Contents:

1. New Antiretroviral Strategies: Interview with Marcus Conant, M.D.
2. 3TC: Now Available Again Up To CD4 of 300
3. California: Medi-Cal Can Pay for Human Growth Hormone for Some Patients
4. FDA Reform: Activists' Proposals

New Antiretroviral Strategies:  Interview with Marcus Conant, M.D. by John S. James

Marcus Conant, M.D., heads the Conant Medical Group, one of the largest HIV practices in San Francisco. AIDS Treatment News: How has your approach to treating HIV infection changed since a year or two ago? Dr. Conant: Today when we find that someone is HIV positive, we are using three indicators, instead of one or two, to try to measure where they are in the course of the disease. Historically, the first measurement we had of disease progression was symptoms. It was obvious that people who had fever, fatigue, weight loss, night sweats, who started developing skin conditions or other diseases, were further along in the course of the disease, and therapy might be instituted then. If someone was doing very well and suddenly developed a yeast infection, even if they didn't have any symptoms, even if the CD4 (T-helper) count had not dropped greatly, that would tell us that their immune system was not working as well as it had before, because they could not suppress the yeast any more. Then it became clear that the CD4 count -- or better, the CD4 percentage -- was an important indicator. So we measured CD4 about every four months. The most sophisticated patients knew that it wasn't a drop in the number that was important, it was a drop in the percentage. The classical indicators that had been used in medicine, the history, the physical findings, and the laboratory studies (particularly the CD4 count or percentage, in the case of HIV infection) were what we used until last year to decide who should go on therapy. So if a patient had a CD4 count of 800 and was totally asymptomatic, we did not initiate therapy. If someone had a CD4 count of 550, but had a lot of fatigue, and had had zoster a year ago, and then had developed hairy leukoplakia, many of us would have gone ahead and put that patient on combination therapy -- saying that the CD4 counts looked good, but because of the increase in symptoms and signs, we had clinical evidence of HIV disease progression, and we now needed to be more aggressive. Viral Load Testing In the last year we have added viral load to the formula. So now we are looking at symptoms, measuring the CD4 count, and also looking at viral load. While the information has become more complex, it has actually become easier to use, because the viral load can give us more information than all of the others put together. If we saw a patient who was totally asymptomatic, had no physical finding, no cutaneous or other infections suggesting disease progression, and had a very high CD4 count, say 800, and had a viral load measured by branched DNA (bDNA) or quantitative PCR at less than 10,000 copies, we would not treat that patient, but would repeat the branched DNA test every four to six months. If at any point one of the markers started telling us this patient was progressing -- if the branched DNA, for instance, suddenly went up to 40,000, or the CD4 count dropped precipitously, or the patient started getting lots of symptoms -- then we would likely decide to start therapy. [Note: The branched DNA test -- abbreviated bDNA -- is one technology for measuring the viral load, the number of copies of HIV RNA per milliliter of blood plasma. Other technologies for measuring the viral load are quantitative PCR, and NASBA. Incidentally, each HIV virus particle has two copies of its RNA, so the actual number of copies of the virus is half the number of copies of HIV RNA.] ATN: If the viral load suddenly goes up, would you repeat the branched DNA or other viral load test? Dr. Conant: In my experience, the bDNA test is very reproducible, far more reliable than the CD4. So if I get a bDNA that is elevated, I usually do not repeat it a month or two later to see if it is accurate; instead, I respond to it. But if the patient was totally asymptomatic and had a stable CD4 percent, and the bDNA count went sky high, say from 10,000 to over 100,000, then I would retest to make sure a mistake had not been made. Initial Antiviral Treatment ATN: What antiviral therapies are you using first? Dr. Conant: If there is evidence of disease progression, we are first treating many patients with very high dose d4T. The dose I usually start with is 20 mg. twice a day; then I have the patient increase it by 20 mg. each week, until they get neuropathy, or until we get to 80 mg. twice a day. That is twice the FDA-recommended dose. Why are we going that high? The answer is that the recommended dose of 40 mg twice a day was picked because that was the dose at which 50 percent of the patients in the early trials developed neuropathy. But the studies also showed that you got a four-fold increase in antiviral effect, every time you doubled the dose; from 40 to 80 total daily dose, you get a four-fold increase in suppression. So if patients can tolerate the dose, I go all the way up to 80 mg per day. And in people with high CD4 counts, we can get to 80 in almost all the patients. We are not seeing much neuropathy, if the patient is asymptomatic with a high CD4 count when you start aggressive treatment with d4T. Once I get to the maximum dose of d4T, then about a month later I repeat the bDNA test. With CD4 counts, we used to wait four months or so before repeating it. But with viral load, there is clear evidence that you can see measurable decreases within two weeks of initiating effective antiretroviral therapy. By a month you ought to be able to get a good measure. Say we had a patient whose viral load had gone from less than 10,000 to 40,000 copies, and we put him on 80 mg of d4T, and a month later we measured it, and it is less than 10,000 again. We would continue that patient on the therapy, seeing him or her at