Date: 20 Nov 94 15:46 PST Subject: AIDS TREATMENT NEWS #211 Errors-To: aidsnews@igc.apc.org Lines: 909 AIDS TREATMENT NEWS Issue #211, November 18,1994 phone 800/TREAT-1-2, or 415/255-0588 Contents: Strategy of Hope: Small, Rapid Viral-Load Trials Viral Load, Small Trials, and Immune Recovery Nevirapine Triple Combination: Preliminary Results Released November 17 Hydroxyurea -- Call for Information The Elections: What AIDS Organizations Need to Do Now. Interview with Tom Sheridan, Sheridan Associates AIDS TREATMENT NEWS Talent Search: Board Members for Charitable, Internet Work ***** Strategy of Hope: Small, Rapid Viral-Load Trials by John S. James There is more despair in the AIDS community now than probably ever before. The bad news -- often misreported, misinterpreted, and misunderstood -- is heard again and again, and reaches the minds of people everywhere. Medical and scientific presentations are largely empty of important good news, and people sense that little is happening in AIDS treatment development. We do not share the pessimism, because there are also excellent opportunities to move forward, given the will and the organization to do so. The potential good news is largely unreported in the media, and missing in the ongoing public conversation which largely determines peoples' views. But new developments are starting to save lives now, and could save many more lives in the near future. How many lives will depend on whether people pay attention, understand what is happening, and effectively support its development. Recently AIDS TREATMENT NEWS has published a series of articles with a common focus: developing certain emerging opportunities into a strategy for moving forward, a strategy we can apply today, a strategy which will pay off now and in the near future, as well as the distant future. This is our tenth article this year in this series; for a list of the earlier ones, see below. Last week, at the New Directions in Antiviral Chemotherapy conference (November 10-12 in San Francisco), both the despair and the grounds for hope were evident. After Friday's sessions, what stood out most was the lack of new information. Earlier that day, while one of the speakers droned on, a prominent physician in the audience commented to us that the leading researchers (with most of the medical profession following) were going to continue treating AIDS like hepatitis, and continue to accept the death of all of their patients. But those who showed up early Saturday morning heard Douglas Richman, M.D., one of the leading AIDS researchers, in an aside from his talk on antiviral drug resistance, cite studies from around the world showing that, "In a two-week study, you can show whether a drug works or doesn't work, and you can do a dose-response curve. Now it doesn't tell you what's going to be a useful drug, because it's a chronic disease, so it doesn't tell you what's going to happen long term... In terms of being a useful drug, we need longer studies. But in phase I studies to ascertain whether you've got a drug that works or not, you only need a two-week study." (For more of this transcript, see "Viral Load, Small Trials, and Immune Recovery," below.) What is important in Dr. Richman's talk is: * The concept of small, rapid trials to look for antiviral activity in people; * Evidence that if viral load, as measured by plasma HIV RNA, could be kept down, the immune system could recover spontaneously (see transcript below); and * The rapidly increasing momentum these ideas are getting in the professional community. The ideas are not new. But Dr. Richman's discussion -- a 5- minute aside in a longer talk on resistance to antiviral drugs -- brings together strong evidence in their favor, a coherent interpretation of the evidence, and a clear path for moving forward. Some other researchers have shown a mental split on this issue. On one hand, they say it is unproven that reducing the plasma HIV RNA and keeping it down will benefit the patient, that this must be proven by prospective studies (which in practice will take years to design, conduct, analyze, and publish). But on the other hand, the same people can be seen to be basing their own thoughts and plans on the working assumption that lowering this viral load is the central goal. Many researchers do agree that trials to learn how to lower the HIV RNA is what we should be doing now -- although everyone also knows that we also need more studies on what this marker means for clinical practice. And pharmaceutical companies, which bet money on drug-development strategies, are now including HIV RNA in almost all their trials of new antivirals, providing de facto acceptance of viral load measurement in early human trials to screen new drugs. But in Dr. Richman's talk, as in almost all talks by professional researchers, the only drugs mentioned are those being developed by pharmaceutical companies. If these were the best candidate drugs -- if pharmaceutical companies were efficient in selecting what to develop -- then this