Treatment Issues, Vol 8, No. 10 - November 1994 Gay Men's Health Crisis Table of Contents ----------------- Reports from ICAAC Viral Load Dynamics Maternal Viral Load Predicts Transmission Increased Transmission of AZT-Resistant HIV Blood Transfusions May Increase HIV CD4 Benefits From d4T Protease Inhibitor Studies GEM-91 Trials begin Preventing Fungal Infections Sorivudine (BV-ara-U) for Herpes Zoster Famciclovir for Herpes in Women Foscarnet TB Prophylaxis Disappointing Crypto Studies "Off-Label" Drugs for HIV Validating Viral Load Markers Passive Immunotherapy: New Stories, Same Old Data Future Uncertain for NIH AIDS Drug Discovery Program Treatment briefs by David Gold Correction to Ho article, Vol. 8, No. 9 - October 1994 ***************** Reports from ICAAC by David Gold and Gabriel Torres, M.D. The Thirty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held this year in Orlando, Florida from October 4 to 7. ICAAC has become the most important infectious disease conference in the world, with over 40 percent of the attendees coming from outside the United States. Below are some of the conference highlights relating to HIV and AIDS. Viral Load Dynamics David Ho, M.D., of the Aaron Diamond AIDS Research Center presented a model that describes the dynamics of HIV replication.1 Dr. Ho noted that patients given Abbott Laboratories' ABT-538 protease inhibitor experienced a dramatic decrease in HIV RNA levels within a matter of days. Based on this observation, he infers that nearly half the viral population in the plasma is renewed every day. There is also a constant destruction of CD4 cells in infected persons -- Dr. Ho estimated that approximately 22 million CD4 cells are destroyed each day in the blood and 50 times more in the lymphoid tissue. According to Dr. Ho, the greatest amount of virus is produced in the first two to four weeks after a person becomes infected by HIV. HIV production in that period equals the total amount of virus produced over the next four to five years. This suggests to Dr. Ho that intervention with antiretroviral therapy should be instituted as soon as possible after infection to reduce viral burden and delay disease. In a subsequent presentation, Michael Saag, M.D., of the University of Alabama emphasized the need for the earliest intervention possible with as many active drugs as can be tolerated.2 He stressed his view that monotherapy with one drug will soon become a thing of the past, with combinations of protease inhibitors and nucleoside and non-nucleoside reverse transcriptase inhibitors becoming the state-of-the- art in managing HIV infection. Maternal Viral Load Predicts Transmission A landmark study by a group of New York investigators measured HIV levels in a small group of pregnant women with a technique known as QC-PCR.3 The 27 mothers in the study had HIV measurements at the time of delivery, and their infants were followed prospectively. Eight of the 27 (29.6 percent) mothers transmitted HIV to their infants. The eight were among the eleven study volunteers with very high HIV levels in their blood (more than 175,000 copies of HIV RNA per milliliter of plasma). None of the sixteen mothers with lower viral loads transmitted the virus. The authors concluded that QC-PCR measurements are a far more powerful predictor of transmission than CD4 counts or viral cultures using peripheral blood mononuclear cells. This study provides further evidence for the need to use viral load measurements in clinical practice, since the decision to institute antiretroviral therapy may be guided by the viral load of the mother during pregnancy. Increased Transmission of AZT-Resistant HIV A study presented by researchers from the Walter Reed Research Institute indicated that AZT-resistant strains of HIV are increasingly found in newly infected individuals.4 Three cohorts of patients from the U.S., Australia and Switzerland were evaluated for transmission of AZT-resistant virus. HIV isolates were obtained at the time of seroconversion to assess whether the viral strain was resistant to AZT. From 1988 through 1991, only three percent of the isolates demonstrated AZT-resistance, compared to nineteen percent in the Swiss group and eighteen percent in the U.S. cohort during 1993 and 1994. This rise in the transmission of AZT-resistant strains will significantly limit the ability to treat seroconverters with AZT during acute infection and impair the usefulness of AZT as an early intervention strategy. Blood Transfusions May Increase HIV A small study by researchers from two medical centers, Case Western Reserve in Cleveland and the VA Medical Center in Los Angeles, suggested that blood transfusions may modestly increase HIV replication in HIV-positive patients.5 Of five HIV-positive patients who received blood transfusions, all five had an increase in HIV levels (measured by p24 antigen) one to two weeks after transfusion. CD4 Benefits From d4T AZT-Naive Patients: Researchers from Bristol-Myers Squibb, presented data on d4T (stavudine) in 108 patients, 41 of whom had never taken AZT or any other anti-retroviral drug.6 Not surprisingly, AZT-naive patients had a better response in terms of CD4 improvement. After 24 weeks, these patients had a median increase of 74 CD4 cells. The researchers then compared this CD4 response to that seen in ACTG 116A, where AZT-naive patients were given either AZT or ddI. The cross- study comparison revealed that in AZT-naive persons with similar CD4 counts, d4T produced a CD4 response equal or perhaps superior to AZT. (Comparisons between studies are always difficult to interpret, however.) AZT-Experienced Patients: Lisa Dunkle, M.D., from Bristol- Myers Squibb reported an update on a trial comparing d4T to AZT in people with CD4 counts of 50 to 500 and at least six months of AZT therapy.7 In this trial which is still ongoing, 822 patients were randomized to receive either d4T (40 mg twice daily) or continued AZT (200 mg three times daily). An interim analysis of the first 359 patients showed that the CD4 responses and declines in p24 antigen levels and HIV titers were greater and more sustained in those who switched to d4T than in those who remained on AZT. Furthermore, those who switched to d4T had fewer clinical complaints. Peripheral neuropathy occurred in fifteen percent of those on d4T after one year of treatment, but only six percent required discontinuation of treatment, and there were few cases of pancreatitis. The final analysis of this study will be