AIDS TREATMENT NEWS Issue #173, April 23, 1993 phone 800/TREAT-1-2, OR 415/255-0588 CONTENTS: AZT, Early Intervention, and the Concorde Controversy Federal Employees: Urgent, Insurance Decision Due by April 30 3TC: New Treatment Enters Major Trials Announcements International News Service Now Available California Funding: AIDS Lobby Day May 10 ***** AZT, Early Intervention, and the Concorde Controversy by John S. James The widespread overreaction to the April 2 report of preliminary results from the UK-Irish-French Concorde trial of AZT vs. placebo for early HIV treatment has confused and upset patients and physicians. Seldom if ever have U.S. and British mainstream AIDS researchers been as far apart as they are over the Concorde study. And seldom has information affecting patient care been so widely communicated to the public with so little regard about how it is received. For patients and physicians now, the bottom line is: * For asymptomatic patients, Concorde found no benefit from early use of AZT compared to starting AZT later. But this conclusion contradicts that of all three other major controlled trials of AZT treatment of asymptomatics (1,2,3). For this reason, and because only preliminary and sketchy results are available (eight paragraphs and one table), and because the Concorde study found no reason not to use AZT, U.S. physicians at least are not changing their treatment practices until more information is available. The U.S. National Institute of Allergy and Infectious Diseases (NIAID) said, in an update published April 1, "At this time we see no basis for changing the current recommendation to initiate antiretroviral therapy for HIV-infected persons whose CD4+ T cell count [T-helper count] falls below 500 per cubic millimeter (mm3) of blood." Even in the UK, where unpublished information about the Concorde results has been quietly shared with physicians and patients (information not available to U.S. researchers), and where the Concorde results are widely accepted as correct, there seems to be little rush to change medical practice at this time. (In part this is due to the fact that early use of AZT has been rare in the UK, compared to the U.S. and France; the Concorde results have only reinforced what has already been the prevailing medical strategy.) * The Concorde trial only studied AZT for early intervention, in asymptomatic patients. No one has suggested that these results should affect the treatment of persons with AIDS or with other symptomatic HIV disease. * Concorde only studied the use of AZT as a single-drug treatment. The benefits of AZT were already widely believed to be of limited duration. Concorde has no bearing on combination antiviral treatment, which is likely to have more lasting benefit than AZT alone. * Recent press coverage of the Concorde announcement has been misleading. In part this is due to the April 2 news release of the British Medical Research Council, which carried the story to the world, but did not even summarize the eight available paragraphs correctly. Ultimately, the garbled message was due to the time pressures of a race against news leaks, international failures of cooperation which prevented consultation, and public-relations mistakes by Wellcome, the British developer of AZT. * The conclusion that Concorde shows that T-helper count does not work as a marker for testing new antiviral drugs is, we believe, open to serious challenge (see below). In any case, nothing in the trial discourages use of the T-helper count for monitoring individual patients. Hopefully, a more detailed report of the Concorde results will be available by the time of the International AIDS Conference in Berlin, June 7-11. Concorde may well change medical practice, after enough information is released to allow the worlds' scientists and physicians to evaluate it. Meanwhile, we hope that Concorde serves as a wake-up call to encourage more balanced AIDS treatment research strategies, instead of continuing to rely excessively on a single drug or class of drugs. The rest of this article looks in more detail at: * The Concorde trial itself; * The preliminary results, and how the news was released; * T-helper count for testing antivirals -- and why we believe the Concorde conclusions may be a statistical artifact. The Concorde Trial Concorde, the largest and longest-running controlled trial comparing AZT to a placebo, enrolled over 1700 patients between October 1988 and October 1991, in 65 medical centers in the UK, Ireland, and France. It recruited asymptomatic HIV-positive patients, regardless of T-helper cell counts. The average time on the study has been about three years. The current information release resulted from a planned analysis of the data through December 1992. Followup data is still being collected on the patients. The study itself must be distinguished from the issues concerning its recent news release. Concorde asked the right question for 1988, and it was well designed to answer that question. It appears to have been conducted in an ethical way, with the high survival rate in both arms of the study suggesting that the volunteers received good medical care. The Concorde trial was co-sponsored by the British Medical Research Council (MRC) and the French National AIDS Research Agency. Decisions were made by the Concorde Co-ordinating Committee. Most of the data analysis was done in the UK. The trial was originally designed to find out whether it is better to begin AZT treatment immediately for symptom-free HIV-positive persons, or to wait until HIV-related symptoms develop and begin treatment then. Patients were randomly assigned to receive AZT immediately (250 mg four times a day), or to receive a placebo until symptoms developed, at which time they were switched to AZT. But one year after the trial