limitation might not make much difference. But the industry's selection process is not efficient, because it only looks in certain places; it only considers drugs where the company has, or can readily acquire, exclusive proprietary rights. Usually this means new chemicals, which will take years to develop because they have to go through laboratory testing, animal tests in different species, pharmacodynamic tests in people, phase I dosage tests in people, etc., all the time with many committees and reviews. Another problem is that it usually takes so long to build management and financial momentum for a new product idea, that years are likely to pass between the time a few scientists realize that a new approach is important, and the time that management decides to go ahead and develop an innovative drug. And during this time the data, and often even the existence of the project, are generally secret. This means that innovations are routinely delayed for years, for no scientific or medical reason -- not only delaying the drug in question, but often impeding other projects which could benefit from the information. Industry is usually fixated on getting individual proprietary drugs through the FDA -- which is only part of the job of giving doctors the tools they need to be effective. Meanwhile, natural products, traditional medicines used in cultures around the world, and readily available prescription drugs approved for other uses and often long off patent, are not considered as potential HIV treatments, even when there are excellent reasons to study them. Yet if any one of these were found to be useful in treating HIV disease, that finding would have great public-health importance, since these drugs are readily available, usually inexpensive, and well known in human use. Basic information on dosage, risks, precautions, etc. is already there; the financing of a major development project, the convincing of management, the laboratory and animal tests, etc. are not necessary. There are seldom any supply or manufacturing issues, nor need to fight with companies or the FDA over expanded-access programs. What is needed instead is (1) to find out if there is scientific evidence that an available drug shows antiviral or other potentially beneficial activity in people, and if so, (2) to learn how to use the treatment most effectively -- for example, learning which patients may benefit, what doses are best for HIV treatment, and what additional safety precautions may be required for persons with HIV. While this work is proceeding, the drug can also be tried as an element in combinations, which can include existing approved HIV treatments, experimental drugs under development, and other already-available drugs which have shown promise. The first test for scientific rationale may look for reduction in HIV RNA; or other tests could measure markers of immune function, for example. These other tests may be equally important; we have emphasized HIV RNA because it has several advantages at this time. It has a central rationale in HIV disease, since it directly measures the amount of virus in the blood -- which also appears to be a good indicator of the activity (although not the amount) of the virus in lymph nodes and throughout the body. Tests for HIV RNA have been well standardized, and are known to be highly reproducible from sample to sample; also, early data on average day-to-day variation in patients has been published. The test is commercially available, meaning that researchers and physicians can order it when they need it, instead of spending months in negotiations or years in assay development and standardization, which is often necessary for research tests. Overcoming Drug Resistance HIV resistance to antiviral drugs is a major and growing problem. The conventional approach to overcoming resistance is to combine drugs, either targeted against the same viral protein (for example, AZT plus ddI plus a non-nucleoside reverse transcriptase inhibitor such as nevirapine), or against different proteins (for example, AZT combined with a protease inhibitor). This approach is important, but it is too early to know how successful it will be. There is another approach which may be more successful in overcoming resistance, but which unfortunately is largely being ignored. This is to combine drugs like AZT or protease inhibitors, with different kinds of drugs which inhibit HIV without targeting viral proteins at all. There are many different kinds of such potential drugs, many different mechanism of action. Here are four of them: * Immune-based therapies. An ideal treatment would be a way to restore the body's ability to keep HIV under control. This is because the immune system can control HIV much better than any known drug. Eventually, in most people, it loses this ability, for reasons which are unknown, but which are probably related to some injury to the immune system caused by the virus -- an injury which appears to be reversible, at least in large part, if the virus can be