AIDS Trestment News
November 19, 1999

Contents:

• ddI, d4T, Hydroxyurea: New Pancreatitis Warning
• Restoring HIV-Specific Immunity: Telephone Conference, December 8
• Update on Tenofovir (PMPA) Compassionate Access Study
• National AIDS Treatment Advocates Forum (NATAF), Dec. 11-14, Miami Beach
• FDA Clarifies Rules, Allows Combining Antiretrovirals in Clinical Trials
• Seattle Trade Meeting: What Can Be Done for Treatment Access? (Interview with James Love)
• Internet Fundraising: Online Auctions Now for AIDS Project Los Angeles, San Francisco AIDS Foundation; Online Donation Available

For subscription, donation and editorial information and to read our Statement of Purpose, visit AIDS Treatment News' page here at The Body.

ddI, d4T, Hydroxyurea: New Pancreatitis Warning

This week physicians and researchers received a stronger warning from Bristol-Myers Squibb about the risk of pancreatitis in patients taking ddI (VIDEX®) -- a risk which may be increased if they are also taking d4T, with or without hydroxyurea (Hydrea®). ddI has been known to cause pancreatitis in some patients since before the drug was approved in 1991. The new warning follows four deaths from pancreatitis in recent clinical trials. All four of these patients had a CD4 count greater than 500, and a viral load less than 200 copies. All four were also taking d4T; and two of the four were in a 68-patient study arm which included ddI, d4T, and hydroxyurea (600 mg BID). Three of the four who died had known risk factors for pancreatitis before they started the treatment. If pancreatitis occurs it is important to stop the drugs and get medical attention immediately. The October 1999 "patient package insert" for ddI includes the following language to help those taking the drug recognize the symptoms (bold in original): "Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas. It may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let you doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition occurs more often in patients who have had it previously. It is also more likely in people with advanced HIV disease, but can occur at any disease stage. It may be more common in patients with kidney problems. If you develop pancreatitis, your doctor will tell you to stop taking VIDEX." In addition, a stronger "black box warning" is being included in the new labeling (package insert) for ddI, which has now been approved in a new formulation allowing once-daily dosing. The letter to researchers includes the following "Patient Management" section: "The clinical outcome of pancreatitis may be improved by early identification of the clinical and laboratory signs and symptoms of pancreatitis (abdominal pain, nausea, vomiting, elevated serum amylase and lipase levels) and prompt initiation of appropriate supportive care, including stopping all oral intake. "Didanosine, stavudine and hydroxyurea should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine and/or hydroxyurea after a diagnosis of confirmed pancreatitis should be undertaken with caution. Didanosine should be permanently discontinued in patients with confirmed pancreatitis. "As part of the informed consent process in new or ongoing trials, patients must be provided with written information about study drugs and their potential complications. Investigators may choose to provide subjects with the patient information leaflet for drugs administered, if available. A full informed consent process will assure that patients have the requisite information for other health care providers (e.g. emergency room personnel), should early signs of toxicity occur. "The didanosine package insert warns that individuals with risk factors for pancreatitis should use didanosine with extreme caution and only if clearly indicated. "Some of the known risk factors for pancreatitis include: History of pancreatitis Ongoing alcohol abuse Morbid obesity Hypertriglyceridemia Cholelithiasis Endoscopic retrograde cholangiopancreatography (ERCP) Other medications known to cause pancreatitis (e.g., pentamidine) Medications known or thought to increase exposure to didanosine (e.g. hydroxyurea, allopurinol) "In addition, patients with advanced HIV infection are at increased risk for pancreatitis and should be followed closely. When treatment with life-sustaining drugs known to cause pancreatitis is required, suspension of didanosine therapy is recommended." FDA Warning Letter The new warning follows an October 27 warning letter from the FDA to the Chairman/CEO of Bristol-Myers Squibb, concerning the company's September 28 presentation at the ICAAC conference in San Francisco, titled "Hydroxyurea and its Role in Treating HIV Disease." An FDA investigation found that the company "failed to disclose important safety information" and promoted hydroxyurea for an unapproved use. (Hydroxyurea, brand name Hydrea®, is sometimes used to increase the effect of ddI.) From the FDA's warning letter: "Study ACTG 5025 was a trial funded by the National Institutes of Health (NIH). BMS provided study drugs, including the 600 mg twice daily dose of hydroxyurea for patients in one arm of the study. The study was designed to determine whether switching patients with documented viral suppression from one treatment regimen to another, with or without the addition of hydroxyurea, prolongs viral suppression. The primary endpoint of the study was loss of viral suppression and drug toxicity necessitating discontinuation of randomized antiretroviral treatment. On or about September 24, 1999, NIH terminated study ACTG 5025 because the rate of discontinuation for drug toxicity was significantly higher in patients randomized to the hydroxyurea treatment arm. Moreover, the hydroxyurea treatment arm had two fatal cases of pancreatitis. "It is our understanding that BMS was made aware of these events on or before September 24, 1999, but in the presentation on September 28th, the BMS representative discussed the use of hydroxyurea in HIV disease and promoted hydroxyurea as 'very well tolerated.' Furthermore, he presented information about the use of a total daily dose of 1200 mg of hydroxyurea in the treatment of HIV disease. Although one slide used by the BMS representative stated that 'increasing the daily dose of [hydroxyurea] from 1,000 to 1,500 mg significantly increased toxicity...,' the representative failed to disclose that in NIH study ACTG 5025 there was a finding of greater toxicity and two fatal cases of pancreatitis in patients receiving 1200 mg/day of hydroxyurea. Thus, although BMS was aware of reports of serious adverse effects and fatalities associated with the use of Hydrea or Droxia in the treatment of HIV disease, and knew that this information was not yet widely publicized in the medical literature, it did not disclose this information." The FDA required Bristol-Myers to write to healthcare providers to correct "the misleading message you disseminated as a result of these violations," resulting in the new warning letters to researchers and physicians, which were reviewed and approved by the FDA. The complete FDA letter to the company is available at: http://www.fda.gov/cder/warn/oct99/8409.pdf.

