GMHC Treatment Issues, Volume 9, Number 10 - October 1995 --------------------------------------------------------- Roaches of Inner Space by Dave Gilden The Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) is an annual affair that brings together thousands of infectious disease experts to ponder the progress modern medicine has made in their area of specialty. This year's conference, which was held last month in San Francisco, counted the disappointments as much as the victories in the battle against pathogens. The theme was new and re-emergent disease. AIDS is, of course, the archetypal new disease. It received plenty of attention, especially given the lack this year of an International Conference on AIDS (now held only biannually). In addition, people with AIDS are both the source and target of drug-resistant microbes. This double threat arises because their immune systems do not back up the therapeutic effect of drugs the way competent immune systems do. Drug-resistant germs have a greater opportunity to evolve in such an environment, which is precisely the environment in which the need for potent drug therapy is greatest. In the following pages, we describe research presentations at ICAAC related to HIV and AIDS. The virus has turned out to be the most modern of bugs -- like the cockroach, HIV's high reproduction rate gives it a supreme capacity for mutating to evade the toxic chemicals attacking it. But, there has been at least incremental progress made in formulating strategies to circumvent this issue. A More Prolific Virus... At ICAAC, David Ho, M.D., director of the Aaron Diamond AIDS Research Center in New York, presented a continuation of his group's observations on the rapid pace of the HIV infectious cycle. (See these researchers' earlier observations in Nature, January 12, 1995, pages 123-6.) These results are based on following the blood levels of HIV and infected cells after patients begin receiving the powerful protease inhibitor ritonavir. According to Dr. Ho's current estimates, at least ten billion HIV particles, on average, are produced each day in people infected with HIV. The lifespan of those free virions averages about eight hours, and the cells they infect live for an average of 2.2 days after infection. Dr. Ho calculated that the time between the creation of a new virus particle and the point that particle starts producing its own progeny within the cell it infects is about 1.2 days, making for about 300 replication cycles per year. These calculations show the high frequency with which we can expect mutations in the virus, which apparently undergoes the equivalent of thousands of generations of human evolution in the course of a single person's disease. Dr. Ho claims that any single mutational change in any of the HIV genes probably occurs multiple times per day in a given human being, and forms of a single HIV gene with multiple mutations probably occur as well in the course of a day. Mutations alter the amino acid sequence and shape of an HIV enzyme or protein, and such alterations nullify the action of antiviral drugs or immune defenses that bind to and neutralize specific amino acid chains. Steven Wolinsky, M.D., of Northwestern University, who gave one of the lectures at the ICAAC opening session on AIDS, pointed out that the ability to rapidly evolve may be the central reason why HIV ultimately defeats the immune system. The immune response to HIV depends on detecting specific portions of HIV's structural protein (epitopes) either on the virus itself or on the surface of HIV-infected cells. Cytotoxic lymphocytes (CTLs) kill cells recognized as infected, and antibodies bind to their target regions on free virus particles and neutralize the virus. This activity creates selective pressure in favor of mutant HIV with proteins not targeted by existing CTLs and antibodies. The immune system may at first be able to engender new CTLs and antibodies to catch the escaping HIV, but eventually HIV comes up with so many diverse strains that an individual's immune system cannot take care of them all (the "diversity threshold" is exceeded). (Much of this material was described by Martin Nowak and Andrew McMichael in the June, 1995 Scientific American.) The HIV evolutionary system that works to evade the natural hazards posed by the human immune system also functions efficiently to escape the perils posed by antiviral drugs that bind to the reverse transcriptase and protease enzymes. In the lecture preceding Dr. Wolinsky, John Coffin of Tufts University in Boston examined the rapid rate of appearance of resistance to our most powerful antiviral drugs. The rapid appearance of resistance is testimony to the vast diversity of virus variants always present in the body, according to Dr. Coffin. He thinks mutant viruses with at least modest resistance to a given drug exist even before a person starts taking that medication. These mutants may not be detectable because they do not multiply quite as fast as the dominant "wild type" strain, but they rapidly takeover when HIV is exposed to a particular drug. Dr. Coffin cited the example of 3TC. A mildly resistant mutant strain is indeed detectable before therapy, and then a more highly resistant single mutation shows up a few weeks after 3TC administration begins. "There is no way to hit the virus hard enough to prevent mutations," he concluded. A final problem is that a few infected cells are chronically infected and do not naturally succumb at the rate Dr. Ho predicted. (These latently infected and/or long-lived, slow producers of HIV, probably macrophages and quiescent CD4 cells, are often termed "virus reservoirs.") Since present drugs only block HIV replication and cannot eliminate infected cells, there persists a small amount of virus production (0.1 to one percent of normal production even for the most powerful protease inhibitors). Virus reservoirs inescapably limit how hard any of the present medications can "hit" HIV over the short term, and mutant escape versions of HIV continue to have the opportunity to arise after drug therapy commences. Dr. Ho calculates that the solution to the problems HIV variation poses is not necessarily powerful therapy, but more varied therapy. "We need combinations of drugs that force the virus to mutate at multiple points, preferably more than four, before the numbers favor the host," he said. Previously, combination therapies have been promoted because of the drugs' additive or synergistic effects in reducing HIV replication. Dr. Ho is speaking about combination therapy from a different perspective, inhibiting the evolution of unwanted drug-resistant HIV strains by both reducing HIV replication and requiring an untenable number of mutations. And a Proliferation of Resistance Factors More and more researchers are accepting Dr. Ho's contention that the ultimate failure afflicting all current anti-HIV therapies is strictly associated with genetic mutations conferring drug resistance. And combination therapies seem a logical way to defeat HIV's talent for these mutations. A satellite conference held after ICAAC explored these two assumptions further. The first lecturer, Daniel Kuritzkes, M.D., of the University of Colorado warned that all is not so straightforward. Citing two government-sponsored studies, ACTG 116B/117 and ACTG 192, Dr. Kuritzkes remarked that switching to ddI after AZT use apparently confers benefits regardless of whether a patient's HIV is still susceptible to AZT. More remarkably, the people with AZT-resistant virus do worse after switching than those with susceptible HIV. This is counter-intuitive: one would think that ddI would have the biggest impact in people with AZT-resistant HIV. They are the ones receiving the most minimal benefit from their present drug, and there is no evidence from laboratory cultures that AZT-resistance alone causes any decrease in susceptibility to ddI. Fears have been raised for the past several years that some mutation in AZT-resistant HIV causes an increase in the virus' virulence. A similar, though less serious phenomenon is present during d4T and ddC therapy: CD4 count falls and disease progression do not seem related to the emergence of resistant strains. This is true, too, for saquinavir, Roche's protease inhibitor. According to the ICAAC report on using high dose saquinavir (ICAAC presentation LB-5, also see Treatment Issues, September, 1995, pages 6-7), HIV plasma levels bottom out and begin to rebound four weeks after starting the 7.2 gm/day dose, yet resistance mutations do not start to appear before the twentieth week of therapy. One must remember all the factors that contribute to drug failure. The first of these is that since the currently approved HIV therapies are not really very good at stopping viral