stopped (see "Viral Load, Small Trials, and Immune Recovery," below). If we knew specifically what caused this loss of immune function, it would probably be possible to intervene pharmaceutically, creating a new HIV treatment entirely separate from antiviral drugs -- which could still be used in addition, if necessary. * Hydroxyurea, etc. Another approach is to reduce the level of substances which HIV needs, but which are produced by human cells, not by the virus. Viruses always rely on many substances which they cannot produce themselves. Of course it is necessary to find a drug which can inhibit the virus without harming the human cells, which often need the same substances. But once such a drug is found, it will probably be difficult for the virus to work around it, as there is no viral protein which is being directly targeted and can evade the drug through mutations. One such drug now in the news is hydroxyurea, which has been used for decades in treating certain cancers (see "Hydroxyurea -- Call for Information," below.) In laboratory tests, it greatly inhibits HIV at concentrations which are easily achievable in the blood. Laboratory tests also indicate that it might work especially well when combined with ddI. So far only a handful of people have tried hydroxyurea as a treatment for HIV, apparently with quite promising results; because of safety concerns, however, most physicians understandably want trials to be run first, before they prescribe the drug for their patients. But, in a tragedy which would also be a scandal if it were not so common, no trials have been run (except for a small study recently started in France), despite great efforts by researchers to get a trial going. The problem seems to be that the clinical- research system is built around the assumption that drugs will be developed by well-financed pharmaceutical companies; and in this case, no company has an incentive, since the drug is off patent. The critical need is for the first, small study, to get credible data which will provide momentum for further research, as well as data about safety and side effects in persons with HIV. Such a trial would not need to be very expensive. But neither government nor private research organizations have succeeded in getting a study going, and activists have not followed the situation or raised an alarm about the lack of research. * LTR inhibitors. A third approach is to reduce viral activation of the LTR (long terminal repeat) of HIV, which acts as a master switch which makes the virus more active. AIDS TREATMENT NEWS has reported on this mechanism of action, which has been largely ignored in conventional drug development. Some treatments which work this way will probably be susceptible to HIV drug resistance, but might still be useful in combinations with other classes of drugs. Other approaches, less susceptible to resistance, may slow HIV progression by reducing abnormally high levels of certain substances, such as TNF (tumor necrosis factor), which are naturally present in the body and known to stimulate HIV. * It appears to be possible to slow HIV progression by aggressive diagnosis and treatment, suppression, or prophylaxis of certain opportunistic infections, which may stimulate HIV. If it is true that continuous acyclovir use can extend average survival in persons with AIDS, as some evidence suggests, it may be working indirectly by suppressing certain herpes viruses which may activate HIV. Drug Mechanism of Action, and Viral Load With small, rapid trials, many leads can be followed up quickly, and new combinations can be rapidly developed. Whenever a treatment does look promising, the trials set up to test it should, of course, be followed indefinitely. The first challenge is to reduce the viral load; but the most difficult challenge will be to keep it down. Testing for viral load (usually by measuring plasma HIV RNA, which is the most feasible viral-load test today) is clearly useful for trials of antivirals which directly target viral proteins; in this case, we know what to expect if the drug works (see "Viral Load, Small Trials, and Immune Recovery," below). It now seems clear that hydroxyurea greatly reduces the level of HIV RNA in people, so the same test should be able to measure its activity -- although less is known about this drug, since no trials have been done. For drugs with other mechanisms of action, however, viral load tests will need to be used with care, sometimes in an exploratory mode where researchers are looking to see what happens, rather than trying to confirm or deny a pre-existing hypothesis. For example, an immune-based therapy may reduce viral load indirectly, by helping the body control the virus. But at first, certain immune-based therapies may actually increase viral load temporarily, by causing immune stimulation which can activate HIV. There might also be treatments which reduce the damage that HIV causes to cells, but do not reduce the level of virus. In this case the treatment could be beneficial, even if