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AIDS Trestment News
May 7, 1999

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Amprenavir, New Protease Inhibitor, Approved

by John S. James


The protease inhibitor amprenavir (AgeneraseTM) was approved for marketing by the FDA on April 16. This approval was based on two 24-week controlled trials in adults, plus safety data in over 1,400 patients, under the FDA's accelerated-approval regulations. Amprenavir is also approved for children age 4 and above, based on pharmacokinetic studies in 84 children from ages 4 to 12.

Amprenavir is taken twice a day, with or without food, but it should not be taken with a high-fat meal, as that would decrease the absorption of the drug.

The most common side effects are gastrointestinal (nausea, vomiting, and/or diarrhea), rashes, and oral paresthesia (a tingling sensation around the mouth). Patients should know that severe or life-threatening rash has occurred is 1% of recipients (4% of those who develop a rash), and that "amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms" (quoted from the FDA's official labeling of the drug, which will be printed in the Physician's Desk Reference). Pregnant women should not use amprenavir unless it is medically necessary, because of concern about harm to the fetus in some animal tests (there are no human data). Also, several prescription drugs must not be taken with amprenavir, and several others require blood tests to monitor drug levels. Patients should receive written information about amprenavir, including these and other precautions, from their physician or pharmacist.

Amprenavir was developed by Vertex Pharmaceuticals Inc., using modern technology of rational drug design, and is being marketed by Glaxo Wellcome. It is the first new HIV protease inhibitor approved in more than two years.


Potential Advantages

Based on laboratory tests, Glaxo Wellcome has suggested that amprenavir may have certain advantages, but only clinical trials and clinical experience will tell if these possibilities are real for patients.

  • Studies of lipid biochemistry have suggested that amprenavir may be less likely than other protease inhibitors to be associated with certain problems of lipid metabolism (see AIDS Treatment News #315, March 19, 1999). No one knows today whether there will be a practical difference for patients, since these problems became prominent only after protease inhibitors had been used for some time. The labeling for amprenavir notes one case in which a "buffalo hump" did develop in a patient taking amprenavir plus other antiretrovirals in a clinical trial. However, there have been some such cases in persons who have never taken a protease inhibitor, or never taken antiretrovirals at all.

  • Amprenavir may have a different resistance profile from other protease inhibitors -- which might or might not mean less problem with cross resistance. But it is not known at this time how much persons who have become resistant to other protease inhibitors could benefit from amprenavir -- or conversely, whether those who start with amprenavir and become resistant to it can use the other protease inhibitors effectively. (One of the two efficacy trials on which amprenavir approval is based was in treatment-experienced patients; however, they were protease-inhibitor-naive, so the issue of cross resistance was not studied.)

  • In laboratory tests, amprenavir appears to be synergistic with abacavir (ZiagenTM), another Glaxo drug, meaning that they might work well together. But there is a practical problem with the combination, especially if the two drugs are started at about the same time -- for if a serious drug reaction occurs and both drugs must be stopped, there may not be any way to determine which of them caused the problem.


    Comment

    Amprenavir is important because it provides an additional treatment option. The trial which compared it with indinavir found that, on the average, the two drugs were comparable, although the patients taking indinavir were somewhat more likely to have their viral load go below the 400-copy cutoff used in that study.

    But no individual is average, as people vary greatly in which drugs will or will not work for them. Each new option means that some patients will be able to be treated effectively when otherwise they could not be. Unfortunately it is still hard to predict which drugs will likely work safely for a particular patient, so the process is often one of trial and error.



    • VIAGRA: New Warning with Protease Inhibitors

    by John S. James


    VIAGRA® (sildenafil) doses must be low when the drug is used with HIV protease inhibitors (especially ritonavir), because these antiretrovirals reduce the metabolism of sildenafil in the liver, resulting in abnormally high blood levels which can cause adverse effects. The combination apparently does not affect blood levels of protease inhibitors.

    Sildenafil, used to treat erectile dysfunction, is supplied as tablets in three doses: 25, 50, and 100 mg, and is taken half an hour to four hours before intercourse; physicians often start with 50 mg and then lower or raise the dose if needed. But according to an April 21 "Backgrounder for HIV Treatment Advocates" from Pfizer Inc., "Given the magnitude of the interaction between sildenafil and protease inhibitors, ongoing discussions with the FDA indicate that a maximum single dose of 25 mg of sildenafil in a 48 hour period should not be exceeded in patients receiving these agents concurrently."

