Date: 14 Jan 1999 13:42:09 From: aidsnews.org@igc.org Subject: AIDS Treatment News #310 AIDS TREATMENT NEWS Issue #310, January 8, 1999 phone 800-TREAT-1-2, or 415-255-0588 CONTENTS 1999: Treatments, Issues to Watch Ziagen(TM) (Abacavir) Approved: Caution Essential Improving Drug Development: Exploratory Clinical Studies Robert Gallo Calls for New Treatment Approach Altered Body Shape: Teleconference January 20, Recording, Transcript Available West Indies Conference: Report on Web Writer Needs Help: Legal Defense Fund San Francisco: HMO Coverage of Acupuncture AIDS TREATMENT NEWS Financial Disclosure Update ***** 1999: Treatments, Issues to Watch by John S. James This year more than most, it is unclear where AIDS research is heading. There may be a better sense of direction after the Retroviruses conference (6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4). Politics and treatment access issues are also unpredictable this year. From what we do know today, here are some of the areas we will be following most closely in 1999: * The antiviral T-20 (see AIDS TREATMENT NEWS #293, April 17, 1998; #300, August 7, 1998; and #306, November 6, 1998). This potential treatment, which for the foreseeable future must be given by injection, is known to be highly active against HIV- 1 in people. And because it uses a completely different mechanism of action from any treatment now in use, it is likely to open a new approach to therapy, and have no cross- resistance with existing drugs--especially important for those who have already had extensive HIV treatment. Still unknown: how rapidly will resistance to T-20 develop in practice? * Research on other new classes of drugs, some based on recently discovered potential targets (such as the specific mechanisms of viral entry involving co-receptors). Although basic research has proceeded rapidly, it is likely to take some time before new treatments using these approaches are ready for human testing. (T-20 is essentially one such drug which happened to be discovered early.) * Research on how the body loses its natural ability to control HIV (except in long-term nonprogressors, who may be able to control HIV indefinitely without treatment). When HIV infection first occurs, the virus reaches very high levels, often causing symptoms of a severe flu-like illness. Then the body's immune response greatly reduces the level of the virus; the immune system itself, at first, does much better at suppressing HIV than any known drug. But later, usually over a number of years, the body gradually loses this ability to keep the virus in check, and the resulting high levels of HIV cause more immune damage, leading to symptomatic disease and AIDS. * A new measurement technique to study the natural production and lifespan of immune cells in the body. Newly created CD4 cells can be marked with deuterium, a harmless non- radioactive isotope of hydrogen, which can be detected with special equipment. A major paper published this week in NATURE MEDICINE used this method to show that HIV interferes with the production of CD4 T-cells--challenging the prevailing model of greatly increased production and rapid killing of these cells. If confirmed, this finding could lead to new kinds of treatment focused on maintaining normal production of immune cells. * HIV-specific CD4 helper response. When HIV is well suppressed by antiretroviral drugs, immune responses to various opportunistic pathogens usually return, more or less rapidly in different patients. But the ability of CD4 helper T-cells to recognize HIV is lost very rapidly (except in long-term nonprogressors), and even when the virus is suppressed, that ability returns very slowly or not at all. Some early results suggest that it may be possible to restore this response by immunization (see AIDS TREATMENT NEWS #298, July 10, 1998); there may also be other immune-based strategies which could work. At this time, however, there is no proof that restoring this response will result in clinical benefit. * Body-shape changes and abnormal fat metabolism associated with HIV treatments, especially protease inhibitors. Here the most important research, we believe, will be (1) to find the mechanisms of action, so that treatments can be rationally designed, and (2) meanwhile to find and study empirical treatments (ones which seem to help, although no one knows exactly how). * Laboratory tests of viral resistance to drugs. These tests (both phenotype and genotype) will become increasingly important in medical care, but are likely to be valuable only in specific situations. For example, when a combination treatment is failing to control the virus, a resistance test may help decide what new combination to change to; in this case, the test must be done while the patient is still taking the drugs which are failing (since without the drugs, the resistant virus is likely to be replaced by the original non- resistant virus, and decline to very low levels which the tests will not detect--yet be ready to come back almost immediately if the drug is resumed). Another potential use is for people who are likely to have been infected by a resistant virus (for example, if they were infected in San Francisco or other cities where