, some CTLs will certainly kill the cell. Others will release various cytokines that are suppressive for virus replication. So one of the immediate questions that would help the field a lot is to resolve this issue. Are these CD8 cells simply HIV specific CTLs? And I haven't seen anybody doing experiments to answer that question in a more direct way. I have encouraged some in our lab to address that in a more direct way. TI: So as far as the long-term survivors go, what would you say is a more significant immune response: antibodies or CTL? David Ho: It would be hard for me to answer that question. In each case we have analyzed, we see great neutralizing antibody titers. We see, quantitatively speaking, a lot of these CD8 cells. And which is more important? I don't really know. Acute HIV Infection TI: Your group has done a lot of work on acute HIV infection. Should antiretroviral therapies be used in treating a patient with acute infection? David Ho: A Swiss study suggests that treating reasonably early, in the first six months of infection, has some short-term benefit in terms of progression of various parameters. But theoretically it has always made sense that if you could control the virus really well, early on, with antivirals, you potentially could decrease the number of viral variants that first populate the patient. And you should have less problem in terms of variance and likelihood of developing drug resistance. TI: If you were treating someone with acute infection what would you recommend? David Ho: I personally believe that it makes sense to knock the virus down the best we can. If it were me, and I had all the currently available drugs in front of me, I would probably take multiple drugs over the short course. The ones that have been shown to have in vivo activity, say, the Merck protease inhibitor, AZT, and nevirapine. Put them all together. At least short-term, you know the major toxicity problem is not going to be a big issue, and resistance is not an issue. So if you could decrease virus very early on, there are a lot of theoretical advantages, but I have absolutely no empirical data. Reinfection in HIV-Positive Individuals TI: Couples who are both HIV-positive are told to use condoms because of the risk of "reinfection." Is the risk of "reinfection" real? David Ho: There is little evidence to document that an additional "super" infection [or "reinfection"] with a second strain of HIV occurs at a period of time after initial infection. However, there is now plenty of evidence that you can have two strains circulating simultaneously. We just submitted a paper on an acute seroconverter who had multiple partners one night and got multiple strains of HIV. There is also a case where multiple units of blood were transfused into one person and coinfection occurred. So we know multiple strains can occur, at least simultaneously ["coinfection"]. Whether it can occur sequentially ["reinfection"], I don't know. But aside from HIV, you have to worry about other infectious agents and we know that other organisms can affect HIV activation and replication. HIV Vaccines TI: Is there any basis to believe that therapeutic vaccines will be a useful therapy for HIV. David Ho: I still need to be convinced. If someone comes up with a very original idea to use various viral components to induce an immune response, I'm willing to listen. If it is suggested that giving the patient a gp120 or gp160 or one type of viral particle would stimulate a useful immune response, my response would be that the body sees more variants on a regular basis, compared to these proteins a few times a year. And the major problem seems to be, if you give the envelope protein, you are trying to induce primarily an antibody response. But that antibody response is very ineffective against circulating strains of HIV. But I am still optimistic about developing a vaccine for HIV. We know vaccines are possible because Ron Derossier has an attenuated vaccine that works in animals. It would be nice to go and figure out in those monkeys what is mediating the protection. TI: But they haven't been able to do that? David Ho: They haven't done that yet. Superficially they have looked at neutralizing antibody titers in those protected monkeys versus monkeys that were not protected by other forms of vaccine. And, in fact, the neutralizing antibody response was lower in the protected animals. So, I am encouraged by the fact that protection is possible. We just don't know how to do it in ways that are more acceptable. So we have to be more creative. TI: Do you think it was a mistake not to initiate a large trial of the gp120 vaccines? David Ho: I was not in favor of pushing ahead, given the available information. I do not know whether that decision ultimately would be proven right or wrong. I just think that these vaccines will only induce an antibody response. So when antibodies have no activity against the viruses that are in the community, the rationale falls apart. Beyond Protease Inhibitors TI: Is there anything beyond the protease inhibitors that interests you and could be available within the next few years? David Ho: This is something that we have talked about on the National Task Force on Drug Development. Many large pharmaceutical companies had some program on reverse transcriptase inhibitors and protease inhibitors. But there is precious little beyond those two targets, and that is a concern. How do you get the pharmaceutical companies to think about all the other targets that are out there? Such as tat, rev [HIV proteins needed for replication] and integrase [an HIV enzyme needed for infecting new cells]. But there are other targets that are less well known that are discussed in the basic literature. We know gag [HIV core protein] is a requirement for viral activity. And there are assays to screen for drugs that would block its interaction. Do you see a lot of companies thinking about that? Steve Garth's group shows that gag interacting with cyclophilin [a cellular transport protein] is a requirement for its activity. And there is a good assay that screens for cyclophilin inhibitors. Sandoz, because of its position in cyclophilin, has an interest in this area. But I see very little interest from others. Similarly, you could go down the line: integrase - you could try to block protease dimerization [a step in constructing the HIV protease enzyme]. I see very little activity there. With protease, everybody is focusing on the catalytic side. But you could screen for inhibitors that would block the interactive surface. Nobody is working on that, as far as I know. And, there is evidence that the integrase must bind to a transcriptional factor. That sounds like a nice target. And there is a nice assay. So we have to create a mechanism for the large pharmaceutical companies to use their chemical library on these targets using the assays. There is a real gap in anti-viral research, and we must try to fill it. TI: What