Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

October 1998 Table of Contents

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News Briefs

Liz Highleyman

Changes at BETA

There have been several recent changes at the San Francisco AIDS Foundation (SFAF) that affect BETA and our other publications. As of July 1998, former Editor-in-Chief Ronald Baker is Director of the Treatment Advocacy Department. Former Managing Editor Mark Bowers has resigned his position.

SFAF's treatment publications are now produced by the Treatment Education and Support Unit within the HIV Services and Treatment Support Department, under the supervision of Tim Teeter. Leslie Hanna and Liz Highleyman are Acting Editors of BETA. Christopher Gortner continues as Editor of the Spanish edition of BETA and of Positive News/Noticias Positivas. Paula Fener is the new Design and Production Manager.

The San Francisco AIDS Foundation remains committed to producing excellent treatment publications, and we welcome your comments and feedback (e-mail beta@sfaf.org; phone 415-487-8060; postal address P.O. Box 426182, San Francisco, CA 94142-6182).

FDA Approves Efavirez

On September 18, the Food and Drug Administration (FDA) approved efavirenz (Sustiva, formerly DMP-266), DuPont Pharma's new non-nucleoside reverse transcriptase inhibitor (NNRTI). Efavirenz has shown good results in trials of over 2,000 participants for up to 24 weeks; early data suggests that the drug may be as effective as protease inhibitors for some people when used as part of a combination regimen (see Protease-Sparing Combination Regimens). Efavirenz is the first anti-HIV drug to be approved for once-daily dosing; it can be taken with or without food. The drug should only be used in combination with other antiretroviral drugs, since monotherapy can lead to the rapid development of resistance.

Efavirenz is described by DuPont Pharma as "fairly well tolerated"; the main side effects seen in studies so far are nervous system symptoms (e.g., dizziness, insomnia, abnormal dreams) and skin rash. Long-term side effects are not yet known. The drug was approved for both adults and children. Because of reported birth defects in animals receiving the drug, pregnant women should not take efavirenz.

DuPont Pharma has priced efavirenz at $3,942 per year ($10.95 per day) for high-volume purchasers such as ADAPs; the retail price paid by some consumers will be higher. The standard adult dose is 600 mg per day. For efavirenz reimbursement counseling and payment assistance, call 800-334-4486. For more information about the drug, see the website at www.sustiva.com.

Advocates Call for Fair Drug Pricing

A group of treatment advocates known as the Fair Price Working Group has called on Glaxo Wellcome (the maker of abacavir, a nucleoside analog) and DuPont Pharma (the maker of efavirenz, a NNRTI) to set prices for their new drugs similar to those of other reverse transcriptase inhibitors, rather than those of the more expensive protease inhibitors. DuPont Pharma has already set the price of efavirenz at a level that advocates believe is too high. The working group noted that programs that pay for anti-HIV drugs, such as Medicaid and AIDS Drug Assistance Programs (ADAPs), are already under financial strain, which would only worsen with the addition of more expensive drugs to their formularies. The advocates contend that high prices are not justified on the basis of research and development or production costs, but are solely based on what the market will bear. Supporters have been asked to sign on to a consensus statement. Over 100 organizations, including the San Francisco AIDS Foundation, and nearly 200 individuals have endorsed the statement, which was presented to the companies in September.

Amprenavir Expanded Access Program Begins

On September 21, Glaxo Wellcome began enrollment for its expanded access program for amprenavir (Agenerase, formerly 141W94). The program has three options: 1) an open-label clinical trial to determine the drug's effect on body fat metabolism in people who are already experiencing lipodystrophy or high blood fat levels on their current protease inhibitor regimen, 2) an open-label study to evaluate amprenavir in combination with other protease inhibitors, and 3) distribution to people whose current antiretroviral regimen is failing or who cannot tolerate their current drugs, and who need amprenavir to construct a viable regimen. For all options, participants must have received prior treatment with another protease inhibitor. The drug will be provided free of charge. Amprenavir is taken twice daily, with or without food. The company is expected to apply for FDA approval later this fall. To enroll in the expanded access program, physicians may call 800-248-9757.