replication, they do not halt the progressive immunologic decline leading to AIDS. With less and less immune system backup, any drug will perform less and less well (this circumstance was described for CMV therapies in Treatment Issues July/August, 1995, page 1). Another factor is cells' increased ability to avoid metabolizing nucleoside analogs like AZT into their active, or phosphorylated, form (this "cellular resistance" was described by Michael Dudley in ICAAC presentation S110). Finally, the present drugs do not reach all the cell types harboring HIV. All these elements abet the rise of drug resistance by allowing further HIV replication and more mutations. The final outcome of the genetic rearrangement that evolves, as the virus attempts to optimize itself in the presence of drugs, is uncertain. Although it is obviously important to look at the whole environment in which HIV and drugs interact, an elegant report by Charles Boucher, M.D., at the satellite resistance conference, showed how well merely following the HIV genetic response to chemical therapy can explain the observed results. Dr. Boucher and his associates looked at a group of trial participants in Amsterdam who first received 3TC monotherapy, to which AZT was later added. The unique, rapidly appearing mutant that creates 3TC resistance is supposed to block the effects of the AZT resistance mutations, but Dr. Boucher says that this is only true for the initial alteration of the reverse transcriptase that causes low-level AZT resistance. The succeeding mutations, which result in high-level resistance (and possibly greater viral virulence), are little affected. In the Amsterdam 3TC-resistant patients, high-level AZT resistance occurred later than usual, in the second year of AZT/3TC therapy, via several of the usual mutations plus a novel one. The ability of high resistance to AZT to coexist with 3TC resistance suggests that it will not help so much to add 3TC to the regimens of people with lengthy experience on AZT (in whom the mature AZT-resistant genetic pattern is frequent). And indeed, the long-term observed antiviral effect in clinical trials of adding 3TC to prior AZT monotherapy was comparable to adding ddC. (See Treatment Issues, February, 1995, pages 3-4.) Dr. Boucher nevertheless held out the hope that all these mutations will render reverse transcriptase a less functional enzyme, and the HIV producing it will replicate less well. The extent to which this holds true, as well as the physical benefit patients receive, will have to be determined in clinical trials. A previous attempt to create "replication- deficient" HIV -- through the so-called convergent combination therapy -- was not very successful (see Treatment Issues, January, 1995, page 6). Beyond the Valley of the Drugs A combination therapy that includes AZT, ddC and Abbott Laboratories' protease inhibitor ritonavir is performing significantly better than any past regimen, with HIV levels continuing to decrease in a handful of patients, so far, out beyond at least five months (see page 6). An ongoing trial testing AZT plus 3TC and indinavir (the Merck protease inhibitor) may show that this combination performs as well as the ritonavir-containing one. Abbott investigators are already talking about "draining the reservoirs" of HIV. It is quite a leap to think that this type of combination can completely clear the body of HIV, though. One immediate problem is that protease inhibitors penetrate the brain poorly if at all. Most likely, people with HIV will be required to take an effective drug therapy absolutely every day for the rest of their lives, regardless of side effects. If therapy is missed for just a few days, HIV replication will start to return, with the heightened possibility of a virus evolving that is both virulent and drug-resistant. This scenario is similar to the one that exists for tuberculosis, only worse. We still have a hard time controlling TB, and drug-resistant tuberculosis is becoming a major problem. For ultimate HIV control, then, maybe we will have to hit the virus not just "hard," but from different directions. Hydroxyurea, as reported in our last edition, and other compounds that make the cellular milieu less compatible to HIV, offer a variety of new approaches. Compounds that break HIV's "zinc fingers" are also a possibility here (see page 7). Immune-based therapies, which work by ameliorating the immune response, could be the final answer since they would work on the heart of the problem -- the lack of immune backup to chemotherapy. Unfortunately, the initial attempts have not worked well. IL-2 (see Treatment Issues, February, 1995, pages 7-11), for example, failed to lower HIV levels over twelve months of treatment although, as in the past, it did double CD4 counts (ICAAC presentation LB-8). No clinical benefit from IL-2 has yet been demonstrated, either. Another approach has been the so-called therapeutic vaccine, in which synthesized HIV proteins or killed HIV stripped of its outer coat has been injected into people with HIV in the hope of coaxing a broader immune defense that reacts to more critical HIV epitopes. Like IL-2, these vaccines have had no confirmed benefit in terms of HIV levels or patients' health. There were two early reports at ICAAC on the most sophisticated therapeutic vaccine yet, Viagene's gene therapy product which induces cells in the body to mimic HIV infection by producing HIV proteins. The presenters claimed improvements in immune response, but detected no significant change in HIV levels or CD4 counts (presentations I75 and I76). An alternative way of modulating the immune response to HIV would be to reduce aspects of that response that are considered counterproductive. Use of thalidomide to inhibit the inflammatory cytokine and HIV-stimulator tumor necrosis factor (TNF) has been widely discussed (see Treatment Issues, May 1995, pages 3-6). At ICAAC, one report described using a fusion protein including part of cells' TNF receptor to "mop up" excess TNF. A pilot study of this molecule again observed no effect on HIV levels or CD4 count (presentation I78). Nevertheless, immune-based therapy seems like an important avenue to pursue at this point. "It's clear that antiretroviral therapy has been limited by a number of factors that are quite straightforwardÉ It might make sense to refocus our thinkingÉ on the virus-host interaction," contended Robert Schooley, M.D., of the University of Colorado, during a review of immune-based therapies (presentation S51). We need to identify the responses that keep HIV in check early in disease and in long-term nonprogressors. A successful immune-based therapy would then reinforce or recreate such responses in the human body. As drug therapy keeps HIV levels low, a powerful and properly cultivated immune response could seek out and eliminate the last vestiges of infection wherever they may be. ****************** ACTG 175 and Delta by Gabriel Torres, M.D. First-line treatment may need to be re-evaluated according to the findings of two studies, ACTG 175, and Delta. ACTG 175 was a National Institute of Allergy and Infectious Diseases (NIAID) sponsored study, presented at ICAAC (abstract LB-01). The data from Delta, a European/Australian co-operative trial, were reported in September at the Fifth European Conference on the Clinical Aspects and Treatment of HIV Infection in Copenhagen, Denmark, September 26-29, 1995. ACTG 175 compared monotherapy with AZT or ddI to combination therapy with AZT/ddC and AZT/ddI, as well as benefits of immediate vs. delayed combination therapy. The study population included both antiretroviral-naive and -experienced people with HIV and CD4 cell counts between 200 and 500. The trial involved a higher proportion of women, African-Americans, Hispanics and injecting drug users than in previous ACTG studies. The study's primary endpoints were the times to a 50 percent decline in CD4 cell count or a clinical condition, namely an AIDS-defining condition or death. Participants who reached either the CD4 or clinical endpoint were switched in a blinded manner to receive combination therapy with AZT/ddI or AZT/ddC if they had previously received AZT or ddI monotherapy or to receive the alternate combination if previously on combination therapy. This allowed for a comparison of immediate versus delayed combination therapy. At the conclusion of the study, 69 percent of the endpoints occurred in the antiretroviral experienced group, and 31 percent in the naive group. Over two-thirds of the endpoints were declines in CD4 cell counts. The rate of side effects in this study was 19 percent and did not vary significantly among the treatment arms (although in the naive group there were more adverse events in the AZT monotherapy arm). More