available after December 1994, when the trial is scheduled to close. Protease Inhibitor Studies Data presented at ICAAC emphasized the different anti-viral effects of the most-studied protease inhibitors: Roche's saquinavir and Merck's L-735-524. As measured by PCR techniques, Saquinavir can achieve a two-fold reduction in blood- borne HIV particles (at the dose currently being studied). The Merck drug can achieve a three-fold to 1,000- fold reduction (average of 30-fold). But the key question is: how long can these decreases be sustained? Both companies are studying higher doses of their drugs to see whether they can achieve greater and more sustained reductions in HIV levels. Merck Protease Inhibitor: Merck researchers presented data on sixteen patients who received the L-524 drug for six months at a dose of 400 mg every six hours.8 Over 70 percent of the patients achieved greater than ten-fold reduction in viral titers during the first several weeks. Resistance to L-524 was noted in five of fourteen patients after six months. (At a subsequent meeting at Merck headquarters, researchers reported that within four to twelve weeks after initiation of L-524, HIV levels start to increase, and by week 24 almost all patients return to baseline levels.) The trial participants entered the study with a median CD4 count of 71 and had increases of 70 to 100 cells after a few weeks. These increases were maintained for up to six months. In addition, most patients had improvements in white blood cell counts, neutrophil counts, platelet counts and hemoglobin levels. Most also gained a median of eighteen to nineteen pounds in body weight. The only side effect seen from the Merck protease was a transient increase in blood levels of bilirubin, which is normally removed by the liver. Abbott Protease Inhibitor: A "late breaker" session included a report on the first pharmacokinetic study of ABT-538, the protease inhibitor under development by Abbott Laboratories.9 Researchers from other companies consider the Abbott compound, along with Merck's L-524, to be among the most active and bioavailable of all protease compounds in clinical trials. ABT-538 exhibited potent activity in the test tube (in vitro) against HIV-1 and HIV-2 and achieved impressive blood concentrations when given orally to rats, dogs and monkeys. Humans in phase I trials absorbed the drug even better than the animals. Resistant virus was eventually isolated. Further preliminary results from the phase I trials will be announced at the Second International Conference on Drug Therapy and HIV Infection in Glasgow, Scotland. GEM-91 Trials begin GEM-91 is an antisense oligonucleotide being developed by Hybridon Inc., a Massachusetts-based company. In the first human study of the drug, GEM-91 was administered to six HIV- positive individuals by intravenous infusion. No drug-related side effects were seen.10 GEM-91 locks onto and sparks the destruction of exposed HIV RNA within cells. It reputedly targets a number of steps in the HIV life-cycle, including the integration of HIV genes into the nucleus of newly infected cells and the production of new virus particles in cells' cytoplasm. GEM-91 is now entering Phase I/II trials at a number of sites, including New York Hospital. For information, call 212/746-4393. Preventing Fungal Infections William Powderly, M.D., of Washington University in St. Louis gave an excellent overview of prophylaxis for fungal infections in HIV-positive patients.11 Between 70 and 90 percent of people with AIDS will develop oral candidiasis (thrush), about 20 percent develop esophageal candidiasis, and five to ten percent contract cryptococcal meningitis. The most widely studied anti-fungal agent in HIV-positive patients is fluconazole. Itraconazole is another approved anti-fungal agent. Dr. Powderly described fluconazole as an effective agent in preventing fungal infections, but also noted that fluconazole-resistant candidiasis is a significant problem and itraconazole-resistant histoplasmosis and aspergillus are also emerging. Once resistance develops, patients are forced to rely on amphotericin B, an intravenous therapy with major toxicities. Dr. Powderly also noted the high cost of fluconazole (approximately $20 per pill) and remarked that fungal prophylaxis probably should be considered only for those who are at highest risk for developing cryptococcal meningitis, such as people with CD4 counts below 50. In a study that demonstrated how common fluconazole-resistant fungal strains are becoming, Swiss researchers took oral swabs from 401 HIV-positive patients who showed evidence of fungal infections.12 Twenty-eight percent of these samples contained organisms resistant to fluconazole. AIDS researchers from Bowman Gray School of Medicine in Winston-Salem followed six patients with less than 50 CD4 cells who developed fluconazole-resistant thrush while on fluconazole prophylaxis.13 All six failed to respond to a higher dose of fluconazole (800 mg per day). Two of the six were susceptible to itraconazole, but all six ultimately needed amphotericin B therapy. Sorivudine (BV-ara-U) for Herpes Zoster A new agent for the treatment of herpes zoster called sorivudine was studied in a randomized, double-blind trial, which compared it to acyclovir given at a dose of 800 mg five times a day.14 Sorivudine has the advantage of requiring only one daily dose (40 mg per day). Trial participants receiving sorivudine healed their zoster lesions quicker, had fewer new lesions and required less use of analgesics than patients receiving acyclovir. Time to resolution of the pain associated with the zoster was similar in both groups. Sorivudine is the second new drug being developed for the treatment of herpes zoster. Famciclovir (Famvir, manufactured by SmithKline Beecham) was recently approved. It is similar to acyclovir, but has the advantage of twice daily administration. Famciclovir for Herpes in Women According to a study by University of New Mexico researchers, famciclovir can limit the recurrence of new herpes outbreaks in women with chronic herpes infections.15 In the double blind, placebo controlled study, 375 women of unknown HIV status were randomized to either placebo or six doses of the drug. Women who were given 125 mg or 250 mg twice per day had a significantly prolonged time before new herpes outbreaks. When these doses were taken only once daily, no significant benefit was seen. The median time to recurrence of herpes outbreaks was 2.7 months on