began, in October 1989, the Concorde study was modified for ethical reasons. A major U.S. trial (ACTG 019), which also compared AZT to placebo in asymptomatic patients, was terminated for patients with T- helper counts under 500, after finding that those given placebo were about twice as likely to progress to AIDS as those given AZT. As a result, Concorde was modified to allow patients with T- helper counts of 500 or fewer, as shown by at least two different blood tests at least one month apart, to switch to AZT if they wanted to. Under this rule, 282 of the 872 patients in the deferred treatment group (the group starting with the placebo) eventually switched to AZT "before developing symptomatic disease." But under the statistical rule by which the study was analyzed (called "intent to treat"), these patients were still counted with those taking the placebo, no matter how long they had in fact been taking AZT. Many experts believe that this October 1989 modification changed the nature of what the study was measuring. Concorde started as a comparison between giving AZT to every asymptomatic person with HIV (no matter what their T-helper count), vs. waiting and giving AZT only when HIV-related symptoms developed; we could call that study Concorde I. It changed to comparing AZT for everyone, vs. something closer to a widespread de facto standard of care, which is to evaluate patients individually when their T-helper count drops below 500, and decide on a case by case basis when to start AZT. We could call this second study Concorde II. Since this change occurred only one year into a three-year recruiting period, it is possible that most of the study volunteers were never in Concorde I at all -- and it is certain that the great bulk of patient years in the study occurred in Concorde II. Therefore, instead of saying that the Concorde trial found no benefit of using AZT in "asymptomatic" patients -- the message given to the world's press -- it would be more accurate to say that it found no benefit (during an average followup of three years) in using the drug in all asymptomatic patients, vs. using it selectively in those asymptomatic patients whose T-helper counts drop below 500. A practical difference in these two statements is that the latter does not imply that asymptomatic patients now taking AZT in accordance with U.S.-standard medical practice should stop. But the message that was in the press does. It may needlessly interfere with medical care, and make it more difficult to convince persons at risk of HIV that they should be tested and receive treatment if necessary. The April 2 Report The only Concorde results generally released so far are the eight-paragraph letter published in the April 2 Lancet(4), an April 2 news release from the MRC, and quotes from an April 2 MRC news conference. The letter and other materials were not peer reviewed by The Lancet. The letter reported: * That there were no significant differences between the immediate-treatment (AZT) group and the deferred-treatment group, either in survival or in progression to AIDS. The three-year survival rates were fairly good for both: 92 percent for the group that started AZT immediately, 93 percent for those that started on placebo (and often switched to AZT later). The rate of progression to AIDS or death was 18 percent in both groups. The rate of progression "to 'minor' ARC, AIDS, or death" was 29 percent in the immediate- treatment group, and 32 percent among those who started on the placebo. None of these differences is statistically significant. * That comparing the groups was valid, despite the change in the study which allowed 282 asymptomatic patients to switch from placebo to AZT if their T-helper counts went under 500, because of the very different amounts of AZT use in the two treatment arms. * That the toxicity of AZT in this study was relatively low -- despite the high dose of the drug used, and the long time that patients were taking it, compared to other studies. There were no new or unexpected toxicities. * That there was a significant difference in T-helper counts between the groups. Those who began AZT immediately had gained a median of 20 cells by three months. Those who began with placebo had lost a median of ten by that time. This difference of about 30 in T-helper counts persisted; at six and at 12 months it was slightly larger than 30, and it was observed for up to three years. * That the difference in T-helper counts, without a difference in disease progression or survival, casts doubt on the value of T-helper counts to measure whether an antiviral is working. The final paragraph of the Lancet letter states the main conclusions: "In conclusion, Concorde has not shown any significant benefit from the immediate use of zidovudine compared with deferred therapy in symptom-free individuals in terms of survival or disease progression, irrespective of their initial CD4 count. The discrepancy between this result and the significant effect of immediate zidovudine on CD4 cell counts casts doubt on the value of using changes over time in CD4 count as a predictive measure for effects of antiviral therapy on disease progression and survival. Concorde provides a valid comparison of the strategies of immediate versus deferred treatment with zidovudine since there was a striking difference between the two groups in the amount of zidovudine taken on study before progression to ARC or AIDS. A more detailed analysis is being prepared and follow-up continues in all patients." The most widely distributed message was not the letter but the April 2 news release from the MRC Press Office. This release, written by press experts not AIDS experts, changed the letter and made the results appear more definitive. For example: * The opening sentence of the news release reads, "The