Twice-Daily Indinavir Dosing Not Recommended

On September 18, Merck and Company announced that it was discontinuing clinical trials involving twice-daily use of its protease inhibitor indinavir (Crixivan). Interim results indicate that the experimental regimen of 1,200 mg twice daily was not as effective in reducing HIV viral load as the standard adult regimen of 800 mg three times daily. Researchers had hoped to reduce the number of daily doses in order to make the regimen more convenient and to help improve adherence. Studies are continuing on twice-daily dosing when indinavir is used in combination with other protease inhibitors. For now, Merck recommends the standard three-times-daily regimen for people taking indinavir in combination with nucleoside analogs such as AZT and 3TC.

Ritonavir Manufacturing Problems

In late June, Abbott Laboratories announced that it had discovered manufacturing difficulties that affect its protease inhibitor ritonavir (Norvir). The problems involve the formation of crystals that affects the way the capsules dissolve. This problem does not apply to capsules currently on the market; ritonavir capsules now at pharmacies are safe and effective.

Abbott regularly tests samples of each batch of ritonavir produced, which is how the problem was discovered. As of mid-September, the company had not yet been able to resolve the manufacturing difficulties and projected that existing supplies of ritonavir capsules would run out before the problem could be solved.

Abbott will provide pharmacies with the liquid formulation of ritonavir until capsule supplies can be re-established. The amount of drug in four capsules of ritonavir is equivalent to 5 mL (1 teaspoon) of liquid ritonavir; the liquid formulation comes with a measuring cup and instructions for converting capsule doses to tablet doses. Liquid ritonavir should not be refrigerated and should be used within 30 days; shake the liquid well before use. The bad taste of ritonavir liquid can be improved by mixing it with chocolate milk, Ensure, or Advera. When possible, ritonavir should be taken with food to improve its absorption. Once consumed, there should be no differences in effectiveness or side effects between the liquid and the capsules, since the drug's chemical structure is the same in both formulations. For more information, call Abbott at 800-637-2400 or visit the company website at www.norvir.com.

Protease Inhibitors may be Associated with Premature Births

In late July, the National Institutes of Health (NIH) announced that it had temporarily suspended enrollment of pregnant women into perinatal trials of protease inhibitors because it appears that the drugs may increase the risk of premature delivery. Enrollment is being halted for Pediatric AIDS Clinical Trials Group (PACTG) studies 353, 354, 358, and 386. The NIH emphasized that its concerns are based on very preliminary data, and that women currently taking protease inhibitors should continue to do so.

U.S. studies to date have included only a very small number of pregnant women. In PACTG 354 (ritonavir/3TC/AZT), three of five deliveries were premature. No premature births have been seen in PACTG 353 (nelfinavir/3TC/AZT) or PACTG 358 (indinavir/3TC/AZT). At the 12th World AIDS Conference in July, it was reported that in a Swiss study of 37 pregnant women taking combination antiretroviral therapy (16 used a regimen that included a protease inhibitor), 11 premature births occurred (see Highlights on Women and Pregnancy from the 12th World AIDS Conference).

It is unclear whether the premature births are due to protease inhibitor drugs, the use of combination therapy in general, or some other factor(s). The NIH, the FDA, and the PACTG investigators are carefully evaluating the possible causes of the premature births, and physicians are being asked to monitor their pregnant patients taking antiretroviral therapy.

FDA Approves Fomivirsen, Famciclovir, and Thalidomide

In late August, the FDA approved fomivirsen (Vitravene) as a treatment for cytomegalovirus (CMV) retinitis. Formivirsen is an antisense drug that prevents CMV replication by binding to the virus' genetic material; it is the first drug using antisense technology to receive approval. Retinitis is an inflammation of the retina that can to lead to blindness. Clinical studies have shown that fomivirsen halts progression and leads to prolonged remission of CMV retinitis (see Drug Watch, BETA, April 1998). The drug is injected into the eye weekly or every other week. Fomivirsen was developed by Isis Pharmaceuticals and will be marketed by Novartis. Currently FDA approval is limited to use in patients for whom other anti-CMV therapies (e.g., ganciclovir, cidofovir, foscarnet) have failed.

