>From aidsnews@igc.apc.org Sat Jan 8 04:37:26 1994 >Date: 07 Jan 94 11:58 PST >From: "John S. James" >Subject: AIDS Treatment News #190 AIDS TREATMENT NEWS Issue #190, January 7,1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: 1994 Outlook Research Strategy Proposal: High-Tech Exploitation of the Unexpected Major Antiviral Conference Surveys AIDS Research Trimetrexate (NeuTrexin) Approved for Pneumocystis Clarithromycin (Biaxin) Formally Approved for MAC Acyclovir-Resistant Herpes: Trial of Topical HPMPC CMV Retinitis: New Trial of HPMPC As First Treatment Medical Marijuana: National Press Coverage, No News AIDS Private Funding: New Survey Published Barbara McClintock Project to Cure AIDS: Strategy Session, Jan. 22 ***** 1994 Outlook by John S. James Much is happening in AIDS treatment and research today, but no one knows which developments will be important. This article outlines several areas we find most interesting now. LTR Inhibitors One way to look for antiviral AIDS/HIV treatments is to use laboratory tests to find substances to inhibit the long terminal repeat (LTR) of HIV. The LTR is a part of the virus responsible for its activation. If the LTR is inhibited, the virus does not reproduce or otherwise do harm. It is relatively easy to find LTR inhibitors in the laboratory. But unfortunately, this approach has barely been used for drug development (it is used more often in basic research). But when it has been tried, it has suggested some highly practical leads -- drugs or other substances already in human use, meaning that if they work at all, they are immediately available, without the need to create new technologies or test a new chemical entity. One potential treatment found with a test for LTR inhibitors is curcumin, a chemical found in turmeric, the mild spice used in curry. SEARCH Alliance, a community-based research organization in Los Angeles, is completing a small trial to see whether curcumin can reduce HIV activity in people. The results, now being checked and analyzed, will be available soon. Meanwhile, the anecdotal reports which AIDS TREATMENT NEWS is receiving about curcumin and about turmeric continue to be few, but positive. We plan to publish an in-depth article about LTR inhibitors in the near future. Also, we will report the curcumin results when they are available. For background on LTR inhibitors, see AIDS TREATMENT NEWS #174, May 7, 1993, and #188, December 3, 1993. For background on curcumin, see #174, and also #176, June 4, 1993. New Viral Tests The blood tests now in general use to measure viral activity (especially the p24 test, and even the improved ICD p24), are increasingly regarded as unreliable by scientists. The problem is that these tests can give low numbers, often zero, when actually the virus is very active. New tests, which measure the HIV RNA which is produced by the virus, seem to provide a much more accurate measure of viral activity. This is important for at least three reasons: * First, more accurate tests will make it much easier to determine whether a potential drug is working in people. With reliable results, fewer volunteers will be needed for each trial. This means that many treatment leads which otherwise would be ignored can be tested. It also means that many "alternative" treatments can at last be tested scientifically. The most obvious clinical-trials use for these new methods is, of course, to test antivirals. But the same viral tests may also be useful in evaluating immune therapies. A major problem in developing immune therapies is that we do not know what to look for in order to measure them, because so much is unknown, both about the immune system and about HIV disease. But for many years after infection, the immune system does a much better job of controlling clinical HIV disease than any drug known. If an immune treatment can restore some of that ability, as measured by a significant drop in viral activity, then the treatment is probably working. * The second use for better viral tests is for individual patient management. By indicating which drugs or combinations are working -- and when they stop working -- the tests can guide physicians in the better use of existing drugs. * The third major importance of better viral tests is that they will help researchers gain a better understanding of HIV disease itself. For background on two new tests for HIV RNA -- quantitative PCR, and the branched DNA assay -- see "Better Viral Tests: Interview with Mark B. Feinberg, M.D., Ph.D.," AIDS TREATMENT NEWS #186, November 5, 1993. New Efforts to Evaluate and Improve AIDS Research In 1993 a number of projects have been organized to seriously evaluate what has been done in AIDS research until now, what has worked and what has not, and to make changes so that treatment research and development will be more successful. These efforts sometimes differ and sometimes overlap; it seems that different teams have responded independently to the same compelling needs. This is not necessarily bad, since nobody knows which efforts will work; some redundancy gives additional assurance that reform will occur. We believe that potentially the most important of these efforts is the National Task Force on AIDS Drug Development (for background, see AIDS TREATMENT NEWS #188, December 3, 1993), because it