Restoring HIV-Specific Immunity: Telephone Conference, December 8

A free one-hour telephone conference, "Boosting Immune Function: The Next Step in HIV Therapy?" will take place Wednesday, December 8, 1999, 5 p.m. Pacific time (6 p.m. Mountain, 7 p.m. Central, 8 p.m. Eastern). This teleconference is free, but you must register in advance. If you miss the call, you can phone in later for a recording (no registration required), but of course you will not be able to ask questions of the panelists. Panelists are: Calvin Cohen, M.D., Research Director, Community Research Initiative of New England, and Research Consultant, Harvard Vanguard Medical Associates in Boston; Eric S. Rosenberg, M.D., Instructor of Medicine at Harvard University, and Clinical Assistant in Medicine at Massachusetts General Hospital; Michael S. Saag, M.D., Professor of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham (UAB), and Director of the AIDS Outpatient Clinic at UAB; and Ronald Baker, Ph.D. (moderator). If you want to register for the teleconference, call 1-800- 880-5121 (9 a.m. to 5 p.m. Eastern time) in advance; reservations are limited. You will be asked for your first name only. If you want to hear the recording later, it should be available about 24 hours after the teleconference. Call toll free 1-888-207-2647 and when requested, enter passcode 5161. This teleconference is supported by an unrestricted educational grant from Agouron Pharmaceuticals.

Update on Tenofovir (PMPA) Compassionate Access Study

Our article in issue #330 "Tenofovir (PMPA) Compassionate Access Study Opens" should have noted that in some cases persons with a CD4 count between 50 and 150 and a recent opportunistic infection can qualify for the current program. Here is an updated announcement with additional information: A small compassionate access study of tenofovir DF, an experimental antiretroviral which is a prodrug of PMPA, has started enrolling patients between 18 and 65 years old. [Tenofovir DF is given orally, and changes to PMPA (tenofovir) inside the body; PMPA itself is not being developed as a treatment, because it would have to be administered by injection.] Because of limited drug supply, priority is currently given to patients with a viral load of at least 10,000, and a CD4 count under 50 (those with a CD4 count of 50-200 and documented evidence of an AIDS-defining active opportunistic infection within the last 90 days may also be eligible). For enrollment information, physicians can call Gilead Sciences' Tenofovir Compassionate Access Study, 1-800-276-0231, 8:00 a.m. to 6:00 p.m. Eastern time, Monday through Friday.