The FDA also approved famciclovir (Famvir) for the treatment of HIV-related herpes simplex virus (HSV) infection. HSV type 1 typically affects the lips ("cold sores"), while HSV type 2 typically causes genital lesions. Famciclovir is the first oral anti-HSV drug to be approved for use in people with HIV-related herpes. Famciclovir is related to acyclovir, and has been shown in studies to be as effective, but it can be taken twice instead of five times daily. The drug is also approved for the treatment of varicella zoster virus infection (shingles).

Finally, Celgene's thalidomide (Synovir) received limited approval in July for the treatment of leprosy. Thalidomide has been used successfully in clinical trials to treat AIDS-relating wasting and recurrent aphthous ulcers (see Drug Watch, BETA, April 1998); although it is not approved for these uses, physicians may prescribe the drug as they see fit. Because thalidomide is associated with birth defects, women taking the drug will be required to use two forms of birth control.

New Breast-Feeding Recommendations

In late July, the United Nations (UN) issued recommendations regarding breast-feeding by HIV-infected women. The issue of breast-feeding was heavily discussed at the Geneva AIDS Conference, and women from developing countries stressed the need for more complete information about the risks of the practice. Under the new recommendations, the UN now discourages breast-feeding by women with HIV. Previously, the agency had been in favor of breast-feeding regardless of HIV serostatus. The change is intended to reduce the transmission of HIV from mother to child in the breast milk. Use of AZT has dramatically reduced vertical HIV transmission, but transmission still occurs through breast-feeding at an estimated rate of 5% in developing countries, according to data published in the August 22, 1998 issue of The Lancet. In some parts of the world, suitable substitutes for breast milk are not available or are not affordable, and women may face stigma if they fail to breast-feed. The UN emphasized that the decision about whether or not to breast-feed must be made by each mother.

New HIV Strain Found in Africa

In September, French researchers announced that they had discovered a new strain of HIV-1. The previously known strains of HIV-1 belonged to either the "M" group or the rarer "O" group. The strains that infect most people in the U.S. (primarily subtype B) and the developing world (subtype E and others) are of the "M" group. The new strain cannot be classified into either the "M" or the "O" group. The strain, designated YBF30, was first found in stored blood from a Cameroonian woman who died of AIDS in 1995; it has since been seen in three other people, all also from Cameroon. The strain appears to be related to both HIV and the simian immunodeficiency virus (SIV), a virus that causes an AIDS-like disease in monkeys. Standard HIV screening tests do not detect the new strain; however, Anthony Fauci, MD, director of the National Institutes of Allergy and Infectious Diseases (NIAID), said that the strain is "unlikely to become a threat to public health." Researchers reported the discovery in the September issue of Nature Medicine.

GP120 Structure Identified

In June, researchers from the Dana-Farber Cancer Institute and Columbia University announced that they had identified the crystal structure of gp120, an HIV envelop surface glycoprotein. The gp120 protein must bind with receptors on human host cells in order for HIV infection to occur. The new 3D X-ray image revealed a so-called "bridging sheet" that binds to the host cell co-receptor CCR5. The gp120 protein structure is surrounded by sugars, which enable it to escape detection by the immune system. The discovery, reported in the June 18, 1998 issue of Nature and the June 19, 1998 issue of Science, will aid researchers in the development of agents that inhibit cell infection by HIV.