large Anglo-French Concorde randomized trial of zidovudine in asymptomatic HIV-infected individuals shows that there is no significant clinical benefit in terms of survival or disease progression to AIDS or AIDS-related complex (ARC) in those who started zidovudine immediately rather than those who waited for the onset of symptomatic disease." Note that the Lancet letter only claims that "Concorde has not shown any significant benefit," while the news release claims it does show there is none. * The news release clearly implies that it is just as good to wait for symptomatic disease as to start AZT early. But the letter only says that Concorde "was designed in 1988" to determine that; as we have seen, what the study was designed to do in 1988 and what it did do are not be the same. * In reporting the amount of time those assigned to placebo were actually on AZT instead due to the October 1989 change in the study, the news release only mentioned a figure of 7 percent at 18 months; it gave no hint that the Lancet letter also included a figure of 14 percent at three years. Also, the news release cited "the large number of patients in the study" as part of the reason a valid comparison was still possible; the letter, written for a professional instead of lay audience, does not suggest that a large number of patients overcomes a selection bias, which is the issue here. * And where the letter "casts doubt" on using T-helper counts to measure the effectiveness of an antiviral, the news release "casts serious doubt." The news release, in short, pushes beyond the letter in discouraging early treatment with AZT. Top U.S. government AIDS experts had only two days' notice before the public release of the Concorde results. U.S. experts have questioned why the release could not have waited a short time (as there was no emergency in terms of patient care, because the two groups in the study did equally well) so that it could include an executive summary to give physicians and researchers more guidance and information. To address these questions, AIDS TREATMENT NEWS interviewed Tim Peto, M.D., of Oxford University. Dr. Peto is the scientific secretary to the British Medical Research Council AIDS Trials Committee, and also a member of the Concorde Co- Ordinating Committee. On April 14, Dr. Peto explained the timetable of the information release. After the data cut-off on December 31, 1992, it took over two months to collect the data from the 65 sites and do preliminary checking and analysis. The data was unblinded in mid March; the CCC got the results only about two weeks before the Lancet letter. It had to share the results with the physicians at the trial sites, who would tell their patients. Clearly the story would soon reach the news media; to prevent garbled information from going out, it was decided that there should be a basic statement of results released to everybody. Also, it was feared that the inside information would be used in the financial markets if not released quickly. So on the morning of Thursday, April 1 (the day before the Lancet letter was published), the trial physicians were told the results, and on that afternoon the press was told. As for NIAID, which first heard on Wednesday, March 31, Dr. Peto noted that, "When we completed our analysis, we told them." Dr. Peto also noted that the Concorde result was no great surprise, since the trial had gone well beyond the time it would have been stopped if a clear difference had been seen. As far as we can determine, almost no details of the study have left the borders of the three Concorde countries. Therefore, AIDS experts elsewhere were only bystanders while a strong conclusion was inserted into the world's press. They were locked out from effective dialog due to lack of data. At issue is the standard of care for tens of thousands of people, current drug approvals (especially in Europe), procedures for approving drugs in the future, questions around the developing theories of AIDS pathogenesis, and the kinds of drug-development strategies and trials which are most appropriate in the current epidemic. As one researcher put it, to come to such far-reaching conclusions likely to affect widespread medical treatment would normally be done with exquisite care, after opening the data to scrutiny and professional critique, and responding to questions, concerns, and objections. She noted "the enormity of the conclusions, without allowing any of us to access the whole body of data." Others have commented that the Concorde researchers are very reputable scientists, well respected in the UK and in the U.S., and clearly acting with good intentions in getting the bottom-line information out quickly. Among the information researchers most want to see now is the standard Kaplan-Meier curves, showing when the deaths, progressions, treatment changes, or other events occurred. They also want a subset analysis showing how the patients who elected to switch from placebo to AZT compared with those who did not make that choice -- at the time they switched, and later. However, Dr. Peto told AIDS TREATMENT NEWS that the MRC never plans to do this analysis. Following the "intent to treat" philosophy, he explained that it would be invalid to analyze subsets which were not determined at the time of randomization. Self-selection into those groups, he said, would cause biases which could make the analysis invalid. We did not have time to run this statement by U.S. AIDS researchers. We expect that some of them would point out that self selection had already affected the study, and they needed the analysis in order to understand what had happened and make any possible corrections. As for the news release, Dr. Peto told us that the MRC Press Office wrote it, saying that they were the experts in communication with the