patients discontinued AZT/ddC than other regimens due to adverse effects, mostly peripheral neuropathy. The study found no significant difference between immediate versus delayed combination therapy. Other findings are summarized in the table on page 2. Delta compared AZT to AZT/ddI and AZT/ddC in AZT-naive (Delta I) or -experienced (Delta II) individuals with CD4 cell counts between 50 and 350 (see table). The average CD4 cell count for participants in Delta I was around 200, much lower than in the naive population of ACTG 175. Delta I was also larger than the naive subset in ACTG 175, and more convincing because of the greater number of clinical endpoints counted. Delta II was comparable in size to the experienced cohort in ACTG 175, but participants in this study again had much lower CD4 cell counts than the AZT-experienced cohort in ACTG 175 (189 versus 338). More patients stopped AZT/ddI than AZT/ddC due to side effects, mostly nausea and vomiting. Delta's findings are also summarized on page 2. The recommendations potentially resulting from these trials include: 1) for antiretroviral naive patients, initiate therapy with either AZT/ddC or AZT/ddI or (according to ACTG 175) ddI monotherapy. This latter finding contradicts the results of a previous ACTG trial (116A) which found AZT monotherapy superior to ddI monotherapy in naive patients. It is consistent with the results of ACTG 152 which showed superior survival for ddI or AZT/ddI over AZT in children. 2) Again, based on ACTG 175, for AZT experienced patients: switch to or add ddI rather than staying on AZT monotherapy. Adding ddC to AZT in the experienced group did not provide additional benefits. This is consistent with ACTG 155, a trial that found no clinical benefit (in terms of progression of disease or survival) to AZT/ddC therapy in people with previous long AZT experience. Final guidelines utilizing the results from both studies are expected to be forthcoming from a state-of-the-art panel which will review the data in the near future. This must await the results of the NuCombo trial. This study is being conducted by the Community Programs for Clinical Research on AIDS (CPCRA) in the U.S. and compares AZT to either AZT/ddC or AZT/ddI in advanced patients with CD4 counts below 200. Results from this trial should be available by the end of the year. Summary of Data from ACTG 175 and Delta Trials These trials compared AZT to AZT plus ddI or ddC and also (in ACTG 175) to ddI alone. Trial participants either had prior experience with AZT or were AZT-naive. The following conclusions from the trial are based on the effect of each treatment on progression to AIDS or death. ACTG 175 AZT-naive: AZT/ddC was superior to AZT monotherapy. AZT-experienced: AZT/ddI was superior to AZT monotherapy. (Overall: AZT/ddI and ddI monotherapy were superior to AZT monotherapy.) Delta AZT-naive: either AZT/ddI or AZT/ddC was superior to AZT monotherapy. AZT-experienced: all drug regimens were equal. (Overall: AZT/ddI and AZT/ddC were superior to AZT monotherapy.) For more details and the implications of these trial's findings, see pages 3 and 4. [ACTG Table omitted from electronic addition] ***************************** Making Sense of 175 and Delta by Theo Smart Some activists and researchers have heralded the findings of ACTG 175 and Delta as "the most important trial results ever." Much time already has been spent pouring over the studies' statistics, comparing populations, and drop-out rates in a valiant attempt to understand what these studies mean. What it all boils down to is that AZT monotherapy is not the best treatment available, whether as initial therapy or in the drug-experienced. This finding does not impress some. "Treating clinicians have known this for years," said Stacy Kreiswirth, a nurse practitioner from New York attending ICAAC, "show me something that will help my patients." It is hard indeed to get excited about ddI and ddC, drugs that have been around for so long and that clearly do so little, as evidenced by Delta II, in which more than a quarter of the participants had died by the end of the two- year study, regardless of the treatment received. These studies' findings do little to expand people's treatment options. Some of these studies' findings are counter-intuitive. Why didn't AZT/ddI fare better in delaying disease progression or death than ddI alone? In the experienced population this may have been due to AZT resistance, but in the naive population, one would expect to have seen at least a trend in favor of the combinations AZT/ddI and AZT/ddC. Both did have a more pronounced effect on viral load than ddI in these patients, as reported by Daniel Kuritzkes, M.D. (ICAAC abstract LB-02), but in the experienced patients AZT/ddC performed substantially worse clinically than ddI. ACTG 175 appears to call into question the clinical utility of viral load tests. Delta II, which is still continuing, found no difference between combination and monotherapy in antiretroviral experienced people, and so contradicts the findings of ACTG 175. The participants in Delta II were at a much later stage of disease, though, so comparisons are difficult. There also could have been more resistance to AZT, which could decrease the benefit received from treatment with ddI or ddC (see page 14). The findings of these studies may become quickly irrelevant because of new and more potent drugs being added to the therapeutic arsenal. Where will d4T or 3TC fit into the picture? Certainly, AZT/3TC is a much more potent combination, although we have little clinical information. Glaxo-Welcome has requested approval for AZT/3TC as first- line treatment. Meanwhile, test tube data suggests that virus resistant to 3TC is less susceptible to ddI and ddC. How should this effect treatment decisions? Also, clinical data on the protease inhibitors will soon become available. Treatment options are increasing, but when to employ which regimen is affected by such issues as cross-resistance, synergy and toxicity. Without the clinical data, it is impossible to know which variable is more important in making treatment decisions. Finally, neither study provides information about the optimal time to start therapy or when to switch regimens, and there are no studies currently underway that will answer these questions soon. ACTG 175 and Delta did yield some precious, though somewhat contradictory data on clinical benefit. How to apply the lessons learned beyond the particular populations and regimens under study remains a mystery. ***************************************** More Clinical Data on Protease Inhibitors by Theo Smart The four companies whose protease inhibitors are furthest along in clinical development all presented clinical information on their respective drugs at ICAAC. Overall, a number of studies suggested that higher doses of these drugs, and combination with nucleoside analogs appear to produce more potent and durable antiviral effects than seen in earlier protease inhibitor studies. Ritonavir: The combination of Abbott Laboratories' ritonavir, AZT and ddC rapidly achieves a CD4 count jump of more than 110 cells, and a greater than 99 percent reduction in viral load which is sustained for the duration of a twenty week study. Still more strikingly, there is an increasing proportion of participants whose HIV level becomes so low that it is below or at the limit of detection by the PCR assay used to detect viral load. Daniel Norbeck, M.D., of Abbott presented this very preliminary data from a French study, conducted by Jacques Liebowitz, M.D., in twenty-nine volunteers (not all of whom have completed twenty weeks of treatment). After two months, five of 27 participants had undetectable HIV levels. Seven out of twenty had undetectable HIV after five months, while four more experienced 99.9 percent of the maximum detectable reduction in viral load. Dr. Norbeck suggests that "the reservoirs of virus are emptying," in the treated population. By reservoir, he means that the longer-lived infected cells, such as macrophages and monocytes, which continue to produce virus for weeks (unlike an actively infected CD4 cell, which dies in two days). Many researchers believe that since present drugs do not kill infected cells, their use can only eliminate all of the virus from the body if they can keep suppressing HIV replication, even in the face of mutations that confer partial drug resistance, for a period longer than these cells' lifetimes. It is debatable whether Dr. Norbeck can claim such success on the basis of one small study. Abbott appears even more excited about the promise of combination therapy with ritonavir and Hoffmann-La Roche's protease inhibitor saquinavir (abstract LB-7). Although cross-resistance between protease inhibitors is a