    There are several other medications which require caution if used with sildenafil (and some which must not be combined at all); patients should obtain this information from a medical professional, or from a recent copy of the official labeling of the drug. [Note: The current labeling, dated February 1999, is considerably less cautious than the Pfizer backgrounder quoted above. The backgrounder is conservative because discussions with the FDA are ongoing, and it is not known what the final recommendations will be. Technical information will be posted by the National AIDS Treatment Advocacy Project, www.natap.org.]

    The labeling also warns that anyone with an erection lasting more than four hours needs medical assistance immediately, because of the risk of tissue damage to the penis which could cause permanent loss of potency.


    VIAGRA and Poppers

    VIAGRA must not be combined with nitrite inhalants ("poppers") or any form of nitrates, because the combination may result in dangerously low blood pressure, which could be fatal.



    Interrupting HAART; Hydroxyurea; Five+ Drug Therapy -- Report from the RIGHT Conference

    by Jules Levin, NATAP


    Jules Levin of the National AIDS Treatment Advocacy Project (NATAP) attended the April 18-19 meeting of the Research Institute for Genetic and Human Therapy (RIGHT), in Washington, D.C. Here is an edited version of his report, reprinted with permission. The full report is on the NATAP Web site, www.natap.org.


    Interrupting Therapy

    The possibility of interrupting or stopping HAART [highly active antiretroviral therapy] was discussed at length in the conference and in the hallway with researchers. Researchers are fully aware of the need to try and understand why a few individuals were reported at the Retroviruses conference (Chicago, February 1999) to maintain an undetectable viral load after interrupting or stopping HAART. A number of researchers from Europe and the USA told me they are planning or have already started studies to explore this issue.

    The U.S. AIDS Clinical Trials Group will begin a study (A5063) on this question. People who have had a viral load below 50 copies will be asked to interrupt therapy, and they will be followed closely. If viral load rebounds to a certain level, they will be placed back on therapy, and interruption will be tried again after a specified period of time.

    I know a number of individuals considering doing this on their own. I would not do it; let the researchers try to sort this out. The study is still in planing stages and first must be approved at the National Institutes of Health and by the FDA, so it could be 2 months or more before starting.

    Another study likely to start soon will give Remune [the HIV immunogen developed by the late Dr. Jonas Salk] to individuals who have undetectable viral load on HAART. Therapy interruption will be explored in this study.

    In France, Dr. Brigitte Autran has started a study exploring HAART interruption.

    [Note: AIDS Treatment News published related reports from the Retroviruses conference; see "Restoring HIV-Specific Immunity," issue #312, February 12, 1999.]


    Hydroxyurea/ddI Studies in South Africa

    Researchers reported on several open-label observational studies conducted in South Africa using hydroxyurea + ddI or hydroxyurea + ddI + d4T. The results were surprisingly good, with higher than expected percentages of people achieving undetectable viral load. If a person's viral load is relatively low, these combinations may be a viable option for initial therapy -- saving the non-nucleoside RT inhibitors, the protease inhibitors, and possibly the RT inhibitor abacavir as options for future use.


    Third-Line Therapy with Five or More Drugs

    Possibly the most important data at the meeting was Dr. Michael Youle's update from his study of 63 highly treatment experienced volunteers receiving a very intensive regimen consisting of two protease inhibitors, plus efavirenz (a few switched to nevirapine), ddI, d4T, and hydroxyurea; this study was first reported last December, then again at the Retroviruses meeting.(1) Most of the volunteers received ritonavir plus indinavir at various dosing combinations, but some received other protease-inhibitor combinations, since the double protease inhibitor was individualized based on what the person had been able to tolerate when they used these drugs before. The median baseline viral load was 63,000 copies, but many had a much higher viral load, over 750,000 copies.

    After 28 weeks with 20 individuals available for analysis, 85% of the volunteers achieved a viral load below 400 copies. The median CD4 increase was 120. But the higher the starting viral load, the less chance it would go below the 400-copy limit. Dr. Youle is now analyzing the results using a more sensitive test with a 50-copy limit.