can government do to encourage companies to do this type of research? David Ho: Government has got to provide incentives for the companies to do that. Because AIDS is such a difficult and controversial area, some companies just say it's not worth it. There is concern that there are too few companies that are truly devoted to finding something for AIDS. So, at the basic level, government must provide some incentive in terms of funding to get the companies with expertise into some of these new target areas. Exactly how, I think, is a difficult thing. Government Sponsored AIDS Research TI: Should the NIH be emphasizing targeted or investigator-initiated AIDS research? David Ho: They are always trying to balance the two. The example I just gave you about providing incentives sounds like targeted research. And so there are situations where a targeted approach is useful. But in general, I favor what has accounted for most of the American success in science, and that is investigators pushing and developing their own ideas. A lot of the creativity is going to come from that. But if you have one obvious gap, where you see after extensive survey, almost nobody working on it, then in those situations, a targeted approach is required. TI: You were one of the first well-known researchers to support the Office of AIDS Research [OAR] reforms at the NIH. Are you optimistic about these reforms? David Ho: I like the new direction that has been taken. Of course, the new OAR really will only begin to have an impact on the '96 budget and thereafter. But some of the concepts that have been discussed by [OAR director] Bill Paul, I think, are right on. He's developed the plan after substantial input from many people outside NIH. TI: What specifically do you like? David Ho: For one, I like the idea of putting greater emphasis on basic research. In the therapeutic area, basic research will help generate a greater infusion of new targets and new drugs into the developmental pipeline. This pipeline goes from drug discovery all the way to clinical trials and so on. And the infrastructure needs to be reexamined each step of the way. That is what the OAR is doing. Does it make sense to have a huge infrastructure to test drugs, with very few promising drugs flowing through the developmental pipeline? TI: How would you make the clinical trials program more efficient? David Ho: In terms of the ACTG [NIH AIDS Clinical Trials Group], you have to look at what the accomplishments were over the years and what dollars have been consumed by that process. And almost go through it program by program. TI: And how do you feel about the ACTG? David Ho: This is a very controversial area. I think they have made contributions. There are a lot of groups out there that may be doing good work. The question is, does it apply to every single area? And that has to be evaluated. TI: Can what has been done here at the Aaron Diamond Center be replicated on a government level? David Ho: I think it is difficult. Here, they took a chance and committed the money and allowed us, with guidance from our boards, to go out and pick personnel first. That is not how government operates. With government you have to spell it out. It is better done as a private enterprise. In San Francisco, they have the Gladstone Institute which was founded, again, by a foundation. And they were able to go and pick people. We were also able to do something very few places have been able to do - go and pick promising researchers with complementary skills and interests to form teams. A lot of institutions just put together their AIDS researchers whether they fit in with one another or not. TI: Proposals for a "Manhattan Project for AIDS" focus on putting together people in different fields of AIDS. What do you think about such proposals? David Ho: First of all, I would never call any project a Manhattan Project. I think teams along this line might be reasonable. Huge teams congregating at one site are probably not practical or even necessary given how easy it is to communicate. So I would not favor the type of arrangement that developed the atom bomb. TI: In terms of the overall U.S. government AIDS research effort, what are we doing right and what could be done better? David Ho: There is a large pool of very talented scientists working here. And the esprit de corps among scientists is much better now than before and there is a lot more positive interaction among scientists. In the journals, there is a lot of scientific development about HIV every month. So a good deal of incremental knowledge is being generated. Obviously we need more to get to a level where the clinical translation occurs in terms of therapy. We are fortunate in this country that the funding for AIDS research is quite large compared to funding in other countries and funding in other areas. So many of those things I am pleased with. And I think it is just a matter of juggling the priorities. If you say, what are we doing wrong, we need, as the OAR is doing, to look at the entire research portfolio and examine the priorities. Is it appropriate to put, you know, X amount on the front end, Y amount in the middle and Z in the back end? All of these need to be examined and some priority adjustments are required. 1 Mayers D et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; I(abstract 253B):75. 2 Kahn J. Tenth international conference on AIDS program book. Aug 7-12 1994; session RT-1:26. ============================ ============================ Anti-HIV Therapies at Yokohama by Gabriel Torres, M.D. The problem of drug-resistant HIV dominated many of the proceedings at the Tenth International Conference on AIDS this August. Existing therapies such as the nucleoside analogs AZT, ddI, ddC and d4T progressively lose their effectiveness when used alone. Many researchers hoped that combining therapies will so reduce HIV replication that strains resistant to multiple medications will not evolve. This article will concentrate on the reports about nucleoside analogs as well as some other studies concerning AZT combined with another class of similar-acting compounds, the non- nucleoside reverse transcriptase inhibitors (NNRTIs). AZT Monotherapy The debate regarding early treatment with AZT among asymptomatic HIV positive persons was rekindled by the presentation of the final results of the trial known as ACTG 019.