California Increases ADAP Funding; SFAF Now an ADAP Site

The California state budget signed by Governor Pete Wilson in late August included a $30 million increase in funding for the AIDS Drug Assistance Program (ADAP), which pays for HIV/AIDS drugs for uninsured or underinsured people with low or moderate incomes. The increase brings the total ADAP budget to $122 million, which has allowed the state to nearly double the number of drugs available through the program. Among the new drugs added are anti-diarrhea medications, anti-depressants, pain relievers, and the hepatitis B vaccine.

In related news, the San Francisco AIDS Foundation is now an ADAP enrollment site. Individuals with incomes less that $50,000 are eligible for some level of ADAP assistance. Photo identification, a letter of diagnosis, and proof of income are required. Both SFAF clients and non-clients can enroll with a financial benefits counselor at the agency's offices at One Sixth Street. To make an appointment, call 415-487-8000, or come to the financial benefits drop-in clinic (Wednesdays and Thursdays, 1:00-3:30 p.m.) for more information.

New Federal Appointments Announced

In July, Health and Human Services Secretary Donna Shalala announced that

Jeffrey P. Koplan will be the new director of the Centers for Disease Control and Prevention (CDC). Koplan's most recent position was president of Prudential

Center for Health Care Research. He had previously worked at the CDC as an epidemiologist for 22 years, and was the first director of the National Center for Chronic Disease Prevention and Health Promotion. His past achievements include helping to eradicate smallpox, working to ensure the safety of the blood supply in the early years of the HIV/AIDS epidemic, and promoting breast and cervical cancer screening. Outgoing CDC director David Satcher is now Surgeon General.

Later the same month, Anthony Fauci announced the appointment of Margaret Johnston as Assistant Director for HIV/AIDS Vaccines at NIAID. She will also act as Associate Director of the Vaccine and Prevention Research Program, part of NIAID's Division of AIDS. Johnston was previously Deputy Director of the Division of AIDS and Scientific Director of the International AIDS Vaccine Initiative. Johnston has emphasized the need for increased government resources for both basic research and vaccine product development.

Obituary: Jonathan Mann and Mary Lou Clements-Mann

Jonathan Mann, MD, and Mary Lou Clements-Mann were among those killed in the crash of Swissair flight 111 on September 2. Mann was a strong advocate for the human rights of people with HIV/AIDS. In 1984, he founded Project SIDA in Zaire. From 1986-1990, he was the first director of the World Health Organization's AIDS Program. In 1992, while working at the Harvard School of Public Health, Mann was chair of the VIII International Conference on AIDS; that conference was moved from Boston to Amsterdam due to U.S. government restrictions on the travel of people with HIV/AIDS. At the time of his death, Mann was dean of the school of public health at the Allegheny University of Health Sciences. Clements-Mann was a involved in HIV vaccine research and was the founder of the Center for Immunization Research at Johns Hopkins University.

12th World AIDS Conference Held in Geneva

Over 13,000 researchers, healthcare workers, people with HIV/AIDS, and advocates attended the 12th World AIDS Conference, held in Geneva, Switzerland, from June 28 through July 3. While the previous conference in 1996 was characterized by optimism about protease inhibitors, the mood in Geneva was more subdued, as participants faced the difficulties of antiretroviral regimens and the reality that resources are unavailable for the majority of the world's people with HIV.

Treatment News

The major news on the treatment front involved protease-sparing regimens, combination therapy that consists of drugs (in particular efavirenz, abacavir, and hydroxyurea) from classes other than the protease inhibitors. These regimens may allow people to avoid side effects associated with protease inhibitors, including body fat redistribution and high blood fat levels, which were a common topic of discussion at the conference.

Researchers also presented data on double protease inhibitor combinations, the use of abacavir in HIV positive children, and results of studies of new, experimental drugs including amprenavir, ABT-378, tipranavir, FTC, FddA, S-1153, and calanolide A.

The importance of adherence in reducing the development of drug resistance -- and of devising simpler regimens with fewer pills and less frequent dosing -- was often emphasized. The International AIDS Society-USA presented updated guidelines for anti-HIV therapy (these appeared in the June 24, 1998 issue of the Journal of the American Medical Association; the British HIV Association published its own updated guidelines in the July 25, 1998 issue of The Lancet). Currently there is no consensus about an overall best regimen or best time to start treatment.