many people have been treated extensively); in this case the test can be done before treatment is started, to avoid drugs which are unlikely to be effective. * New tests to see if opportunistic infection prophylaxis is still necessary. Researchers are developing tests which may be able to tell if a patient's immune system is responding well enough to specific opportunistic pathogens that prophylaxis for them is no longer necessary. Today, this decision is often made on the basis of CD4 count recovery after successful antiretroviral therapy; the new tests, when they are available, should allow more accurate determination. * Alternative/complementary treatments. Many treatments are not developed by the pharmaceutical mainstream because of lack of commercial incentive, even when there is reason to believe they may have value (an example is DHEA). Nutrition, exercise, stress reduction, and other lifestyle improvements are also under-researched, for similar reasons. Usually such potential treatments are far less dangerous and far less expensive than high-tech, patented pharmaceuticals. They deserve attention for several reasons: to possibly complement mainstream treatments in helping reduce disease progression; to improve quality of life, for example by helping to control certain side effects of drugs; and for developing countries, where they may be the only treatments affordable for most people. * Treatment access issues include: - Serious problems with reimbursement for HIV care by many managed-care organizations--which cut their costs by refusing to recognize HIV care as a specialty, and pay only the healthy-adult capitated rate for taking care of patients with HIV disease or AIDS. - Medicaid and ADAP funding, and rules on working while disabled. - Lack of trials of salvage therapies. - Drug pricing. - International access to treatment, especially use of compulsory-licensing rules to enable the use of certain critical drugs in countries where people would otherwise do without. - Inferior treatment for the U.S. homeless and marginally housed, even when they can adhere well to the antiretroviral regimen. - Needle-exchange, both to prevent new infection and to bring drug users already infected into medical care. - Inadequate pain relief when needed in serious illness. - Legal access to medical marijuana. - Freedom of information, including potential excesses in copyright legislation, Internet sexual censorship, and embargoes of taxpayer-funded research results by medical journals and conferences. ***** Ziagen(TM) (Abacavir) Approved: Caution Essential by John S. James On December 18, the U.S. Food and Drug Administration announced the accelerated approval of Glaxo-Wellcome's abacavir (trade name Ziagen; previously known as 1592) for treatment of HIV infection in adults and children, in combination with other antiretrovirals. Abacavir is a nucleoside analog (in the same class as AZT), but has a stronger antiretroviral effect. This drug must be used with caution, because it can cause a serious side effect, called a hypersensitivity reaction, in about five percent of patients, usually (but not always) within six weeks of starting the drug. There is no known way to predict who is at high or low risk. If the drug is stopped permanently, the hypersensitivity reaction generally goes away without further treatment; but if the drug is later restarted after the reaction, it causes a much more severe recurrence which begins rapidly and can be fatal within a day. It is urgent that patients as well as medical professionals be well informed about this problem, so that they can recognize the hypersensitivity reaction if it occurs, and get medical attention and permanently stop using the drug. On December 18, 1998 the FDA published a short "talk paper" on abacavir, which we reproduce in full. If you use this drug, be sure to check the Medication Guide and wallet card that comes with each prescription, for information on how to recognize hypersensitivity. "FDA Approves Abacavir for HIV-1 Infection "FDA approved today abacavir (trade name Ziagen) for the treatment of Human Immunodeficiency Virus-1 (HIV-1) in adults and children. The following can be used to answer questions: "Ziagen, an oral medication taken twice daily, is one of a class of medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs) and is taken in combination with other anti-HIV medications. This combination of medicines helps to lower the amount of HIV found in the blood. "This new drug offers another choice for the treatment of HIV, a virus that mutates quickly and may become resistant to current treatment. Ziagen, available in tablet and liquid form is approved for adults and pediatric patients older than three months of age. "A potentially fatal hypersensitivity, or allergic reaction, has been associated with the use of Ziagen in at least 5 percent of patients. Symptoms of this reaction may include skin rash, fever, nausea, abdominal pain and severe tiredness. "A written list of the hypersensitivity symptoms is printed on a warning card and is provided along with a Medication Guide to patients by pharmacists. Anyone who experiences a hypersensitivity reaction must stop taking the medicine and call their health