[1] ACTG 019 is the largest and longest study comparing AZT to placebo in HIV-positive, symptomless persons with CD4 counts greater than 500. It enrolled more than 3,200 participants from 32 medical centers in the United States. In August of 1989, analysis of participants with baseline CD4 counts below 500 revealed slower disease progression among those taking zidovudine. Investigators then modified the trial so that those with CD4 cells greater than 500 were randomized to three groups: The 1,637 trial participants either deferred taking AZT until their CD4 count dropped below 500 or immediately began therapy with either 500 or 1,500 mg of AZT. Once CD4 counts dropped under 500, all participants were given open-labeled AZT at a dose of 500 mg per day. The results of the study indicated that the rates of disease progression (as measured by the occurrence of AIDS-defining events or death) were similar for the three groups over the mean follow-up period of 2.6 years. The time to a drop in CD4 cells below 500 was slightly shorter overall in the deferred therapy group (1 year) than in the AZT groups (1.5 years), but the differences in time to a CD4 count under 500 were not significant for those who started with CD4 counts less than 650. The low intrinsic risk of progression at high CD4 counts, the brief time on blinded treatment and the drop-out rate of approximately 25 percent in this trial may have contributed to the inability of detecting much benefit of early AZT use in persons with CD4 counts exceeding 500. In reporting on ACTG 019, Paul Volberding, M.D., of the University of California San Francisco concluded that the data do not support initiation of AZT while CD4 counts are above 500. Still, Dr. Volberding continued to recommend AZT for those with CD4 counts under 500. Specific patients with high HIV blood levels and CD4 counts below 500 may also benefit from therapy, although this remains to be demonstrated through clinical trials. Sequential Monotherapy Sequential monotherapy implies switching from one drug to another, either after a fixed amount of time or after one drug has failed to yield further benefit. Several published U.S. studies have indicated a benefit from switching to ddI after as little as eight to sixteen weeks on AZT. In Yokohama, several more studies supported this idea. A study reported by Julio Montaner, M.D., of the Canadian HIV Trials Network compared switching to ddI versus continuing on AZT in a group of 245 patients with baseline CD4 counts between 200 and 500.[2] Those switching to ddI had a higher and more sustained elevation in counts at 48 weeks than those remaining on AZT. The time to the first AIDS-defining illness or death was also significantly longer for those switching to ddI than those continuing on AZT after two years of follow- up. Changing to ddI did not slow the development of AZT resistance or the emergence of the more virulent type of HIV known as SI (syncytia-inducing). Another comparative study of sequential monotherapy versus combination therapy was described in a poster.[3] In this retrospective study, 162 AZT-treated patients (mean baseline CD4 of 121) were switched to either ddI or combination AZT/ddC and followed for new AIDS-defining infections or death. After a mean follow-up of 32 weeks, there was no difference in rates of new infections, hospitalizations and survival, although there was a trend favoring those switching to ddI. Douglas Mayers, M.D., of the Walter Reed Army Institute of Research presented data on the virologic response to ddI after AZT monotherapy in a small group of 32 patients with CD4 counts over 400 who had enrolled in an observational study.[4] The objective of the study was to observe the impact on HIV load of switching from prolonged AZT monotherapy to ddI. The average time on AZT in the group was two years, and the mean CD4 at the time of switching was 93. Twenty-six percent of the study group had significant increases in viral burden after switching to ddI, 29 percent had decreases and 45 percent were stable. Neither baseline HIV level nor any of the individual virus characteristics (such as resistance to AZT) were predictive of a study member's response. Patients' experience when switching to second-line medications has never been stellar. This continuing problem was reflected in the retrospective, observational data presented by Marcus Conant, M.D., of 96 patients (mean CD4 count of 100) he treated with d4T after failure or intolerance on both AZT and ddI.[5] He reported an adverse effect rate of 53 percent. Half of his patients developed peripheral neuropathy, a rate much higher than that reported in d4T's phase I and II trials. In addition, 36 percent of his patients experienced psychiatric disturbances, ranging from insomnia to anxiety and panic reactions. Forty-one percent discontinued d4T, though no deaths were attributed to the drug. A third had rises in CD4 cells and 62 percent had declines in this cell population. Combination Therapy with Nucleoside Analogs Various conference papers supported the claim that combination therapy is superior to AZT monotherapy or even sequential monotherapy. According to the reports, combining treatments yields greater increases in CD4 counts and lower HIV levels than monotherapy does. One of these reports was an analysis from the Multicenter AIDS Cohort Study (MACS), which tracked 853 gay men who started AZT prior to AIDS.[6] The MACS investigators found that the men who at some later point added a second anti-HIV medication to their regimen had a 34 percent lower risk of dying at any given time than those who remained solely on AZT or switched to another monotherapy. The occurrence of AIDS also was 23 percent less per year in the combination group, although this difference was not statistically significant. Melanie Thompson, M.D., presented a poster that also described the differential impact on survival of AZT monotherapy and sequential or combination antiretroviral therapy.[7] In her cohort of 2,044 Georgia patients, she found combination therapy (mainly AZT plus ddC) to be superior to AZT monotherapy in those with CD4 counts below 500 and to sequential AZT-ddI therapy in those with CD4 counts below 100. An interesting study from the National Cancer Institute in the U.S. examined HIV plasma levels and the development of mutations in 26 patients receiving long-term combination or alternating AZT-ddI therapy.[8] This study found that AZT is more potent in activated, dividing cells, whereas ddI is more potent against HIV in resting cells. Study participants had a greater initial suppression of virus if the drugs were given together than if the drugs were alternated. Virus levels remained reduced for at least two years, but by then there was little difference between the alternating and combination regimens. AZT-ddI combination therapy also prevented the emergence of a major mutation related to ddI resistance (at codon 74 on the HIV genome), yet did not prevent a similar AZT-related mutation at codon 215. In this study, no correlation was found between changes in CD4 counts and changes in plasma viremia. A Dutch study examined the safety and efficacy of adding AZT to lamivudine (3TC) monotherapy.