has the high-level support and involvement that was so missing during the first years of the epidemic. In the past, when it was clear that something needed to be done, there was no one to tell about it, since there was no one even remotely in a position to deal with the fact that the research underway could not possibly have met the public need even if it was technically successful. AIDS TREATMENT NEWS often published proposals for more productive approaches, with full knowledge that they had no chance of being considered in any context in which implementation was possible -- since there was no such context. Now there is a chance to move forward, although of course there is no guarantee. Other efforts to improve research include the Inter-Company Collaboration on AIDS Drug Development; Future Directions in AIDS Research; Project Immune Restoration; and the Barbara McClintock Project to Cure AIDS. High-Tech Mainstream Experimental Treatment Approaches In this area we include technologies such as protease inhibitors, various gene-therapy approaches, and new immune treatments like IL-12 and cell expansion. Some news from these fronts is included in the report in this issue from The First National Conference on Human Retroviruses and Related Infections (see below). While these treatment developments need to be watched, it is clear to almost everyone that mainstream treatment research and development have been disappointing. We believe that the main problem is that the U.S. research effort, by far the world's largest, got started in some wrong, or limited, directions early on -- which is normal in early research. But now much momentum has developed, and it is hard to move to better ways of doing things. As a result, researchers' efforts are spent in maintaining ongoing efforts which cannot produce important advances. ***** Research Strategy Proposal: High-Tech Exploitation of the Unexpected by John S. James What do we believe should be done differently in AIDS research? In the history of medical advances against other infectious diseases, but our impression is that the key discoveries have usually been unexpected -- not the result of institutional programs based on the theories of the day. Therefore, we propose a research strategy of being prepared to make the best possible use of the unexpected -- for example, by "mining" the hundreds of available research leads which are known, and often published in scientific journals, but which are largely ignored today because of the institutional mindset which controls research direction and funding. This empirical approach to research (being guided first by what works, and building theories later, instead of using theories to set research direction) could be far more effective today than it ever could have been in the past, for at least three reasons. First, biological technology is much more developed now, compared to the times when major advances were made against other infectious diseases. Second, there are far more scientists today than in the past, so more work is being done; many more interesting research leads come into existence, allowing better opportunities to be chosen for development. And third, modern communication technology makes possible more effective sharing and use of the information produced by the scientific world. How does this proposal differ from what is being done already? Research leads are always being selected and followed up. But there are two major problems. First, the academic need to look good in committees, by having a well- supported case and not risking being wrong, biases the system in favor of well-worn research tracks (such as AZT and similar drugs) which offer little opportunity for major advance. And second, so much momentum is required to get a new treatment approach into the earliest human tests, that usually nothing happens unless there are commercial or technological rewards outside of AIDS to drive the work. Just the chance to save lives has not provided enough momentum to get past the pre-clinical barriers. As a result, most of the creative treatment development work has gone into the building of elaborate, difficult technologies, while more practical approaches (such as screening for LTR inhibitors) have been neglected. It will be hard to change the current momentum, because research funds are extraordinarily scarce; the intense competition for funding encourages old-boy networks and discourages new, creative approaches. One possible strategy is to develop professional support for the seemingly unlikely combination of high-tech, rational methodology, with the willingness to take a leap of faith (and chance of being wrong) on high-risk, high-reward (but usually low cost) ventures. If top scientists and physicians will support this approach to research, then it can be implemented little by little, as options for movement become available. ***** Major Antiviral Conference Surveys AIDS Research by Dave Gilden The First National Conference on Human Retroviruses and Related Infections was held in Washington, D.C., from December 12 through 16. The first of an annual series of meetings, it was a low-key alternative to the huge International Conference on AIDS, with only 1500 people attending and 750 papers and posters presented -- compared to at least 10,000 people