placebo, 3.9 months on 125 mg twice a day, and greater than four months on 250 mg twice a day. Foscarnet A study by European researchers suggests that five days per week treatment with foscarnet may be preferable to seven days in patients with CMV esophagitis or colitis.16 In the study, 33 patients were randomized to receive foscarnet either five or seven per week. Foscarnet was only slightly more effective when given seven days a week, and the added benefit was not statistically significant. Two studies in animals suggest that liposomal formulations of foscarnet may increase the drug's therapeutic efficacy while decreasing its renal toxicity.17,18 Clarithromycin for MAC Prophylaxis A long-awaited trial contrasting clarithromycin (500 mg twice daily) with placebo for primary prevention of Mycobacterium avium complex (MAC) was presented by researchers from Abbott Laboratories.19 The international trial was randomized and double-blinded. It enrolled 684 HIV-positive volunteers with CD4 counts of less than 100. The average follow-up was eight to nine months. There were fifteen instances (4.5 percent) of MAC bacteremia in the clarithromycin group compared to 42 cases (12.5 percent) in the placebo group, a highly significant difference. There also were fewer deaths in the treatment group (74) than in the placebo group (98), a 30 percent reduction in death rate. Patients receiving clarithromycin experienced more gastrointestinal side effects and taste perversion than the control group. Unfortunately, nine (60 percent) of the fifteen MAC isolates in the clarithromycin group were resistant to the drug, whereas none of the isolates in the placebo group exhibited resistance. These findings support the use of clarithromycin for MAC prophylaxis and suggest that it is more effective and less toxic than rifabutin. MAC breakthrough rates during rifabutin prophylaxis are approximately eight percent. TB Prophylaxis A short course prophylactic regimen may be effective in preventing tuberculosis (TB) in HIV-positive individuals, according to a study by Spanish researchers.20 Twenty-two of 70 HIV-positive individuals (who were either positive on the TB skin test or anergic) received the short course regimen of 300 mg a day isoniazid and 600 mg a day rifampin for three months. None developed TB. Of those not given the short term prophylaxis regimen, five developed TB. Disappointing Crypto Studies Two studies of anti-cryptosporidiosis therapies ended disappointingly. In a randomized multicenter study of Bovine Anti-Cryptosporidium Immunoglobulin (BACI), cryptosporidia oocysts (the parasite's fertilized reproductive cell form ) in patients on BACI were reduced, but no difference in either stool volume or frequency was seen.21 BACI is derived from the colostrum of cryptosporidia-immunized cows. Another study of hyperimmune bovine colostrum, infused into two people with AIDS-related cryptosporidiosis, also showed no clinical benefit from the therapy.22 "Off-Label" Drugs for HIV A survey of 386 physicians in the U.S. found that over 40 percent of all drug therapy administered to people with AIDS involves "off-label" use of medications.23 Drugs prescribed off-label are compounds approved by the Food and Drug Administration (FDA) for some situations, but not for the particular one the physician is treating. According to the survey, over 90 percent of people with AIDS receive at least one off-label drug. Frequently, off-label use of a drug merely anticipated FDA approval for that use (for example, Bactrim as prophylaxis for pneumocystis pneumonia). Half of the doctors surveyed nonetheless reported having problems obtaining insurance reimbursement for off-label prescriptions. Not surprisingly, patients who had no insurance or were members of health maintenance organizations (HMOs) had less chance of receiving off-label therapies, as did African-Americans. 1 Ho, D. 34th ICAAC. October 4-7, 1994. Orlando, Florida. Symposium 1. 2 Saag, M. Symposium 1. 3 Fang G, et al. Abstract LB-A6. 4 Mayers DL, et al. Abstract LB-A11. 5 Mudido P, et al. Abstract I126. 6 Anderson RE, et al. Abstract I60. 7 Dunkle LM, et al. Abstract LB-3. 8 Deutsch P, et al. Abstract I59. 9 Kempf D, et al. Abstract LB-A4. 10 Zhang R, et al. Abstract LB-A5. 11 Powderly W. Symposium 3-2. 12 Chave JP, et al. Abstract I219. 13 Horn CA, et al. Abstract I221. 14 Dehertogh D, et al. Abstract LB-A7 15 Mertz GJ, et al. Abstract H3. 16 Schrappe M, et al. Abstract H99. 17 Guembel H, et al. Abstract 145. 18 Dusserre N, et al. Abstract H75. 19 Pierce M, et al. Abstract LB-A2. 20 Solera J, et al. Abstract I183. 21 Fries L, et al. Abstract M21. 22 Sluiters JF, et al. Abstract M19. 23 Brosgart C, et al. Abstract I139. ********* Validating Viral Load Markers by Dave Gilden The most dramatic change in atmosphere between the Ninth International Conference on AIDS last year and the Tenth International Conference this year concerned the newly available measurement techniques for HIV load. The new HIV assays -- involving branched DNA (bDNA from the Chiron Corporation) and quantitative polymerase chain reaction (principally Hoffmann-La Roche's RT-PCR, but also Genelab's QC-PCR) -- for the first time provide a relatively easy, reproducible way of estimating the amount of HIV in an infected person's bloodstream. PCR and bDNA tests do not count actual HIV particles directly, but assess the amount of HIV genetic material present. Results are recorded as the number of viral "copies" or "equivalents" per unit measure. The tests for HIV RNA discussed here measure free virus particles in blood plasma. The production of new HIV reflects current viral replicative activity, which therapy can rapidly inhibit. Similar assays for HIV DNA measure the number of infected cells with HIV incorporated in their genes. Since present and most upcoming treatments do not directly eliminate infected cells or the HIV therein, HIV DNA is a more stable quantity less sensitive to changes in therapy. Infected cells may be actively producing new virus particles, or, much more commonly, they possess quiescent or defective HIV genes. The latter cells may live for many months. Utilizing Viral Load Assays HIV load analyses could be applied in two distinct manners: * In medical practice, they could be used to make individual treatment decisions. Rising HIV levels in a patient's blood could be taken as a sign of increasing failure on the part of the immune system or current drug treatment to control the virus. A physician could