[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 8 no. 6 Gay Men's Health Crisis: Treatment Issues > House Cuts AIDS Research Budget >> Pat Moynihan and AIDS >> Act Now to Protect AIDS Research Funds > An interview with Dr. William Paul > AIDS Drug Interactions: Part I > Treatment Briefs by David Gold >> Sulfasalazine Studied as HIV Treatment >> Large Vaccine Trials Rejected >> d4T Approved by FDA >> Long-Term Asymptomatics >> Tim McCarron Leaves TI ============================== ============================== House Cuts AIDS Research Budget by Derek Hodel An appropriations subcommittee of the House of Representatives recommended a paltry increase of $40.5 million (3.1 percent) for AIDS research in fiscal year 1995 (FY95). This represents a significant reduction from President Clinton's proposed increase of $78 million and is a full percentage point below the biomedical research inflation rate. However, activists were relieved when the subcommittee (the House Appropriations Subcommittee on Labor, Health and Human Services and Related Agencies) rebuffed Republican efforts to unravel the consolidated appropriation for AIDS research, one of the hard-won gains of the National Institutes of Health (NIH) Revitalization Act of 1993. The act vastly enhanced the authority of the Office of AIDS Research (OAR) at the Institutes and combined the various AIDS research budgets into a single item coordinated by the Office. Now the bill must travel to the Senate, where as usual in Washington, anything could happen. Cut in President's AIDS Research Budget The battle for AIDS dollars began in February with President Clinton's budget, which requested substantially more money than anyone had to spend. For AIDS, Clinton's package included two investments: a $78 million increase (six percent) for AIDS research at NIH and a $93 million increase (sixteen percent) for the Ryan White CARE Act. For AIDS prevention programs at the Centers for Disease Control and Prevention, the President apparently decided that the investment was not worth it, and requested no increase in spending at all. President Clinton's proposed six percent increase in AIDS research - tiny compared to last year's big $227 million (21 percent) increase - was set against a backdrop of flat funding for virtually every other program at NIH, save breast cancer and certain high-performance computing projects. Though less so than last year, it was another budget that, by virtue of inadequate support for other critical programs, pitted AIDS against other diseases. (The American Heart Association took the opportunity to exploit the numbers to their fullest advantage, pointing out that vastly more research dollars per death are spent for AIDS than for heart disease, while failing to examine the average age at which people die or the horrific worldwide AIDS projections over the next decade.) To make matters worse, during the debate the Administration surreptitiously shopped around some alternate numbers, suggesting to House subcommittee members that the President could live with a little less than he had requested publicly. The silently spoken numbers included reductions in spending for NIH ($189 million, distributed across all programs, including AIDS), Ryan White ($12 million) and AIDS prevention ($11 million - amounting to a 2 percent reduction in current spending). The tactic, saying one thing publicly while presenting a different picture behind closed doors, is a Washington standard but ultimately went nowhere. The subcommittee declared that they would have nothing to do with the revised request and would interpret the President's original request as planned. And interpret they did. For both AIDS research and Ryan White programs, the subcommittee recommended increases amounting to only half of what the President requested: research received a $40.5 million (3.1 percent) increase and Ryan White a $46.6 million (eight percent) increase. The subcommittee made clear its intention to treat the AIDS program as it would any of the individual institutes at the NIH. The three percent boost meted out to AIDS research was applied across the board to all the NIH institutes. In spite of the disappointing AIDS research and Ryan White numbers, Nancy Pelosi (D-CA), a staunch community ally, pulled off a brilliant organizing campaign among friendly subcommittee members that led to a veritable bonanza for AIDS prevention funding. Pelosi scored by assembling a $163 million Public Health Service prevention package that featured a substantial addition for HIV prevention (a $63 million, or 11.6 percent, increase), as well as enough other pet programs to consolidate the support of six subcommittee members - enough to convince the new appropriations subcommittee chair, Neal Smith, to adopt the proposal as his own. The fate of AIDS appropriations for FY95 now lies in the hands of the Senate. At this writing, the Senate Labor, Health and Human Service and Education Subcommittee is scheduled to report on the budget as early as July 14, although this date strikes many Capitol Hill veterans as a decidedly optimistic schedule. Congress is supposed to wrap up the entire budget by the end of this fiscal year, September 30. We'll see. Consolidated OAR Budget Saved The news about the rather bleak numbers for AIDS research was offset by the President's request for a consolidated appropriation for all AIDS research at NIH, consistent with the NIH Revitalization Act. The single line account would be the first time in years that the entire AIDS research portfolio was appropriated in a unified fashion ($1.378 billion with the President's increase). AIDS advocates believe such a mechanism is critical to the ability of OAR to reshape the overall AIDS research program. Some subcommittee members opposed the President's request following substantial agitation from subcommittee staff director Mike Stephens, who declared the consolidation was not "required by law." Stephens' objections to the consolidated appropriation surprised and infuriated AIDS advocates, who had been under the impression that the long fight was over when the President signed the Revitalization Act in June of 1993. The AIDS advocates were not the only ones who were surprised. The congresspeople responsible for writing the legislation were also under the impression that the consolidated appropriation was a done deal, and said so in a letter to subcommittee chair Neal Smith. John Dingell (D-MI) and Henry Waxman (D-CA), chairs of