Pathogenesis and Immune Restoration

News was presented about how HIV works and how the immune system fights the virus, which may lead to future treatment and prevention advances. Robert Siliciano, MD, and David Ho, MD, presented conflicting evidence about the decay of HIV in "reservoir" sites such as resting CD4 T-cells. Several researchers discussed the possibility of activating these latently infected cells to "purge" the virus and make it vulnerable to anti-HIV drugs. Anthony Fauci, MD, suggested that it may not be necessary to eradicate all HIV; if viral load can be reduced to a low enough level, the immune system may be able to keep HIV in check.

Fred Valentine, MD, reported that the activity of CD4 T-cells directed against HIV was restored in patients receiving Remune, an experimental HIV treatment vaccine. French researchers reported that immune system improvements can take place even in some people with advanced HIV disease taking HAART. Research was presented about how HIV enters cells using co-receptors. HIV disease appears less likely to progress if a person's HIV can only enter cells through the CCR5 co-receptor; disease progression is more rapid if HIV can use multiple entry points.

AIDS-Related Conditions

Various researchers reported that in the HAART era, the occurrence of opportunistic infections has declined, in some cases by up to 90%. Several reports suggest that it may be possible to safely discontinue Pneumocystis carinii pneumonia (PCP) and cytomegalovirus (CMV) prophylaxis with sustained successful HAART if CD4 T-cell counts rise above 200 cells/mm³. However, people with HIV remain at risk for other illnesses. CDC researchers reported that in the U.S. the occurrence of tuberculosis in HIV positive people is over 40 times higher than in HIV negative people. People with HIV are more likely to have TB both in the lungs and in other parts of the body (see page XX). CDC researchers also presented new information about how sexually transmitted diseases (STDs) can promote the transmission of HIV. In people with certain STDs, epithelial cells lining the cervix and the prostate do not function properly, and gaps form between cells that make it easier for HIV to enter.

Transmission and Prevention

Disturbing news was presented from San Francisco and Switzerland confirming that multidrug-resistant HIV can be transmitted sexually (the San Francisco case was reported in the July 30, 1998 issue of the New England Journal of Medicine). Both the San Francisco and the Swiss cases involved unprotected anal sex between men where the HIV positive partner had been treated with multiple anti-HIV drugs. These findings have important public health implications for both HIV positive and HIV negative persons.

In more optimistic news, researchers confirmed the effectiveness of a short-course AZT regimen in preventing perinatal HIV transmission; such a regimen can reduce mother-to-child HIV transmission by 50%. Others showed that delivery by cesarean section along with AZT can reduce transmission to about 2%. However, infants remain at risk from breast-feeding.

Among men who have sex with men in the U.S., rates of high-risk sexual behavior appear to be increasing, even while the rate of new HIV infections is holding steady.

Bridging the Gap

Peter Piot, MD, of the UN reported that an estimated 31 million people worldwide are infected with HIV and 16,000 more become infected each day. The theme of this year's AIDS conference was "bridging the gap," and many presentations focused on the lack of treatment and care available to people in developing countries, where 90% of people with HIV/AIDS live.

There are also discrepancies in who gets care in developed countries. Researchers from the University of California at San Francisco reported that in that city only about a quarter of the urban poor receive any HIV/AIDS treatment, and only 8% receive protease inhibitors.

Bristol-Myers Squibb, Abbott Laboratories, Roche Laboratories, and Glaxo Wellcome announced that they will provide discounted anti-HIV drugs to developing countries, and the UN announced plans to provide short-course AZT to 30,000 HIV-infected pregnant women in 11 developing countries to prevent mother-to-child transmission; unfortunately, treatment for the women will not be continued after their babies are born.

Page last updated 9 November 1998

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