concern, the initial resistance mutations arising with ritonavir and saquinavir therapy are distinct, and the hope is that two- protease combination therapy could suppress viral replication enough to delay the emergence of resistance indefinitely. Saquinavir's antiviral effect, however, is limited by the low blood levels of saquinavir achieved with the current dose and formulation. People are not getting enough saquinavir, because the little that is absorbed is rapidly broken down in the liver. Abbott may have a solution: ritonavir shuts off the metabolic pathway in the liver that breaks down saquinavir as well as ritonavir. In rats, co-administration of the two drugs led to an eighteen-fold increase in peak levels of saquinavir in the blood (from a single dosing) and extended the drug's half- life fifteen-fold. (The cumulative increase in drug levels from multiple dosing could be much higher.) Dr. Norbeck concluded that ritonavir and saquinavir may have a "two- dimensional synergy." Follow-up studies must be done immediately to see whether the interaction occurs in people. Although no dose-limiting toxicities have been encountered yet with saquinavir, no one knows about higher blood levels, and an effect of this magnitude may be extremely dangerous. As GMHC's David Barr remarked, "people may want to trade in their livers after using this combination," if this interaction is indeed seen in people. It may not be. The antifungal medication ketoconazole also slows down the same liver pathway. According to Noel Roberts of Roche Laboratories in Great Britain, co-administration of ketoconazole and saquinavir also dramatically boosted saquinavir levels in rodents, but the increase was much less impressive in humans. Still, just a three- or four-fold rise in blood levels could be helpful, particularly in those people receiving low doses of saquinavir in the current phase III trials and expanded access program. [As Treatment Issues went to press, Miklos Salgo, M.D., Roche's director of clinical research notified us that Abbott and Roche have reached an agreement to start drug interaction studies in both dogs and people before the end of the year.] Indinavir sulfate (Crixivan): Higher doses of this Merck protease inhibitor have a much more profound and sustained effect in naive patients than lower doses, reported John Mellors of the University of Pittsburgh (abstract I172). The findings come from a study comparing indinavir to AZT, discussed previously in Treatment Issues (January, 1995, pages 1-2). In this study, the dose of indinavir was increased to 600 mg four times a day after Merck found that HIV quickly becomes resistant to lower doses. Increasing the dose had little effect in the patients who had initiated therapy at lower doses, but researchers suspected that the CD4 and viral load responses would be better in patients who begin therapy at a higher dose. This proved to be the case in the sixteen trial participants who had been randomized to AZT and were crossed over (at week 24) to the protease inhibitor at the 600 mg four times a day dose. These patients began indinavir therapy with median CD4 cell counts of 110. After six months of treatment, the majority of these patients had sustained reductions in viral load, although there was a trend back toward baseline. At week eight, half of the patients had more than a 1.98 log (almost 99 percent) suppression in viral load. At week 24, half maintained at least a 90 percent reduction in virus, and a third still had 99 percent less virus than when they started therapy. Median CD4 counts remained more than 100 cells above baseline. The findings were similar in a 24 week study comparing indinavir sulfate (600 mg four times a day), AZT, and indinavir and AZT combined (abstract LB-6). This study enrolled 73 volunteers with CD4 cell counts below 500 (median 221) and viral load levels greater than 20,000 copies per ml, (median of approximately 80,000 copies per ml). At the point of maximum antiviral effect, AZT monotherapy produced around a 75 percent reduction in viral load (0.6 log), while indinavir monotherapy and combination therapy reduced viral load by medians of 99.5 and 99.75 percent, respectively (2.3 and 2.6 logs). At week 24, viral load was only slightly (0.2 log) below baseline for AZT monotherapy. The viral load was still significantly below baseline for indinavir monotherapy and combination therapy, 1.5 log and 2.5 log, respectively. Although the difference between the combination arm and indinavir monotherapy arm was not statistically significant, there was a clear trend toward a rebound in viral load on monotherapy compared to a more sustained suppression of HIV on combination therapy. CD4 cell analysis was not complete for this study, yet there already is a clear benefit in favor of the arms containing indinavir. In a meeting with activists several weeks before ICAAC, Dr. Jeffrey Chodakewitz of Merck reported data from a dose- ranging indinavir monotherapy study in more than 70 people. For the 800 mg thrice daily dose (the dose now used in Merck's trials), median viral load reductions were slightly greater than 99 percent at maximum, with a slight trend back to baseline by week twenty. CD4 counts increased by an average of more than 100 cells. Activists asked Merck whether the company plans to run any studies of indinavir in perinatal transmission. Merck has expressed an interest in such studies, but the increase in bilirubin levels that indinavir induces are a more serious problem in infants than adults. Bilirubin can pass through the immature blood/brain barrier and cause severe disability. AG1343 (VIRACEPT): Graham Moyle, M.D., reported on the British low-dose study, (abstract LB-3) previously reported in Treatment Issues (June, 1995, page 4). Six out of 22 patients had a greater than 90 percent reduction in viral load at day 28. This response was sustained for the duration of treatment (three to four months), and participants gained an average of 100 CD4 cells. Diarrhea was the most common side effect, occurring in eight out of ten of the people on the highest dose tested. Marty Markowitz, M.D., of the Aaron Diamond AIDS Research Center in New York, announced the results of a dose-ranging study (that went higher than the British study) in people with CD4 cell counts greater than or equal to 200, and viral load levels greater than or equal to 20,000 copies per ml (abstract LB-4). The study evaluated three doses -- 500 mg, 600 mg and 750 mg -- all twice daily in 30 subjects. At day 28, CD4 counts had increased by more than 100 cells; the greatest response was seen in the patients on the highest dose. Several HIV-related conditions such as lymphadenopathy, hairy leukoplakia and candida resolved or improved in a number of patients. The average maximum decrease in viral load ranged from 90 to 94 percent, and in some patients viral load dipped below the level of detection. There was no difference in anti-HIV effect by dose, although the viral load on the low dose did appear to begin to rebound toward baseline levels. However, Dr. Markowitz noted that individuals with higher drug levels in their plasma had more profound responses -- but higher doses did not always achieve higher blood levels of drug. Overall, 21 participants had a greater than one log reduction needed to continue on VIRACEPT after the initial 28 day trial period. This criterion for study continuation caused consternation with AIDS activists on the West Coast, who noted that some participants who were dropped had desired to continue on therapy, largely because of improvements in CD4 cell counts. Dr. Markowitz countered that in patients who were not seeing at least a one log reduction, long-term therapy might induce cross resistance to other protease inhibitors, so treatment discontinuation was in their best interest. The activists felt that this decision should rest with the individual and their primary care provider. Another area of concern to activists is VIRACEPT's shaky position as fourth protease inhibitor in a race for approval, where pivotal studies for the three competing drugs have already begun. Hoffmann-La Roche has already filed for approval of Saquinavir, and Merck and Abbott both plan to file for approval in the first quarter of the coming year. Agouron's pivotal clinical endpoint study in people with less than 50 CD4 cells is not slated to begin until the end of the year. The competing drugs almost certainly will be approved before this study is completed. It is unlikely that people with less than 50 CD4 cells will be compliant to the protocol when comparable drugs become available. Agouron's best chance of salvaging its phase III program would be to dramatically increase the size of this trial. This would decrease the time it would take