FDA Clarifies Rules, Allows Combining Antiretrovirals in Clinical Trials by John S. James

In November 1999 the FDA wrote to all pharmaceutical companies running clinical trials in the U.S. to encourage studies in treatment-experienced patients, and to clarify the rules on combining antiretroviral drugs. Traditionally, the FDA was very reluctant to allow more than one unapproved drug to be used in a clinical trial -- partly for safety reasons, and partly to make the data more interpretable. But in HIV treatment, when a regimen fails it is usually important to switch to a regimen with multiple new drugs, so that the virus cannot develop resistance to each drug successively. Advanced patients who have already had multiple treatment failures may not have enough approved drugs that they can still use, and therefore may need to start more than one experimental antiretroviral at the same time, in order to prevent resistance development. Our impression is that FDA policy has not been a major problem here for some time. But pharmaceutical companies which did not want to test their drug in advanced patients anyway (because they are harder to treat, markets are smaller, and the companies have to work with their rivals to develop rational regimens) could hide behind the FDA; negotiations between the company and the FDA are confidential. The recent FDA letter makes it clear to everyone that the FDA expects studies in these patients, and will not block them on the grounds that experimental antiretroviral would need to be combined. From the letter: "...it is expected that most new drug applications for antiretrovirals submitted under the accelerated approval mechanism will include some clinical data in patients with limited treatment options. "Scientific data clearly support the principle that HIV should be treated with combination therapy to maintain durable virologic suppression. Whenever possible, all trial participants should have the opportunity to receive combination therapy with several potentially active drugs. Therefore, in studies involving patients with limited approved treatment options, combining multiple investigational agents may be necessary. We would like to clarify that neither the Division of Antiviral Drug Products (DAVDP) nor the regulations prohibit the use of more than one investigational agent in a clinical trial or expanded access program. In fact, DAVDP encourages the study and/or treatment use of multiple investigational agents as appropriate for patients with limited treatment options." The FDA sent this letter in response to a meeting with community groups at the "Salvage Workshop" in Toronto in May 1999. This success illustrates the importance of treatment and policy advocacy in improving drug development, and treatment options for patients.

Seattle Trade Meeting: What Can Be Done for Treatment Access? Interview with James Love by John S. James

Next week in Seattle, the world's trade ministers will open a new round of international trade negotiations which could reshape the World Trade Organization (WTO) -- the first step in a major negotiation process expected to take several years. Also expected in Seattle are 20,000 to 30,000 protesters, mostly concerned that the WTO is destroying national laws to protect labor and the environment. Medical issues, including treatment access in developing countries, will get less attention. We asked James Love, of Ralph Nader's Consumer Project on Technology (see "Compulsory Licensing for Bridging the Gap," AIDS Treatment News #314), what could be done now to help overcome economic barriers to access to essential medical care around the world. ATN: You mentioned the goal of getting a working group within the WTO, on access to medical technologies -- a working group of nations, which any interested nation could join. Love: There are already such groups that work on services, on intellectual property rights, on electronic commerce, for example. Usually they are driven by the agenda of big businesses that have some issues they want addressed by the WTO. The way decisions are made in the WTO is that people try to control the agenda; they try to control the topics that are talked about, they frame questions. If there were an initiative about access to medicines, that would frame the issue in a positive way. It would say the issue is how do you get people access to drugs, and bring in public-health people in the various countries, and look through the various international agreements to find out where the problems are. It would be quite helpful. ATN: Are there any such working groups in the medical area already, or would this be the first in medicine? Love: I'm not aware of anything like this in the WTO now. There are initiatives to look at labor, and at the environment. Environmental groups have been disappointed at what has emerged. You need to think about how the WTO should be structured, and then you need to lobby to get movement. It's not easy; you have to do lots of different things to make progress happen. But having a working group on treatment access would be a magnet to address certain concerns, for example the export issue [whether any country can export pharmaceuticals to a country which uses compulsory licensing, but is too small to have a local industry which can manufacture the drug], or the health registration data issue [whether a country can be prohibited from using publicly available data in its approval process, and required to either run new human trials or buy the drug at monopoly prices from the company that developed it originally]. In these and many other issues in implementing the WTO treaty, you have to get agreement among WTO member countries on what is reasonable to do. These issues can be challenged in the WTO's dispute-resolution panels. To position yourself for a good result, you try and create a consensus of world opinion, or at least raise the understanding of your position early, so that when the tribunal meets, it is more likely to come out where you want to be. There are many such nuances of the WTO agreement; each one in itself is hard to campaign on, because it's not the big picture and is hard to explain. But taken together, they are real problems for access to health care. So you need a single vehicle you can use to hammer away at these, to drive home a pro-access, pro-consumer position. ATN: What resistance would you expect to the idea of adding a working group on access to pharmaceuticals and other medical treatment, much like the working groups that already exist in other areas? Love: The pharmaceutical companies will be opposed. They don't like you talking about access to drugs; they want to talk about issues like drug counterfeiting. Their main goal is to eliminate parallel importing, which is permitted under the WTO agreement; they want to reverse that position. They want to restrict the grounds of compulsory licensing. They are trying to use issues in government procurement at the WTO to attack nations' efforts to control drug prices. It's important to have a power base within the WTO for public-health positions. ATN: And if we don't get the working group on treatment access in Seattle? Love: We can get it later. There are ministerial meetings at least every two years, often about every 18 months. And there are many other councils that meet between the ministerial meetings. You could use the meetings at Seattle to raise this as a proposal, and then campaign after that to have it implemented.