least once every four months, reassessing where we are with their antiviral measurement -- and reassessing their history and physical signs, and CD4 count. If we see viral escape -- if the viral load starts going up again -- I would add ddI to the d4t, and I would continue that, monitoring every four months. AZT and 3TC If the patient's CD4 count still drops -- and if it drops low enough so that they could qualify for the 3TC expanded-access program -- we often put those patients on AZT plus 3TC. But we wait to start AZT until we could start 3TC simultaneously. Because it did not seem to make sense to put them on AZT alone for a year or two, let the virus get resistant to that drug, and then add the drug that helps to prevent the emergence of resistance. If the patient could not qualify for the 3TC access program, I would probably wait, and continue to play with d4T and ddI -- and maybe even add saquinavir -- and hold the AZT until I could combine it with 3TC. ATN: How is this different from your approach a year or twoago? Dr. Conant: The change in view you are hearing from me is that we have traditionally used AZT as the first drug of choice. That was the first drug we had, and we continued to use it first. And yet, nothing says that we cannot first use drugs that may not be as effective as AZT, and use up their efficacy, and then go to stronger drugs later on. If tomorrow the FDA approved 3TC, then I would probably begin with a combination of AZT plus 3TC plus ddC, much earlier in the course of the disease. But in San Francisco you have an aging epidemic; most patients have experienced these drugs in some dose, for some period of time, over the last five years. So my recommendation is that the patient and physician sit down, find the drugs that were tolerated the best, and try to combine two or perhaps three of those. For example, if the patient could take AZT and had no problem with ddC, combine the two drugs, and see what happens to the viral load. If the viral load goes down, monitor them every four months; and if the viral load starts going up again, shift to ddI and AZT. Play with the drugs to get the viral load down as low as possible. With saquinavir now available on expanded access, if I were the patient, even though that drug in the dose being used is not as effective as the new protease inhibitors coming along, I would add that to my cocktail, using the bDNA about a month after I changed to see how effective the treatment was. If the viral load goes down, great; then I would wait another four months and check it again. ATN: The Consensus Symposium on Combined Antiviral Therapy is being held in Lisbon July 25-27. My concern is that there is not much consensus, and we might end up with a lowest common denominator kind of recommendation. Dr. Conant: More and more my colleagues are using similar strategies. They are starting with combinations earlier, and they are using bDNA to tailor what the combination is. ATN: I have heard of a few people who had very low CD4 counts who were treated with AZT plus 3TC, and in a few cases their total lymphocyte count went way down, but the CD4 and CD8 counts stayed about the same or decreased only a little. Have you noticed any problem like that, perhaps where the hematological toxicity of AZT was getting amplified? Dr. Conant: We have not seen that. In our experience, 3TC has been the best tolerated of the antiretrovirals. Many patients feel better after they start taking it. There can be problems with peripheral neuropathy -- especially in patients who have had peripheral neuropathy in the past. And there are occasional reports of minor dizziness, hair loss, or joint pains. CD4 Percent Vs. CD4 Count ATN: You mentioned that the CD4 percent is actually a better measurement that CD4 count, even though the latter is the one generally used. With CD4 percent, what danger points do you watch for? And could you explain why the percent is the better measure? Dr. Conant: When the CD4 percent goes below 20 I start getting concerned. We need to keep stressing to patients that if your CD4 count drops a little -- from 300, for example, down to 230 -- then look at changes in your CD4 percent. If the percentage was 21 percent, and the count dropped to 230 but you still have 21 percent, there really has not been a drop. This is because of the way the CD4 count is calculated. You start with the white blood count and see what percent of those cells are lymphocytes. Then you see what percent of those are CD4 cells. For example, if your white count is 4000 per milliliter, and your percentage of lymphocytes is 50 percent, then that means that 2000 of the cells are lymphocytes. And if the percent of lymphocytes that are CD4 cells is 25 percent, that means that 500 of them were CD4 cells, so your CD4 count would be 500. Why is the CD4 percent more important than the CD4 count? Because your white blood count can vary from hour to hour, just because of time of day, or exercise, or a small infection. If the white blood count changes for these minor reasons, it may look like the CD4 count has gone down or up. It is well known that the percentage is most important; and yet patients, unfortunately, are still stuck on the number. We doctors did that; we continued to talk in terms of numbers instead of percentages, although as early as 1988, at the International Conference on AIDS in Stockholm, it was clear that percentage was really the most important figure. Future Directions ATN: Where do you see AIDS treatment heading in the near future? Dr. Conant: We are very excited about both the Abbott and the Agouron protease inhibitors. We are seeing drops in viral load of two to three logs (100 to 1000 fold), and preliminary data suggests that those reductions are sustained for extended periods of time, without the emergence of resistance. I would predict, based on the data we are seeing today, that we may well see protease inhibitors, instead of nucleoside analogs, as the first line of therapy.