[9] In the laboratory, a mutation at codon 184 confers resistance to 3TC but simultaneously reverses resistance to AZT. This led investigators to believe that adding AZT could result in salutary effects. In the phase I/II 3TC study, which was open-labeled and non-randomized, 30 patients with greater than one year of previous 3TC (either 200 or 600 mg/day) therapy or clinical failure on 3TC started also taking AZT at a dose of 600 mg/day. Baseline CD4 count was 110. CD4 counts increased and were above baseline for at least a year. Plasma HIV RNA viral load had a rapid decrease after adding AZT (over 90 percent) but had a slow and steady rise towards baseline by week 36. Side effects included nausea, fatigue and neutropenia. The authors concluded that adding AZT to 3TC is effective in patients with 3TC-resistant virus. ddI and ddC would not be expected to combine well with 3TC since 3TC-resistant virus has been shown to be cross-resistant to both ddI and ddC. Lest one conclude that by adjusting nucleoside analog combinations one can easily stay ahead of HIV and its evolving resistance to therapy, another National Cancer Institute report[10] described how combination therapy using AZT plus ddI or ddC can give rise to a set of novel HIV mutations. The evolving set of changes in the virus's reverse transcriptase make it insensitive to all three drugs (the decrease in sensitivity to the drugs was 125-, 16- and 30- fold to AZT, ddI and ddC, respectively). The mutations appear as a successive group of seven changes in the reverse transcriptase amino acid sequence. In one patient, virus levels increased as the mutations developed over 38 months. NNRTIs One class of compounds that could supplement nucleoside analog combinations is the so-called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Like the nucleoside analogs, NNRTIs block HIV's infection of new cells. An NNRTI fits into the reverse transcriptase's active site so that the enzyme can no longer transcribe the HIV genome into a DNA form insertable into the cell's normal genetic machinery. (Nucleoside analogs are faulty DNA building blocks that cause DNA transcription to terminate prematurely.) There have been repeated problems with rapid emergence of HIV resistant to NNRTIs, however, and their usefulness seemed limited in the past. But various reports at Yokohama on these compounds' synergism with nucleoside analogs may prompt a second look at NNRTIs, especially at the new members of this class --delavirdine and loviride. Bill Freimuth, M.D., from the Upjohn Company presented data on the surrogate marker responses in the completed two trials of delavirdine.[11] These trials were either open-labeled or dose-escalating studies of delavirdine in combination with AZT or AZT plus ddI in persons with prior experience on these drugs. Both trials found that adding nevirapine to the combination gave CD4 counts a boost and decreased HIV levels in the blood. One important observation was that the response to delavirdine was improved if the virus was sensitive to AZT. Resistance to delavirdine was observed over time and was associated with baseline AZT resistance and the virulent SI virus type. Loviride is an NNRTI manufactured by Janssen Pharmaceuticals. A double-blind placebo-controlled study was reported by a German group.[12] HIV-positive patients with CD4 counts more than 400 were randomized to receive either loviride, placebo or R18893 (a compound similar to loviride). After 24 weeks of follow-up, the loviride group had the best CD4 responses with an average increase of approximately twenty percent over baseline. None of the known mutations conferring resistance to loviride were detected. Further trials are planned for this very promising compound. Conclusion For early-stage patients with higher CD4 counts, combination therapy may result in greater reductions in viral load, improved clinical outcome and perhaps a delay in the emergence of resistance. The final word on this issue awaits the results of larger trials currently underway. For more advanced patients with very low CD4 counts, combination therapy still has not proven to be better than monotherapy and may be associated with more toxicity. The NNRTIs seem to have considerable potential, at least in combination with two nucleoside analogs. Resistance apparently does develop rapidly, but the observed lack of resistance to loviride is encouraging. Protease inhibitors are new agents that will increase the number of possible combinations immensely. How the addition of one or more such compounds affects the activity of combination or sequential drug regimens remains to be answered, perhaps at the next international conference. 1 Volberding P et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; II(abstract 355B):16. 2 Ruedy N et al. Tenth international conference. II(abstract 358B):16. 3 Barr M and Torres RA. Tenth international conference. I(abstract PB0266):209. 4 Mayers DL et al. Tenth international conference. II(abstract 359B):17. 5 Conant M et al. Tenth international conference. I(abstract 003B):7. 6 Graham NMH et al. Wellcome satellite symposium at the tenth international conference on AIDS. Aug 7 1994; abstract 5. 7 Thompson M et al. Tenth international conference. I(abstract PB0279):212. 8 Mitsuya H et al. Tenth international conference. I(abstract 056B):21. 9 van Leeuwen R et al. Tenth international conference. I(abstract 057B):21. 10 Shirasaka T et al. Tenth international conference. II(abstract 377A):21. 11 Friemuth B et al. Tenth international conference. II(abstract 512B):59. 12 Staszewski S et al. Tenth international conference. II(abstract 513B):59. ============================ ============================ Immunosuppressive Therapy for HIV Infection by Craig Sterritt Researchers have long tried to reconcile the fact that while the activation of CD4 cells is required for effective anti-HIV immune responses, it also leads to increased HIV replication and the susceptibility of uninfected CD4 cells to HIV infection. In addition to facilitating the viral life-cycle, activation of CD4 cells from people with HIV has been found to lead to a phenomenon called programmed cell death or apoptosis, which is thought to contribute to the overall loss of CD4 cells in HIV infection. The overactivation of CD4 cells in HIV can also lead to other deleterious events, including aberrant cytokine secretion, the overproduction of antibodies and chronic inflammation, all of which may also be involved in the development of HIV-related disease. Supporting a correlation between CD4 hyperactivation and CD4 depletion was a presentation at the recent International AIDS Conference that described a French study[1] of prednisolone, a gluccocorticoid with anti-inflammatory and immunosuppressive effects. The French group administered prednisolone to 243 asymptomatic and twenty mildly symptomatic persons with HIV in this non-placebo-controlled trial. Investigators reported that they observed a peak gain of over 200 CD4 cells per mm3 of blood after fifteen days of therapy. One year later, trial members still were a median of 100 CD4 cells above their baseline counts. HIV p24 antigen as well as viral DNA, RNA and mRNA remained stable in all patients over the course of the trial, indicating that prednisolone treatment does not promote HIV replication. Obviously, too, the increase in CD4 counts was not caused by reduced virus levels. Immune system and CD4 cell activation markers in the prednisolone recipients decreased significantly, although cytotoxic lymphocyte (CD8 cell) counts remained unchanged. In addition, swollen lymph nodes (lymphadenopathy) disappeared in sixteen of the twenty mildly symptomatic patients, indicating reduced lymph node activity. No major side effects or opportunistic infections occurred during the course of the study. In vitro (test tube) tests done in conjunction with the trial revealed that prednisolone exerts its positive influence on CD4 counts by preventing apoptosis. Prednisolone was not found to inhibit normal functioning of cells: Cells treated with prednisolone could still produce the cytokine interleukin-2 and proliferate following exposure to antigen (such as HIV protein). 