Internet Fundraising: Online Auctions Now for AIDS Project Los Angeles, San Francisco AIDS Foundation Online Donation Available by John S. James

Online fundraising is here and will become increasingly important for charitable organizations. Two current examples: From November 4 through December 2, "the general public can bid on original artwork created by celebrities for AIDS Project Los Angeles' 1999 Holiday Card campaign on Yahoo® Auctions (http://auctions.yahoo.com). Fifteen celebrities from the world of film, television and fashion created highly unique designs for the campaign which will help fund direct services that APLA provides to more than 8,000 men, women and children living with HIV/AIDS." Designers include Tom Hanks, Bronson Pinchot, Jennifer Aniston, Kevin Bacon, Christine Baranski, Carrie Fisher, and Jasmine Guy. From November 15 through November 22, Yahoo Auctions is also hosting a benefit for the San Francisco AIDS Foundation (also at http://auctions.yahoo.com). Among the items being auctioned are "first class tickets on American Airlines, autographed CDs, deluxe hotel packages, works of art and much more." Long-Term Importance Online auctions are new but already huge, with thousands of people making their living by selling items through them. Yahoo! Auctions has over a million items for sale at any one time, in more than 3,000 categories. eBay, the oldest and largest online auction, has over 2.5 million items for sale. Both do charity auctions. There is no cost to participate in these auctions unless an item is sold, in which case the seller pays a fee to the service (which may be waived for charity benefits). The online auction companies are urgently seeking to build market share, so they are motivated to work with charities, who can get new people involved in the process. Clearly this is a time for nonprofit organizations to investigate this new source of potential funds. Online Donations A different fundraising approach is online donations. Currently an organization with a Web site and a merchant account (able to accept credit cards) can put an icon on their Web site that users can click to reach a page where they donate by credit card, with funds immediately transferred to the recipient. One company providing this service is Entango (http://www.entango.com), which charges no setup fee, and 5% of the donations. A disadvantage of online donation today is the cost; 5%, for example, sounds low compared to other fundraising methods, but that is only for the transfer of the money. If the donor sent a check, the cost would probably be less. But the donor may want the convenience -- and may never get around to writing the check later, but can donate online without leaving their current activity, if they are inclined to do so while visiting the Web site. The real potential for online donation will not be for replacing checks, but for making new kinds of philanthropic marketing possible (especially as various forms of online cash and credit become more available, so that donors do not need to keep re-entering their credit-card information). Examples include smaller donations, one-click donations, various sharing and co-fundraising arrangements, and donation-plus-purchase offers which include automatic tax accounting so that donors get an itemized total of their tax-deductible amounts for the year. We expect an online rush in the charity world (as in the business world) as the advantages become more apparent. There is still time to beat the rush. ISSN # 1052-4207 Copyright 1999 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.