the House Energy and Commerce Committee and the Subcommittee on Health and the Environment, respectively, notified Smith that they would oppose any effort to reconsider the consolidated budget question via an appropriations bill, and urged the subcommittee to appropriate the money as requested. Meanwhile, Stephens maintained that the consolidation would set an undesirable precedent (a "that's not the way we do things around here" approach), would make AIDS research funding more vulnerable to attack ("years from now, you'll thank me," a variation on the it's-for-your-own-good theme), and would open the floodgates for a variety of disease-lobbyists from Alzheimer's Disease to Breast Cancer, each demanding their own consolidated appropriation at NIH. AIDS advocates, led by the AIDS Action Council, began immediate lobbying efforts, for once with the assistance of the administration. An impressive array of scientists were corralled to defend the OAR and its new director, William E. Paul, M.D. A letter-writing campaign (organized by a coalition that included Nobel-laureate David Baltimore as well as noted researchers Barry Bloom, Bernard Fields, David Ho and Arnold Levine) attracted almost 200 scientific signatures. The debate finally turned a corner when NIH Director Harold Varmus weighed in with a powerful letter to the subcommittee. The opposition, under the direction of John Porter (R-IL), still refused to budge. Even after Porter, an ardent, longtime NIH supporter, met personally with Bill Paul, he continued to make it a priority to undo the consolidation. Ultimately, though, Porter remained silent at the subcommittee's final hearing, choosing instead to battle about vocational/technical schools and the national vaccine strategy. (Porter also tried unsuccessfully to increase NIH spending overall by swiping money from drug treatment programs, among others.) And Now the Senate Many believe that it is possible to get the Senate appropriations subcommittee to increase the amount allocated for overall NIH research and for AIDS research in particular. Individuals and organizations are urged to write to Senator Tom Harkin (D-IA), the chairman of the Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies. If you reside in a state whose Senator sits on the subcommittee, please contact that Senator without delay (see box for a list of these Senators and a sample letter). Your telephone calls or letters could mean that more desperately needed funds are allocated for AIDS research. >Derek Hodel is the treatment and research director at the AIDS Action Council, a Washington based lobbying organization representing nearly 1,000 Community based AIDS organizations nationwide. In July, Derek joins GMHC as Director of Federal Affairs.< Pat Moynihan and AIDS ===================== Senator Patrick Moynihan (D-NY) is chairman of the Senate Finance Committee and one of the most powerful members of the U.S. Senate. As the senior senator from New York, he represents a state with over twenty percent of all AIDS cases in the U.S. By 1998, over 100,000 of Senator Moynihan's constituents will be dead from AIDS. Although Senator Moynihan has a respectable voting record on AIDS issues, most observers agree that he has not taken the initiative in advocating for more effective AIDS policies. Jeff Levi, former lobbyist for the AIDS Action Council, said "Senator Moynihan has not shown any leadership on AIDS - which is doubly tragic since he represents the epicenter of the U.S. epidemic and has one of the most influential positions in the Senate." Other AIDS advocates complain that it is difficult even to schedule a meeting with the Senator. Brian Connolly, press spokesman for Senator Moynihan, told Treatment Issues that the Senator supports increased funding for AIDS research and that he will be speaking to Senator Harkin, the chairman of the Appropriations Subcommittee personally about the issue. Readers from New York State may want to call Senator Moynihan's office at 202/224-4451 (ask for Chief of Staff Lawrence O'Donnell) or fax 202/228-3827. Let the Senator know that you are a New York State resident and that you expect him to use his considerable influence to restore the AIDS research funds cut in the House and to promote biomedical research at the NIH. Senator Moynihan is running for re-election this year. The Democratic primary will be held on September 13, 1994 and the general election is November 8, 1994. New Yorkers may want to call the Moynihan campaign office to say that their vote will depend on how the candidates respond to the AIDS issue. The number is 212/684-1994. Ask for Bill Cunningham, the campaign manager. -- David Gold ============================== ============================== Act Now to Protect AIDS Research Funds The Senate Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies could finalize (or "mark up") its budget bill as early as July 14, 1994. Your telephone calls or letters might make a world of difference, particularly if you live in any of the following states since members of Congress are much more responsive to their own constituents: Tom Harkin (IA) 202/224-3254 (phone); 202/224-9369 (fax) Robert C. Byrd (WV) 202/224-3954 (phone); 202/224-8070 (fax) Ernest F. Hollings (SC) 202/224-6121 (phone); 202/224-4293 (fax) Daniel K. Inouye (HI) 202/224-3934 (phone); 202/224-6747 (fax) Dale Bumpers (AR) 202/224-4843 (phone); 202/224-6435 (fax) Harry Reid (NV) 202/224-3542 (phone); 202/224-7327 (fax) Herb Kohl (WI) 202/224-5653 (phone); 202/224-9787 (fax) Patty Murray (WA) 202/224-2621 (phone); 202/224-0238 (fax) Arlen Spector (PA) 202/224-4254 (phone); 202/224-1893 (fax) Mark O. Hatfield (OR) 202/224-3753 (phone); 202/224-0276 (fax) Ted Stevens (AK) 202/224-3004 (phone); 202/224-2354 (fax) Thad Cochran (MS) 202/224-5054 (phone); 202/224-9450 (fax) Slade Gorton (WA) 202/224-3441 (phone); 202/224-9393 (fax) Connie Mack (FL) 202/224-5274 (phone); 202/224-8022 (fax) Christopher (Kit) Bond MO 202/224-5721 (phone); 202/224-8149 (fax) Address Senator's mail as follows: The Honorable (Name of Senator) United States Senate Washington, D.C. 20510 Write, phone or fax your Senator and also Appropriations Subcommittee Chairman Tom Harkin (see model letter below for both): The Honorable Tom Harkin, Chairman Senate Appropriations Subcommittee on Labor, Health and Human Services, and Related Agencies SD-186 Dirksen Senate Office Building Washington, D.C. 20510 Dear Senator Harkin, I strongly urge you to increase funding