care provider immediately. Ziagen should not be taken again after a reaction occurs because more severe symptoms will arise within hours and may include life- threatening low blood pressure or death. "An abacavir hypersensitivity reaction registry has been established--physicians should register patients developing symptoms of hypersensitivity by calling 1-800-270-0425. "All NRTIs can cause lactic acidosis--a fatal metabolic disturbance that causes an abnormal buildup of lactic acid-- symptoms may include an enlarged liver. "Additional reported side effects of abacavir include nausea, vomiting, fatigue, headache, diarrhea, and loss of appetite. "Accelerated approval of Ziagen was based on analyses of surrogate markers in three controlled studies of up to 24 weeks in duration. At present there are no results from controlled trials with Ziagen evaluating long-term suppression of HIV infection or AIDS. "Ziagen is manufactured and marketed by Glaxo Wellcome Inc., of Research Triangle Park, N.C." * * * Comment On November 2 the FDA Antiviral Drugs Advisory Committee met to consider the approval of abacavir. The Committee voted 7 to 2 to recommend accelerated approval, but with much reluctance because of serious weaknesses in the package of data presented. As one Committee member put it, "I voted for accelerated approval. I agree with virtually everybody else that I would have liked to have seen a more complete set of data to justify that, but on balance I came down on yes." Here are some of the gaps in current knowledge: * Little is known about the mechanism of the hypersensitivity reaction, and no risk factors are known. (Glaxo has agreed to do further work on the mechanism, on the clinical issues, and on the use of educational materials and their effectiveness, and bring the results back to the FDA when abacavir comes before it again for traditional approval. * Of the three trials most relied on by the Committee, none had data beyond 24 weeks at that time (the studies are ongoing). And two of the three trials compared abacavir plus AZT plus 3TC, vs. AZT plus 3TC only, looking for a statistically significant difference in markers of disease progression, especially viral load; this is an easy test for a drug already known to have a strong antiretroviral effect in humans. At least one of these trials will never produce much long-term comparison data, as volunteers already switched out of the two-drug arm. The third trial, abacavir plus AZT plus 3TC vs. indinavir (Crixivan(R)) plus AZT plus 3TC, is a good comparison test, but the results are not conclusive at this time. * There were other trials which failed to find a statistically significant result in favor of abacavir--for unexplained reasons. * No clinical-trial results are yet available for combining abacavir with nucleoside combinations besides AZT plus 3TC. This is unfortunate, as there is significant cross resistance between abacavir and AZT plus 3TC. Probably due to this cross-resistance, many patients with extensive prior use of AZT plus 3TC seemed to benefit little from adding abacavir (although prior short-term use of the two-drug combination-- for example, for 12 or 16 weeks--did not seem to reduce abacavir's effectiveness, at least in the short-term data available so far). The panel's patient representative, Jeff Bloom, questioned whether approval now might do more harm than good, since a patient's first antiretroviral combination is so important, and potentially better combinations have not been studied. Mr. Bloom, who voted symbolically against approval (the community representative's vote does not count in the official total) was especially concerned that the only comparison with the current standard of care (the head-to- head comparison with the indinavir combination) had a 24% drop-out rate which was not explained. He also told AIDS TREATMENT NEWS that he learned from other panelists that Glaxo is running tests with other abacavir combinations, but did not present these to the FDA as part of its accelerated- approval package. * A dementia trial surprisingly failed to show efficacy, and Glaxo did not ask for an indication for this use. * There were also technical issues. One of the trials had a trend toward worse CD4 response in the abacavir three-drug arm than in the two-drug control, and nobody knows why. Also, a major pediatric trial was designed years ago, with a goal of getting patients below a viral load of 10,000--which has become problematic since some of the children started with a low viral load already, leading to such a high percentage of "responders" to the two-drug control that it would be hard for any drug to prove superiority, diluting the trial's ability to get a positive result. (A lower viral-load endpoint, such as 400, could be substituted today; but to prevent good-news shopping, the FDA is reluctant to give much weight to an analysis which was not planned when the trial was designed and started. Also, it is very difficult to get the viral load below 400 in children with extensive prior antiretroviral treatment.) * The place of abacavir in HIV treatment today remains unclear. For treatment-naive patients, the drug works well with AZT plus 3TC to reduce viral load for at least 24 