then recommend either beginning anti-HIV therapy or altering the present regimen to stave off further disease progression. Changing treatment in this manner is called a medical strategy approach and involves not just prescription of successive single-agent therapies against HIV, but juggling any of the proposed multidrug combinations as soon as their components are available. * In clinical trials, a treatment's antiviral activity could be measured in terms of the reduction in the amount of HIV in trial participants' blood. Single compounds or multidrug combinations that cause the greatest decreases would be candidates for further testing and possibly accelerated approval by the Food and Drug Administration. The bDNA and PCR techniques have an intuitive appeal. The obvious goal of antiviral therapy is to inhibit HIV and thus allow an infected individual to maintain or recover health. The tests can monitor drugs' effect on HIV in an immediate, "real-time" fashion that can never be duplicated by CD4 counts, which vary more slowly in response to therapy while fluctuating sharply for extraneous reasons. The Uncertainties But serious questions remain concerning the significance of these tests. It may not be so difficult to establish that rising HIV levels correlate with and even predict declining immune function and worsening physical symptoms. (Several reports1,2 already suggest that this is true.) It is also possible to chart the decline in HIV load that occurs immediately after someone begins a new antiviral therapy.3 Whether this artificially induced drop in virus produces better health is a more knotty issue, however. Consistently low CD4 cell counts are considered a very accurate predictor of future physical symptoms. But it turns out that raising CD4 count over the short term through antiviral therapy has had disappointing results. Physical condition has not improved correspondingly during clinical trials.4 (In one study of people with advanced disease, though, trial participants experienced an increase in survival greater than their CD4 count rises would indicate.5) Resolving this issue runs up against the modest, transient effects that current anti-HIV medications have. Stronger, more sustained increases in CD4 counts, for example, might have an incontestably positive effect on physical health. Also, HIV infection focuses on the center of immune activity in the lymph nodes and other lymphoid tissue, not in the blood. Detecting a lowering of HIV in the bloodstream may not reflect what is occurring in the lymph system. One study presented at the Tenth International Conference6 found that in people with high CD4 counts (average of 654), initiating AZT therapy did not alter the production of new HIV particles within lymph nodes or the number of infected cells. Adding ddI to prior AZT therapy did decrease new HIV production in the lymph nodes in four of six patients, but this decrease was not statistically significant. An underlying problem is that HIV is a subtle infection because there are no outward symptoms of immune deficiency per se. Directly monitoring a treatment's effect requires some way of precisely describing immune function. CD4 cell count by itself is not sufficient because it does not indicate how well those cells or the immune system as a whole are functioning. Even if therapy-induced reductions in the amount of blood-borne HIV do trigger a rise in CD4 counts, this does not guarantee that the immune system will recover. Surrogate Marker Conference Reports In an effort to find a way out of this labyrinth, many of the chief contributors to recent developments in the surrogate marker field -- including various measurements of HIV activity and immune function -- attended a three-day conference in Arlington, Virginia from October 12 to 14, 1994. The presentations at the conference comprised a vast review of the subject, although many of the data had been released previously, at the Tenth International Conference and elsewhere. [The studies mentioned below were reported at both conferences, although in greater detail at the October surrogate marker event. Footnote references will refer to the International Conference Abstract Book, volumes I and II, because this is a published, publicly available source.] Walter Reed Army data: One of the chief reports supporting the utility of viral load assays comes from a. U.S. Army study7 investigating the relationship between HIV level and the emergence of AZT resistance in those on long-term AZT therapy. The 100 trial participants had a mean CD4 count of 252 and were followed for two to three years. As reported by Douglas Mayers, M.D., of the Walter Reed Army Institute of Research, researchers found that emergence of AZT resistance was associated with HIV levels of more than 100,000 copies of HIV RNA per milliliter of blood plasma. The strongest predictors of death in the group turned out to be low CD4 count and even more significantly, HIV levels of more than one million HIV RNA copies per milliliter of plasma. Another Army study8 presented by Dr. Mayers followed 32 individuals over two to three years after they had switched from AZT to ddI monotherapy. In this group, only low CD4 count (less than 100) was a statistically significant predictor of death, with high plasma HIV load (an RNA copy number of greater than 300,000 per milliliter) being not quite significant. Veteran Affairs review: A report9 suggesting that reductions in HIV level brought on by therapy do indeed lead to clinical improvement has been prepared by William O'Brien, M.D., of the Veteran Affairs Medical Center in Los Angeles, and his colleagues in a nationwide trial known as VA CSP 298. The group analyzed old blood samples from this trial, whose original results were published two years ago.10 (VA CSP 298 was the first major study to conclude that AZT therapy early in HIV infection, before CD4 count drops below 200, delayed progression to AIDS but did not prolong survival compared to later treatment, starting when CD4 count falls below 200.) Using a statistical model, investigators found that increases in CD4 count in response to treatment could account for only 37 percent of the observed delay in progression to AIDS from early AZT therapy. By comparison, meaningful reduction in virus levels seemed to account for 67 percent of the clinical benefit. But the study could say nothing about the association between reducing HIV load and prolonging survival. AZT's inhibition of HIV is too temporary