for the NIH, and for AIDS research in particular. We cannot afford to let NIH funding drop below the level of inflation. At minimum, it is critical that all NIH programs, including AIDS research, receive an increase of at least 4.1 percent. In addition, I strongly support the President's request for a consolidated appropriation for AIDS research, a critical component of the NIH Revitalization Act of 1993. Thank you for your support for AIDS research. Sincerely, (Your Name) -DH ============================== ============================== An interview with Dr. William Paul Dr. William Paul is the Director of the Office of AIDS Research (OAR) at the National Institutes of Health (NIH). On June 15, 1994, Dave Gilden and David Gold of Treatment Issues interviewed Dr. Paul at the NIH campus in Bethesda, MD. Dr. Paul was appointed OAR Director earlier this year after Congress passed legislation greatly enhancing the power of the OAR. He is considered to be a world-class immunologist and has spent his entire scientific career at the NIH. In interviews and public appearances, Dr. Paul does not dazzle his listeners with soaring visions. He has great - perhaps too much - confidence in the traditional model of investigator-initiated research and in the overall quality of work at the NIH. Yet, there does appear to be a sense of decency and commitment in Dr. Paul which, one hopes, will serve him well in this critically important position. Treatment Issues (TI): For the benefit of our readers, how much is the NIH investing on therapeutic research for AIDS? Dr. William Paul: I don't have the exact numbers in front of me. Let me answer it this way. Of the five large areas, therapeutic research is the largest single component, probably in excess of 40 percent of the budget. Vaccine research is probably not more than ten percent. There is also a substantial portfolio in the study of etiology, or pathogenesis, which we would hope would feed into both vaccine and therapeutic research. TI: From what you've been able to tell so far, are the taxpayers getting their money's worth? Paul: Let me put it differently. Ours is a very large enterprise, and I would hesitate to say that I yet understand it with the detail that really is required. As soon as our staff is in place we want to begin a process in which we take big chunks of the program, and set in motion an evaluation process - not consisting of me, but bringing in the experts. Getting a serious report. How are we doing? Are we well- organized? Are we spending our money well? The clinical trials program is probably our first target. TI: When do you expect to have evaluation committees set up? PAUL: I hesitate to say specifically. We're right now recruiting senior staff. The key to that process is in this case the person who would be our expert in therapeutics. It will take three or four years to do everything, because it's got to be an institutionalized process. I want to put in motion a sensible program for review that is continually on- going. TI: Why do you think there hasn't been such a process already? PAUL: That's a very good point and I can't answer that definitively. I would probably respond in the following way. During the period of rapid growth, we were just struggling to find mechanisms to deal with spending the money well - the development of the Division of AIDS for example, from virtually nothing to a very substantial enterprise. One doesn't stop in the beginning, when you're developing a program, to think about the review and quality control. The OAR restructuring gives more of an opportunity to commission reviews that might be somewhat removed from the group that's actually operating the program. TI: Who is responsible for making sure that the directors of AIDS research programs at NIH are doing their job properly and attracting quality researchers and managers? PAUL: That responsibility would have to be shared between the leadership of each NIH Institute and OAR. TI: So you're not going to be responsible for hiring or directing of individual AIDS research programs at the Institutes? PAUL: No. The role of the OAR is not to replace the institutes. The OAR is always going to be a small organization. The goal is not to create another bureaucracy. All you would do is install on top of everything yet another step, yet another hoop that everyone has to jump through. TI: So what actual decisions will you be making at OAR? PAUL: My job is to decide where we're going to put the money. To make the plan and to put it forward. Once we've got a process that works, I don't think I should march in and make all the decisions. TI: Are you satisfied with the amount of authority you have? PAUL: I don't think it's good for one person to have all of the authority, [but] ask me in a year when I've had a chance to explore. TI: How many people work in the OAR? PAUL: Very few right now. We're in the process of trying to recruit a staff. We hope to make the announcements soon, but we will never be a big office. TI: Some claim that the NIH is a huge bureaucracy where it is not easy to make changes, replace people not up to speed, or act decisively. How do you respond? PAUL: The bulk of research done is not at NIH. Only about fourteen percent of funds are for research done on campus - and it's very good research - but this is a national enterprise. And when you're supervising $1.37 billion of AIDS research it's got to be a substantial enterprise. The ability to act decisively really depends on the amount of money you're getting. For example, many people had hoped that OAR would do things that are different, more effective or more creative. And we want very much to do that. But that can only be achieved if there are funds available. The way the Office is set up, we have a responsibility or authority only over those funds not in the commitment base [grants and contracts awarded in previous years that have to be honored]. Now, if in any given year, the increase to the NIH is relatively modest, then the amount of money the OAR has authority over, becomes very small. The available money becomes even smaller since even things not in the commitment base have to be continued at some level. For example, in 1996, the AIDS Clinical Trials Group (ACTG) is up for recompetition [renewal]. Whether you think that's well run or badly runÉjust because it's up for recompetition, doesn't mean we can take that money and do something completely different with it. We have a responsibility to see that