lay news media. "We planned to make them mean the same," he said, speaking of the Lancet article and the press release. "The differences were not meant to be substantive." In the U.S., NIAID did not know about the press release until over a week later, when AIDS TREATMENT NEWS happened to fax them a copy. This is not the only communication problem between U.S. and British AIDS researchers. We have heard complaints from others that British scientists and physicians have had trouble obtaining executive summaries and other information from NIAID; in one case, only a leaked copy got the information to British physicians. We have also been told of letters from leading British researchers which have been repeatedly ignored by their U.S. counterparts. We could not investigate further by press time. But these complaints, as well as the U.S. complaints about the handling of the Concorde news, suggest that behind the surface solidarity, there is often a failure to communicate. Dr. Peto noted that there is no intentional communication problem, and "When we meet in person, everything is fine." Conspiracy Concerns Because of the atmosphere of confusion and lack of information, the sudden death of one of a leading Concorde statisticians, who was hit by a car while riding his bicycle to work in the UK about two weeks before the news release, led to disquiet among researchers. Hundreds of millions of dollars have changed hands in the financial markets as a result of the news; if there had been a conspiracy to drive down the price of Wellcome stock, a single technician who broke ranks and released contradictory or ambiguous information could have deflated it. This is because AZT's defenders were desperately looking for any scraps of data on which to build their case, but finding none, due to the tight control of the information released. If they had anything, even the ambiguities which must always exist in a study of this size, the story would have been changed from "AZT doesn't work" to a technical dispute among experts -- of little interest to the press. Reports of a second death of another Concorde statistician, this time in France, only increased the concern. But this death may not have happened; the rumor may only reflect an erroneous report that the UK death had occurred in France. We are aware of no evidence of foul play, and we believe it is very unlikely. But completeness requires reporting what concerns have arisen and why. A different concern is that the MRC Press Office faxed its news release to anti-AZT activists several hours before the financial markets had the news. One copy left the MRC Press Office at 15:40 on April 1, London time; the routing information added by various fax machines or computer cards traced its path, which included arrival at AIDS TREATMENT NEWS about an hour later. It was still morning in New York, yet the price of Wellcome PLC American depository receipts closed unchanged on the New York Stock Exchange that day. The issue is not financial misuse of the information -- there is no evidence of that -- but whether the MRC favored the anti- AZT view -- as was already suggested by how it restated the Lancet letter in its press release. We have been assured that there was no favoritism, that the MRC sent the same news release that afternoon to mainstream publications which respect its press embargo. We believe this is true; still, it seems unusual that news of such financial value would circulate widely in newspaper offices without the stock markets finding out. The next morning, Wellcome stock fell 12 percent in London on the strength of the same press release; it partly recovered, but had lost over $500,000,000 within a few days of the Concorde news. T-Helper Conclusion: A Statistical Artifact? The Lancet letter (in the paragraph quoted above) said that the lack of clinical benefit from early AZT, in contrast with the substantial T-helper count difference between the two treatment groups, cast doubt on using the T-helper count as a "surrogate marker" (to substitute for death or disease progression in trials) when testing new antivirals. This issue is important, because without a surrogate marker, any trial of a new AIDS treatment is likely to take years; since HIV develops slowly, it would take that long to achieve a statistically significant number of deaths or disease progressions in the comparison group, even if the new treatment worked perfectly. The press amplified the doubts; for example, the one Lancet sentence became a major article questioning surrogate markers in THE NEW YORK TIMES, April 6. The FDA's accelerated approval system is based entirely on surrogate markers (so far, only on the T-helper count), and any move away from faster testing could be disastrous for people with AIDS -- not only because of delays, but because many drugs would not be tested at all. While researchers hope for better surrogate markers soon, especially high-tech viral tests, the tests themselves may need to be validated by clinical endpoints in lengthy trials before they can be used for drug approvals (unless the tests can use frozen blood from patients whose future progression is known). But does Concorde really show what it claims to show, that there are doubts about T-helper counts? Most U.S. researchers believe that this question must be addressed by case-by-case analysis of whether individual patients whose T-helper counts rose after starting the drug seemed to show improved prognosis as a result. It is not enough to simply compare groups medians, as the Concorde preliminary analysis did. For different but related reasons, we believe, there is a strong possibility that both Concorde conclusions (that AZT does not work for early intervention, and that the T-helper count does not work as a surrogate marker) may be statistical artifacts -- illusions resulting from how the study was done, not reflecting what is happening in reality. Some of the following concerns, so far as we know, have not been raised before. The analysis below is complex, and readers who get lost can skip to the summary at the end. Concorde compared two treatment strategies for asymptomatic HIV infection: treating everyone immediately with AZT, vs. treating patients selectively. The selective group all started on placebo; later, many but not all of them began AZT for one of two very different reasons: because they reached an endpoint as defined by the protocol, or because they voluntarily switched to open-label AZT (only available for those with T-helper count under 500, and only after the protocol change of October 1989). Those switching voluntarily were still counted with the placebo group, however, under the "intent to treat" analysis rule, which groups patients according to what drug they were assigned to, not what drug they actually took. 282 of the 872 patients who started on placebo took this option and switched to AZT voluntarily without reaching an endpoint. No data has been released about who decided to switch to AZT, but we can reasonably assume that those doing poorly must have been the most likely to do so. And one little-known fact is that Concorde used its own definition of "asymptomatic," meaning that certain minor HIV-related symptoms could occur without constituting an endpoint. Patients and physicians, therefore, had actual symptoms potentially available, as well as blood work, to help them decide when they needed to choose AZT. What Concorde showed is that a selective treatment strategy could work as well, on the whole, as treating everyone with too high a dose of AZT. But notice that the mere fact that a selective strategy worked equally well as a universal one automatically guarantees the "discrepancy" that Concorde noted between T- helper count and clinical benefit -- whether or not T-helper count really works as a marker of drug effectiveness. This is because (as has long been known) AZT treatment causes median T-helper counts to rise, compared to where they would have been with no treatment, and to remain higher than they would have been for long periods. Therefore, in the group where everyone gets the AZT, the median T-helper count will rise above that of the other group -- while clinically, the two groups are equivalent by definition -- creating the "discrepancy." Basically, the patients likely to get sick within the time- frame of the study were likely to start AZT at the earliest sign of problems, creating the clinical equivalence between the selective-treatment group and the other group where everyone started with AZT. But the more stable patients, who were unlikely to contribute endpoints in any case whether treated or not, got AZT in one group and placebo in the other, creating the T-helper difference. It gets worse. The selection bias caused by the voluntary switches to AZT biased the clinical and the T-cell results differently, because patients with higher T-helper counts to begin with tend to have a higher numerical rise than those with lower counts. Clinically, the switch to AZT brought the two groups closer together, because those likely to develop endpoints moved toward similar treatment. But the same targeting meant that the patients most likely to be treated differently were the very ones likely to develop the biggest T-helper count differences as a result. The Lancet letter addressed the concern about selection bias by noting that, at three years, the group which switched voluntarily to AZT had used AZT for only 14 percent of its time on study. If AZT were helpful, then wouldn't the majority of time off the drug cause greater disease progression than in the group where everyone started with AZT and most stayed on it? We are not convinced of that, because: * The 14 percent of time spent on AZT was probably critical time, since both physicians and patients were highly motivated to notice any signs of impending trouble and start treatment then. * All the selective treatment needed to do was to push the endpoints (death or disease progression) out past the December 1992 end of the study, in order to avoid them counting as endpoint. The three-year figure, above, of 14 percent of time on AZT implies that most of those who chose to switch to AZT did so relatively late in the study (or the percentage would have been higher). AZT causes an initial boost in the T-helper count, lasting for an average of about six months, and this boost might well have been enough to hold off trouble, in many cases, until past the end of the study. Even if the earlier lack of treatment had allowed more immune damage to occur, it might not catch up with the patient until after Concorde was over. * Similarly, the benefits of early intervention may not show themselves early. A difference of 30 does not matter much is it is 500 vs. 530; but it does matter if it is 20 vs. 50. In many if not most patients, disease progression due to lack of treatment would not be expected to show itself until past the December 1992 end of the Concorde study. * The AZT dose, 250 mg four times a day, was about twice the dose now in common use. Previous studies have suggested that too high a dose not only increases toxicity, but actually reduces efficacy compared to the correct dose. This may be because side effects force more people to drop treatment entirely -- especially those with most advanced illness who may need treatment most -- or for other reasons. Whatever the reason, the excessive dose would suppress the performance of the universal-treatment group, making it easier for the selective-treatment group to equal it, than if a better dose had been used. * The table published in The Lancet does show a