weeks. However, these patients have many options; and with the strong belief today that the first combination is one's best shot, they are likely to choose a combination about which more is known, at least until longer-term abacavir data becomes available. Meanwhile, those who are out of options and do need a new drug have probably already had extensive use of AZT plus 3TC; they might benefit from abacavir in another combination, but with little data to guide them, they will need to rely on intelligent guesswork. Some Committee members were concerned that physicians less experienced with HIV might choose abacavir for its convenience--twice a day dosing with no food or water restrictions--without thinking through long-term strategies for the particular patient, or the risk of hypersensitivity reaction, especially with a physician inexperienced in treating HIV. On the positive side, Glaxo received much credit for running a phase III pediatric trial, which the FDA strongly encouraged but did not require. It is widely agreed that data from the pediatric trial is relevant to all age groups. Also, a phase III pediatric study was necessary in this case, to learn if the hypersensitivity reaction is equally common in children, and has the same symptoms (it does seem to be the same as in adults). Our impression from a transcript of the hearing (we did not attend the meeting) is that due to the company's cooperation on the pediatric study, the FDA may have been less skeptical than it would otherwise have been, and more encouraging of wavering Committee members to vote for approval. Over 11,000 people have already used abacavir. Due to this experience, there is substantial agreement in the AIDS community that this drug is important and necessary, and its approval was correct, even though the data available now is inadequate. Abacavir is expected to be available in pharmacies in January. The price to wholesalers will be $3,540 annually, which is less than had been expected; ADAP (the AIDS Drug Assistance Program) will pay about $3,000 per year. (In early January we checked a retail price at a major pharmacy in San Francisco; the price was $369.09 for a bottle of 60 300 mg capsules, a 30-day supply--about $4429 per year. Hopefully mail-order or other pharmacies and their wholesalers and distributors will charge less than $889 ($4429 - $3540) to move 12 bottles of pills from the manufacturer to the patient.) Abacavir has already been approved by California's ADAP (AIDS Drug Assistance Program), and approval is expected soon in most states. For More Information The most extensive information about abacavir is the transcript of the November 2 Advisory Committee hearing, available on the FDA Web site. Note that this transcript has not been edited and has transcription errors. The transcript on the FDA Web site is hard to find. Go to http://www.fda.gov; then select Dockets, then select FDA Advisory Committees. Under 1998, select Center for Drug Evaluation and Research (CDER); then select Antiviral Drugs Advisory Committee. The transcripts are listed by date, so look for 11/2/98; then you can download either an rtf or a pdf file. Usually the rtf file is easier to download and use; the pdf file is over 40 times as large because it provides images of the pages. But the pdf file preserves the original pagination, and includes an automatic index listing every page and line where words of interest appear. ***** Improving Drug Development: Exploratory Clinical Studies by John S. James The difficulties in developing abacavir, and the widespread concern about the limitations of the data currently available (see "Ziagen (Abacavir) Approved: Caution Essential," in this issue) show some of the limits of clinical trials, and also suggest ways to improve future research, to better provide the information doctors need when they use a new drug. Even in retrospect it is not clear how abacavir should have been developed. Is there any ethical or practical way today to obtain long-term superiority data (which means that some patients are on long-term inferior treatment)? How can a research program provide the information doctors need, when the needs change faster than trials can be designed, conducted, analyzed, and published? One change clearly needed in AIDS drug development is more research on mechanisms, on understanding what is happening and why, instead of blind pursuit of an arbitrary level of statistical confidence that, on the average, the drug is better than some standard alternative. Why are some patients responding and others not? What is the role of viral resistance, vs. individual differences in absorption or metabolism, vs. other mechanisms that might explain how a drug works well for some but not others? What can be done to predict who will respond--and to treat the others effectively? Some regulatory reform may be needed, as the current system is designed mainly for large trials with rigid protocols. But exploratory work needs small trials early in a drug's development--sometimes with only a few patients, or only one. These trials must be flexible to allow changes as more is learned about what does or does not work for an individual. Such studies do occur today, but they can be