to reach a conclusion, since increasing the number of participants will increase the number of endpoints that can be counted. Otherwise, the study may not find statistically significant evidence of the clinical benefit of the drug, and the company may have to start all over again, in a world where the other protease inhibitors are standard of care. ************************** Protease Drug Interactions The following drug interactions have been reported for the protease inhibitors: Ritonavir (Abbott): Cannot be taken together safely with codeine, Demerol, Darvon, Feldene, Nizoral, Monostat-4, Tranxene, Valium, Versed (anesthesia), Halcion, Zanax, Tambocor, Rythmol, Vascor, Hismanol, Seldane, Tagamet, Paxil, Clozaril. Also: the dosage of clarithromycin should be reduced when taken concurrently with ritonavir. Indinavir (Merck): elevates blood levels of rifabutin, so the dose of rifabutin must be halved when administered with indinavir. ********************************************** Update on Protease Inhibitor Compassionate Use Indinavir: Merck is increasing the size of its indinavir compassionate use protocol to enroll 850 additional people from 23 foreign countries. There has been much activist criticism of the course of the U.S. program, though. Merck had promised to get drug into 1,400 PWAs by the end of the year, and the company is taking its time doing it, doling out drug to 125 more lottery winners each week. Many people who were chosen in the lottery assumed that they would receive drug much sooner. Let us hope that they survive the wait! Saquinavir: Hoffmann-La Roche is increasing the size of the saquinavir access program, as reported in last month's Treatment Issues. The lottery will be held on November 3, 1995, and will supply drug to 2,000 more people, for a total of 4,280 individuals in the U.S. The program has enrolled 1,700 in the rest of the world. Participants who did not win in the first drawing will be rolled over into the second lottery. VIRACEPT: In a meeting with AIDS activists during ICAAC, Agouron announced its intention to open a compassionate use protocol subsequent to enrollment and interim analysis of its pivotal phase III studies. -- TS ****************************************** Zinc Fingers -- The Next Antiviral Target? by Theo Smart The next target for antiviral drugs may be HIV's zinc fingers, according to data presented by researchers from the National Cancer Institute (ICAAC abstracts I134, I135, and I136). Zinc fingers are chains of amino acids found in cellular proteins which bind to DNA or messenger RNA, and play important roles in a cell's life cycle. They are called zinc fingers because they capture a zinc ion, which contributes to the array's binding to RNA or DNA. Zinc fingers found in nature can have one of a number of structures. In HIV's zinc finger, four amino acids are responsible for capturing the zinc ion. The sequence is unique, found elsewhere only in other lentiviruses, the family of retroviruses that includes HIV-1 and 2, cancer causing HTLV, feline immunodeficiency virus, and murine leukemia virus, to name a few. There are two zinc fingers in HIV's nucleocapsid (NC), a core viral protein. The zinc fingers are involved in binding and packaging viral RNA into new virions budding from an infected cell. Experiments in which the zinc fingers have been deleted have shown that new budding virions do not incorporate RNA, which instead spills out of the infected cell. The NC protein and zinc fingers also play some role during the process of reverse transcription. The exact role of the protein is unclear, but it may anchor the RNA molecule while the reverse transcriptase enzyme builds HIV DNA from the RNA template. HIV that lacks zinc fingers is unable to infect new cells. The zinc fingers are therefore essential for two phases of the viral life cycle. Since both zinc fingers structures are identical, the same compound could inhibit both (two targets for the price of one). Researchers at the NCI have altered the structure of these zinc fingers to see whether they could mutate and still work. They cannot; changes in even one of these amino acids in the array make the zinc fingers dysfunctional. In another study in which the entire zinc finger array was replaced with the types of zinc fingers commonly found in cellular proteins, RNA could be successfully incorporated into budding virions, but the resulting virus was non-infectious. HIV may not be able to mutate and escape the effects of drugs targeting its zinc fingers. The team at the NCI has developed a laboratory test to quickly screen for compounds that bind to HIV's zinc fingers. In their first mass screening of substances in their chemical library, they quickly found about 60 different active substances that eject the zinc from the zinc finger, altering its function. Many of these compounds were active against HIV at doses that were not toxic in cell cultures. One of the first, but least potent, of these compounds was disulfiram (Antabuse), a drug that has been on the market for years as a treatment for alcoholism. Unfortunately, this compound didn't work when used in monkeys with SIV. Since HIV's zinc fingers are identical to the zinc fingers of retroviruses which infect rodents, cats, and monkeys, animal models may be useful in the preclinical evaluation of these drugs. Some lead compounds have been evaluated in mice infected with murine leukemia virus. In one study, untreated mice survived an average of 35 days, while mice treated with one of these compounds lived ten to fifteen days longer (which is significant for laboratory mice). Preclinical data on two of the leading compounds were presented at the ICAAC meeting in San Francisco. One class of compounds is being developed by Parke-Davis Pharmaceuticals, and another by Octamer Inc., a six-year old biotech company in Mill Valley, California focused on AIDS and cancer research. The Parke-Davis compound may be further along. It is currently being studied for activity, toxicity and bioavailability in monkeys with SIV. Although shown to be very safe in mice, the doses required to sustain adequate blood levels were very high (250 mg per kg of body weight, twice a day). If the doses are similar in people (and absorption and metabolism may be much different in humans), this could add up to more than thirty grams a day. Such high doses could tax Parke-Davis' production facilities and may have toxic effects in the body. It is not yet clear what dose will be necessary with the Octamer drug, but if dosage is a problem, at least the compound's structure is simple enough that it should be cheap to produce, according to Octamer's president, Ron Brown, Ph.D. The current lead compound, 4-Iodo-3-nitrobenzamide, is a prodrug that becomes active in the cell, with very little cellular toxicity. Octamer is currently studying its bioavailability and efficacy in mice infected with retroviruses. If the drug works well in the mouse model, the company plans to approach the FDA to go directly into humans studies. Other active compounds could be awaiting discovery in other pharmaceutical companies' drug libraries. To ferret these out, the NCI has opened a CRADA (co-operative research and development agreement) offering to screen any company's drugs for anti-zinc finger activity and to possibly help with the development of such compounds. ****************************************************** Opportunistic Infection Highlights from the 35th ICAAC by Gabriel Torres, M.D. Several important studies evaluating treatment and prevention strategies for opportunistic infections were presented at ICAAC. Especially noteworthy were a variety of presentations on cytomegalovirus and mycobacterium avium complex, both of which are undergoing rapid advances in treatment and prophylaxis. The effect on HIV levels of opportunistic infections also received considerable attention. Epidemiology A report from the Centers for Disease Control and Prevention (CDC) examined HIV-related mortality data from 1987 to 92 (ICAAC abstract I22). The authors found a significant drop in death related to pneumocystis pneumonia (PCP) (from 32.5 percent to 13.8 percent of annual HIV-associated deaths), cryptococcal meningitis (from 7.7 percent to 5.0 percent) and candidiasis (from 2.3 percent to 1.7 percent). The cause of the decline in death rates are probably attributable to prophylaxis with anti-PCP drugs and anti-fungal agents such as fluconazole. In contrast, death due to other conditions increased. Complications with a rising death rate included mycobacterium avium complex (MAC) (from 6.7 percent to 12.2 percent of annual HIV-related deaths), cytomegalovirus (CMV) (from 5.2 percent to 9.9 percent), bacterial sepsis (from 9.0 percent to 11.5 percent) and non-Hodgkin's lymphoma (from 