nothing at all is seen on the viral-load tests. Or consider the case of acyclovir, which does not have any direct effect against HIV. If this drug does improve average survival of persons with late-stage HIV disease -- and the evidence which suggests it does is controversial -- it is probably doing that by suppressing other viruses which activate HIV. If so, then it is possible that some patients might be getting a large benefit, while others who do not have those viruses might be getting none at all. Viral-load and other blood tests could be used to explore this hypothesis. For example, a controlled trial could assign one group of patients to use acyclovir continuously, while others used it only when necessary for suppression of herpes; the latter group would have HIV viral load measured whenever a herpes recurrence occurred but before acyclovir treatment was started, and then have repeated viral-load measurements while the acyclovir treatment continued. Such a trial might help researchers understand the mechanism of action (if any) of acyclovir in improving AIDS survival, and perhaps make it possible to identify groups of patients most likely to benefit. Some Drugs to Test One cause of the prevailing pessimism about AIDS treatments is the sense that there are no drugs to test. So we started a list of candidate drugs which are already in use in people, and have some rationale suggesting that they should be tested for possible use in treatment of HIV disease. The list of 27 potential treatments below is just a beginning. We only included drugs, nutrients, etc. which are already in human use for other purposes. And we only included the drugs which came to mind in the last two weeks; we have not yet done literature searches, nor talked to experts in micronutrients, or in Chinese or other systems of traditional medicine, etc. As we do these things, the list below will certainly grow longer. (Also, this list only includes potential treatments for HIV disease, not for opportunistic infections.) Note that most of these drugs are not antivirals; in some cases, the mechanism of action, if any, is unknown. For such drugs, results of viral load and other tests will have to be interpreted especially carefully. We will add to this list in the future. You can help by suggesting other treatments which should be considered. For this particular list, we are interested in treatments which are already in human use for some purpose, so that they can be tested quickly for possible use in HIV, without the need to go through animal studies, etc. Also, we have not included drugs which are already in major development projects, since in that case the testing which we are proposing is already being done. Note that this is a list of research possibilities, not treatment options. Some of these drugs can be quite dangerous; and while there is a rationale for further research, the evidence in hand showing actual benefit to patients is usually slim to non-existent. We were reluctant to publish the list, at least without first completing the library and phone-interview research on each of the drugs, to gather the information which is already known. But that process would take months or years, and by then there would be new drugs to list anyway. So we expect to keep an ongoing list of drugs needing research as possible treatments for HIV disease, and publish it from time to time. We hope this will encourage public interest and advocacy, to get the necessary research done. If even one of these 27 drugs is found to be useful in HIV treatment, that finding would be immensely important. (Our guess is that several will be found useful -- if the studies are done.) Initial list of drugs already in human use which need small, rapid trials to look for possible activity as HIV treatments (in alphabetical order): Acyclovir (indirect effect); aspirin; cimetidine; co-enzyme Q; curcumin; DHEA; doxycycline; DNCB; glycyrrhizin; HCG; hydroxyurea; hypericin; isoprinosine; NAC; papaverine; pentoxifylline; peptide T; ranitidine; ribavirin; sulfasalazine; thalidomide; thymomodulin, etc.; topotecan; tricyclic antidepresants; vitamin B6; vitamin C; warfarin. Strategy of Hope: Previous Articles in AIDS TREATMENT NEWS Our most important previous articles on the AIDS treatment development strategy discussed here are: * Research Strategy Proposal: High-Tech Exploitation of the Unexpected, issue #190, January 7, 1994; * Antivirals and Immune Recovery: Interview with Michael S. Saag, M.D., issue #200, June 3, 1994; * AIDS Research Strategy: Rapid, Small Trials for Promising Treatment Leads, issue #201, June 17, 1994; * HIV RNA: New Blood Test for Individualized Therapy and Faster Trials, issue #204, August 5, 1994; * AIDS Pathogenesis: New Understanding, issue #206, September 2, 1994; * Why AIDS Drug Development Has Failed, issue #206, September 2, 1994; * "Surrogate Markers": Current Status, Future Directions (Part I), issue #209, October 21, 1994; * Maternal Transmission and Viral Load, issue #209, October 21, 1994; and * HIV RNA -- Time to Wake Up and Save Lives, issue #210, November 4, 1994.] ***** Viral Load, Small Trials, and Immune Recovery The following is our transcript of a section of a talk by Douglas D. Richman, M.D., on viral resistance, given November 12, 1994 at the recent New Directions in Antiviral Chemotherapy conference in San Francisco. This presentation is important because it cites studies from many researchers which strongly support the feasibility of small, very rapid trials to screen drugs and combinations to find out which ones have initial antiviral effect in humans, and to learn the doses required. Such trials do not prove that a treatment is useful, since it may stop working later; but they can rapidly and flexibly provide a rational basis for planning further research. This talk also makes the point that lowering viral load, as measured by HIV RNA count in blood plasma, is likely to result in immune-system recovery, even without special therapies for immune reconstitution. This information changes the outlook for AIDS research, creating opportunities for much faster progress. Note: We were unable to run this transcript by Dr. Richman, as he was out of the country as we went to press. To avoid changing his meaning inadvertently, we did not edit the oral presentation for readers who do not have access to the slides he was using. As a result, the following text is sometimes difficult to follow. Dr. Richman: "Shifting gears a bit, this is a point almost related to pathogenesis, something that Mike Saag brought up yesterday. These are two patients given nevirapine, and almost like a PK [pharmacokinetic] study looked at daily plasma HIV RNA levels. Here's a person with 8,000, and here's a person with 35,000, at baseline; at 24 hours after the administration of drug, no change here, slight change here. 48, 72 hours, an incredible drop; basically by day four or five, everything that the drug is going to do has been done. The same sorts of data have been shown by Clive Loveday in London with AZT, and Charles Boucher in Amsterdam with 3TC, and David Ho with protease inhibitors, also; the same phenomenon is occurring with all of the antiretroviral drugs. "There are two major take-home lessons that I think are very important about this. One is, as Mike mentioned yesterday, the turnover rates, the half-lives here, even if you assume that the drug is inhibiting replication 100 percent, which is a worst-case phenomenon, probably unlikely, the half-life here is 24 hours, or even less. So that these ten to the five levels of plasma RNA that we're seeing, those hundred thousand copies, weren't there yesterday; those are today's virus. The implication is that, with this high turnover, if you can stop the production, you significantly down-shift what's going on. "And in terms of pathogenesis, a similar phenomenon has been shown; the very nice data with the Abbott compound that David Ho showed in Atlanta, that unfortunately we didn't get to see yesterday, showed that with more potent drugs, as with the Merck protease inhibitor and the Abbott compound, this same phenomenon occurs, but you get two and three log drops, instead of a one or one and a half log drop. And in association with drops of that magnitude, instead of getting 75 or 100 [T-helper] cell rises, they were seeing two, three, four, five hundred CD4 cell rises, in a couple of weeks. The implications of that are (and I think somewhat different from the Ashley Haas model that Mike was talking about) -- my perception is that there's a stem-cell population, CD34 cell population, that is producing CD4 cells; and if you can arrest the replication, the high turnover rate of new cells will reconstitute the immune system. The implications of that are that immune reconstitution is not necessary if you can block virus production. That also means that the stem cell population isn't being infected -- and there are other studies showing that the CD34 cell population is not CD4 positive, is not susceptible to the virus. And that's good news, we have a stem-cell population that is not infected. If it were, I would argue that this wouldn't be a chronic disease. "There's one other implication of all of this. And that is, with all of these drugs we're seeing the same kinetics. That means that in a two-week study, you can show whether a drug works or doesn't work, and you can do a dose-response curve. Now it doesn't tell you what's going to be a useful drug, because it's a chronic disease, so it doesn't tell you what's going to happen long term. And this virus -- and we're doing studies with Scott Eastman, to do the allele-specific characteristics of this virus -- we've shown in seven days a drug resistant virus emerging. So that this is going to be resistant virus, this is sensitive virus. So in terms of being a useful drug, we need longer studies. But in phase I studies to ascertain whether you've got a drug that works or not, you only need a two-week study; and there is a protease inhibitor that we've just finished evaluating