and about 5,000 presentations at each international AIDS conference. The "state of the art" lectures and roundtable discussions gave an extensive overview of the latest AIDS research. Other sessions reported data, much of it preliminary, from scientific studies. The overviews and discussions were necessary, since much of the information was conflicting, and the researchers themselves had a hard time sorting out the implications. "We don't have the basic paradigm yet, the E=mc(2) of AIDS," commented Conference chair Robert Schooley, M.D., of the University of Colorado. A New Class of AIDS Drugs The most interesting drug reports at the Conference concerned protease inhibitors. After four years of slow progress, data is finally coming out of the first human trials. About a dozen companies are now developing this new class of drugs, which block a viral enzyme (protease) that controls an essential step in the assembly of new HIV particles within infected cells. This step does not closely resemble any normal cell process, so the drugs' disruption of normal cell operation should be negligible. Conference reports also indicated that drug resistance is more difficult to develop and that drug resistant mutations usually, but not always, impair the efficiency of the HIV protease (abstracts #265-267 and #418) -- meaning that the resistant virus is not likely to work as well. In addition, there does not appear to be any cross-resistance: Each protease inhibitor requires a different resistance mutation. According to Martin Bryant of G.D. Searle & Co., it may be possible to use several protease inhibitors in combination, thus hitting several sites at once on the protease enzyme. Bryant said that Hoffmann-La Roche Inc. is "right at the cusp of the dose response curve." He expects that higher doses will show major benefits. Unfortunately, though, the Roche product is not readily absorbed in the digestive track and has to be infused into a vein. Merck, G.D. Searle and other companies have created compounds with high availability when taken by mouth, and Dr. Martin claims that one of the Searle products is relatively simple to manufacture -- difficult synthesis has been another stumbling block for protease inhibitors (abstract #262). Merck and Searle plan to enter phase II human testing later this year with their most advanced products. Merck generated considerable attention at the conference with a report on the initial human testing of its protease inhibitor L-735,524 (abstract #L8). Eight volunteers on this compound showed major drops in their blood HIV levels after 12 days. The decreases observed so far were similar to what is seen when people first start taking AZT. Other Promising Anti-HIV Medications Merck unveiled a new kind of potential drug at the conference: an integrase inhibitor (abstract 518). This compound attacks yet another stage of HIV's life cycle, when HIV genes combine with the cell's normal genetic makeup. Another potential treatment worth noting was a derivative of the immune-suppressive drug cyclosporin. The derivative seems to suppress HIV preferentially, without disturbing helper T- cells' normal activity (abstract #519). In another test-tube study (abstract #583), cyclosporin itself "significantly (>80%) or completely suppressed acute HIV infection with both AZT-sensitive and resistant isolates of HIV-1." Cyclosporin worked well with AZT in the laboratory, allowing reduction in both drugs' effective concentrations. While waiting for new drugs to become available, there also was some encouraging reports that should speed development of two older therapies that have stirred community interest. One of these reports concerned using AZT in combination with the anti-herpes drug acyclovir. Two years ago, a British study found that people with AIDS survived longer when AZT was combined with acyclovir. That result has been contested, but the acyclovir-AZT combination remains popular in the community. In the present study, 800 HIV-positive men from the Multicenter AIDS Cohort Study who began AZT prior to contracting AIDS-related symptoms were followed for up to five years. Five hundred of the men also took acyclovir at some point after beginning AZT. Use of acyclovir was significantly associated with longer survival time but not AIDS-free time. The effect was not dependent on dosage but seemed related to length of uninterrupted use of acyclovir. Some long-awaited data also was released concerning the effect of the new reverse transcriptase inhibitor d4T on HIV levels in the blood (abstract #432). Monotherapy with d4T reduced virus levels ten to 100 times, but after a year those levels seemed to be heading up again. Single vs. Combination Therapies The British-French Concorde trial on early use of AZT provided a somber backdrop for Conference discussions. Although only a one-page cursory description of the trial has been published (in the April 17, 1993 issue of Lancet; more information was presented in talks last summer at the International Conference on AIDS in Berlin), its conclusion that beginning AZT early in the course of disease confers no advantage over starting late was widely accepted at the Conference. But Michael Saag, M.D., of the University of Alabama still recommended starting AZT in asymptomatic patients: "In three to five years