3.9 percent to 5.7 percent). There were smaller increases in the incidence of progressive multifocal leukoencephalopathy (PML), bacterial pneumonia, cryptosporidiosis, or pneumonias due to unspecified organisms. In 1992, unspecified pneumonia (18.6 percent of annual HIV- related deaths) and Kaposi's sarcoma (KS) ranked with PCP as the leading fatal opportunistic conditions. Valaciclovir for CMV Prophylaxis The final results of ACTG 204, an international study on preventing CMV infection sponsored by both the National Institute of Allergy and Infectious Diseases and the Glaxo- Wellcome company, were presented by Judith Feinberg, M.D., now at the University of Cincinnati (abstract I214). This double-blind randomized trial compared the acyclovir prodrug valaciclovir (Valtrex) -- which achieves acyclovir blood levels thought sufficient to inhibit CMV -- to either high dose acyclovir (800 mg four times per day) or low dose acyclovir (400 mg twice daily) in HIV-positive individuals with CD4 counts below 100 and evidence of prior CMV exposure (positive CMV antibody). The valaciclovir dose was two grams four times per day, the equivalent of about eight grams of acyclovir four times per day. ACTG 204 enrolled 1,227 participants who were followed for the development of CMV end organ disease (e.g. retinitis, gastrointestinal disease). Two-thirds of the patients had CD4 counts below 50 on entry, most were gay males, and 80 percent were concurrently receiving antiretroviral therapy. After an average of 33 weeks of treatment and 57 weeks of follow-up, those receiving valaciclovir had developed fewer confirmed CMV endpoints (11.7 percent) as compared to those receiving either high or low dose acyclovir (17.5 percent). This represents a 33 percent reduction of CMV disease, most of which (79 percent) was CMV retinitis. The time to confirmed CMV disease was significantly longer for those receiving Valtrex. There was, however, a strong trend toward earlier death in those receiving valaciclovir. The final mortality difference was not statistically significant, but it did lead to early study closure after an interim analysis. Causes of death were similar in all three groups. More patients on valaciclovir had to discontinue study medication due to toxicity. The most common side effect associated with valaciclovir was gastrointestinal distress, which occurred in 14.5 percent of the participants. Dr. Feinberg concluded that Valtrex reduced CMV disease rates by one-third. This reduction is similar to what has been reported in the Syntex Laboratories study of oral ganciclovir. (See Treatment Issues, July/August, 1995, page 4-5.) On the other hand, the Syntex study found a trend favoring improved survival on oral ganciclovir. The cost was a greater frequency of adverse events from oral ganciclovir than were observed with valaciclovir in ACTG 204. Oral Ganciclovir for Preventing CMV Dr. Carol Brosgart from Berkeley, CA reported the results of CPCRA Study 023, which compared oral ganciclovir (3 grams a day) to placebo for primary prevention of CMV end organ disease in AIDS patients with CD4 counts below 100 and prior CMV exposure (abstract LB-10). This study was amended in July, 1994 when the results of the Syntex study became available, allowing patients in both arms the option of open- label ganciclovir. A total of 994 patients were randomized in a two to one ratio to oral ganciclovir or placebo and followed for CMV disease endpoints. Patients did not have mandatory ophthalmologic evaluations on entry or at routine intervals to screen for CMV retinitis but rather were identified at the time of the onset of symptoms such as deterioration of vision. The median follow-up was fifteen months. Statisticians performed an intent-to-treat analysis, which separated trial participants as if they had stayed on their original medication -- oral ganciclovir or placebo -- for the entire time. This analysis found that the rate of CMV disease was similar in the oral ganciclovir and placebo groups, as were the death rates. Patients receiving oral ganciclovir experienced more adverse effects, including neutropenia (25 percent vs. sixteen percent). Dr. Brosgart concluded that the results did not support the use of oral ganciclovir for primary prevention of CMV disease. The results of this study contradict those of the Syntex study, which found an extraordinarily high rate of CMV retinitis in its placebo arm, 39 percent, which was reduced by half in the oral ganciclovir arm. The Syntex study relied on scheduled retinal exams with fundoscopy for detection of early CMV retinitis. Dr. Brosgart claims that some sixty percent of the participants in the CPCRA trial also had regular fundoscopic exams on their own. There nevertheless remains considerable controversy as to whether the looser requirements of the CPCRA trial meant that much early CMV retinitis was missed both at study entry and during the follow-up period. Syntex (now Roche Bioscience) is also criticizing the use of open-label oral ganciclovir by members of the CPCRA placebo arm, which could have obscured the observed benefits of ganciclovir. How significant this contamination of the placebo group with oral ganciclovir is in dispute. In the CPCRA trial, exposure to oral ganciclovir averaged 9.3 months in the group originally randomized to the drug and 2.1 months in the initial placebo group. Roche Bioscience, meanwhile, has filed an application with the Food and Drug Administration to market oral ganciclovir for prevention of CMV. While the arguments fly, clinicians must decide whether oral ganciclovir prophylaxis is worthwhile in persons with HIV and very low CD4 counts (below 50). Everyone agrees that oral ganciclovir prophylaxis should be more precisely targeted at those most at risk of CMV, if it is used at all. New assays to assess CMV activity, such as PCR, quantitative cultures and pp65 antigenemia, may help select the appropriate population who could benefit the most from preemptive CMV therapy. Resistant CMV In a preliminary analysis (abstract 135), researchers from the Syntex oral ganciclovir prophylaxis trial found that the incidence of ganciclovir-resistant CMV was very low (one percent). One patient with resistant virus failed to respond to intravenous ganciclovir treatment after developing active CMV retinitis. Several posters, meanwhile, reported cases of CMV infections in which viral isolates were resistant to several well-known CMV drugs after treatment with only one of the drugs. In one study (abstract H115) from the University of California San Diego, CMV resistant to foscarnet was isolated after only two months of foscarnet therapy in two patients, whose CMV had previously been found resistant to ganciclovir. In a follow-up study of nine patients with ganciclovir- resistant strains, reduced sensitivity to foscarnet was observed although the patients had not yet been treated with foscarnet. A genetic analysis of these individuals' CMV found mutations in the virus's gene for DNA polymerase, an enzyme necessary for virus replication. These mutations, which cause lowered sensitivity to foscarnet in laboratory cultures, probably indicate that treatment with foscarnet will rapidly fail. In another report (abstract H114), CMV strains isolated from two patients after prolonged ganciclovir therapy were resistant to both ganciclovir and cidofovir (HPMPC). The second patient's strain also had greatly reduced sensitivity to foscarnet. A genetic analysis of the first patient's CMV found a mutation in the UL97 gene as well as in DNA polymerase gene. The UL97 gene creates the CMV enzyme (thymidine kinase) which converts ganciclovir into its active, phosphorylated metabolite. The UL97 mutation renders the thymidine kinase inactive and is well known for causing resistance to ganciclovir but not the other drugs. On the bright side, herpes simplex virus with reduced thymidine kinase activity was found resistant to acyclovir but more sensitive to cidofovir (abstract H10). But laboratory strains of CMV resistant to both ganciclovir and cidofovir could be bred by investigators from Gilead Pharmaceuticals, the makers of cidofovir (abstract H117). The Gilead researchers could achieve this cross-resistance by adding increasing concentrations of either ganciclovir or cidofovir to a CMV lab culture. It was not necessary for the CMV to have been exposed to both of the drugs at any point. Cidofovir (HPMPC) for CMV Cidofovir previously has shown promise in the treatment of refractory CMV disease. At ICAAC, a late breaker presentation (LB-9) described 60 patients with relapsed CMV retinitis who were randomized to receive different regimens of cidofovir (5 mg/kg of body weight once weekly for two weeks, then 5 mg/kg once every other week, or 3 mg/kg once every other