to make a judgment on this score, according to Dr. O'Brien. "It's not just how low virus load goes, but for how long," he notes. (Trial participants in the early treatment arm started AZT at the beginning of the trial and experienced a 70 percent average decrease in HIV level by the second month. This level returned to baseline by the eighth month on average.) ACTG look-back: Another review of an older study came to similar conclusions as the VA CSP 298 review. At the October surrogate markers meeting, Seth Wells, Ph.D., Sc.D., a senior statistician at the Harvard University AIDS Clinical Trail Group Analysis Center, described findings gleaned from blood samples taken in the course of the ACTG trial 116B/117. This trial tracked the effect of switching to ddI after at least four months of AZT therapy. High HIV levels at study entry were associated with more advanced disease and quicker disease progression, and those whose HIV levels increased had a greater risk of further progression regardless of their initial viral load. Trial participants who continued to receive AZT experienced on average a persistent increase in HIV load whereas those who were changed to ddI had a modest reduction (of one-half logarithm or about three-fold) that bottomed out at week eight. Interestingly, this decrease was not reflected in any appreciable CD4 cell augmentation. This result differed from the results in ACTG 116A and VA CSP 298, which included people who had not yet started therapy and whose immune deficiency was less advanced. In an interview, Dr. Wells observed, "I'm encouraged by the data, but the patients in the 116B/117 trial were a very select population [with advanced disease] and you can't generalize from that data to other groups, including the people in 116A." Complicating Factors An indicator that works on a generalized population level might not work when applied mechanically to individuals because each personal response to HIV infection differs from the composite average. One of the co-investigators in ACTG 116-117, Robert Coombs, M.D., Ph.D., of the University of Washington, described some of the interacting factors that might explain different individual and subgroup outcomes to changing HIV burden. The first factor is initial virus load. In people with low levels of HIV particles in their blood -- RNA copy numbers of less than 10,000 per milliliter -- there is little detectable treatment-induced reduction, and changes in CD4 count are related to changes in CD4 proliferation rates and the virulence of a patient's particular viral strain. (The appearance of a so-called syncytia-inducing, or SI, strain of HIV is one major sign of increased virulence.) In ACTG 116B/117 (remember, these were people who were previously taking AZT and had advanced immune deficiency), many of the patients who were switched to ddI experienced some reduction in HIV load and an accompanying increase in CD4 count. The trial participants kept on AZT largely saw just the reverse: a continuing increase in viral load and a decrease in CD4 count. This is a sign of AZT's waning benefit over time. There were some participants in 116B/117, though, who perversely had an increase in both viral load and CD4 count. Dr. Coombs thought this phenomenon was due to higher CD4 cell replication rates in such people. Another subgroup witnessed a simultaneous decline in both viral load and CD4 cell count. Most of these people possessed a virulent SI strain of HIV, Dr. Coombs noted. All these interacting elements make it hard to determine the role viral load can play in clinical trials, and harder still in individual treatment decisions. Dr. Wells' group at Harvard is formulating ways to validate viral load as a surrogate marker. He says, "Viral load seems like a great marker for phase I and II testing [for screening new drugs for anti-HIV activity]. But we will need to follow extraordinary numbers of people to assess how well viral load works as a surrogate for [clinical] outcomes. The size of the studies has to do with the magnitude of the treatment effects we're observing." Dr. O'Brien concurs in this assessment. "There is not enough data to change our whole policy," he says. Before viral load can enter into wide-scale use as a predictor of increasing immune deficiency in HIV infection, its relationship to physical symptoms will have to be convincingly demonstrated. The rate of opportunistic conditions has long been considered the "gold standard" for gauging therapies' benefits. Given the lack of a more direct measure of immune function, it is considered a real measurement of disease progress and ranked as a "clinical" endpoint rather than a surrogate. Difficulties with Clinical Endpoints Frank Rhame, M.D., an AIDS researcher who heads the HIV clinic at the University of Minnesota, goes a step further and argues, "You have to ground surrogates in studies showing a survival difference not in those counting up AIDS-defining events, which is itself a surrogate marker." At the October surrogate marker conference, Dr. Rhame explained in great detail the practical problems that have arisen when relying on the incidence of new opportunistic conditions to decide the outcome of clinical trials. One of the major difficulties encountered when interpreting data on opportunistic conditions is that there is no ranking system for judging the seriousness of illnesses, which can range from comparatively minor candida infections to life- threatening conditions. Also, trials usually count only the first event during follow-up, ignoring whether a given individual experiences a whole string of infections or not. Finally, trial sites may misdiagnose illnesses or miss them entirely when trial participants fail to return for follow-up -- frequently because they are too sick. Unfortunately, survival has its own drawbacks for evaluating the effect of antiretroviral drugs. It is time-consuming and unethical to wait for a sufficient number of deaths before judging the utility of a therapeutic technique. In addition, death depends on the history of opportunistic conditions, not just on HIV, and this history is affected by therapies unrelated to antiviral medications and their effect on surrogate markers for immune decline. Another concern is that focusing on survival really focuses on the rapid progressors who provide a disproportionate number of a trial's fatal events. Rapid progressors' performance in a trial may not be representative of what happens in other subgroups. Many