3TC: Now Available Again  Up To CD4 of 300

In April, Glaxo (now Glaxo Wellcome) restricted its expanded- access program for 3TC, due to unexpected demand and a resulting shortage of the drug. The most important restriction instituted at that time is that patients had to have a CD4 (T-helper count) under 100, instead of under 300, to qualify. But now there is more drug, and starting in late August, persons with a CD4 up to 300 can qualify again -- but those with counts under 100 will still be given priority. A total of 650 new participants per week will be allowed in the program, instead of only 350, as has been the case from April until late August. Physicians will still need to submit lab slips to verify CD4 count, as they have had to do since April. Note: The decision to give priority to persons under 100 reflects sentiment at two community meetings of persons with HIV and their advocates, which Glaxo called to discuss how best to handle the unexpected drug shortage. It was not an a priori decision of the company. A Glaxo spokesperson told us that since the beginning of the open-label program, over 24,000 people have been enrolled. A large but unspecified number of them are also taking AZT. The spokesperson acknowledged that many participants are also combining 3TC with ddI, ddC, or d4T, or with various non-FDA approved treatments, such as NAC or hydroxyurea. She said that Glaxo cannot endorse or encourage these other combinations. Meanwhile, enough data has been collected from controlled trials of 3TC that a New Drug Application (NDA) was filed with the FDA on June 30. Glaxo Wellcome, the newly merged company, is requesting that 3TC, combined with AZT, be approved for treating individuals with CD4 counts below 500. To register as a clinical investigator in the 3TC Open Label Program, physicians should call 800/248-9757. Registering new patients can be done by fax, and the drug is shipped within a few weeks. The blood draws required by the protocol are largely routine, and the paperwork required to monitor participants is not unreasonable.

California: Medi-Cal Can Pay  for Human Growth Hormone  for Some Patients by John S. James

As this issue goes to press, AIDS Treatment News has heard that Medi-Cal will pay for human growth hormone through the Serono treatment IND, for some patients, starting August 1. Serono will start processing Medi-Cal applications on that date. Physicians and patients will still apply for the program in the same way, by calling the Serono phone number below, as Serono handles the reimbursement paperwork. To qualify for the Serono program (regardless of whether or not one is applying for Medi-Cal reimbursement), a physician must determine that a patient has AIDS-related wasting, with loss of at least 10% of body weight. The patient must be on antiretroviral treatment, and must be 18 or older. Until recently, the program also required the patient to fail both Megace and Marinol, which are FDA-approved for wasting; but due to a recent protocol amendment, patients now must only fail one of those drugs, and that requirement can be waived if the physician determines that both of them are medically contraindicated. In order to enroll patients, a physician must first qualify as a site with Serono. Later, less paperwork is required to add each individual patient. Physicians should begin the process by calling the Serostim Information Line, 800/714- AIDS (800/714-2437). Patients also can call this number for information. Comment As is often the case in AIDS care and activism, a number of people behind the scenes deserve particular credit for making this potentially life-saving treatment more available.