week). To minimize kidney toxicity, intravenous saline and probenecid were co-administered. The median time to progression was 114 days for the 5 mg/kg group and 49 days in the 3 mg/kg group, a difference that was not deemed statistically significant. Side effects of cidofovir included kidney dysfunction in 7 percent, and probenecid reactions (fever, nausea and rashes) in 48 percent of trial participants. Survival was similar in both groups (39 percent vs. 36 percent). Cidofovir is now available through a "Treatment IND" for patients with CMV retinitis who have relapsed or cannot tolerate ganciclovir and foscarnet. Call 800/GILEAD5 to obtain the drug. Mycobacterium avium complex (MAC) A large French study called Curavium, comparing two oral drug regimens for the treatment of disseminated MAC, was presented at a late breaker session (abstract LB-19). The study compared clarithromycin (two grams for two months, then one gram thereafter) in combination with either clofazimine 200 mg daily for two months then 100 mg daily thereafter (two- drug combination) or with rifabutin 450 mg daily and ethambutol 1200 mg daily (three-drug combination). One hundred twenty-three patients with CD4 counts of greater than 100 and positive blood cultures for MAC were enrolled and randomized to one of the two regimens. They were followed with serial blood cultures. The three-drug combination proved superior to the two-drug combination with improved survival after 24 weeks. Breakthrough MAC bacteremia was more common with two drugs (eighteen cases) than with three drugs (six cases), and emergence of clarithromycin resistance was less common using the three drug regimen. Side effects included gastrointestinal distress from clarithromycin and uveitis from rifabutin. In a Canadian study (abstract LB-20), the three-drug combination of clarithromycin, rifabutin, and ethambutol was superior to a four-drug combination of rifampin, ethambutol, ciprofloxacin and clofazimine. The rifabutin dose was halved (from 600 mg daily to 300 mg daily) due to the development of uveitis at the high dose. Rates of MAC clearance from the blood were 69 percent and 24 percent for the three- and four-drug combinations, respectively. A significant survival difference (258 days versus 153 days) also was seen in this study. Both studies indicate that clarithromycin and rifabutin are the most active drugs in the treatment of MAC and can be used together. Opportunistic Infections and HIV Viremia A study from Henry Ford Hospital in Detroit examined HIV RNA plasma levels in patients suffering from acute opportunistic infections (abstract I236). Increases in HIV plasma levels were found (median 36,000 copies/ml) in eight patients with the advent of an opportunistic infection. With recovery from disease, there was a decline in the HIV plasma level (median change was -30,000 copies/ml). In contrast there were no changes in p24 antigen levels or CD4 counts with either the advent or recovery from opportunistic infections. The authors concluded that opportunistic infections increase HIV production and may exacerbate immune decline. These OIs also may confuse the interpretation of disease progression and drug failure based on changes in HIV load (see Treatment Issues, September, 1995, pages 12-14.) A similar study showing increases in HIV levels following herpes simplex reactivation in ten HIV-positive patients was presented as a poster (abstract I235). The median increase in HIV viral load was 55 percent, and the extent of viremia seemed to be related to the size and number of herpes lesions. It remains to be determined whether acyclovir suppression of HSV can influence HIV viremia. Immunizations Very disturbing reports of the effects of influenza and pneumococcal immunizations on HIV viral load received considerable attention at the conference. One study (abstract LB-11) compared influenza vaccine to placebo in 47 HIV-positive patients. This double-blind randomized test found significant increases in plasma HIV levels in the vaccinated group four to six weeks after the injection. Three months after the vaccine, the CD4 percentage had dropped by 1.8 percent in the vaccinated group as compared to a rise of 0.2 percent in the placebo group. The authors concluded that annual influenza vaccination for HIV- positive persons may be harmful, although the study was unable to demonstrate any clinically significant adverse outcome to the vaccine. In another study (abstract I237), twelve asymptomatic HIV- positive volunteers with an average CD4 count of 374 who received the pneumococcal vaccine (Pneumovax) had their plasma HIV levels assessments by quantitative PCR before and after vaccination. Immunization with Pneumovax was followed by a rapid and sometimes profound increase in viral burden (mean rise of 83-fold). This rise correlated with the volunteers' antibody production in response to the vaccine and with the extent of their CD4 cell activation. HIV levels in four patients remained increased twelve to sixteen weeks after the vaccine. Although these studies are small, and neither showed adverse consequences to the patients' health status, they indicate need for further placebo-controlled studies of the vaccines and due caution when administering them to patients with high viral loads. ************************** Cryptosporidiosis at ICAAC Even the most rigorous of water purification systems could not keep the intestinal parasite cryptosporidia out of the tap water according to one poster presented by Susan Goldstein of the Centers for Disease Control and Prevention (CDC) (abstract K63). This study investigated the cause of a 1994 outbreak of 78 cases of cryptosporidiosis in Clark County, Nevada (Las Vegas). People with AIDS made up 81 percent of these cases. The CDC found that the only risk factor for the infection was drinking tap water (the subgroup of cases with CD4 cell counts less than 100 were twelve times more likely to have drunk tap water than matched controls). This outbreak occurred despite Clark County's state-of-the- art water filtration system, which produced a water quality better than what the national standard mandates, and despite the fact that no cryptosporidia could be detected either in the source or in the finished water. These findings led the CDC to suggest that immune-compromised people drink either boiled or bottled water. On the treatment front, one study evaluated the use of total parenteral nutrition (TPN) in eight people with cryptosporidiosis and weight loss (abstract I42). Although the four participants who survived for more than five months did eventually gain weight, it was not clear whether this was due to TPN or these patients' better prognosis. The authors concluded that more study was needed to determine which patients were more likely to benefit from the expensive procedure (more than $800 a day). A number of studies meanwhile evaluated new anti- cryptosporidia treatments in the laboratory. A group of researchers from Emory University found dramatic activity with a number of herbicides, at doses that may be safe enough to administer to humans (abstract E42). Researchers from the University of Texas and DuPont Merck reported that compounds inhibiting an enzyme unique to cryptosporidia block an essential phase of the parasite's life cycle (abstract B56). Although the compounds utilized in this study are not absorbable in the gut, this finding may lead to new drugs eventually. More effective therapy for cryptosporidiosis might require combination strategies. One cell culture study at the University of Arizona found synergistic activity with two available drugs, paromomycin (Humatin) and clarithromycin, (abstract E43). This combination could easily be evaluated in people. Currently, the National Institutes of Health is conducting test tube studies of combinations of NTZ (see Treatment Issues, September, 1995, page 14) and other compounds. - TS ******************** Candidiasis at ICAAC by David Barr and Theo Smart Several presentations on oral candidiasis treatment occurred at ICAAC. Unfortunately, there were no human studies on treatments for vaginal candidiasis. One study (ICAAC abstract I221) compared fourteen day treatments of an oral suspension of fluconazole (100 mg daily) to liquid nystatin suspension (five ml swished or gargled four times daily). A total of 166 patients were enrolled, 83 in each arm. Of the evaluable patients, 59 out of 68 patients on fluconazole were clinically cured compared to only 33 of 68 cured on nystatin. Those on nystatin also had significantly higher rates of relapse. Overall, fluconazole was found to be clinically superior to nystatin. A Canadian/European study (abstract I-219) compared oral fluconazole to an oral itraconazole solution for treatment of oral candidiasis (thrush). The oral itraconazole solution has improved bioavailability, can be administered without meals and has a topical effect. The study included 244 patients with thrush who received the itraconazole solution (100 mg twice daily for seven days or 100 mg daily for fourteen days), or oral fluconazole (100 mg daily for fourteen days). Patients had weekly assessments of symptoms and oral cavity cultures. The itraconazole solution seems to be a reasonable alternative to oral fluconazole in the management of thrush. Results showed that all three regimens were equivalent as were the rates of relapse (20 to 22 percent). Side effects were also similar. In a similar study, (abstract I220), oral itraconazole solution appeared better than oral fluconazole. One hundred ninety patients were randomized to receive itraconazole (200 mg daily for seven days or 200 mg daily for fourteen days) or fluconazole (100 mg daily for fourteen days). The fourteen- day itraconazole regimen produced the best results (97 percent success rate with the lowest rate of relapse). The seven day itraconazole arm was comparable to the fluconazole (response rates of 83 and 87 percent, respectively). Note, though, that a total of seven itraconazole patients stopped therapy because of adverse events compared to only one fluconazole patient. The advantages of the itraconazole solution include that it can be given along with rifabutin, rifampin and drugs that suppress gastric acid (Tagamet, Pepcid) and that it has an additional topical effect. How useful it will be in patients with fluconazole-resistant candidiasis needs to be determined. Janssen Pharmaceuticals, which makes itraconazole, had no comment on whether it plans to market the new oral formulation any time soon. Drug Resistance Since the organism that causes Candida albicans is a natural part of the intestinal and vaginal flora, and thrush is merely its overgrowth, drugs that keep candidiasis in check may never completely eradicate it. The continued presence of the organism during treatment makes the selection of resistance more likely. Therefore, many clinicians do not prescribe antifungal prophylaxis, for fear of creating yeast strains resistant to treatment. Instead, they opt to treat thrush as it occurs. It is unclear whether this approach is any better. Based on a study of 153 patients, researchers from Dijon, France had previously reported that prophylaxis with fluconazole can cause resistance. At ICAAC, they reported that they saw just as much resistance in 142 people who have not received fluconazole prophylaxis (abstract C102). Some of those with less susceptible yeast had been treated for thrush with fluconazole or ketoconazole. A Spanish study of 130 episodes of oral candidiasis in 95 people also found that fluconazole resistance was not significantly more common in people recently treated with the drug (abstract I103). A NIAID sponsored study, ACTG 816, in 202 people (56 percent of whom became fluconazole resistant) appeared to disagree with the Spanish researchers findings (abstract I101). This trial found that reduced susceptibility to fluconazole was highly correlated with both more than three episodes of candidiasis in the previous year and previous treatment to fluconazole. Doctors at Cochin Hospital in Paris evaluated the factors that led to failure on fluconazole in fourteen patients (abstract E62). While resistance was the most important factor, concurrent use of other medications such as rifabutin and rifampin, which lower the levels of fluconazole in the blood was common in 43 percent of these patients. Other cofactors, such as tobacco use and poor oral cavity condition were also common. Treatment with doses of fluconazole at 400 mg a day was successful in 66 percent of these cases. Those who failed these doses also did not respond to higher doses. Such patients may have few treatment options, as a number of studies reported that previous therapy with ketoconazole or fluconazole could cause decreased susceptibility to the whole azole class of antifungal drugs (abstracts E63, I102, and I105). **************** Washington Watch by Derek Link New NCI Director Confronts Troubled Agency In his new role as Director of the National Cancer Institute (NCI), 44-year-old Richard Klausner oversees the largest federal biomedical research institute, with a budget of $2.4 billion. Dr. Klausner also is a leader in AIDS research. The NCI received $213 million for AIDS research this year, ranking it second among the 24 federal agencies that receive AIDS research funds. Dr. Klausner has spent most of his career at the NIH. Before his NCI appointment, Dr. Klausner served as the Chief of the Cell Biology Branch at the National Institute of Child Health and Development. He is one of the most published researchers in the fields of molecular biology and immunology. His work includes the biochemistry of a gene involved with human kidney cancer, the function of T-cell receptors, and iron metabolism. Dr. Klausner takes control of a troubled agency. Several recent reports have criticized the NCI for lack-luster science and mismanagement. The most prominent report, "A Review of the Intramural Program of the NCI," popularly called the "Bishop Calabresi Report" after Michael Bishop and Paul Calabresi, the co-chairs of the panel that wrote the 43 page document, minces no words. The report describes the "evolution of an elaborate bureaucracy" at the NCI, which resembles a "fragmented feudal structure." The report documents "cronyism" in the NCI's operations, calls its organizational structure "unnecessary and wasteful", and cites a "lack of financial accountability." The report makes the scientific impact of these organizational and administrative problems clear. It says many NCI programs "cannot even be considered the best in their particular field of inquiry." The Bishop Calabresi report uncovered some very disturbing problems specific to the NCI's AIDS research effort. The report notes that the NCI's in-house program alone spent $105 million on AIDS research in fiscal year 1994. The report said this high level of AIDS funding was due, in part, to "liberal definitions of what research might be related to AIDS." The report noted that the NCI's AIDS programs are not integrated with the overall national AIDS research effort, and recommends greater coordination of NCI AIDS research by the Office of AIDS Research. The report says a "significant reduction" in NCI's AIDS research funds may be in order, and that these funds should be used to increase the national AIDS research effort overall. The report says NCI's AIDS research funds might best be put "under control of a different institute." Dr. Klausner is aware of the report's implications for AIDS research at the NCI. In press reports, Dr. Klausner said the report uncovered "something that is a real problem." He acknowledges that it is "stretching it" to define much of the NCI's so-called AIDS research as AIDS research. The NCI component that receives $213 million represents over 16 percent of the entire federal AIDS research budget, a sum considerably larger than any other single segment of the AIDS research effort. Placing such a huge investment of federal AIDS research funds in one site expects too much of a single research community and shortchanges the rest of the AIDS research enterprise. In a meeting with AIDS advocates in September, Dr. Klausner said he has ordered a thorough review of all AIDS expenditures at NCI, with the goal of re-programming and re- classifying the money. He said he has already made $6.5 million of NCI AIDS research funds available for legitimate AIDS research expenses and expects millions more to become available. In another move greeted by AIDS advocates, Dr. Klausner appointed Philip Pizzo, a noted pediatric AIDS researcher, to lead the NCI's clinical sciences division. Dr. Klausner hopes to create a more collegial atmosphere with his fellow institute directors. He told AIDS advocates that the "Treaty of Bethesda" has been nullified. The Treaty of Bethesda refers to an informal agreement reached in the mid 1980s between the National Institute of Allergy and Infectious Diseases (NIAID) and the NCI. At the time a bitter power struggle had erupted between the two institutes over control of the AIDS research budget. NIAID director Anthony Fauci prevailed, gaining the largest share of AIDS research funds and making NIAID the "lead" institute for AIDS research. Since that time, relations between the NCI and NIAID have been strained, with collaboration and cooperation difficult. Dr. Klausner hopes to integrate the NCI's AIDS programs more closely with those of NIAID and other institutes. Copyright (c) 1995 - GMHC Treatment Issues. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+