we'll have better agents [to replace AZT] -- it makes sense to start antiretroviral therapy as early as possible." Dr. Saag was speaking at a roundtable discussion on "How to Use Antivirals in Clinical Practice." One the other participants, San Francisco AIDS specialist Marcus Conant, M.D., who has long been a proponent of early, energetic treatment of HIV, acknowledged the changing mood by discussing how he now evaluates a patient's clinical symptoms before embarking on therapy with AZT or combinations of antiretrovirals. Outlining the progression of skin conditions as immune deficiency encroaches, Dr. Conant said, "The symptoms alert doctor and patient that the time has come to be more aggressive." Elsewhere in the Conference a survey of zidovudine (AZT) prescription in Ontario, Canada found that AZT use dropped by 45.4 percent in the months following publication of the Concorde data. A 13 percent decrease was seen even in people with AIDS, to whom the Concorde findings do not apply (abstract #435). Doctors Conant, Saag and others in conclusion pinned their hopes on combination therapies as a way to avoid the weaknesses of prescribing AZT alone. In one lecture, Martin Hirsch, M.D., of Boston's Massachusetts General Hospital, described a great number of combination regimens. He said, "The more drugs you use the better it seems, no matter what those drugs target." None of the new combinations presented at the conference showed convincing results, however. In the first data from a "convergent therapy" trial involving three reverse transcriptase inhibitors (nevirapine given to volunteers already taking AZT plus ddI or ddC), the addition of nevirapine to the other two resulted in a sharp drop in blood levels of HIV's p24 antigen (abstract #270). By day 56, levels were tending back to baseline, unfortunately. A combination that added Merck's "L-drug" (L-697,661: like nevirapine, a reverse transcriptase inhibitor that works by a different mechanism than AZT) to AZT was so discouraging that the company decided to abandon the drug (abstract #L9). Use of the L-drug alone in previous trials had led to great reductions in viral levels and leaps in T-helper cell counts, but the compound lost its effectiveness within weeks as HIV developed resistance to it. Merck hoped that co-administering its L-drug with AZT would so dampen HIV replication that drug-resistant HIV mutants would take much longer to appear. Genetic analysis showed that this was not the case, and the HIV in all trial participants bore evidence of the feared mutations within six to 12 weeks. Worse yet, the Merck presenter noted that one mutation that previously seemed to confer only mild, low-level resistance to the L-drug now conferred high-level resistance in a person whose HIV also contained AZT-resistance mutations. Drug Resistant Strains of HIV The significance of drug resistance took up a large amount of Conference time. Resistance to a particular drug by a particular strain of HIV is measured in test-tube experiments, and the implications of such experiments for human beings remain controversial. Nonetheless, presentations suggested that drug resistance poses serious obstacles for combination therapies. Victoria Johnson, M.D., of the University of Alabama, reported preliminary data from the nevirapine "convergent therapy" trial that suggested resistance could develop against all three drugs at once (session #14; note that sessions are available on audio tapes; for information on how to order them, see below), thus defeating the triple combination's purpose. This may be the cause of the therapy's apparently short-lived period of benefit. Daniel Kuritzkes, M.D., of the University of Colorado gave a report on the drug resistance issue in the large ACTG 116B/117 trial, which looked at the benefits of ddI in people with a history of taking AZT. The study found that participants with AZT-resistant strains did not do as well on ddI as those who harbored no mutant virus (abstracts #1 and #460). This data may have relevance for the Merck L-drug plus AZT trial described above, where most participants had HIV with mutations known to confer resistance to AZT. In contrast, a Canadian group observed that changing to ddI after six months on AZT was universally beneficial (abstract #2): "Our study demonstrates that an early change to ddI leads to a sustained increase in [T-helper cell] count, prevents in vitro resistance and often leads to a decrease inI AZT resistance [if] present." The question of whether drug resistance in the test tube has any consequences for humans was taken up by a group led by Donald Mayers, M.D., from the Walter Reed Army Institute for Research. The Army researchers reported that in patients on AZT monotherapy, the occurrence of AZT-resistant mutant HIV presages a rapid decline in T-helper cell count in the course of the next year. But does drug resistance cause this drop, or does the emergence of more rapidly replicating HIV late in the course of disease lead to more resistant mutants? The latter was the view of Dutch researcher Charles Boucher, M.D., who explained the views of his research team at a roundtable discussion on the resistance phenomenon (session #14). At the same roundtable, Douglas Richman, M.D., of University of California San Diego, put more emphasis