    References

    1. Youle M, Mocroft A, Johnson M, and others. Surrogate marker responses to multidrug combinations comprising hydroxyurea, efavirenz, double protease inhibitors and nucleoside analogues in protease inhibitor failures. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract 400].



    Gates Foundation Donates $25 Million for AIDS Vaccine


    On May 3, IAVI (the International AIDS Vaccine Initiative) announced that it has received a $25 million five-year grant from Bill and Melinda Gates, through the William H. Gates Foundation in Seattle. This gift, the largest so far in the AIDS pandemic, will allow IAVI to more than double vaccine development efforts. IAVI is already developing two potential AIDS vaccines, and is now looking for three more, convening scientific think tanks to find the best ideas from around the world.

    IAVI is using contracts and other business arrangements to make sure that a successful vaccine will be affordable in developing countries.

    16,000 new HIV infections occur every day, and experts agree that a vaccine is ultimately the best way to stop the epidemic. But the major pharmaceutical companies have done little to produce an AIDS vaccine -- making the role of private philanthropy all the more important.

    The William H. Gates Foundation had previously donated $1.5 million to IAVI -- and $100 million to a new program to speed the delivery of new and existing vaccines to children in the poorest countries.

    For more information, see www.iavi.org, or www.gatesfoundations.org.



    Lipodystrophy Conference, June 26-28 in San Diego


    The 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV will take place June 26-28, 1999, in San Diego, California. Abstracts must be submitted both by mail and electronically by May 14. The deadline for registration is June 14. Registration is $725, which includes hotel and meals. This workshop is sponsored by Glaxo Wellcome and Merck.

    Major sections are Introduction; Physiology; Investigations and therapy; Lipodystrophy in HIV -- recent cohort studies and the evolution of a case definition; and Reaching a consensus -- lipodystrophy case definition.

    For more information, see www.intmedpress.com/lipodystrophy, or contact: Organizing Secretariat, International Medical Press, 2989 Piedmont Road, Atlanta, GA 30305, phone 404-233- 6446, fax 404-233-2827.



    Managed Care Problems: San Francisco Hearing Set for May 13

    by John S. James


    The San Francisco Board of Supervisors has scheduled a hearing May 13 into complaints that Brown & Toland, the dominant physicians' practice association in the city, has excluded the seven gay doctors who see 90% of the HIV patients at the former Davies Medical Center (now the Davies campus of California Pacific Medical Center), which is located a short walk from the center of the heavily gay Castro district -- while inviting seven non-gay colleagues in the Davies Medical Group to join. The excluded doctors include some of the leading HIV specialists in the city; and without membership in Brown & Toland, it is often difficult or impossible for an independent San Francisco physician to be reimbursed by HMOs and other health insurance plans.

    The practice association has denied "that any physician has been denied membership into Brown & Toland on the basis of sexual orientation or on the basis of their patient population having HIV" (quoted in "AIDS Redlining Charged," by Mike McKee, in the May 3 issue of The Recorder, a legal newspaper in San Francisco). For background, see that article (www.callaw.com; select Archive, then search for 'Toland'). AIDS Treatment News has reported on this controversy in issue #311, January 22, 1999 ("New Healthcare Economics Threaten HIV Specialization, Patient Choice, & Quality Care"), and #313, February 19, 1999 ("San Francisco: New HMO Problems Threaten Access to Care"). For a different look at Brown & Toland and its contributions toward establishing standards for health care, see AIDS Treatment News #278, September 5, 1997, and #280, October 3, 1997).

    The May 13 hearing, intended to allow the issues to be explored in a public forum, has been scheduled for the Public Health and Environment Committee; for meeting information, call Greg Hobson at the Board of Supervisors, 415-554-4441.


    Comment

    The larger issue is that capitated managed care (where the health plan pays a fixed amount per patient per month, regardless of how much care they turn out to need) creates powerful incentives to ditch expensive patients and the doctors who treat them -- especially in the case of a disease like AIDS, which is in fact a specialty but is not formally recognized as such. Independent practice associations (IPAs) like Brown & Toland can be caught in the middle, because they must negotiate with health plans seeking the lowest possible cost.

    It is known that patients with HIV disease have substantially better survival when they are treated by expert physicians.(1) Forcing experts to close their practices or leave their specialty seriously threatens access to quality care.