Markers, Few Treatments The surrogate marker conference heard presentations describing the utility of at least seventeen candidate surrogate markers, including various measurements of HIV level and virulence, lymph node condition and immune status. Different kinds of therapy affect the AIDS disease process in different ways, so probably no one marker will prove universal enough to be used alone. Viral load and CD4 count for now promise to be the most applicable and informative combination, but it will take considerable effort to sort out the contribution all these different lab values can make, both for testing new drugs and determining patients' individual treatment strategies. Thomas Merigan, M.D., a co-chair of the surrogate marker conference, said, "We're trying to use surrogate markers to license drugs with slight effect. How can we be definite?" Evaluating strong treatments can be accomplished in a clear- cut manner. The lack of such treatments creates both the need for surrogate markers and the uncertainties concerning their application. 1 Saksela K et al. Proceedings of the national academy of science USA. Feb 1 1994; 91(3):1104-8. 2 Mellors J et al. First National conference on human retrovirus infections. Dec 1993; (abstract 274):103. 3 Dewar RL et al. Journal of infectious diseases. Nov 1994; 170(5)1172-9. 4 Fleming T. Statistics in medicine. Jul 30 1994; 14(14):1423-35. 5 De Gruttola V et al. Journal of acquired immune deficiency syndromes. Apr 1993; 6(4):359-65. 6 Cohen O et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; I(abstract 001B):7. 7 Vahey MT et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; I(abstract 253B):75. 8 Mayers DL et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; II(abstract 359B):17. 9 O'Brien WA et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; I(abstract 254B):75. 10 Hartigan PM et al. New England Journal of Medicine. Apr 16 1992; 326(16): 1037-42. ********** Passive Immunotherapy: New Stories, Same Old Data by Dave Gilden A conference in London sponsored last month by proponents of passive immunotherapy (PIT) sparked a new round of interest in the therapy, with reports appearing on both CBS and BBC television. Because of the interest that has been generated by these reports, Treatment Issues is providing a brief report on PIT. What is Passive Immunotherapy? PIT involves the transfer of plasma (the fluid portion of the blood without the cells) from asymptomatic HIV-infected donors with high HIV antibody levels to individuals with advanced HIV infection or AIDS and low levels of HIV antibodies. The hope is that the HIV antibodies in the transferred plasma will help preserve the recipient's health. PIT's originator and chief promoter is Abraham Karpas, Sc.D., an AIDS researcher from the University of Cambridge in Britain. Dr. Karpas published his first paper on PIT in 1988.1 No New News There is actually little new to report on PIT at the moment. The occasion of the conference was the publication in Blood2 of the results of a PIT study conducted by a small California company known as HemaCare. (HemaCare is not a research company. Its main business is blood tests.) The study was originally released two years ago, at the 1992 National AIDS Update Conference in San Francisco. Since then, HemaCare has been negotiating with California health authorities to allow a larger phase III trial including up to 900 persons. The interchange proved fruitless and HemaCare is now seeking approval from the U.S. Food and Drug Administration. One of HemaCare's problems may be the equivocal conclusion of the previous study. Half of the 220 trial participants had baseline CD4 counts of under 50, and for them, there was no evidence of benefit. The same was true for the trial as a whole. HemaCare then analyzed the 72-person subgroup with CD4 counts of 50 to 200. The company found slight advantages in terms of CD4 count and survival after twelve months of "full- dose" PIT (a monthly 500 ml plasma infusion) compared to half-dose PIT or placebo. No reduction in opportunistic infections was observed in any group. A number of concerns have been raised about the way HemaCare handled this study -- including breaking off relations with its original statistician. His analysis of the study data was less positive than the published one described here. (For further details on the initial problems, see this author's article in AIDS Treatment News, number 165, December 18, 1992, pages 1-3.) A small French PIT study presented at the London conference, and also a year ago in Washington, D.C.,3 did find a two- thirds drop in the incidence of AIDS-related opportunistic infections. The 82 participants had less than 200 CD4 cells per milliliter of blood and symptoms of advanced immune deficiency. The 40 people in the placebo arm received plasma from HIV-negative donors. A published report on this study has not yet appeared, so interpreting its findings is difficult. Future Studies of PIT The London conference could be dismissed as a public relations move designed to garner support for further research. The studies may be weak, but the data they contain plus various anecdotal reports do provide argument for further research on PIT, especially in people with fewer symptoms. PIT has no well-funded backer, nor is it cheap. One U.S. practice that performs this technique is the Southern New England Community Consortium (SNECC) in Greenwich, Connecticut. SNECC charges recipients $900 a month. The organization's director, Gary Blick, M.D., claims that even at this price, PIT has been a financial disaster. Finding enough eligible plasma donors also has been difficult. Dr. Blick and HemaCare both have suggested that there may be some benefit for those who are donating plasma with HIV antibodies. (The benefits are certainly not financial -- SNECC does not pay donors for their plasma). There is little data, however, to indicate that donating plasma either helps or hurts donors. 1 Karpas A et al. Proceedings of the national academy of sciences of the United States of America. Dec 1988; 85(23):9234-7. 2 Levy J et al. Blood. Oct 1 1994; 84(7):2130-5. 