handicapped by the need to keep a low profile and not be considered "research," and to avoid using experimental drugs. Meanwhile, large trials are designed around statistical concepts to produce a go/no-go for marketing, when the designers do not know what is happening medically. Much of the real advance in medical knowledge happens almost incidentally, for example in further analysis of the data from government trials after they have been run. Several years ago the FDA methodically analyzed its drug- approval process, identified unnecessary obstacles, and redesigned a more efficient system. But this highly successful effort to create a more rational process was focused on the later stages of drug development. A new analysis should ask whether more flexibility in early research could significantly improve the design of the large clinical trials, so that they will better address the most important issues and produce data more useful for clinical practice. ***** Robert Gallo Calls for New Treatment Approach On December 22 Dr. Robert Gallo, Director of the Institute of Human Virology at the University of Maryland in Baltimore, said the Institute would research "viable and effective biological therapies for AIDS in the year ahead." "I am determined to go into the new Millennium armed with natural, patient-friendly, nontoxic treatments so that we can reach those who are on current treatments as well as those who are less economically fortunate and cannot afford treatment now... We are determined in the next year to develop and implement biological therapies that are affordable worldwide and to Americans in impoverished areas." The Institute noted United Nations predictions of 62 million deaths from AIDS by 2015 in sub-Saharan Africa (unless effective treatment is available). ***** Altered Body Shape: Teleconference January 20, Recording, Transcript Available "Altered Body Shape in HIV Disease: A Side Effect of Therapy?," a one-hour interactive telephone conference allowing patients and medical professionals to question leading experts, will take place Wednesday, January 20, starting 5 p.m. Pacific time (8 p.m. Eastern time). There is no charge, but participants must register in advance. Later, anyone can hear a recording by telephone, or obtain an edited transcript from the Web. The panelists are: * Donald Kotler, M.D., Professor of Medicine, Columbia University College of Physicians and Surgeons; * Andrew Carr, M.D., Staff Specialist, HIV Medicine and Immunology, St. Vincent's Hospital, Darlinghurst, Australia; * Ramon A. (Gabriel) Torres, M.D., co-director of the Bentley-Salick Medical Practice, PC, New York City; * Matthew Sharp, person with AIDS, ACT UP/Golden Gate; * Ronald Baker, Ph.D., editor-in-chief, HIVandHepatitis.com (a new Internet publication, scheduled to begin operation on February 1). "Some people on anti-HIV therapy, including those using protease inhibitors, are experiencing a loss of fat in their arms and legs, but also an increase in abdominal fat. Others have developed fat deposits ("buffalo hump") at the base of the neck and severe wrinkling of the facial skin; some women report similar changes as well as enlarged breast size. In addition, instances of diabetes and serious heart disease have been linked to the syndrome. The teleconference panel will discuss and answer questions about this unexpected new phenomenon, its characteristics, possible causes, potential treatment, and ongoing and planned studies" (from the teleconference announcement). This teleconference is sponsored by The AIDS Wasting Foundation (212-481-2460, or email to aidswasting@earthlink.net), with an unrestricted educational grant from Serono Laboratories, Inc. To join the teleconference, you must register in advance; call 800-880-5121 Monday through Friday 9 a.m. to 5 p.m. Eastern time. No registration is needed to hear a recording, which will be available within 24 hours after the teleconference, 24 hours a day, for replay by telephone with fast-forward and backward options; call toll-free 888-207-2647, access code 1967. Also, within ten days of the teleconference an edited transcript will be published at www.HIVTreatmentLive.com. ***** West Indies Conference: Report on Web Daily summaries from the International Conference on the Discovery and Clinical Development of Antiretrovirals conference, December 13-17, 1998, in St. Thomas, West Indies, are available at http://www.healthcg.com/hiv/confs/icdcd98/. Also, the conference official site, http://www.intmedpress.com/icdcd/, has a Webcast of slides and audio from the meeting, which will be available through March 1999. The daily summaries on the healthcg site are written by William Bishai, M.D., Ph.D., Steven Deeks, M.D., and Mike Youle, M.B., Ch.B. Topics include new treatments, new drug targets, monitoring plasma drug levels, viral resistance, gene therapy, first-line treatment, salvage treatment, and adverse effects of antiretrovirals. ***** Writer Needs Help: Legal Defense Fund by John S. James Bruce Mirken, a well-known reporter who focuses on gay/lesbian youth issues and HIV/AIDS, and writes for AIDS TREATMENT NEWS, was arrested last July while investigating a story of a troubled gay teenager. After corresponding online, they