1 Andrieu JM et al. Tenth International conference on AIDS abstract book. Aug 7-12, 1994; 1(abstract 157B):46. ============================ ============================ OI Update from Yokohama by Gabriel Torres, M.D. Opportunistic infections may have received less attention at the Tenth International Conference on AIDS compared to previous conferences, but a number of presentations did yield helpful suggestions for managing advanced HIV disease. Treatments for cytomegalovirus, pneumocystis pneumonia, MAC, TB and bacterial pneumonia all were the subjects of informative reports. Cytomegalovirus Infection The long-awaited trial using oral ganciclovir to prevent CMV disease was not formally presented at the conference, although a summary of the data was presented by W. David Hardy, M.D., at a satellite symposium sponsored by the UCLA AIDS Institute on the day after the conference. The trial enlisted 750 HIV-positive patients with CD4 counts below 50 (or below 100 plus a history of AIDS-related illnesses). Subjects were randomized to receive 1,000 mg of oral ganciclovir or placebo every eight hours and followed with ophthalmologic exams every two months for the development of CMV retinitis. An interim analysis found that at ten months, only sixteen percent of the oral ganciclovir group had contracted CMV retinitis, compared to 30 percent of the placebo group. This was a highly statistically significant difference. An on-going trial by the Community Program for Clinical Research on AIDS (CPCRA) that followed almost 1,000 patients with CD4 counts less than 100 has not observed a delay in the onset of symptomatic CMV with oral ganciclovir. Participants started with slightly higher CD4 counts on average than in the first study, though, and their observational period was three months shorter. Also, they did not have the ophthalmologic exams, so some asymptomatic CMV infections may have been missed. Participants in both trials now will be given the option of open-label oral ganciclovir therapy. Several posters provided helpful data for managing active CMV infections: - A 31-person Spanish study[1] evaluated ganciclovir (ten milligrams per kilogram of body weight) or foscarnet (100 mg/kg) given as thrice weekly infusions for maintenance therapy in patients with CMV retinitis. There were seventeen relapses (51 percent) and 22 deaths (66 percent) after a mean follow-up of seventeen weeks. These rates are similar to those seen with the standard daily or five times weekly maintenance therapy using either drug. Similarly, a German study[2] of gastrointestinal CMV found little difference in effectiveness whether induction therapy with foscarnet infusions were administered for five or for seven days per week over a period of three weeks. The option of skipping infusion days, especially on weekends when clinics are closed, will reduce the extent of hospitalizations required for CMV disease. - Two posters[3,4] described the use of ganciclovir, foscarnet or a combination of both drugs for the treatment of CMV polyradiculopathy, a spinal cord and nerve root inflammation. CMV polyradiculopathy usually leads to paralysis and incontinence. At least half of the patients exhibited improvement in neurological function and clearing of CMV from blood and cerebrospinal fluid. - Various studies also examined the usefulness of the CMV blood antigen test to monitor patients with CMV disease during antiviral therapy. One poster[5] described how bloodborne CMV antigen rose prior to the clinical deterioration and also correlated with the appearance of drug-resistant CMV. The authors concluded that the CMV antigen test may be an important tool for detecting both failing CMV therapy and the emergence of ganciclovir- or foscarnet-resistant viral strains. Pneumocystis Carinii Pneumonia Many PCP reports at the conference focused on the problem of patients' intolerance to available drugs. Some presentations looked at the use of desensitization techniques to overcome allergies to the sulfa component of Bactrim or Septra: These allergic reactions seem to be related to an inability to metabolize sulfa breakdown products due to a glutathione deficiency common in HIV-positive patients. One regimen presented by the Conant Medical Group[6] showed an 84 percent success rate in a retrospective analysis of 100 sulfa-allergic patients given a standard desensitization regimen with trimethoprim/sulfamethoxazole (TMP/SMX, the generic name for Bactrim and Septra). Since only one successfully desensitized patient (1.2 percent) developed PCP and toxoplasmosis, the researchers concluded that desensitization should be offered to all sulfa-allergic patients. Unfortunately, no comparative prospective study comparing desensitization merely to deferred rechallenge with a single or double strength tablet of TMP/SMX has been reported to date. A 214-person Italian study[7] compared monthly to twice monthly dosage of aerosolized pentamidine (AP) (300 mg) for preventing PCP after a first attack (secondary prophylaxis). After a median follow-up of 200 or 240 days, depending on the group, fourteen episodes of PCP occurred in the once monthly group, compared to five in the twice monthly group. The researchers concluded that twice monthly aerosolized pentamidine is superior to once monthly treatment and suggested that the drug be used in cases of sulfa intolerance. Studies conducted by the U.S. AIDS Clinical Trials Group (ACTG trials 081 and 021) have demonstrated that aerosolized pentamidine is just as effective as dapsone for primary prophylaxis, yet significantly less effective than TMP/SMX for secondary prophylaxis. For those persons intolerant to both dapsone and TMP-SMX, twice monthly aerosol pentamidine seems a reasonable alternative. Dr. Hardy at the UCLA symposium presented a summary of the data from ACTG 108, a three-week study comparing three oral treatment regimens for mild-to-moderate PCP: trimethoprim/sulfamethoxazole, dapsone/trimethoprim and clindamycin/primaquine. This study enrolled 247 patients with mild PCP and found no difference in efficacy or toxicity among the three regimens, a reassuring fact for those who treat PCP with alternative regimens in an outpatient setting. Mycobacterium Avium Complex Prevention of disseminated MAC infections in patients with advanced HIV disease was the subject of two major reports: - The rifabutin treatment IND data were presented[8] describing the experience of 2,560 people on the open-label. The median duration of prophylaxis was 260 days. Abdominal pain, nausea and diarrhea were common side effects. Breakthrough MAC infections occurred most frequently in participants with CD4 counts below 50 (5.3 percent). - Preliminary information from an Abbott Laboratories placebo-controlled trial of clarithromycin was described in an oral presentation.