3 Vittecoq D et al. First National conference on human retrovirus infections. Dec 1993; (abstract L12):153. ************ Commentary Future Uncertain for NIH AIDS Drug Discovery Program by Vincent Pieribone, Ph.D. The National Institutes of Health (NIH) appears to be stifling one of the most important AIDS drug development programs with hardly a murmur of protest from AIDS activists. The program -- the $10 to 15 million dollar a year National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV) -- has been the responsibility of the National Institute of Allergy and Infectious Diseases (NIAID), the NIH branch that conducts the bulk of AIDS- related research. NIAID's plans to curtail its support for this program will increase the distance between the Institute's growing basic research portfolio and its large, albeit inefficient, system for clinical trials of new antiviral drugs. The NCDDG-HIV was established in 1986 specifically to provide financial support for scientists interested in developing innovative anti-HIV therapies. Scientific investigations into the virus's lifecycle are largely performed at academic research institutes supported by the NIH. Drug screening and clinical trials are performed by sponsoring drug companies and NIAID's AIDS Clinical Trials Group. Very often, though, observations made about the HIV lifecycle that might have therapeutic application go unexplored by academic researchers and drug companies. This large gap, between studying the virus's lifecycle and screening candidate drugs, is where the NCDDG-HIV stepped in. By nurturing collaborations between basic scientists and drug companies, NCDDG grants attracted proven researchers with sound therapeutic concepts into embarking on risky drug discovery projects. Collaborating companies could guide the scientists until their concepts were ready for the company to test. The progress made through NCDDG-funded grants have been substantial. Research funded by this program has resulted in the development of assays for measuring gag-gag and integrase-integrase interactions (both necessary for viral infectivity) that are now used to screen potential treatments. A screen for novel reverse transcriptase inhibitors created through an NCDDG-HIV grant identified inophyllum B as a potent inhibitor. This compound is now in pre-clinical trials at the National Cancer Institute. Many grant recipients consider NCDDG-HIV funding to have been indispensable to their projects' advancement. One such researcher is Jef D. Boeke from Johns Hopkins University, who is investigating capsid-targeted viral inactivation mechanisms (which destroy the HIV genes within the viral core). Dr. Boeke was unable to obtain any funding to work on HIV drug discovery until his group received an NCDDG-HIV award. He then obtained further support and transformed an interesting idea into a novel and exciting therapeutic possibility. Restrictions on the NCDDG-HIV will lead to the loss of crucial and rare collaborations. Although the program is not being killed outright, it faces two severe constraints: a phased-in reduction in the number of projects supported and a loss of the special "set-aside" fund that maintained the program as a whole. A 1991 ad hoc NIAID committee reviewing the NCDDG unanimously concluded that "investigator initiated, collaborative, consortium type research directed at drug discoveryÉ should be fostered." But the review committee recommended that NIAID should decrease number of groups funded by the NCDDG-HIV from 27 in 1991 to eight to twelve. Its reasoning was that the "present numbers of grants of high quality do not appear to support [the current] level of funding." The lack of quality proposals may be a sad reflection on the NIH's ability to inspire clinically related research from the hundreds of HIV basic research grantees. The agency's ability in this respect will further diminish under the current NIAID proposal to eliminate the special budgetary allocation reserved for financing the NCDDG-HIV. In defense of this move Jack Killen, M.D., director of NIAID's Division AIDS (DAIDS) said, "We are committed to maintaining a program of eight to twelve NCDDG-HIV grants. We used to set aside money to get the program running. There is no need for that now that the program is set up. We will issue a program announcement, now being prepared, saying we welcome NCDDG-type drug design applications involving collaborations with industry." NIAID insists that researchers who no longer obtain funding from the NCDDG-HIV can apply for traditional researcher- initiated grants (R01, or program project, grants) to continue their research. But the NCDDG was established precisely because the usual researcher-initiated granting scheme generally does not fund drug discovery research. The standard R01 review process is much too conservative to properly assess exploratory research that seeks to develop assays and therapeutic agents. R01 grants also are highly competitive. Only ten to fifteen percent (or less) of the R01 grant applications judged to have merit actually receive funding. The worst scenario would be to require the R01 grant reviewers to evaluate all NCDDG-type research, as is now under consideration. The NCDDG-HIV had specific requirements for grants that narrowed the field of applicants, thereby increasing each applicant's chance of success. The ad hoc review committee report on the NCDDG-HIV commented, "It was agreed that the proposed cooperative agreement (U01) objectives, including 1) therapeutic endpoint, 2) multiple institution collaboration, 3) added value achieved by the collaborations, and 4) high risk innovative research, clearly distinguished this funding mechanism from R01 funded research." Nonetheless, Dr. Killen's statement appears to represent an improvement in NIAID's position on the NCDDG-HIV. In July of this year, DAIDS' therapeutics development chief Carl Dieffenbach, Ph.D., reportedly told the National Task Force on AIDS Drug Development that the NCDDG-HIV was being phased out and that researchers could apply for other grant programs. When reproached that obtaining many grants involved a lengthy process, Dr. Dieffenbach responded that the grants he was referring to took "only two years." NIAID furthermore recently announced a new program know as SPIRAT (Strategic Program for Innovative Research on AIDS Treatment) that is also designed to fill the gap between basic research and clinical studies. Though AIDS researchers and activists applaud the SPIRAT program, it is clear from the design of this program that the majority of projects now funded by the NCDDG-HIV would not be eligible for SPIRAT money. SPIRAT is focusing on a narrower, purportedly more advanced range of products and emphasizes phase I human trials of gene transfer and immune modulation research. In a letter sent to NIH officials Drs. William