FDA Reform: Activists' Proposals by John S. James

A number of proposals for changing the FDA -- mostly to get treatments to patients faster -- or to avoid changing the FDA in ways people do not want, are now circulating in Washington and across the country. This article looks at reform efforts by AIDS activists. Also, a number of FDA reforms have already been introduced in Congress; and industry, government, and other organizations and individuals have also proposed reforms. It is important for the AIDS community to know what ideas are on the table, so that our interests can be represented in this discussion. AIDS Community Proposals We know of three major proposals on FDA reform initiated by AIDS activist organizations. Unfortunately, despite some overlap in people and recommendations, the three groups have seldom talked to each other. This disunity reflects long-term divisions over AIDS treatment policy. We will describe these three FDA proposals in more or less chronological order. The "Principles of FDA Reform" A consensus letter on FDA reform is now being circulated for sign-on by AIDS and other organizations. This letter lists 11 (originally 12) principles proposed as the basis for any FDA reform. The 11 principles: "The FDA's mission should remain protection and advancement of public health. "Federal regulation of the safety and efficacy of drugs, diagnostics, medical devices, and biotechnology products is essential. "FDA must allow pre-approval access to experimental drugs that show promise for serious and life-threatening diseases. "FDA must regulate drugs for serious and life-threatening diseases differently than drugs for routine and treatable diseases. "Post-marketing research is a critical component of drug development and regulation. "FDA approval provides a foundation of knowledge, upon which present and future doctors and patients decide how, when and in whom to use the drug. "FDA must retain regulatory flexibility. "FDA must ensure data are gathered on all populations likely to use a new drug. "While retaining its independence, FDA must be held accountable. "FDA must have sufficient resources to perform its duties. "FDA and industry must collaborate and communicate effectively in all phases of drug development." The consensus letter with these 11 principles, including short explanations of each, has been signed by ten major AIDS organizations, mostly located in or with a presence in Washington. While these principles themselves are designed to be inoffensive and hard for anyone to disagree with, this effort to focus the AIDS community's involvement in FDA reform has not been free of controversy. A number of people -- including some who signed on, despite personal doubts, after negotiating some changes in the wording -- are concerned that this list fails to ask for what we as a community want. They signed this letter to show unity, but with the expectation that specific, positive reforms would also be put on the table for national discussion, in a separate document (see "FDA Reform Consensus Statement," below). While a number of people from the ten signing organizations, and some others, developed the eleven principles, the Treatment Action Group (TAG) is generally regarded as the main organizer of this effort. Derek Link, in a Dear Colleagues letter from Gay Men's Health Crisis, explained: "... The philosophical underpinning of these principles is that legislative changes to FDA's statutory authority are not needed for effective and responsible FDA reform. We need further FDA reform, but the Republican Congress is not the place for us to achieve this. The message is that we still need to push for FDA reform, but that we can do it directly with the FDA not with Mr. Gingrich. It is important for everyone to remember that the FDA regulates 25% of everything we buy -- that is, the core things in life (drugs, food and beauty products!). FDA regulates some very large and powerful interests. FDA reform in the Congress is not about people with serious diseases, it's about making life easier for the drug industry, agribusiness, and Revlon. The Republican Congress does not have our interests at the top of its list of priorities. Once FDA's legal authority is opened up by the Congress, it will be quite dangerous. Well-funded lobbyists for all sorts of corporations will attempt to manipulate the process in ways that may be in opposition to our needs." For a full copy of the Principles of FDA Reform, to sign on, or for additional information, contact Derek Link, 212/337- 3502. FDA Reform Consensus Statement Draft This very different document is a draft of a consensus statement being prepared by five AIDS activists, mostly on the West Coast. It focuses on what many people in the AIDS community want most -- avoiding unnecessary delays and streamlining the process of getting new treatments to people faster. "The thinking behind it," according to Martin Delaney of Project Inform, one of the authors, "is to find places to squeeze chunks of time out of the drug development and approval cycle." He described it as focusing on specific areas where we can make practical progress today, without dismantling the overall system. The current draft addresses five different areas: Improving compassionate access; Accelerated approval refinements; Institutional review board approval of phase I academic research; Creation of an appeals process; Information distribution about off-label drug use. Because this proposal is too long to reproduce in full in AIDS Treatment News, we quote the entire introduction and then summarize the five areas. The Introduction: "There is a public groundswell for FDA reform and a multitude of approaches are currently being proposed. For individuals facing life-threatening illnesses, broader and earlier access to promising therapies is a critically important outcome of any FDA reform effort. While we recognize the need for the FDA to regulate the safety and efficacy of new drugs, we also believe that