on the effects of resistance itself. In trials, people with a history of AZT use don't do as well on the new drug, he observed. The poor showing is curious because mutant genes by themselves should make HIV less virulent by rendering the reverse transcriptase enzyme less efficient in helping HIV infect new cells. In test-tube cultures, drug-resistant HIV is outgrown by non- mutant strains. Finally, Dr. Richman concluded that AZT resistance may be a marker for some other ability that the virus has gained, such as greater mutability or greater exploitation of human cells' natural chemistry. This comment brought Dr. Richman's position closer to Dr. Boucher's. It also helps explain the observation of the Canadian group mentioned above (and of the main results from ACTG 116B/117), that early switching from AZT to ddI is beneficial. Switching early may give HIV less opportunity to adapt to conditions in the host. Immune-based Therapy One of the reasons why the benefits of anti-HIV drugs are so transient, and the question of drug-resistant mutations so critical, is that normally a medication for a disease does not have to completely kill the infection, just seriously reduce it and allow the immune response to take care of surviving microbes. In HIV, the immune response is insufficient, and medical treatments have to shoulder the major burden. One way to overcome this problem is by adjusting the human immune response so that it has a more positive role to play. The Conference heard reports on a wide range of "immune-based therapies." Many of the proposed therapies utilize some of the most advanced techniques of biotechnology and are in need of further refinement before they can be used in humans. The farthest along of the hi-tech immune-based therapies utilizes periodic infusions of IL-2, a natural immune activator that stimulates proliferation of immune cells. This therapy had been tried previously as a steady regimen, but with that dosage and schedule, the drug was very toxic and rapidly lost effect. However, intermittent infusions (five days every two months) produced 75 percent increases in 10 volunteers' T-helper cell counts after a year of therapy (abstract #301). Improvements in immune responsiveness tests also occurred. Whether these induced changes have any clinical importance remains undetermined, however. IL-2 also has so many side effects that eight of the ten volunteers had to have their dose reduced. Much less benefit and more toxicity were observed in a separate trial with people who had T-helper cell counts of less than 200. The simplest immune-based therapy is to extract antibodies against HIV from healthy infected people with high antibody levels and give them to people with more advanced disease and lower antibody production. (Antibodies are molecules tailored by the immune system to adhere to and neutralize a specific microbe like HIV.) French doctors reported at the Conference that this kind of passive transfer significantly reduced clinical symptoms and deaths during a year-long trial in a group of people with AIDS -- some of the most promising human trial data that Conference attendees heard (abstract #L12). The 86 trial participants were infused with antibody-rich serum or placebo every two weeks. After a year, there were seven deaths (including one suicide) in the trial's treatment arm and 11 in the placebo arm. Also, volunteers who received placebo experienced almost three times the AIDS-defining events as those in the treatment arm. In a roundtable symposium on immune-based therapies, (session #47), Judy Lieberman, M.D., of the New England Medical Center in Boston described a nine-person trial that involved removing white blood cells from volunteers' blood and selectively culturing the killer cells (cytotoxic CD8+ lymphocytes) that are tailored by the body to seek out and kill HIV-infected cells. After infusion of the new cells, all patients had an immediate increase in T-helper cell counts, and the drop-off after the six-month therapy period was not dramatic; improvements in killer cell numbers fell after the end of therapy but seemed to rebound later on. HIV-specific killer cell expansions were also discussed by a Johns Hopkins University group (abstract #112). This focused approach represents an improvement over proliferating all the CD8+ cells present in somebody's serum, because it gives a higher concentration of the desired cells. It also avoids the "promiscuous cytotoxic lymphocyte" phenomenon -- the finding that some killer cells in people with HIV attack uninfected helper T-cells (abstracts #322 and #326). Introducing Protective Genes Expansion and reintroduction of T-helper cells was also discussed (abstract #111), but a concern here is that you may just be feeding the HIV present in patients' bodies. A proposed way around this would use gene therapy. Genes could be introduced into the helper T-cells to protect the cells from HIV infection. Flossie Wong-Staal, M.D., of University of California San Diego gave a talk (session #68) describing how to insert a gene for a ribozyme (which has been called a "molecular scissors" in press reports) in cells before culturing them and returning them to the patient. These ribozymes would have the ability to link up with and cut out a section of HIV genetic material should HIV