there is a functioning, useful, clinical trial mechanism. Clearly, if new monies are small, the ability of any leader of this Office to reconfigure - if one wanted to do that - AIDS research in a new direction is very limited. TI: Would there be other ways to organize AIDS research? Do you see a usefulness in putting together all the AIDS researchers so that the person, in say, your position, could hire and set up his or her own program. PAUL: You mean having the equivalent of an AIDS Institute? TI: Yes. Right now, outside of OAR, you don't have any direct say in the hiring of the people who are going to be implementing the strategic plan your office is creating. PAUL: Creating a single AIDS Institute means creating a redundancy for the kinds of talents you need. In the allergy [and infectious diseases] institute, they really have first- rate people in infectious disease and immunology. In mental health, they have mental health experts. We would have to recreate all of those things in OAR. We'd basically be creating a mini NIH, and I am not sure that would be efficient. Even if you thought that this was a reasonable method of organization, I'm not sure whether it would be wise to junk the working organization to start again. It would cost time, money, and would be cumbersome. My view is that this system can work. Whether we would have created it this way if we were starting from ground zero is an interesting question, but I can't see a lot of justification for not adhering to the current mechanisms. TI: Do you think there's a problem already in that AIDS experts are too insular and aren't in communication with people in other fields - virology, immunology, or people who study other diseases? PAUL: That would be a big disadvantage of an AIDS Institute because you would enforce such insularity. The fundamental lessons we have learned about how viruses replicate are often being learned in the study of other viruses, not necessarily in the study of HIV. They should be available to those working on HIV. TI: The House appropriations subcommittee voted on the NIH budget yesterday and AIDS research received an increase of just $40 million dollars. (See accompanying article by Derek Hodel.) Before, you said if the increase is modest in a given year, you have very little authority to do anything new because all the money is already committed. Is that true for next year? PAUL: It would be a problem for fiscal year '95 (FY95) which was prepared six months before I was appointed. [But] I'll have some role in trying to adjust what we get, if we get less than what we asked for. The OAR will distribute those adjustments across the Institutes' boundaries, as efficiently as we can. Most of our energies so far have been in planning the FY96 budget, which we've already submitted to the Assistant Secretary [of Health]. TI: What would you like to do if you had the funds? PAUL: We've got to more aggressively support investigator- initiated research. With a modest increase this is really going to be hard to do. There are certain kinds of areas that we need to spend money on. In understanding this disease and developing new molecular targets, we've really been at a serious deficiency because we don't have any models to study. The Macaque monkey model [with simian immunodeficiency virus], is better than it's been given credit for, but it hasn't been used as effectively as it might, and part of that is because the resources aren't available to do it. Unfortunately, with the FY95 numbers we see, the new grants we fund are going to be substantially less than FY94 and the success rates will go down. I regard that as a very serious problem. New ideas are going to come more from [independent] investigators than from people here at NIH who say, "Well, how about putting out an RFA [request for applications - a more directed type of research] in a given area?" We'd like to use RFAs as sparingly as we can. There are certain things for which they are important, but in most areas, money should be used in ways that allow the bright investigator to come forward with a new idea. TI: What are your impressions of the proposals coming out of Project Inform's Future Directions for AIDS Research conferences? PAUL: I went to the meeting in Madison, and I think the notion of focusing scientific attention is a very valid one. The concept of saying, "Let's identify all the questions and when we have answered all the questions, we'll be that much closer to understanding the disease" has merit. But it implies you know the questions. Unfortunately, what often happens when you say, "Let's put all the questions on the blackboard" and then say, "Let's design experiments to solve all the questions" is, you usually don't know the right questions to put on the blackboard. So, I'm a little nervous about a very focused effort to develop a research agenda based on such an approach, because it removes the essential element of asking the new question that hasn't been asked before. Phrasing the question is almost invariably the critical step in advancing science. I'm not enthusiastic about trying to change the basic organizational structure of the research enterprise because such a [focused or directed] structure is not well-suited to gain completely new kinds of knowledge. TI: Are there any central questions where a more directed effort would have value? PAUL: Well, there are directed research efforts. For example, the whole RFA mechanism is, in effect, a directed research effort. That is, you identify something and say, "I'm going to ask for ten applications to solve this question." That's what a request for applications is. Once it's clear that an issue is important, it really doesn't need this kind of approach. At that stage, you've built the scientific momentum, and what works is going to go on. What you need is the wisdom to recognize early that something is likely to be very important and invest in it. That's very important to do, but it's a very risky business because you may guess quite wrongly on many things. You run the risk of wasting large sums of money by over-structuring a process. TI: What are the practical effects of Bernard Fields' article in Nature and the discussions about basic research versus clinical research and what deserves priority right now? PAUL: Dr. Fields' article outlines his view that unless we reinvest in the fundamental research, we're not going to solve the problem of AIDS. What he didn't stress - [although] I think he aimed