trend toward more early progression in the selective-treatment group, in all three T-helper count ranges reported, as the theory outlined above would predict. The selective-treatment strategy may be pushing endpoints past the study end rather than building long-term health, which recent pathogenesis work suggests might require antiviral therapy at all times. Summary It seems entirely possible (based on everything we know about Concorde, and also consistent with what we know about AIDS) that: * AZT does help in early intervention. * T-helper cell count does work as a measure of antiviral efficacy. * The Concorde selective-treatment group allowed physicians and patients, using their best clinical judgment, to provide AZT at critical times and push death and progression beyond the study's December 1992 end -- well enough to equal the outcome of the other group, which gave too much AZT to everyone. As a result, Concorde reached the wrong conclusion about the efficacy of AZT in early treatment. * Meanwhile, the universal-treatment group naturally had a higher median T-helper rise than the selective-treatment group -- due mainly to the contribution of healthier patients who were not going to produce clinical endpoints in any case. As a result -- combined with the above -- Concorde reached the wrong conclusion, also, about T-helper count not working as a marker. We are not convinced that these possibilities are true; perhaps Concorde is right. But we do believe that serious doubts exist about the accuracy of Concorde's major conclusions, and that these doubts must be resolved (by much more debate in the medical-scientific community than we have had so far) before they are widely applied to patients, or to the process of testing new treatments for HIV. The Future A number of technical meetings are being planned to clarify what we know about using AZT: * A meeting between Concorde and NIAID researchers may occur by early May. * The Berlin international conference in June should include major presentations on Concorde. * Shortly after the Berlin meeting, NIAID hopes to organize a consensus conference, including U.S. and Concorde researchers, to develop current guidelines for physicians. * The Concorde researchers want to do a "meta-analysis" of all the controlled-trial AZT data. This cannot be done adequately from the published papers alone, but requires close cooperation and sharing of the data files. These plans are encouraging. But we must also remember that AZT by itself is not an adequate treatment. AZT can be improved by use in combination with other antivirals; it may also be improved by new tests to tell which patients it is likely to help. But AZT has long received too much attention and resources, at the cost of different treatment approaches (for example, antioxidant nutrients and drugs -- a treatment possibility which deserves much more research than it has been given). Concorde will help if it encourages more exploration of new directions. It will hurt if it leads to endless debates and tinkering over AZT. References 1. Volberding PA, Lagakos SW, Koch MA, and others. Zidovudine in asymptomatic human immunodeficiency virus infection -- A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. NEW ENGLAND JOURNAL OF MEDICINE. 1990; number 332, pages 941-949. 2. Merigan TC, Amato DA, and Balsley J. Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. BLOOD. 1991; number 78, pages 900-906. 3. Cooper DA. The efficacy and safety of zidovudine therapy in early asymptomatic HIV infection. VIII International Conference on AIDS, Amsterdam, July 19-24, 1992 [abstract # PoB 3718]. 4. Aboulker, JP and Swart, AM. Preliminary analysis of the Concorde trial. THE LANCET. April 2, 1993. ***** Federal Employees: Urgent, Insurance Decision Due by April 30 Only until April 30, all civilian Federal employees located anywhere (and also employees of the local government of the District of Columbia) can obtain life insurance, or increase the policy they now have, to up to more than five times their annual salary, without medical underwriting (i.e., without a physical, regardless of their health status). If they later retire on disability, they can convert their government policy to private life insurance, again without medical questions. Those with a terminal illness can then sell their insurance, usually for 60 to 85 percent of face value, to "viatical settlement" investor firms while they are alive. Doing the right paperwork now to take advantage of benefits these employees already have (but could easily lose) can often provide $100,000 or more in cash. But after April 30, the ability to buy or increase one's Federal life insurance without a physical will go away -- and not come back again for about 10 years. The three most important things HIV-positive Federal employees need to do are: * By April 30, increase their FEGLI (Federal Employees' Group Life Insurance) coverage to the maximum: basic coverage, plus standard option, plus five additional options. * If they retire due to age or disability, unless they meet all of the technical requirements to keep FEGLI in force during retirement -- and unless their only goal is to leave the policy to a beneficiary after their death -- they must immediately convert their FEGLI coverage to an individual commercial policy; again, this is done without medical underwriting. * Learn about other critical technicalities, such as the need to stay on active service for one month after enrollment and actually work at least 32 hours in a post enrollment pay period, and the importance of making sure that certain clauses, which are now forbidden by FEGLI regulations, are not inserted into the individual policy when insurance is converted. Note: New Federal employees can buy the maximum life insurance without medical underwriting on