    References

    1. Kitahata MM, Koepsell TD, Deyo RA, Maxwell CL, Dodge WT, and Wagner EH. Physicians' experience with the acquired immunodeficiency syndrome as a factor in patients' survival. New England Journal of Medicine March 14, 1996, volume 334, number 11, pages 701-706. Also note comment and discussion in the New England Journal of Medicine, August 1, 1996.



    Model AIDS Program Housed in African-American Church

    by John S. James


    On April 20, an HIV testing, prevention, and referral center opened in specially constructed facilities inside the Antioch Baptist Church in Cleveland, Ohio. Its founders hope this program will become a national model for addressing the very serious problems of HIV disease among African Americans -- problems which community leaders and media as well have often ignored. In the U.S., African Americans are far more likely than whites to be HIV positive; the epidemic is growing very rapidly among African Americans, and they often have poor access to medical care.

    This new project, called the AGAPE Program, developed remarkably quickly as a collaboration between different institutions: the Antioch Baptist Church, a leading religious institution in the area; the Cleveland Clinic Foundation, a major medical center; the AIDS Task Force of Greater Cleveland; the local chapter of the American Red Cross; and two pharmaceutical companies, Bristol-Myers Squibb and Agouron Pharmaceuticals, which provided start-up grants. Organizing started only seven months ago, when Antioch's pastor, Rev. Marvin McMickle, Ph.D., talked with a church member who has AIDS, and then met with leaders of the Church, the Clinic Foundation, and the Red Cross; but the program now has an HIV facility newly constructed for this purpose inside a large room within the church building -- including counseling rooms, a teaching center, and a large and well-equipped childcare facility so that children can be attended while their mothers visit. This center does not provide medical treatment beyond HIV testing, but refers clients to several medical facilities in the area.

    We visited the Agape Program on April 20 and asked what had been learned which could help others to develop similar programs. Kelvin Berry, a deacon of the church who coordinated the steering committee which brought the project together, said that organizers should be aware of the following:

  • Don't try to pull the partners together too quickly -- to force personalities to work together. Instead, organizers spent about two months to understand what each partner wanted -- the church, the medical clinic, the pharmaceutical companies, and others.

  • It was essential to find people who could lead the process. Here, it was agreed that the church and the clinic would take the organizational lead. In addition, someone within each organization had to commit themselves to leading internally, to bringing others along.

  • The steering committee opened and closed every meeting in prayer, to help people come together on one central mission, reducing the conflicts which could result from conflicting egos of the very different personalities. "For the Antioch Baptist Church, our primary focus was the ministry, being led by Christ to help those who have trouble helping themselves," said Berry.


    For More Information

  • For more information about the Agape Program, contact The Antioch Baptist Resource Center, 216-791-0638, or visit www.antiochofcleveland.org/agape.

  • The Balm In Gilead, Inc., is a national nonprofit organization whose mission is "to work through Black churches to stop the spread of HIV/AIDS in the African American community and to support those infected with, and affected by, HIV/AIDS." For more information, call toll-free 888-225- 6243.

  • In San Francisco, the Glide-Goodlett HIV/AIDS Project offers testing, prevention case management, HIV case management, street outreach, and health education in the jails; also, non-HIV programs at the Glide Memorial United Methodist Church can help with housing, food, clothing, and transportation. Most of the clients are from the Tenderloin (by far the poorest neighborhood in the city), and most are African-American or members of other minority groups; for more information, call Joan Benoit at 415-567-2273. Glide Church also runs a Free Health Clinic (in partnership with the UCSF School of Nursing, and Catholic Healthcare West), and many other services, usually not HIV-specific; for information, see www.glide.org.



    • Africa and HIV/AIDS: Email Communication List


    A new regional email forum for Africa (in English and French) now includes over 850 people and organizations working in or with African nations to respond to the epidemic. You can use the forum either through the Web, or with email only.

    If you have full Internet access, visit http://www.hivnet.ch:8000/af-aids/tdm; previous postings remain available. If you have email only, send a message to:

    af-aids@hivnet.ch, with the work 'join' in the subject line, to receive each day's messages.



    African American Treatment Advocacy Funding Available, May 14 Deadline


    Glaxo Wellcome will fund "peer-based treatment advocacy initiatives designed to link HIV-positive African Americans to HIV treatment programs."