to make this point - is that there needs to be a balance. We've got to invest both in an effort to find new agents now, and also go back to understanding basic mechanisms [of HIV and the immune system's response to the virus]. My responsibility in the OAR is to recognize there's got to be a balance, although there's a lot of merit to what Dr. Fields said. I'm very sensitive to his argument, but I can't move too far in his direction without running the risk of not adequately supporting the drug discovery program and the drug development program. TI: Can the drug discovery program be made more efficient? PAUL: More likely, I suspect, it's the drug testing [clinical trials] program where inefficiencies can be found. It could almost certainly be managed in a better way. I'm hopeful that we will achieve equal effectiveness at a lower cost. TI: What are your thoughts on the quality of AIDS clinical trials programs at NIH? PAUL: I would still reserve judgment. I want to conduct an in-depth review -. TI: When will that be completed? PAUL: I really haven't constructed a time table yet. We might start the process in the fall and a serious review means we're not likely to get a good answer until the spring [1995]. TI: Some suggest that the ACTG, in terms of antiviral research, is inefficient, fails to undertake cutting edge studies, and is run by an insular group who basically approve each other's trials without any sense of accountability. Is this the case and if so, who is responsible? PAUL: We're going to have a recompetition in 1996 [where we look] at the quality of work at the individual ACTG sites. [In terms of] the overall quality of the whole ACTG enterprise the responsibility for management and quality does lie with the NIH. TI: Who in particular and where does the buck stop? PAUL: I'm not certain who specifically oversees the clinical trials program. I would have to examine the set upÉ Dr. Killen [Jack Killen, Director of the Division of AIDS at NIAID], Dr. Fauci [Director of NIAID] and I. We all bear responsibility. None of us should be able to escape responsibility if it's being badly done and we should all get a little credit if it's well done. If we've set up a bad system we all deserve to be held to its consequences. TI: Many drug companies don't want anything to do with the ACTG system. It's been frustrating to see the NIH not operate effectively in encouraging pharmaceutical companies to conduct specific types of HIV-related research. Do you have any plans in this area?. PAUL: The place to look for this is in the Drug Discovery Task Force [a joint government-industry-community committee organized by the Assistant Secretary for Health]. One of the key questions they have to grapple with is the notion that drug companies identify agents and decide that they're not really interested in pursuing them even though they may have merit. Or that no one wants to tackle a particular topic even though it looks meritorious. Is this real? And if so, what can we do to respond to it? TI: There's a couple of concerns that people have about you. Almost everyone agrees that you're a person of impeccable scientific credentials, but some, including Dr. David Baltimore [a leading researcher at Rockefeller University], suggest that while you're a nice "grandfather type," we need a more vocal and visible leader. How do you respond to that? PAUL: I agree with the view that the leadership of this office has a responsibility to set a tone and to provide statements. I also believe, however, that our chance to have real effectiveness is our ability to guide where the money goes. If we don't have that ability, we can talk all we like. There are a lot of people who want to give leadership, but leadership is linked to our influence on the budget. If this budget grows at a very modest rate, then what we have to control is very little. And in the end, our ability to be effective is linked directly to the amount of money we can control. We will be passionate, useful leaders when we're in the position to see where the money goes. This enterprise should be judged on what it achieves, rather than on what the appearance is. TI: Another concern people have is that you don't have specific AIDS experience and that you haven't had experience running a large research program with all its politics. PAUL: On the first point, I agree entirely. I know a lot of immunology, and I have a pretty good understanding of the etiologic aspects of the disease, although not as sophisticated as those who've worked on it for a long time. I have learned an enormous amount already and hope to learn a great deal more. But it's a fair criticism of my appointment that I wasn't deeply involved in the disease. [But] some regard that as a virtue. As for the second issue: We are not managing a large research enterprise in the sense that this is a big administrative job. I don't have and will never have, 300 people working for me. Congress decided that's not what they wanted the OAR to do. So I don't think that's a fair criticism. It is reasonable to ask how are my skills in dealing with the political problems because much of the effectiveness of this job will lie in the ability to solve those problems. To the extent that we can get better budgets and help deal with certain things - that's a reasonable way to judge the performance here. TI: Do you think you're up to that? PAUL: I hope so. I'm working pretty hard. You'll have to judge whether I am successful or not. But it looks as if the single appropriation [the unified budget for NIH AIDS research - again, see accompanying article by Derek Hodel] has emerged intact. We worked very hard on that. We're not as happy with the magnitude of the appropriation. We want to do better. We know these are difficult times for NIH and for the appropriations subcommittee. They're limited in the funds they have available. But there are a lot of opportunities that we may miss with a very modest budget. TI: Two years from now, how should we judge whether you've been successful? PAUL: I'd like to see a budget process in place which puts the money in the areas with the greatest promise. I would like to see some effective drugs on the table, but honestly, if they are on the table in two years, they are probably in the pipeline now. We know how long it takes. We want progress in helping people who are infected and preventing people from becoming infected. In the end that is the only serious bottom line we have. Now can you judge