in which the decision to stop the development of the drug was based on two-week studies, and 48 patients who had plasma RNA levels, sequentially, not one of them had more than a three-fold variation. So that with a half-log change, you only need [few] patients and if you have half-log changes, that's different than you're going to see in the natural course over a short period of time in the patients." Note: The audio tape of Dr. Richman's talk, "Antiviral Drug Resistance: Genetic and Phenotypic Mechanism -- Clinical Significance," is available from J. Schimmel Associates, 10251 Granada Lane, Shawnee Mission, Kansas 66207, 913/649- 5743; ask for tape #94-14 from the New Directions in Antiviral Chemotherapy conference. The price is $10, which includes shipping. You can also get a list of the 16 audio tapes available from the conference; while few of the talks have new information, they do have useful reviews on a number of topics, including combination therapy, early intervention, delavirdine, nevirapine, the Abbott and Merck protease inhibitors, cytokine therapy for HIV, gene therapy for HIV, treatment for CMV, and treatment for hepatitis.] ***** Nevirapine Triple Combination: Preliminary Results Released Nov. 17 by John S. James In early 1993 there was great excitement about the "convergent combination" approach to antiviral treatment. This theory holds that there may be limits to how much a virus can mutate and still be able to reproduce, and therefore there might be certain drug combinations, targeted against THE SAME viral protein, which could stop the virus permanently by preventing the development of resistance. (Traditional combination therapy seeks drugs which target DIFFERENT steps in the life cycle of the virus, bacterium, etc.) It turned out that some of the early data supporting the convergent combination approach was in part the result of laboratory error; but even so, the idea remained worth testing. (AIDS TREATMENT NEWS covered these developments in issue #170, March 5, 1993, and issue #181, August 20, 1993.) A clinical trial was quickly organized, and it began in May 1993; it was fully enrolled by July. The trial lasted 48 weeks, then data analysis began, and a preliminary report was released this week. Much more analysis is still to be done, however, and some of the more interesting results may come later. This study enrolled a total of 398 subjects. They had T- helper counts less than or equal to 350; the median count at entry was 138. All had at least six months of prior treatment with AZT, ddI, or ddC; the median prior treatment was 25 months. These volunteers were randomly assigned to either receive AZT plus ddI, or AZT plus ddI plus nevirapine, an experimental HIV treatment. All three drugs target the reverse transcriptase enzyme of HIV; when used alone, nevirapine has a very strong anti-HIV effect at first, but then the effect diminishes as the virus develops resistance to the drug. At 48 weeks, the main preliminary results were: * T-helper counts were 25 percent higher for patients assigned to the triple combination, compared to those assigned to AZT plus ddI. * The infectivity of PBMCs (peripheral blood mononuclear cells) was lowered by 50 percent more in the triple combination arm than in the AZT plus ddI control arm. [Note: viral measures were only done on a subset of 198 of the 398 subjects.] * HIV RNA showed a significant difference in favor of the triple combination at first, but according to the November 17 executive summary, the difference was not statistically significant at 48 weeks. [However, after the executive summary was finalized, it was learned that the reason the PBMC virology but not HIV RNA virology remained statistically significant at 48 weeks may have been because of the different ways these numbers were collected and analyzed.] * There was no indication of a survival or disease- progression benefit. Seventeen percent of those on triple combination died or experienced HIV disease progression (as defined by the study), vs. 14 percent of those on AZT plus ddI. This difference, which was not statistically significant, was in the wrong direction. While the study was not designed to detect clinical benefit in death or disease progression, and did not have enough patients to do so reliably, still it seems unlikely, in view of these results, that there is any substantial clinical benefit of the triple combination. * There were more side effects from the triple combination. The biggest difference between the groups was in skin rash, with severe rashes affecting 8 percent of those on triple combination, vs. two percent of those on AZT plus ddI. The overall rate of severe adverse reactions was high: for signs and symptoms, 30 percent on triple combination vs. 24 percent on the two-drug combination; for hematology and chemistry abnormalities, 30 percent on triple combination vs. 26 percent in the AZT plus ddI control arm. These overall rates were not significantly different between the arms. This study collected important