agreed to meet in a Sacramento park. In fact there was no teenager; the messages were from the Sacramento Police Department's sting to catch online pedophiles. When Mirken went to interview the youth, he was arrested for felony "attempted lewd acts" with the nonexistent minor. Mirken has vehemently denied the charges, calling them "absolutely, totally false." (For more information, see "Journalist Cyberstung" by Andy Hsiao, VILLAGE VOICE, October 6, 1998, currently available at http://www.villagevoice.com--search for 'Mirken'.) Although a judge called it an "extremely close" decision whether the case should even go to trial, Mirken has already spent $30,000 on bail and legal expenses, and more will be needed if the trial takes place. Contributions (which are *not* tax deductible) can be made to: Bruce Mirken Legal Defense Fund, P.O. Box 14954, San Francisco, CA 94114. ***** San Francisco: HMO Coverage of Acupuncture In 1995, San Francisco passed legislation to provide its employees with health-insurance coverage for acupuncture and prescribed herbs. The intent was to encourage HMOs to integrate traditional Chinese medicine into Western medical care--which could benefit many people other than city employees. But the law was implemented differently, with San Francisco providing separate coverage to its employees through self-insurance, not through HMOs. New legislation, supported by major labor unions representing San Francisco employees, practitioners of traditional Chinese medicine, and others, would require HMOs which sell health coverage to employees of the City and County of San Francisco to offer coverage of acupuncture and prescribed herbs to these employees. For more information, and to learn how San Francisco residents can support this measure, contact George Wedemeyer, 415-487-9377 ***** AIDS TREATMENT NEWS Financial Disclosure Update by John S. James In May 1996 we published a statement of our policy on pharmaceutical-company income ("AIDS TREATMENT NEWS Policy on Pharmaceutical-Company Revenue," issue #247, page 7). None of those policies have changed since then. Except as disclosed in the May 1996 article, AIDS TREATMENT NEWS has never accepted grants or contributions from organizations whose products we cover or might cover. And we have never carried advertising. AIDS TREATMENT NEWS is almost entirely funded by subscriptions. And companies or other organizations we report about can subscribe to the newsletter. We were concerned then, and remain concerned now, about developing undue dependence on large orders from companies. From January 1996 until the May 17 issue went to press, large orders (more than five subscriptions or copies to a single company) accounted for less than 13 percent of our income. This month we re-did the same calculation for all of 1998; the proportion of our income from large orders has grown to 18.4% Of the remaining subscription income (not the large orders), 50% was from individuals, 40% from businesses, and 10% from nonprofits. In 1996 we overlooked honoraria--payments for speaking to groups--in our disclosure. Honoraria have never been a significant source of our revenue, and accounted for one fifth of one percent of total income in 1998. Our total 1998 income was under $250,000--about 98% from subscriptions. Major expenses include fast-turnaround printing and first-class postage for about 3,000 individually-mailed subscriptions (including free subscriptions for hundreds of prisoners and others who could not pay), salary and health insurance for a staff of four, office rent in San Francisco, travel to conferences, phones, computers, office supplies, and other expenses. ***** 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 email: aidsnews@aidsnews.org useful links: http://www.aidsnews.org Editor and Publisher: John S. James Associate Editor: Tadd T. Tobias Reader Services: Tom Fontaine Operations Manager: Danalan Richard Copeland 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: $270/year. Includes early delivery of an extra copy by email. Nonprofit organizations: $135/year. Includes early delivery of an extra copy by email. Individuals: $120/year, or $70 for six months. Special discount for persons with financial difficulties: $54/year, or $30 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 ***** How to Subscribe Call 800-TREAT-1-2 (800-873-2812), or 415-255-0588. AIDS TREATMENT NEWS is published 24 times per year, on the first and third Friday of every month, and print copies are sent by first class mail. Email is available (see below). Annual Rates: business/professional $270; nonprofit community organization $135; individual $120 ($70 for 6 months). Email: Priority Email Delivery. Business, nonprofit and full- rate individual subscribers can receive a copy by email, in addition to their regular print copy, at no extra charge. These email copies are sent before the printed copies are mailed. Email: Free Delivery for Individuals (delayed one week). For instructions, send email to majordomo@aidsnews.org; the first line must be "info aids-treatment-news" (without the quotes). Back issues are available at http://www.immunet.org/atn. Copyright 1998 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.