my performance without that? I don't know. Outcomes are really what counts. TI: From your background as an immunologist, how far are we from making progress in reconstituting the immune system? PAUL: We still have a lot of work to do. We haven't applied full contemporary immunology here. We need to recruit people with the greatest skills in contemporary immunology who are outside the field [of AIDS]. We need to move them into the field. TI: How do we do that? PAUL: Make it attractive for them. Point out that this is an important and interesting area of study, that there's a possibility of making real contributions and that there's a chance you're going to get funded. We need the money to support this work. TI: Is it possible, from what you know of the immune system, to think that effective antivirals alone can make HIV into a so called "chronic, manageable condition?" PAUL: It might depend on the stage of disease and viral burden at the time you begin therapy. But if we had agents that fundamentally could prevent the virus from replicating we could limit the burden enormously. I would be very optimistic about this. Even in autoimmune diseases, in some of the models of multiple sclerosis, you can interrupt that process in a variety of ways. If we could get terrifically good antivirals and limit HIV replication enormously, I would be very hopeful. Now if someone has no CD4 cells, I don't know what would be the outcome. Even there, if you could limit viral replication, it still may be quite possible to repopulate the immune system from your own bone marrow. There's enormous repopulation potential from stem cells in the bone marrow. So my own view would not be so pessimistic as to that. TI: What's been your greatest frustration on the job? PAUL: The number of budgets I have to write. There is an enormous amount of effort expended on coping with the inevitable governmental problems. They're important, but they divert you from what you'd really like to accomplish. I hope that as we get a staff, those things take up less of my time. TI: Finally, are you committed to continuing at OAR indefinitely? PAUL: I'm not certain about that. As you pointed out, there is a lot of power in this position. To put a certain person in this job over a long period of time runs a risk. To serve too short a time means you don't know what your doing. Bringing in new people with new ideas is always going to be valuable and I'm not prepared to abandon being a working scientist. ============================== ============================== AIDS Drug Interactions: Part I by Gabriel Torres, M.D. People with HIV commonly take several medications at the same time to fight both HIV and its related conditions. These drugs can interact with each other, leading to more toxic side effects and reduced effectiveness. Some drug-drug interactions are related to the way drugs are absorbed by the gastrointestinal system. Absorption is highly dependent on stomach acidity and the rate of absorption, which may be affected by bouts of diarrhea. Drugs that are not absorbed well will not achieve sufficient levels in the blood to exert their effect. This can also happen if a coincident therapy increases or decreases the excretion or metabolism of the first drug. Drugs with similar toxic effects, such as bone marrow suppression (myelosuppression), will usually result in combined toxicity. This can preclude taking both drugs together. We will focus below on the most common drug-drug interactions. Readers can concentrate on the sections of greatest personal interest. Remember that there are thousands of other potential interactions that may or not be important for patients with HIV infections. In this issue we cover interactions among antiretroviral drugs and drugs for PCP and fungal infections. Next month: drug interactions for toxoplasmosis, TB, MAC and CMV medications. Antiretroviral Drugs 1. AZT (zidovudine, Retrovir): AZT's antiretroviral effects vary according to the levels achieved in the blood. Drugs that decrease AZT concentrations may result in a suboptimal antiretroviral effect. Insufficient viral inhibition and lack of a CD4 response may be a sign of this problem. Examples of drugs that lower AZT levels include rifabutin and clarithromycin, the two most common agents used for MAC prevention. Other drugs may increase the amount of AZT in the blood. This reinforces AZT's suppression of bone marrow. The usual result is increased hematologic toxicity, i.e. such effects in the blood as anemia (low red blood cell counts) and neutropenia (low numbers of neutrophils, a type of infection-fighting white blood). Examples of drugs that increase AZT levels are Bactrim, fluconazole and probenecid. Drugs with similar hematologic toxicity as AZT have to be used with caution, since if given together, they may lead to enhanced anemia or neutropenia. These drugs include ganciclovir, Bactrim, interferon, dapsone, sulfadiazine, pyrimethamine, pentamidine, flucytosine, and chemotherapies such as doxorubicin. The combination of AZT and ganciclovir in particular is poorly tolerated due to the combined hematologic toxicity. In one study of patients receiving ganciclovir for CMV disease, 82 percent of those also treated with AZT developed hematologic side effects (anemia and neutropenia), which ranged from severe to life-threatening.[1] 2. ddI: Didanosine (Videx): ddI is another antiretroviral drug, which is used as a second-line agent for those who are intolerant to or failing AZT, or who have been on prolonged AZT therapy, where the drug may have lost its effect. ddI has the disadvantage that to be absorbed, it requires a buffer to counteract the stomach's acidity. Conditions or drugs that increase stomach acidity will lead to decreased absorption and lower blood levels. Substances that boost gastric acidity include acidulin, citrus juices and Coca-Cola. The converse is also true: drugs that decrease gastric acidity will increase ddI's absorption and blood levels and heighten the risk of pancreatic damage (pancreatitis), neuropathy and other ddI side effects. Examples of drugs that lower gastric acidity are Tagamet, Pepcid, Zantac, Axid and Prilosec as well as antacids like Maalox, Mylanta, Tums, Rolaids and Riopan. In addition, alcohol and oral ganciclovir both make ddI- associated pancreatitis more likely. Other drugs that make ddI-associated neuropathy more likely include vincristine, vinblastine, ddC, d4T, alcohol, Flagyl, INH and dapsone. The buffer that ddI comes mixed with can have negative effects on those drugs needing stomach acid for their absorption. These include: dapsone, ketoconazole, tetracyclines, ciprofloxacin, and ofloxacin. The lowered blood levels of these antibiotics will erase their therapeutic effect. The present recommendation is to schedule these antibiotics at least two hours before ddI. 3. ddC (zalcitabine, Hivid): ddC has relatively few drug-drug interactions, though it should not be given with other drugs that induce peripheral neuropathy. The risk of developing painful neuropathy is increased if ddC is taken at the same time as medications like ddI, vincristine, Flagyl and, to a lesser extent, INH and dapsone. The risk of pancreatitis with ddC is less than one percent, yet caution is still recommended when administering it in the presence of other pancreatitis- inducing drugs and alcohol. 