    Proposals can be submitted from 501(c)3 organizations anywhere in the United States. These grants cannot be used to provide medications or medical treatment. Proposals must be received by the close of the business day Friday, May 14.

    The following is from the Request for Proposals:


    "Objective

    "Glaxo Wellcome will fund peer-based treatment advocacy initiatives designed to link HIV-positive African Americans to HIV treatment programs. The number of grants and the amount of each grant will be determined during the proposed review process. Grant sizes may vary with a maximum of $30,000.


    "Criteria

    "Proposals may be submitted for new or existing/ongoing initiatives.

    "Proposals should focus specifically on the healthcare needs of HIV-positive African Americans and linking those individuals to HIV treatment programs.

    "Proposals may be submitted from any geographic location in the United States; both urban and non-urban areas desired.

    "Organizations submitting proposals must provide proof of 510(c)(3)status.

    "Organizations selected for funding may not use grant money to provide medications to treat HIV infection or to provide medical treatment for HIV.

    "Proposals must be received by close of business on May 14, 1999.


    "Application Process

    "Proposals should consist of a three- to five-page document describing the organization and the program/initiative designed to link HIV-positive African Americans to HIV treatment programs. The proposal must include the following information:

    "Project Description (e.g., project purpose/objective, scope of project, time period, budget, staff, results expected, intended audience, number of people to be served, setting/environment, project evaluation mechanism/clearly defined outcomes objectives).

    "Description of Organization (e.g., background, including length of time in existence, current and past funding sources, list of board of directors, how the program fits into the organization's overall mission and objectives, HIV-related medical services, if any, provided by organization).

    "Copy of 501(c)(3) Letter of Determination should be attached to the proposal.

    "Completed proposals may be mailed or faxed to: Doris Campbell Health Care Coalitions Glaxo Wellcome Inc. 5 Moore Drive Research Triangle Park, NC 27709 fax: 919-315-0062."



    U.S. Vaccine Trial: New Email List


    An email list on vaccine activism, especially around the AIDSVAX trial in the U.S., started last week. You can join the list through the Web site www.onelist.com/subscribe/vactivism. More information is available from Joe Wright, aquariumtown@earthlink.net.



    Corrections, Issue #317


  • "San Francisco General Outpatient Pharmacy Problems" incorrectly stated that there is a $10 monthly cap on prescription co-payments by medically indigent patients. We have not yet been able to determine what the assistance policy is.

  • The drug name "Ceredase" was misspelled in "Clinton/Gore Top Staffs: Pharmaceutical Background." The error occurred during editing by AIDS Treatment News; the spelling was correct in the author's original article.



    • International AIDS Candlelight Memorial and Mobilization, May 16


    Candlelight vigils will be held in hundreds of cities throughout the world on Sunday May 16, this year's International AIDS Candlelight Memorial and Mobilization. To locate an event in your area, you can either contact a local AIDS organization, or check the list of coordinators at www.wenet.net/users/candle/pages/page11.html, or if necessary call Mobilization Against AIDS in San Francisco, 415-863-4676, fax 415-863-4740.

    This year events are planned in Argentina, Australia, Brazil, Canada, Chile, Colombia, Cyprus, Czech Republic, Ecuador, Germany, Guatemala, India, Indonesia, Israel, Italy, Japan, Kenya, Malaysia, Mexico, New Zealand, Nicaragua, Panama, Peru, Philippines, Poland, Portugal, Russia, Singapore, South Africa, Spain, Surinam, Tanzania, Uganda, United Kingdom, United States, Uruguay, Venezuela, and Zambia.


    San Francisco Candlelight

    The San Francisco event, organized independently this year, leaves Castro and Market at 8:00 p.m. on May 16 for a candlelight march to San Francisco City Hall, and a program of music, performance, art memorials, and presentation of this year's AIDS Hero Awards.

    For information about the San Francisco march, call ACT UP/Golden Gate at 415-252-9200.



    California Alert: Oppose HIV Names Reporting


    On May 12 the California State Senate Health and Human Services Committee will vote on SB 1029, the HIV names-reporting bill by Senator Ray Haynes (Republican, Murietta). For more information, call Herb Schultz (323-993-1365) or Matt Mutchler (323-993-1628) of AIDS Project Los Angeles.



    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.



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