the agency's overall regulatory mission must appropriately address the differing needs and values of people with life-threatening illnesses, carefully balancing risk versus benefit. We believe that the needs of life- threatened patients, for example people with AIDS or cancer, warrant greater risk-taking in the drug development process. For these individuals, we advocate the fastest cycle of drug development possible without needlessly endangering their safety. We strongly believe that people whose lives are immediately threatened by disease or illness should have the fundamental right to access the most promising therapies in development when they have failed or have become intolerant to all standard therapies. As people with AIDS and their advocates, we respectfully submit the following proposal and urge its adoption for all life-threatening illnesses, without prejudice for or against any other proposals currently under consideration before Congress or the Administration." On compassionate access, the FDA should "routinely encourage" not only parallel track programs after phase I (dosage and toxicity testing) has been completed and the first "surrogate marker" efficacy indications are available, but also emergency access for individuals even before the completion of phase I. The FDA's current program of "accelerated approval," while it has been successful, can be improved by resolving several bottlenecks identified by experience. To avoid months of delays, the FDA should not use advisory committees for all accelerated-approval decisions, but only when "unusual safety risks" or "truly new scientific issues or processes" are involved. FDA should encourage companies to apply for accelerated approval (for treatments for serious or life-threatening conditions) based on data from a single well- controlled study, and should "routinely grant preliminary marketing approval based on summary data within 30 days of submission of an NDA (New Drug Application) for drugs designed for life-threatening illnesses." University-based institutional review boards should be allowed to approve academic (non-commercial) trials, freeing FDA staff to approve other trials more quickly. "In the past, most purely academic clinical research not associated with commercial product development has been initiated upon the authority of local Institutional Review and did not require IND (investigational new drug) applications and approval from the FDA. In recent years, there has been a growing tendency to shift responsibility for approving such research back upon the FDA. One consequence of this is that the queue awaiting approvals for commercially sponsored research is longer than ever..." Drug developers should be able to appeal FDA decisions. "Decisions made by the FDA presently are final and without opportunity for appeal, a process unlike almost any other aspect of the American legal or regulatory systems." Sponsors who challenge a scientific decision of FDA staff should be able to call for a hearing, or call for the appointment of a panel of independent experts. The FDA would have to accept the decision of the appeals board. Sponsors would pay the costs of the process if their appeal was rejected. Companies should be allowed to inform doctors about "off label" uses of approved drugs, when supported by peer-reviewed, published research. "It is well established that as much as 40% of all drug use occurs off-label and that some of the most important uses of drugs are not defined by their label indications. Current agency practice forbids sponsors from providing any information to physicians about such use of drugs..." For a copy of the current draft of the FDA Reform Consensus Statement, or to make suggestions for this effort as it evolves, send a fax to: the Linda Grinberg Foundation, 310/471-4565. Republican AIDS Activists Proposals San Francisco AIDS activist Jim Driscoll, who is the leading AIDS expert for the Log Cabin Republicans (a gay Republican organization in Washington, D.C.), and also for the Progress and Freedom Foundation (a think tank associated with Representative Gingrich), has for several months discussed FDA reform with Congressional offices preparing bills on the subject. Driscoll told us that he is most interested in four specific reforms: The mission of the FDA should be amended, so that the agency makes it its business not only to protect the public against unsafe or ineffective drugs, but also to encourage the rapid development of medical science and technology. University-based institutional review boards should be allowed to approve early clinical trials, in most cases, without FDA approval also being required. Drug companies should be allowed to educate doctors about well-accepted off-label uses of their products. Congressional intent on the efficacy standard should be made explicit, to insure accelerated approval of drugs for AIDS, cancer, and other life-threatening conditions. "FDA Reform will speed AIDS drug development by reducing bureaucratic hitches in phase I clinical testing, and by streamlining FDA review," Driscoll told AIDS Treatment News. Reform can also reduce the cost of drug development, which means that the same amount of research funding can test more drugs and combinations. Research avenues now neglected as too costly will be explored. Those who raise the red flag of safety concerns need to remember that, due to scientific advances, including drugs which are better targeted, drug testing is far safer today than it was 20 or 30 years ago. But FDA is more interested in protecting itself and expanding its bureaucracy than in saving the lives of patients with AIDS and cancer. It is time for Congress to put patients above bureaucrats and hold FDA strictly accountable for the human as well as financial costs of bureaucratic delays. Legislative reform of the FDA is the surest way to speed a cure for AIDS." For more information on Log Cabin Republican regulatory reform efforts, call Jim Driscoll, 415/552-0269.