[9] To date, 682 patients have been enrolled in the U.S. and Europe, of which 308 have withdrawn, many to pursue prophylaxis with rifabutin after its approval. Fifty-seven breakthrough MAC infections occurred, of which 48 remained sensitive to clarithromycin and six were highly resistant. The predicted versus observed incidence rate of MAC indicated that disseminated MAC has been reduced by 40 percent, an effect presumed to be related to clarithromycin. The efficacy data will be unblinded in October, and this inference may be confirmed. Tuberculosis The magnitude of the TB problem worldwide remains staggering: The World Health Organization estimates a current total of 700,000 cases of active TB among the HIV-positive population and that another ten million HIV-positive individuals have latent TB infections. Relapse rates for treated TB vary throughout the world from 6.5 percent in Europe and the United States to 16.7 percent in Kenya. Some of these relapses may be due to reinfections with new strains of TB. The rate of protection using isoniazid (INH) was demonstrated in a study from Zambia, which showed that the drug reduced the incidence of reactivated TB from 16.2 percent to 1.8 percent. Another study from Barcelona showed that within an eighteen month follow-up period INH reduced the risk of reactivation from 18.5 percent to 6.7 percent.10 An important TB prophylaxis study was presented as a poster by a group from Johns Hopkins University.11 Conducted in Haiti, the study compared the effectiveness of two regimens for the prevention of initial attacks of active tuberculosis in HIV-positive, PPD- (skin test-) positive adults. Seven hundred eighty-four participants were randomized to receive either twice weekly isoniazid (800 mg twice weekly) for six months or a combination of rifampin and pyrazinamide twice weekly for two months. During the first ten months of follow- up, the risk of tuberculosis was 0.8 percent in the INH group versus 3.5 percent in the rifampin/pyrazinamide group. After the first ten months, no significant differences were noted in the rates of TB, nor was there a survival difference. The authors concluded that the difference in rates of breakthrough TB appeared to be related to different durations of prophylaxis. A similar CPCRA study is comparing a year of daily INH to two months of daily rifampin/pyrazinamide in the same population. However, enrollment in this study is proceeding quite slowly, and it appears that conclusive documentation of the best TB prevention regimen will take some time. 1 Mallolas J et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; II(abstract PB0587):143. 2 Salzberger B et al. Tenth international conferenceII(abstract PB0519):127. 3 Karmochkine M et al. Tenth international conference. II(abstract PB0520):127. 4 Espinoza LA et al. Tenth international conference. II(abstract PB0521):127. 5 Hansen KK et al. Tenth international conference. II(abstract PB0528):128. 6 King C et al. et al. Tenth international conference. II(abstract 388B):25. 7 Rizzardi GP et al. Tenth international conference. II(abstract PB0612):150. 8 Gordin F et al. Tenth international conference. II(abstract 557B):70. 9 Pierce M et al. Tenth international conference. II(abstract 558B):70. 10 Gatell JM. Tenth international conference. II(abstract PS26):48. 11 Neal CJ et al. Tenth international conference. II(abstract PB0681):166. ============================ ============================ Kaposi's Sarcoma Reports at Yokohama by Gabriel Torres, M.D. One of the most exciting reports on Kaposi's sarcoma came from Robert Gallo's laboratory at the U.S. National Cancer Institute. As reported in Treatment Issues' August edition, Gallo's group observed that nude pregnant mice who had been injected with a KS cell line did not develop tumors during the first trimester of pregnancy whereas KS lesions flourished during the second and third trimester. The researchers concluded that the beta subunit of the hormone human chorionic gonadotropin (HCG), which is high early in pregnancy, was responsible for the anti-tumor effect seen in the mice. Liposomal Chemotherapy Data on the use of chemotherapeutic agents encapsulated within liposomes (tiny fat globules that regulate the passage of the entrapped drug from the blood stream to specific sites - see April 1994 Treatment Issues), were presented by various groups of investigators who have successfully used these agents in patients with AIDS-related KS. - DOX-SL: The best results to date were seen in the International DOX-SL Study,[1] a multicenter European and Australian phase II/III study of 247 KS patients. DOX-SL is a preparation of doxorubicin encapsulated in "stealth" liposomes that deliver significantly greater quantities of the drug to the KS lesions. "Stealth" liposomes incorporate a protective polyethylene glycol (PEG) coating allowing them to circulate in the bloodstream for up to 48 hours or more. Conventional uncoated liposomes are cleared from the blood in a few hours. (By comparison, unencapsulated - "free" - drug disappears from blood in a matter of minutes.) The patients were treated with DOX-SL intravenously using a 30 minute infusion every two weeks. Patients were started at 10 or 20 mg/m2 of body area, and the dose was titrated upward if KS lesions failed to respond. Two-thirds of the trial participants received at least six infusions. Of the 133 for whom response data are available, three (1.8 percent) attained a complete response, 81 (48.5 percent) a partial response and 38 (22.8 percent) had stable disease. Partial or complete responses were typically seen within two or three cycles of DOX-SL. Side effects included nausea (25 percent), vomiting (13.9 percent), stomatitis (11.8 percent), diarrhea (24.9 percent) and hair loss (11.8 percent). Significant neutropenia occurred in 17.9 percent of all treatmentcycles whereas anemia and thrombocytopenia occurred in 21.6 percent and 12 percent of all cycles, respectively. On September 7, 1994, Liposome Technology, Inc., the manufacturers of DOX-SL, filed a New Drug Application (NDA) with the U.S. Food and Drug Administration for the treatment of KS in people with AIDS who cannot tolerate or have failed conventional chemotherapy. (Until this application is approved, people with KS and intolerant to ABV, a standard anti-cancer therapy, can receive DOX-SL through a special open-label trial accessible through 30 sites nationwide. Call Liposome Technology at 415/323-9011 for more information.) - Daunoxome: Daunoxome is the drug daunorubicin encapsulated by a conventional liposome. The first phase II study of daunoxome was presented in Yokohama.