4. d4T (stavudine, Zerit): d4T, like ddI and ddC, causes peripheral neuropathy and (less commonly) pancreatitis. Physicians should monitor the drug- drug interactions with the agents mentioned above that contribute to these conditions. Drugs for PCP 1. Bactrim and Septra (trimethoprim-sulfamethoxazole combination, or TMP/SMX): This commonly used combination of antibiotics for the prevention and treatment of PCP has a variety of interactions and toxicities that need to be monitored. The most common side effect associated with the sulfa component is a skin rash, which is usually allergic in nature. It is also known that the drug can greaten the skin's sensitivity to ultraviolet light, and so excessive exposure to the sun should be avoided while taking the drug. Common drugs that have been reported to interact with TMP/SMX's liver effects include Coumadin (an anticoagulant) and Dilantin (an anticonvulsant). Elevated potassium levels sometimes also occur when on TMP/SMX. High potassium may lead to abnormal heart rhythms and contractions. In the presence of kidney disease, TMP/SMX can accumulate and cause greater toxicity. Kidney-toxic drugs (e.g., amphotericin, foscarnet and aminoglycoside antibiotics (amikacin, gentamicin, paromomycin, streptomycin, etc.) pose a special problem for people taking TMP/SMX, as does potassium supplementation. Finally, TMP/SMX increases the effect of the anticonvulsant Dilantin by inhibiting the liver's ability to break down the drug. 2. Pentamidine: Pentamidine is another drug for treating and preventing PCP. It is known to have many side effects, including low blood sugar, pancreatitis, low blood pressure, neutropenia, and elevation of liver enzyme and potassium levels in the blood. Generally it is felt that pentamidine should be dispensed with caution if given with other drugs that can damage the kidneys (for a list, see previous section). In addition, other substances that cause pancreatic damage, e.g. ddI, alcohol and rifampin, may also be dangerous if taken concurrently with pentamidine. 3. Dapsone: Dapsone is commonly used for PCP prophylaxis in sulfa- intolerant persons. It is known to interact with various drugs, including trimethoprim, rifampin, and probenecid. Rifampin can lower dapsone blood levels seven to ten fold, which can lead to subtherapeutic concentrations and breakthrough cases of PCP.[2] Some practitioners recommend taking higher doses of dapsone (100 mg per day) if the patient will receive rifampin or rifabutin at the same time. The combination of dapsone and trimethoprim raises the blood levels of both drugs and may produce excess toxicity by either compound. In one study, 30 percent of patients receiving trimethoprim with dapsone had to discontinue therapy because of toxic effects, whereas none of those receiving dapsone alone had to discontinue.[3] As mentioned earlier, stomach acid is necessary for dapsone's absorption. Drugs such as ddI, antacids, Tagamet, Zantac and Pepcid should not be administered concurrently. Metroka reported several cases of breakthrough PCP related to malabsorption of dapsone when taken along with ddI.[4] The present recommendation is to take dapsone two hours before ddI to avoid the drug-drug interaction and allow for full ddI absorption. 4. Clindamycin: The most common side effect of clindamycin is diarrhea, so other drugs that also cause diarrhea probably should be avoided. Overgrowth of a bacterium called Clostridium difficile is responsible for the diarrhea during clindamycin therapy. Clostridium infection can lead to a condition called pseudomembranous colitis, characterized by abdominal pain, blood diarrhea, fever and dehydration. Clostridium requires direct treatment with oral vancomycin or Flagyl. Use of any agent that just slows intestinal motility may prolong or worsen pseudomembranous colitis by delaying elimination of the toxin made by the bacteria. Furthermore, use of antidiarrheal agents that contain kaolin or attapulgite (Kaopectate) may decrease the absorption of clindamycin, leading to subtherapeutic effects. Erythromycin also interacts with clindamycin, by interfering with its mechanism of action against bacteria. 4. Atovaquone (Mepron): This recently licensed oral drug is indicated for treatment of mild to moderate cases of PCP as well as for salvage treatment of toxoplasmosis. Its absorption is highly dependent on ingesting it with food, especially fatty food, which increases atovaquone's absorption four or five fold. Atovaquone is known to have many drug-drug interactions, some of which result in synergistic or additive effects against the toxoplasma parasite. It is known to be synergistic with rifabutin, pyrimethamine, clarithromycin and azithromycin against this parasite. Clinical trials of this combination are under way at present. In contrast, atovaquone should be used with caution along with rifampin and fluconazole since they can lower atovaquone blood levels. Atovaquone itself can lower AZT blood levels, though the clinical significance of this reduction remains unknown. Antifungal drugs 1. Fluconazole: Fluconazole has many drug-drug interactions with a wide variety of agents, including those frequently taken concurrently by people with HIV. Some of the most common examples are as follows: a. Rifampin has been shown to decrease the half-life of fluconazole. Physicians may need to increase the usual dosage of fluconazole when they administer the two together. b. Fluconazole may increase the blood levels of Dilantin, resulting in greater toxic effects from this drug. The Dilantin dose may need adjustment when this drug is given with fluconazole. c. Levels of drugs used to control blood sugar are increased when given with fluconazole. Using fluconazole in conjunction with such drugs as tolbutamide, chlorpropamide, glyburide and gipizide can result in hypoglycemia (low blood sugar). d. The metabolism of the common anticoagulant Coumadin is decreased by fluconazole so that taking both drugs together may prolong Coumadin's effect. e. Blood levels of various drugs (rifabutin, AZT, Dilantin and cyclosporine) may increase when taken along with fluconazole. This may exacerbate their side effects. 