data, and there is much more to be learned from it. For example, it is possible that certain subsets of patients may have responded differently to the treatments -- those with less advanced disease, for example, or those who began the study with or without AZT- resistant or ddI-resistant viruses. Comment This study is likely to be cited to argue that viral load and other blood tests cannot be trusted to tell what drugs are working. We think it is too early to draw that conclusion. The viral load differences appear to be marginal; with plasma HIV RNA, whether the difference is even statistically significant at 48 weeks seems to depend on how you look at the data -- and usually it is easy to get statistical significance using this measure, even with far fewer patients, provided that there is any substantial effect to measure. Also, it is likely that many patients had AZT- resistant viruses before they started, so they were never effectively on a triple combination; and nevirapine resistance can develop quite rapidly. If the side effects of this drug balanced a relatively minor virological benefit, then the difference between clinical progression and viral- load changes could easily be explained -- with no need to postulate that viral load does not show drug benefit. Further study of the existing data may help to explain what was actually going on in this trial. The main lesson we draw from this example is that we need more flexible research strategies, with many small trials which can be designed and run rapidly, to quickly check out promising leads which suggest the possibility of big gains in viral-load reductions, in measures of immune health, or in other indicators of activity. Then the larger, confirmatory trials could be better focused, because they would be based on data from human experience, not just on laboratory studies. ***** Hydroxyurea: Call for Information by John S. James Hydroxyurea is a prescription drug which has been used for about 30 years in treating certain cancers, and for a few other diseases. Theory suggests that hydroxyurea might be active against HIV, and that if it is, the virus would be unlikely to develop resistance to it. Laboratory results at the U.S. National Cancer Institute were promising enough that Robert Gallo, M.D., explained this work at his major talk at the Ninth International Conference on AIDS in Berlin, in June 1993; AIDS TREATMENT NEWS covered his presentation in issue #178, July 9, 1993. Earlier this month researchers at the NCI published a detailed report of their laboratory findings with this drug (Franco Lori, M.D., and others, "Hydroxyurea as an Inhibitor of Human Immunodeficiency Virus--Type 1 Replication," Science, November 4, 1994, pages 801-805). THE NEW YORK TIMES interviewed Dr. Lori and published an article on November 8. The published articles are based only on laboratory studies; almost nothing has been done in the last year and a half to follow up the laboratory work with a clinical trial. A small trial has been approved by the FDA but not started because of lack of funding; another small trial has started in France. AIDS TREATMENT NEWS is now trying to find out about clinical experience with hydroxyurea as an anti-HIV treatment. So far we have detailed reports of only two patients, both of whom had large drops in viral load; we have heard indirectly about others. Physicians have been reluctant to prescribe the drug, which can cause serious but reversible suppression of the white blood count, until trials have studied its safety and activity in persons with HIV. If you know of anyone we should talk to about effects of hydroxyurea in HIV disease, let us know immediately at 800/873-2812. We hope to get this article into the next issue, which goes to press on November 29. ***** The Elections: What AIDS Organizations Need to Do Now. Interview with Tom Sheridan, Sheridan Associates by John S. James The November elections created a difficult and dangerous time for those working for an effective U.S. response to AIDS. To look at what should be done now, AIDS TREATMENT NEWS interviewed Tom Sheridan, a professional lobbyist, AIDS organizer, and founder of The Sheridan Group, a government and public-relations organization in Washington. ATN: In view of the elections, what should those concerned about AIDS do now? Sheridan: Organize, organize, organize. I mean three very specific things. First, we must organize internally. We must make sure that our programs are well run; the people we represent are well served; that the work we do is very much in the public interest. Sometimes we forget, on the front lines, that we have to justify our work to the general public. Second, grassroots organizing is a very effective way to combat Congressional complacency and to win over reluctant allies. Some politicians would like to put a "special interest" label on AIDS, and we can't let that happen. Some of them are not disposed to be our friends. But we have to approach these politicians and convince them, in whatever way