[2] Through February 1994, 42 patients had been treated with Daunoxome every two weeks. One-third of the patients had a partial response and the other two-thirds had stable disease. The median duration of the response with the 40 mg dose was 7.5 to nine weeks, depending on the dose. The main side effect was neutropenia, which could be managed with G-CSF (Neupogen). Interleukin-4 The Yokohama Conference heard the first clinical data on the use of interleukin-4 (IL-4) in patients with KS.[3] IL-4 promotes CD4 cell proliferation and also suppresses interleukin-6 production - as well as KS cells in culture. IL-6 is found in high levels in patients with KS and is implicated in the pathogenesis of KS lesions. The phase I/II study (ACTG 224) enrolled patients with biopsy-proven KS who had IL-4 administered subcutaneously in escalating doses. So far, thirteen trial participants have received one of two dose levels. Side effects such as fever, fatigue and headaches were very common. Only three patients experienced a partial response. The dose limiting toxicity to date has been neutropenia. On the other hand, significant decreases (60 percent) in HIV p24 antigen levels were observed in all patients, which raises the possibility that IL-4 is useful as an anti-HIV drug. 1 Goebel FD et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; I(abstract PB0123):174. 2 Wernz JC et al. Tenth international conference. I(abstract 046B):18. 3 Miles SA et al. Tenth international conference. I(abstract 159B):46. ============================ ============================ New York AIDS Trial Sites Cancelled by Saundra Johnson The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) has defunded three of its four New York City sites. This action puts in jeopardy New York's ability to offer HIV/AIDS clinical trials to underserved populations, a goal included in the CPCRA mission statement. The CPCRA, which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), is a network of sixteen community-based organizations that is supposed to carry out studies of new treatments within the context of ordinary medical care. The decision is the result of a "recompetition" in which participating groups and proposed new groups were evaluated to find which can best fulfill the CPCRA's mission. In all, four organizations lost their funding. The defunded New York City groups are: the Addiction Research and Treatment Corporation in Brooklyn, Bronx Lebanon Hospital Center, and Clinical Directors Network of Region II, which is based in Manhattan and also has sites in Newark. The canceled New York sites account for 59.6 percent of the total number of Latinos, 26.7 percent of the total number of African Americans, 39.7 percent of the total number of women, and 47.2 percent of the total number of injection drug users enrolled in CPCRA trials nationally. Moreover, achieving the planned enrollment in the tuberculosis prophylaxis and treatment trials will be impossible without further accrual at the New York sites. NIAID has convened a task force to determine the effect the defunding will have on TB trials in New York and nationally. In addition, state and local officials have questioned the fairness of the peer selection process that reviewed the performance of CPCRA units and are demanding an investigation of how this process was conducted. ============================ ============================ FDA Reaffirms Support for Accelerated Approval by David Gold Freewheeling and emotional testimony was the order of the day during a Food and Drug Administration hearing on the "Early Availability of Drugs for Serious or Life-Threatening Diseases." The September 12 to 13 event, held under the auspices of the FDA's Antiviral Drugs Advisory Committee provided a stage for a wide range of activists, researchers and pharmaceutical company representatives. The backdrop to the hearing was discontent among some activists and researchers about the accelerated approval of ddC and d4T and a proposal by the New York-based Treatment Action Group (TAG) for a "large simple trial" (LST) of HIV protease inhibitors. (See Treatment Issues, August 1994, pages 10-12.) The FDA acknowledged the need for debate about the future evolution of the accelerated approval process. Many of those who testified at the hearings feared that the proposal would delay approval of and impede access to protease inhibitors. They gave passionate statements supporting accelerated approval and the right to access experimental therapies for those with life-threatening conditions. In response, FDA director David Kessler, M.D., strongly reaffirmed his agency's commitment to accelerated approval. In contrast to accelerated approval, the future of the TAG proposal seems far less assured. Hoffmann-La Roche and Merck, manufacturers of the two most widely studied protease inhibitors, claim that the drugs are far too expensive to produce for an LST. Large-scale expanded access programs, like those set up for ddI, ddC and d4T, are likewise extremely unlikely, company officials said. Yet the TAG proposal did accomplish something significant. It focused attention on the lack of real data from which to make treatment decisions concerning anti-HIV therapies. Much of this gap stems from the failure of the FDA to require adequate post-marketing studies of drugs receiving accelerated approval. One committee member, Donald Abrams, M.D., of the University of California at San Francisco argued that there probably was no real niche for a large, simple trial in the preapproval phase of drug development, other than collecting safety data at different dosages. But he said that after a drug was approved, LSTs could help answer strategy questions such as "when to begin, when to combine, and when to switch." ============================ ============================ Cryptosporidia and the Water Supply by the GMHC Nutrition Counseling Department Cryptosporidia are single-cell intestinal parasites that cause chronic profuse diarrhea, dull upper abdominal cramps and severe weight loss. This infection can be fatal for people with severely suppressed immune systems. (See Treatment Issues, September 1994, pages 5-6 for an update on cryptosporidiosis.) Removing cryptosporidia from water requires a filter that removes particles smaller than two microns (less than one ten-thousandth of an inch). New York City's Water Chlorine in usual amounts does not kill cryptosporidia, and New York City does not comply with Environmental Protection Agency regulations concerning correct filtration of public water supplies. Trace amounts of cryptosporidia