Paul (director of the Office of AIDS Research), Anthony Fauci (director of NIAID) and Harold Varmus (overall NIH director), the Treatment Action Group (TAG) expressed its surprise and dissatisfaction at the unwarranted loss of the critical NCDDG-HIV program. (This writer was one the letter's co- authors.) TAG asked for renewed set-aside funds for the NCDDG-HIV or establishment of a similar program. Ironically, NIAID is pruning the NCDDG-HIV just at a time when the blue-ribbon National Task Force on AIDS Drug Development is concluding that bridging basic and clinical research should be a major priority for NIAID and the NIH as a whole. David Ho, M.D., director of the Aaron Diamond Center for AIDS Research and a member of the Task Force, recalled a variety of extremely promising targets in the HIV lifecycle that at present are ignored. (See Treatment Issues, October 1994, for an interview with Dr. Ho). Very few anti-HIV approaches are available to succeed the current crop of new reverse transcriptase inhibitors and protease inhibitors, which have not yet shown a long term anti-HIV effect in initial clinical trials. The present situation is very grave: NIAID should rescue the NCDDG-HIV program by restoring funding levels and actively promoting new research in this vital area. In doing so, the Institute will renew its commitment to bridge the gap between basic and clinical HIV/AIDS research and encourage the more rapid development of anti-HIV therapies beyond reverse transcriptase and protease inhibitors. ************ Treatment briefs by David Gold Consensus Statement to Save CPCRA Sites A coalition of organizations, including GMHC, is circulating a consensus statement calling for refunding of the four sites in the Community Programs for Clinical Research on AIDS (CPCRA) that were recently de-funded (see Treatment Issues, October 1994, page 12). Three of the four defunded sites were in New York City. The three New York CPCRA sites had enrolled 67 percent of all Latinos, 59 percent of all injection drug users, 54 percent of all women and 42 percent of all African- Americans in the CPCRA nationally. Additionally, without these three sites it is difficult to imagine how the CPCRA plans to initiate its new tuberculosis trials. To sign onto this consensus statement, call or fax your organization's name, city, state and contact phone number to: Linda Podhurst, Ph.D., Clinical Directors Network, 212/255-3841 (telephone) or 212/255-4840 (fax). New CDC Treatment Call-In Service The CDC National AIDS Clearinghouse has started a new HIV/AIDS Treatment Information Service. Those interested can call 800/HIV-0440. TDD/deaf access is 800/243-7012. Hours are Monday through Friday, 9 a.m. to 7 p.m. eastern time, and all calls are completely confidential. The service provides federally approved treatment guidelines and information. It also can link callers to other appropriate information resources. Please contact Paul Warren at GMHC by fax (212/337-3656) or mail with any comments you have about using this information service. The feedback will be directed to the CDC to develop and improve this service. Reports on 3TC Data A number of unconfirmed reports suggest that the combination of 3TC (also known as lamivudine) and AZT is achieving impressive antiviral effects in studies of HIV-positive patients. Results of combination AZT/3TC studies are expected to be released this month at the Second International on Drug Therapy and HIV Infection in Glasgow, Scotland. 3TC is a nucleoside analog active in the test tube against both HIV and hepatitis B (HBV). It is at present in phase II/III trials for both HIV and HBV. Resistance to 3TC occurs rapidly when the drug is used against HIV. But test tube studies suggest that resistance to 3TC makes AZT-resistant strains of HIV again susceptible to AZT. Burroughs Wellcome, the manufacturer of AZT, has purchased an option to buy the rights to 3TC for HIV disease. An expanded access program for 3TC is available for HIV-infected adults and children with CD4 counts of less than 300. Eligible individuals must have failed or be intolerant to approved anti-HIV therapies and unable to qualify for ongoing clinical trials. Physicians can call 800/248-9757 for information. Petition for Saquinavir Access The nation's leading AIDS organizations have petitioned the Food and Drug Administration, the National Institutes of Health, and Hoffmann-La Roche to implement without delay an expanded access program for saquinavir, an HIV protease inhibitor. The petition, which was released at the October meeting of the National AIDS Drug Development Task Force meeting, calls for a program that grants immediate access to individuals who are ineligible for on-going studies or who lack other treatment options. The coalition of groups emphasizes that expanded access remains a critical component of AIDS drug development. Hoffmann-La Roche, the New Jersey- based drug company that manufactures saquinavir, has announced no plans for an expanded access program at this time. At a September 12 FDA Advisory committee meeting, FDA Commissioner David A. Kessler said, "The FDA would strongly welcome expanded access for saquinavir." To add your organization's support to this petition, contact Derek Link at GMHC, 212/337-3502. Cryptosporidiosis Trial A trial of IGX for the treatment of cryptosporidiosis will begin at New York Cornell Medical Center in New York under the direction of Rosemary Soave, M.D. IGX is hyperimmunized chicken egg yolk. In the open label 21-day study, patients will drink one-quarter cup of yolk (which some patients have described as a rather tasty "nog") five times a day. The theory behind hyperimmunized egg yolks is that the egg antibodies will fight the crypto parasite in human intestines. Dr. Soave notes that the egg yolks have been irradiated to remove salmonella and other bacteria, and her experience is that the cholesterol is not a problem for most patients. To enroll, call Dr. Soave at 212/746-6320. Correction A wandering zero garbled one of the questions and answers in last month's interview with David Ho. The question concerned measurements of blood levels of HIV by PCR or bDNA. Here is the corrected passage from the article: Treatment Issues: What does it really mean if you have a level of 200,000? 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. Copyright (c) 1994 - Gay Men's Health Crisis. Noncommercial reproduction encouraged. DISTRIBUTED BY GENA/aegis * 714.248.2836 * 8N1/Full Duplex * v.34.