necessary, that AIDS care, prevention, and research are important to this country, to their states and districts, and that AIDS should be a priority. In the early AIDS movement, we did grassroots organizing very well. More recently, we have been less successful. If ACT UP was our early grassroots organization, we can point to it as a source of effective action. Now we are facing an entirely new strategy, and a whole new level of grassroots organizing. We need to mature and develop a certain political savvy -- to hold members of congress accountable -- and it is vital that we do it now. For too long, our movement has looked like a brownie pan -- wide, but not too deep. Grassroots organizing can provide that depth and assure accountability. The third level of organizing is political -- we must communicate with those new members of Congress. We must find out who the new players are and which old players have new positions. We need to figure out how much money it will take to support our friends and challenge our enemies We need to have a very aggressive political agenda, but we have to develop that capacity. You can't watch people like Dan Hamburg lose his election for lack of money, and that's why he lost it; he didn't have the money he needed to beat a right-wing opponent. AIDS advocates need to think about retooling our resource pool, and have real political resources available for friends, and some resources to fight our enemies. We must avoid the politics of division; there are Republican friends who will need our support, and our work, to keep our agenda moving forward: people like Connie Morella, Steve Gunderson, Mark Hatfield, Arlen Specter, John Porter. These are people who have been supportive, who will be in important positions; we need to work with them. Look at Orrin Hatch on Ryan White; he was our original cosponsor, with Ted Kennedy, and remains the program's enthusiastic champion. These will be difficult days, no doubt about it. Some of our biggest enemies are now in positions of great power; and we have very little structural barricades to fight against them. Jesse Helms has opportunity now that he's never had before. The Clinton Administration is going to be very hard-pressed to make sure that they keep a focus and a priority on AIDS, and not to let it go in the face of other things. The Administration is our safe harbor; we will need a lot of extremely tough work with them. One of our biggest losses concerns our institutional base of staff support. Will key people be able to retain their jobs in the Senate and the House, and therefore retain our history in that institution? They are so important to everything we do, they have institutionally carried us through almost every fight we have had. ATN: Aside from the consequences of the elections, what else must we watch out for? Sheridan: We need to join ranks and avoid being caught up in competitive -- zero-sum gain -- discussions on AIDS priorities. I am troubled by potential off-sets in the ACTG (AIDS Clinical Trials Group) program to get better bench science. If we need better bench science we must advocate for it, not transfer it from other program areas. I believe we may face our first full-scale debates on AIDS funding vs. other funding areas. Our solidarity is our survival. ATN: What is the bottom line for the AIDS community? On those three levels of organizing we should get immediately to work. There is a certain discipline that is required. We cannot compete against each other, at a program level or at a community level or at a national level -- research at the expense of care, or care at the expense of prevention. First, those are completely ridiculous constructions; and second, we will get killed politically if we put ourselves into that position. If there is any good news, sometimes a common crisis can pull people together. This community hasn't been together in some years. ***** AIDS TREATMENT NEWS Talent Search: Board Members for Charitable, Internet Work by John S. James AIDS TREATMENT NEWS is starting a new, nonprofit organization to expand our free work in providing AIDS treatment information to underserved communities. This will include more subscriptions for anyone in need, as well as support to organizations serving specific communities including minorities, women, prisoners, the geographically isolated, and the economically disadvantaged. We will use the Internet and other computer communication for low-cost delivery of targeted, practical information to service organizations, and to individuals This will be a fundraising, working board; however, no computer or treatment expertise is required, nor is it necessary to live in the Bay Area, as we expect to conduct most meetings by telephone. If you know someone who would be an ideal candidate to help us support this project, you could help by suggesting that they call John S. James at AIDS TREATMENT NEWS, 415/255-6259. ***** 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: 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.