their first duty day only, even after April 30. But most people don't think to do this. We have been assured that taking advantage of one's rights to increase insurance coverage as described above is entirely legal, as there is never any misrepresentation (such as passing a physical exam while knowingly concealing a health problem). When one has the right to obtain insurance without regard to health status, it is no crime to exercise this right if one's health happens to be poor. It is important to obtain expert advice, however, as the companies involved know all the technicalities, and they have strong incentives to find ways to exclude persons with serious health problems. Note on life insurance policies and viatical settlements (for anyone, not only Federal employees): A legal volunteer with AIDS Benefits Counselors in San Francisco suggested that, for tax reasons, it is best (if possible) to borrow from family or friends, using the insurance policy as collateral, instead of using a viatical settlement company; this way no tax is due from either party. With a viatical settlement, the Federal government is now taxing the amount received as income. Also, while viatical settlements have often worked well, there have been a few cases where people have had problems with some viatical settlement companies, for example when they assign their policy before they have the money in their hands. If the company does not pay, the insured would have to go to court to get redress. Recently, California has started to license "living benefits" (viatical settlement) companies -- the first state to do so -- which should help to prevent such abuses. Perhaps we need a communty organization to make (or to facilitate) loans on life-insurance policies, as an alternative to living-benefits companies for those who do not have family or friends who can make these loans. For more information, call Tom McCormack, Affording Care, Inc., 202/479-2543; unfortunately toll calls cannot be returned. McCormack is the author of The AIDS Benefits Handbook, published by Yale University Press, 1990; he has recently written an article detailing the paperwork to convert insurance as described above. Affording Care is a non-profit insurance advocate for the seriously ill. Another source of advice is AIDS Benefits Counselors in San Francisco, 415/558-9845. ***** 3TC: New Treatment Enters Major Trials by Larry Tate This month, two large studies will begin recruiting patients for efficacy trials of 3TC -- the latest antiviral drug in the class (called nucleoside analogs) that includes AZT, ddI, ddC, and d4T. 3TC does not represent a breakthrough, but it may be a limited advance in controlling HIV, one likely to be used in combination with other antivirals. Background In dosage and safety trials, 202 patients -- in the U.S., Canada and Europe, at varying levels of immune health -- received varying doses of 3TC. A number of patients received doses that turned out to be too low to be effective. Detailed final data from these early studies is not available. But there are a few clear points: 1. The drug, as measured by T-helper cell increases, reductions in common markers of viral activity, and some reductions in viral burden, does appear to have anti-HIV activity. In some tests, this activity appeared to be on a par with that of other drugs in this class. 2. T-helper cell increases, however, were not large and did not last very long. These increases were less than those historically seen with AZT, ddI, and d4T. There was some apparent stabilization of T-helper levels. 3. 3TC appeared to have a favorable safety profile. Such things as headache, fatigue, and diarrhea were seen, but only to the extent those symptoms are normally seen in people with fairly advanced HIV disease. At the highest dose, there was some suggestion of neutropenia (deficiency of a kind of infection-fighting white cell), but that dose was more than twice the dose to be used in upcoming trials (since higher doses showed no increase in anti-HIV activity). Probably the most important side effect that was not seen was neuropathy -- which has been associated to varying degrees with all other nucleoside analogs, especially ddI, ddC, and d4T. 4. Evidence of drug resistance was seen in some patients at doses below the ones to be used in future trials. Work is currently underway to see if there were changes in viral susceptibility at the higher doses. New Trials and Compassionate Use. Because of the limited T-helper increases, the two 3TC trials will mostly use the drug in combination with AZT. Laboratory studies have shown synergy (good interaction) between AZT and 3TC, but not between 3TC and ddI or ddC. For the same reason, the studies will last only 32 weeks. Glaxo (the manufacturer) is calling these trials "early Phase II/III," looking for evidence such as T-helper increases and antiviral activity as measured by blood tests, rather than relief or prevention of disease symptoms. Further trials may be necessary, depending on what's shown by these two. The first study (designated 3001 by Glaxo) will have 320 patients in four arms; the study will be blinded so that nobody knows who is receiving what. The different arms will test single drugs against different doses of 3TC in combination. The first arm will receive 600 mg per day of 3TC. The second will receive the standard dose of AZT. The third will receive the same dose of 3TC with AZT. The fourth will receive half as much 3TC with AZT. (In the early trials, antiviral activity was seen at this dose as well as the higher one.) Patients must have 200 to 500 T-helper cells and no history of using AZT, ddI, or ddC. The sites for this study are in: Atlanta; Beverly Hills; Boston; Chapel Hill; Charlotte; Dallas; Los Angeles; Milwaukee; New York City; Pawtucket; Santurce (Puerto