2. Ketoconazole: This antifungal drug requires stomach acidity for absorption, and, here too, drugs that lower acidity will result in markedly lower ketoconazole blood levels. Ketoconazole also may alter the blood levels of either Dilantin or fluconazole, and taking these drugs together is not recommended. Taking the antihistamines Seldane and Hismanal along with ketoconazole is also not recommended. The outcome can be cardiac toxicity and arrythmias. 3. Amphotericin: Amphotericin is well known for its broad toxicity, which includes kidney damage, low blood potassium and anemia. Synthetic penicillins such as carbenicillin or ticarcillin may further reduce potassium levels when given with amphotericin. Medications that affect kidney function, such as foscarnet, aminoglycoside antibiotics and pentamidine, should be prescribed to patients on amphotericin with extreme caution. 1 Hochster H. et al. Annals of Internal Medicine. 1990; 113(2):111-7. 2 Physicians' Desk Reference. Medical Economics Data Productions Company, Montvale NJ. 1994; 48:1319. 3 Lee BL, et al. Annals of Internal Medicine. 1989; 110(8):606-11. 4 Metroka C, et al. New England Journal of Medicine. 1991; 325(10):737. ============================== ============================== Treatment Briefs by David Gold Sulfasalazine Studied as HIV Treatment Researchers from Cabrini Medical Center in New York City report that four HIV-positive patients given sulfasalazine (SFSZ) had substantial increases in CD4 counts (Journal of Rheumatology 1994; 21:662-664). SFSZ is an approved treatment for a number of autoimmune diseases including rheumatoid arthritis. The four patients were all treated for Reiter's syndrome, an inflammatory joint disease that has been associated with HIV infection. After treatment for the syndrome, doctors noticed that mean CD4 cells increased in the patient group from 315 to 542. CD4/CD8 ratios did not change except in one patient, in whom it doubled. No antiretroviral treatment was used in three of four patients. The effect of SFSZ on viral load was not measured. Although no side effects were reported, SFSZ can be suppressive to bone marrow. With the results from this very small, unblinded study, the researchers are currently working with a manufacturer to develop a larger trial of SFSZ in people with HIV. Large Vaccine Trials Rejected An AIDS advisory committee at the National Institute of Allergy and Infectious Diseases (NIAID) recommended on June 17, against going ahead with large, phase III efficacy trials of two anti-HIV preventive vaccines. The two vaccines consisted solely of the HIV envelope protein gp120. The panel pointed to the $40 million cost for testing the products in 10,000 volunteers and the small likelihood that the vaccines would protect against HIV infection. Dr. Anthony Fauci, the director of NIAID, accepted the recommendation to cancel the proposed trials, calling it a "no brainer." In April, another NIAID panel appointed by Dr. Fauci - the HIV Vaccine Working Group - urged NIAID to go ahead with large gp120 vaccine trials stating that "the scientific rationale supports advancing and expanding clinical trials to evaluate this hypothesis further" (NIAID press release, April 29, 1994). In May, Dr. Fauci outlined a plan for a large "prevention trial" in which some participants would be given gp120 vaccinations. Activists generally viewed the large trials as an expensive waste of money with very little chance that the gp120 products would successfully prevent HIV infection. Don Francis of Genentech (one of the manufacturers of the gp120 products) and major figure in And the Band Played On seemed a bit peeved at the decision not to go ahead, stating that "this is a sad day. It's about deciding how many people you want to sentence to death before *getting on with the business of vaccination*." [emphasis added]. NIAID officials have so far identified thirteen participants in HIV vaccine trials (mostly of the gp120 products) who have become infected with HIV. d4T Approved by FDA The Food and Drug Administration has cleared the anti-HIV drug d4T (brand name: Zerit) for marketing less than a month after its Antiviral Advisory Committee gave the drug a general nod of approval [see last month's Treatment Issues]. d4T is a nucleoside analog similar in structure to AZT. It received formal approval for use in people with advanced HIV disease who are intolerant to other approved therapies, have experienced significant clinical or immunological deterioration while receiving these therapies or for whom such therapies are contraindicated. The recommended dose is 40 mg twice a day. According to Bristol-Myers Squibb, the manufacturer of d4T as well as ddI, the drug will be in pharmacies by mid-July. Its wholesale cost amounts to $6.22 per day. This is about 15 percent less than the cost of AZT. Long-Term Asymptomatics Researchers in Amsterdam followed 61 HIV-positive men who remained asymptomatic for at least seven years and compared them with 142 men who progressed to AIDS (Journal of Infectious Diseases 1994; 169:1236-43). Long-term asymptomatic HIV infection was associated with high levels of antibodies to HIV core proteins and the absence of hepatitis B markers. No association with unsafe sex practices and recreational drug use was found. Additionally, a test given to measure levels of psychological coping found no association between such skills and slower disease progression. Tim McCarron Leaves TI After two years as a full time staff member at GMHC, Tim McCarron has left to pursue his own artistic interests. Tim was responsible for, among other things, developing GMHC's regular series of HIV treatment forums and managing a wide variety of administrative responsibilities related to Treatment Issues. He will continue to oversee some treatment forums as a volunteer. His full-time presence at GMHC will be sorely missed by many adoring coworkers, volunteers and clients.