have been found in New York City's water supply. (Recent samples contained about one organism per 100 gallons of water). These levels may not be high enough to harm people with intact immune systems, but they can be dangerous for people with HIV, and especially AIDS. Safer Water Sources - Distilled water is safe. - Boil all tap water for at least five minutes to make the drinking water safe. Lemon or other flavorings may be added to improve the taste. Pour into clean, dry containers. Dishes, silverware, pots and pans may be washed with tap water as long as they are dry before they are used. - Some bottled "spring water," is filtered well enough to trap cryptosporidiosis. The following brands report that they use safe filters: Deer Park, Great Bear, Naya, Poland Springs, Saratoga, Vivanti, Wissahichon. - Wash all fresh fruits and vegetables with boiled (and cooled), distilled or properly filtered water before eating raw. - Use only boiled, distilled or properly filtered water to make ice cubes, dilute fruit juices from concentrate and brush your teeth. Beware of beverages and ice cubes at restaurants, where they are usually made with tap water. - Commercially bottled soft drinks and seltzers are considered safe. Bottled juices are safe if they have been pasteurized and do not require refrigeration before opening. - Milk is safe if pasteurized. - Be careful not to swallow pool or bath water. Home Water Filtration Systems Some home water filtration systems can separate out cryptosporidia. The following companies claim that their products include sufficiently fine filters: Multi-Pure Drinking Water Systems, 21339 Nordhoff Street, Chatsworth, CA 91311. New York City contact: Krae van Sickle, 212/242-2317 or 516/329-9205 Multi-Pure's models are tested and certified by the EPA and the NSF (National Sanitation Foundation). GMHC clients receive a $15-$25 discount, depending upon the model. Prices range from $189.95 to $329.95. Everpure Water Treatment Products, 660 N. Blackhawk Drive, Westmont, IL 60559, 800/323-7873. New York City contact: Lee Hamer, 212/242-1787. Everpure's models are certified by the NSF to remove particles five microns in size. Prices range from $150 to $500. GMHC clients, volunteers, and staff are eligible for a discount if they call the contact person listed above. Neolife, 155 West Eighty-first Street, #6H, New York, New York 10024, 212/874-6640. The Neolife Water Dome removes particles 0.4 microns and larger. Countertop units cost $199.50 and undercounter units $387.50. Equinox, Tres Jordan, 212/421-4247 Equinox filters particles down to one micron in size. Above all, don't forget to wash and dry your hands before you eat or drink! ============================ ============================ Treatment Briefs by David Gold d4T Trial for Newly Infected In an apparent effort to expand the limited market for d4T (stavudine), Bristol-Myers Squibb is initiating a trial of the drug in individuals who have been infected with HIV within the past six months. The trial will enroll up to 40 patients and will use an initial dose of 80 mg twice daily for the first month and then 20 mg for the next eleven months. Viral Strain and Long-Term Survivors More evidence that long-term survivors may have unique viral strains of HIV can be seen in a study published in The Lancet (September 10, 1994, p. 719-20). In the study, a Red Cross transfusion service in Scotland examined rates of disease progression in individuals who were infected through blood transfusions and whose corresponding donors could be identified. The researchers found that if the donor was a slow progressor (no AIDS within ten years of infection), the transfusion recipient had a significantly greater chance of also not developing AIDS within ten years of infection. A more rapid progression to AIDS and death was seen in those who were infected from the blood of faster progressing donors. Shameful Wait for HIV Testing in NYC New York City residents wishing to be tested for HIV through the Department of Health's anonymous testing program may have to wait as long as ten weeks for an appointment, according to a survey by Chuck Sock of GMHC's Department of Treatment Education and Advocacy. The survey found that waiting times amounted to eight to ten weeks for an appointment at the Chelsea testing site, four to six weeks at the Corona, Queens site, three to four weeks at the Flatbush, Brooklyn site, and two to three weeks at two Harlem sites. Same day appointments are available at other sites in Brooklyn, the Bronx, and Staten Island. These waiting periods do not include the additional two week delay before receiving the test results. For information on New York City's HIV testing program, call 212/447-8200. Hospital Water May be MAC Risk Even before widespread concerns about cryptosporidiosis in the water supply appeared, a report in The Lancet (1994; 343(8906):1137-41) suggested that patients at two hospitals (one in Boston, the other in New Hampshire) may have been infected with mycobacterium avium complex (MAC) while at the hospital. According to the researchers, strains of MAC isolated from the patients' blood were identical to those recovered from the water systems in the hospitals where the patients had been admitted before they were diagnosed with MAC. The possible sources of exposure to MAC include tap water and ice, showers, water used for administration of aerosolized pentamidine, and endoscopes or bronchoscopes sterilized using the hospital's hot water system. The authors recommend that patients with AIDS and CD4 counts of less than 100 avoid institutional showers and contact with non-sterile potable water. They say that MAC-colonized institutional water systems should be sterilized using the same measures used for legionella. Report on Clinical AIDS Research at NIH Derek Link of GMHC's Department of Treatment Education and Advocacy has written a report entitled "Current Directions in AIDS Research: An Analysis of AIDS Drug and Vaccine Development at the NIH." The report provides a detailed analysis of the entire clinical research program in AIDS at the National Institutes of Health (NIH). According to the report, the National Cancer Institute, which is one of seven institutes at NIH involved in clinical studies in AIDS, currently spends a total of $47.6 million on clinical "AIDS research," but $35.9 million of this sum is spent on "research infrastructure." A free copy of this report can be obtained from GMHC. Call Wendee Rogerson at 212/337-3693. GMHC Treatment Fact Sheets The Department of Treatment Education and Advocacy has produced a set of easy-to-read treatment fact sheets in English and Spanish. The first fact sheet series covers toxoplasmosis, cryptosporidiosis, CMV, and MAC. The fact sheets describe the signs and symptoms of these illnesses, drugs used to treat them, side effects and possible prophylaxis. Copies of these treatment fact sheets can be obtained by contacting Wendee Rogerson at 212/337-3693.