Rico); Toledo; and Torrance. (For Canadian cities, see list below.) (Note: questions have been raised by community groups about the advisability of putting some people on 3TC alone, given its history of producing such short T-helper increases, but the comparative brevity of the study should largely answer those concerns.) The second study (designated 3002) will have 225 patients in three arms, and will also be blinded (except for the AZT, because all patients will receive it). The arms will test different doses of 3TC in combination against another combination. The first two arms will receive AZT with either 600 mg or 300 mg of 3TC. The third arm will receive AZT with ddC. Patients must have taken AZT for at least 24 weeks, but never have taken ddC or ddI, and have 100 to 300 T-helper cells. The sites for 3002 are: Atlanta; Boston; Dallas; Durham; East Meadow; Hershey; Houston; Los Angeles; Milwaukee; New York City; Poncho (Puerto Rico); and San Francisco. There will also be sites for both trials in Canada at Ottawa, Montreal, and Toronto. 1-800-TRIALS-A, the national clinical trials information line, will have full details. Glaxo is making special efforts to enroll women, minorities, and IV drug users, and trial sites will provide services such as child care and transportation to help toward this goal. There is no definite date, but Glaxo is also planning a compassionate use program to start when the trials are up and running. It will be for people with fewer than 100 T-helper cells who have failed on, or are intolerant to, the other nucleoside analogs. The company has no clear idea how many people will meet its criteria, but does not envision a large expanded-access program, because of the early stage of development of the drug. Additionally, a dose-escalating safety study of 3TC is continuing in Los Angeles and Bethesda, Maryland, for children up to 17 years old, with a larger efficacy trial to follow at some undetermined point. The compassionate-use program will also cover pediatric cases. It's also worth noting that 3TC has shown activity against the hepatitis-B virus (HBV), and is being, or soon will be, tested for that use in both Europe and the U.S. People co- infected with HIV and HBV might have an extra reason for considering 3TC trials. Comment While nobody can get very excited about another nucleoside analog, and possibly not a very powerful one at that, 3TC does have some advantages. The main one is its apparent lack of side effects, unprecedented among drugs of this class. And, like other nucleosides, 3TC is backed by a large company with the resources to develop it quickly and move it toward approval (which could come late next year); it benefits from the FDA's familiarity with this class of drugs and willingness to license them. Also, the synergy with AZT is encouraging, as AZT is the other nucleoside least associated with neuropathy. AZT plus 3TC may finally offer a workable combination for many people who use other combinations because of this condition. ***** Announcements ** International News Service Now Available AIDS TREATMENT NEWS is now publishing a quarterly international news service for AIDS service organizations and other newsletters. We began the news service after receiving several requests from organizations in developing countries for basic treatment information that could be distributed to people with AIDS. The articles have been edited to reduce the amount of medical terminology usually present in our regular editions. The material is not copyrighted and reproduction is encouraged. The news service is part of a collaborative project with the International Gay & Lesbian Human Rights Commission (IGLHRC). We are forming partnerships with PWA and community-based organizations in Mexico, Brazil, Chili, Kenya, India , Maylasia and the Philippines so that each organization can translate and distribute the information to best serve their communities. Tax-deductible donations can be made to IGLHRC to help fund this project. The first edition of the news service includes an article on antiviral therapy (a backgrounder for those who know little about AZT, ddI, or ddC), as well as reprints from the regular edition of AIDS TREATMENT NEWS on nutrition, Yohimbine (a traditional treatment used for fatigue) and the International Conference on AIDS in Africa. In later editions we hope to utilize articles from other treatment newsletters as well as AIDS TREATMENT NEWS. The quarterly news service is available for $25 a year. AIDS organizations in developing countries that cannot afford a subscription are asked to write to us to request the service free. To subscribe send a check for $25 to AIDS TREATMENT NEWS Service, P.O. Box 411256, San Francisco, CA 94141. ** California Funding: AIDS Lobby Day May 10 The third annual AIDS Budget Lobby Day will take place Monday, May 10th, from 10:30 to 4:00, at the State Capitol in Sacramento. It will include briefings, a rally, and appointments or drop-in visits with one's legislators and their staffs. Persons who can go are asked to register by Friday, April 30, so that appointments can be scheduled. The Lobby Day is organized by the AIDS Budget Coalition, consisting of AIDS Project Los Angeles, AIDS Service Providers Association, California Association of AIDS Agencies, LIFE AIDS Lobby, Planned Parenthood Affiliates of California, Sacramento AIDS Foundation, San Francisco AIDS Foundation, and San Francisco Interreligious Coalition on AIDS. To register, or for more information, call 415/864-5855 x 2537. ***** 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 415/255-4659 fax Editor and Publisher: John S. James Medical Reporters: Jason Heyman John S. James Nancy Solomon 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 1993 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.