be present in the cell nucleus. Gary Nabel, M.D., of the University of Michigan described a similar process involving a gene for a molecule that blocks HIV's "rev" protein (session #98). Rev regulates the construction of HIV's structural components in infected cells. Each of these gene therapies have approval to start human testing. Dr. Nabel indicated that they might be combined into a single therapeutic approach. There are a number of unanswered questions with both genetic repair methods -- the first being how to culture a sufficient number of protected T-helper cells to have an impact. One possibility would be to use bone marrow stem cells instead of helper T-cells. These would divide and mature into helper T- cells after re-infusion into the body. But even if one could generate enough protected T-helper cells, there is still the question of whether these cells could survive. Anthony Fauci, M.D., in two talks (session #69 and #81), claimed that direct HIV-induced cell killing is a rare event. Most cells that die during HIV infection do not themselves harbor the virus and are killed in the lymph nodes due to immune dysregulation. At the same time, the structure of the lymph nodes and also the thymus gland is destroyed. Dr. Fauci warned, "We must consider, in addition to developing safe and effective anti-HIV drugs, how to reconstitute an immune system that may have lost part or all of its ability to regenerate itself." Despite Dr. Fauci's comments, few of the new treatment approaches took into account the structural damage to the organs of the immune system that HIV causes. Tissues like the lymph nodes and thymus gland are essential to immune activation and replacement of lost immune cells. To some extent, at least, the tissues can regenerate themselves if HIV is eliminated. After all, the partial treatments we have now usually result in immediate though transient improvements in immune cell counts and function. Especially in advanced disease, though, the body may need outside help at bringing the immune system back to normal. The next issue of AIDS TREATMENT NEWS will further describe the Conference debate over the immune disruptions that lead to AIDS. Note that abstract numbers refer to the Conference program and abstract book published by the event's sponsor, the American Society of Microbiology in Washington, D.C.. Copies are available for $25 plus shipping from the Society; call Books International, 703/787-3305. Tapes of individual sessions are available from AVW, Inc., 2233 Irving Blvd., Dallas TX 75207., phone 214/638-0024. ***** Trimetrexate (NeuTrexin) Approved for Pneumocystis Trimetrexate (brand name, NeuTrexin) has been approved for treatment of moderate to severe pneumocystis pneumonia (PCP), when the preferred treatment, trimethoprim-sulfamethoxazole (also called co-trimoxazole, Bactrim, Septra, etc.), cannot be used. US Bioscience, Inc., the developer, announced the approval on December 17. A clinical trial by the AIDS Clinical Trials Group (ACTG) of the U.S. National Institute of Allergy and Infectious Diseases found that trimetrexate was more likely to be discontinued for lack of efficacy, whereas trimethoprim- sulfamethoxazole was more likely to cause side effects requiring discontinuation of the drug. The best strategy, then, is to use the standard therapy first (unless it is contraindicated for some reason), and keep trimetrexate in reserve to use if necessary. Trimetrexate must be used with leucovorin, to protect human cells from toxic effects of the drug. The pneumocystis organism cannot absorb the leucovorin. Trimetrexate is expensive (comparable to pentamidine), costing over $2000 to the wholesaler for the standard 21-day course of treatment. There are discounts for Medicaid patients and certain hospitals. For information about reimbursement and patient-assistance programs, patients and physicians can call 800/8-USBIOS, an information line run by U.S. Bioscience. Also, leucovorin is expensive; but its price varies greatly, as much as several fold, with the intravenous preparation costing less, and oral versions costing most, especially in pharmacies. (Hospitals often pay much less; outpatients may be changed much less at their hospital's pharmacy than at other pharmacies.) Patient-assistance programs are available. Also, the drug is off patent, and we hear that the oral formulation is less expensive in Canada and elsewhere than in the U.S. Trimetrexate is only available in intravenous form at this time, but an oral formulation is being developed. Comment The standard treatment, trimethoprim-sulfamethoxazole, is highly effective because of its two-enzyme blockade; the drug inhibits two different enzymes of the target organisms. Trimetrexate is much more powerful than trimethoprim in blocking one of those enzymes, but does not affect the other. A trial to combine trimetrexate and dapsone, to block both enzymes, is scheduled to start in early 1994. A successful trial of trimetrexate to treat pneumocystis was published in the New England Journal of Medicine in 1987. But the drug has not been available until recently, apparently because the company which owned it at that time, Warner- Lambert, was not interested in developing it for AIDS-related infections. U.S. Bioscience made trimetrexate available last year, before approval, through the "treatment IND" procedure of the FDA. ***** Clarithromycin (Biaxin) Formally Approved for MAC On December 28, Abbott Laboratories announced that clarithromycin (brand name, Biaxin) had been approved for treatment of MAC (infection with Mycobacterium avium complex, also called MAI). Clarithromycin was first approved in the U.S. for other infections in November 1991. It was in widespread use for treating MAC even before then, and has long been accepted as standard of care for this condition. The new approval should reduce the risk of insurance companies or HMOs refusing to pay for the expensive drug, using the excuse that it was not FDA-approved for this use -- and also reduce the risk of physicians inexperienced with AIDS prescribing inappropriate care. MAC treatment today consists of either clarithromycin or azithromycin, plus at least one other drug, usually more than one. Clarithromycin should not be used alone for treating MAC, because the organisms often develop resistance to it, unless combination treatment is used. ***** Acyclovir-Resistant Herpes: Trial of Topical HPMPC HPMPC, a experimental drug being developed for CMV, is also very active against herpes simplex, including herpes simplex which has become resistant to acyclovir. Systemic use is limited by kidney toxicity, but this is not a problem when the drug is used topically, applied directly to herpes lesions on the skin. A new trial, at several sites in the U.S. and Canada, is testing this potential use. There have been dramatic results in the handful of patients treated so far -- for example, one lesion shrank from 50 square cm to 2 square cm in a few days, and remained culture negative 30 days after treatment. The trial is placebo controlled and runs for five days. Volunteers are randomly assigned to receive either 1.0 percent HPMPC, 0.3 percent, or placebo. After two weeks, all patients will be eligible to receive the drug. To be eligible, patients must be HIV positive, have acyclovir- resistant herpes, and not currently be using ganciclovir, foscarnet, or other treatments for herpes. The trial will be at sites in Baltimore, Chicago, Houston, Los Angeles (2 sites), New York City, San Francisco (2 sites), Seattle, and Vancouver. HPMPC, also called GS-0504, is being developed by Gilead Sciences, of Foster City, California. For more information, including how to contact a site near you, call Jay Lalezari, M.D., at Mt. Zion Medical Center, 415/476-6356. ***** CMV Retinitis: New Trial of HPMPC As First Treatment HPMPC (also called GS-0504) is more active against CMV than either ganciclovir or foscarnet; early human trials have shown good results in clearing CMV from urine and semen. Unfortunately, HPMPC also causes kidney toxicity, which can be reduced by adjusting the dosage schedule, and by use of probenecid, a drug which reduces the absorption of HPMPC by the kidneys. The key question now is whether the toxicity can be controlled enough for the drug to be generally used as a treatment. The new trial, at several sites in the U.S. and one in the U.K., will test the drug on patients who have CMV retinitis which is not immediately sight threatening. Volunteers will be randomly assigned either to immediate treatment, or to deferred treatment which will begin if CMV progression is seen. They will be examined every two weeks. The drug is given infrequently -- only once per week for the first two weeks, then only once every two weeks. To be eligible, volunteers must have newly diagnosed CMV retinitis, which has not yet been treated with ganciclovir or foscarnet. They will be tested for kidney function, and must not have abnormal lab values. This trial will take place in San Francisco, Los Angeles (2 sites), Boston, Rochester, San Antonio, Chapel Hill, Irvine (California), and at St. Stephen's Clinic, Moorfields Eye Hospital, in London. For more information, including how to contact the sites, call Jay Lalezari, M.D., at Mt. Zion Medical Center, 415/476-6356. ***** Medical Marijuana: National Press Coverage, No News by John S. James A national news story on January 4 and 5 reported that Assistant Secretary for Health and Human Services Dr. Philip Lee said that the ban on medical use of marijuana, imposed by the Bush administration, was being reviewed. In fact, the review has been ongoing for weeks, but no decision has been made; Dr. Lee was not saying anything new. We do not have the text of his statement, but have heard that he told a meeting on healthcare reform that the review had been delayed by the controversy over Attorney General Elders' statement that legalization of drugs should be considered. A reporter may have taken Dr. Lee's remark out of context, resulting in a national media frenzy when actually there was no news. The Department of Health and Human Services (HHS) has received many letters on medical marijuana, almost all supporting access to the drug. They also received many phone calls on the drug-legalization controversy, almost all from conservatives opposing legalization. The two issues are very different. What would help most on the medical-marijuana issue would be letters from persons with late-stage illness (cancer, AIDS, or others) to their representatives in Congress, with a copy to HHS, on their personal experience with medical marijuana, for problems such as weight loss, nausea, chronic pain, or muscle spasms. Congress needs to hear from people who, working with their physician, first exhausted the legal, prescription medications for these conditions -- who found that none of those worked for them, and that smoking marijuana did. A letter from their doctor would be helpful, too. The problem is that people are understandably afraid to write about marijuana use, especially while they are still using it; physicians are also reluctant to write these letters. We do not know how much real risk is involved, although it is probably minimal since the government has lost medical marijuana cases in court and does not want more losses and more controversy; but the fear is real in any case, so Congress does not hear what is happening. We do not know any solution to this problem. Possible ways of addressing it are (1) Finding people who are willing to take the risk; (2) Not actually saying that one has taken marijuana, but only describing the failure of the conventional treatments, as a kind of national code; (3) Finding an organization to tear the names out of letters before submitting them; (4) Relatives and friends describing the value of marijuana for patients who are deceased; or (5) Probably most important, press coverage of individual patients, who can remain unidentified if they want. For those who are willing to write, here are "generic" addresses for any member of Congress. For your representative in the House, write to: The Honorable ____, U.S. House of Representatives, Washington, DC 20515. For each of your Senators, write to: The Honorable ____, U.S. Senate, Washington, DC 20510. Or you could write to them at their local offices. Also send a copy to: Dr. Philip Lee, Assistant Secretary for Health, U.S. Dept. of Health and Human Services, 200 Independence Ave. SW, 7th floor, Washington, DC 20201. ***** AIDS Private Funding: New Survey Published The Washington Blade, a gay newspaper in Washington, D.C., published a survey of private AIDS funding of national organizations, in its December 10 issue. It did a similar survey two years go, allowing comparisons. Some highlights: * The six AIDS groups with the largest income received twice the money of the six largest in 1991 -- a total of almost $40 million. But the number of AIDS cases almost doubled during the same period. These six organizations currently are the American Foundation for AIDS Research (AmFAR), Design Industries Foundation for AIDS (DIFFA), the NAMES Project, the National Minority AIDS Council (NMAC), AIDS Action Council, and the National Leadership Coalition on AIDS. * AmFAR collected about 60 percent of the income of the top six, compared to 80 percent two years ago. * The total money contributed to AIDS is strikingly little compared to charitable contributions in general. Since there are believed to be 18,000 AIDS programs in the United States, exact figures are not available. But the usual pattern is that the top ten organizations receive 10 to 15 percent of the total. By this estimate, the total given annually to U.S. AIDS organizations is between $575 and $850 million. There are single organizations in other fields that receive more than that. Also, churches and religious organizations (which get about 45 percent of all U.S. charitable contributions) receive about 65 times as much money as all AIDS groups together. "But then the amount of money donated to the six largest AIDS groups is more than three times the amount given to the six largest gay political organizations ($12.5 million), according to the Blade survey." * ACT UP/New York (not a national organization, but taken as representing ACT UP nationally), lost about half of its income in the last two years, placing it ninth on the list of national AIDS organizations, compared to second place (behind AmFAR) in 1991. (But its income of $500,000 still greatly exceeded that of the next organization on the list, the National Episcopal Caring Response, which received $102,000.) For a copy of the article, which has much more information than could be included here, send a self-addressed stamped envelope and request for the article on AIDS funding to: The Washington Blade, 1408 U St. NW, 2nd floor, Washington, DC 20009-3916. (Or if you want the whole paper, send $3, which includes first-class postage; ask for the December 10 issue.) Comment What impresses us is how little money is given to AIDS in comparison to other causes, in view of the past, present, and future seriousness of the epidemic. ***** Barbara McClintock Project to Cure AIDS: Strategy Session, Saturday January 22, Washington D.C. The Barbara McClintock Project to Cure AIDS will hold a one- day session on legislative strategy, on Saturday, January 22, starting at 10 a.m., at the Institute for Policy Studies, 1601 Connecticut Avenue NW, Washington, D.C. For more information, call Luke at 202/232-3365. Federal legislation based on the ideas of the McClintock Project, HR 3310, has already been introduced by Congressman Jerrold Nadler, Democrat, New York. Our understanding is that the immediate focus of this effort is to get Congressional hearings on the problems and issues of AIDS research. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1994 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.