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

July 1998 Table of Contents

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BETA News Briefs

By Liz Highleyman

In This Issue

This issue of BETA features articles about advertising of anti-HIV drugs, blood cell deficiencies including anemia and neutropenia, and nutrition in children with HIV disease. This issue's Drug Watch section includes articles on oxymetholone, FTC, cidofovir for the treatment of CMV retinitis, epoietin alfa for anemia, and the newly discovered human chorionic gonadotropin-associated factor.

FDA Rejects Nitazoxanide, Approves TB and Hepatitis Treatments

In May, the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) decided not to recommend approval for nitazoxanide (NTZ, brand name Cryptaz), a treatment for cryptosporidial diarrhea. NTZ manufacturer Unimed Pharmaceuticals presented trial results showing that the drug reduced diarrhea by 50% in over 40% of participants. However, the committee said that it needed more data -- data that is hard to come by now that potent antiretroviral therapy has reduced the number of people with cryptosporidiosis. See the Advocacy section for more information.

In related news, an FDA advisory panel recommended approval of rifapentin (Priftin), Hoechst Marion Roussel's new tuberculosis treatment. Rifapentin is a long-acting formulation of rifampin that can be taken twice weekly (as opposed to daily dosing of rifampin). It is the first new anti-TB drug to be developed in over 25 years.

In June, FDA approved a new combination treatment for chronic hepatitis C. Schering-Plough's therapy, named Rebetron, combines a synthetic version of interferon-alpha (Intron A) and the nucleoside analog drug ribavirin (Rebetol). Both treatments have been used with only marginal success as monotherapy (see "Hepatitis," BETA, January 1998). In clinical trials that included 345 participants, 45% showed no remaining signs of hepatitis C infection after using the combination, compared to under 5% using interferon-alpha alone. The new therapy was approved for use in people who relapse after interferon-alpha monotherapy. The combination can cause serious side effects and is expensive; a 6-month course is $6,000-8,000.

FDA Approves First HIV Urine Test

In June, FDA approved the first test to confirm the presence of HIV antibodies in urine. The new urine test is a Western blot test, as is the widely used confirmatory HIV blood test. In trials, the sensitivity of the new test was 99.7% (that is, it gave the correct result in 746 of 748 samples tested). The test is manufactured by Caltype Biomedical Corporation of Berkeley, CA, and will be marketed by Cambridge Biosciences Corporation. The urine test eliminates the need to draw blood, and thus is cheaper, may encourage testing by people who are afraid of needles, and may reduce the risk to healthcare workers of needlestick accidents that can result in infectious disease transmission. A recent survey found that half of the people questioned would prefer a urine HIV test to a blood test.

Large-Scale HIV Vaccine Trial to Begin This Summer

In early June, FDA authorized the first large-scale trial of an anti-HIV vaccine. The Aidsvax vaccine, made by San Francisco's VaxGen, is based on the gp120 envelope protein of HIV. The Phase III trial is designed to determine the effectiveness of the vaccine in a large population. Tests demonstrating the vaccine's safety and biological activity have already been conducted. In preliminary studies, HIV antibodies were measured in 90% of the HIV-uninfected volunteers receiving the vaccine, indicating that the vaccine stimulated an immune response to HIV. The new trials will include 5,000 volunteers in the U.S. and 2,500 in Thailand. The study will begin this summer in Chicago, Denver, Los Angeles, Philadelphia and St. Louis; it is expected that more sites will be added in the future. The trial will last at least 3 years.

Adefovir Expanded Access Program Broadened

Gilead Sciences has announced that it has broadened the criteria for the expanded access program for its anti-HIV drug adefovir dipivoxil (Preveon). The program now has no limits based on CD4 T-cell counts or viral load, and is open to anyone whose existing combination of anti-HIV drugs has failed and who needs new treatment options. In related news, results of a recent clinical trial show that adefovir is effective in reducing the viral load of hepatitis B virus as well as of HIV. Finally, Gilead has reported to FDA new safety concerns related to the drug's potentially toxic effect on the kidneys. For more information on adefovir, see the Advocacy section. To enroll in the adefovir expanded access program, call 800-GILEAD-5.

Coronary Artery Disease Linked to Protease Inhibitors

Over the past year, increasing numbers of people taking combination anti-HIV drug therapy have reported unusual side effects including high blood fat levels and redistribution of body fat. In May, Keith Henry, MD, and colleagues at the University of Minnesota Medical School reported on 2 cases of premature coronary artery disease in men taking protease inhibitors; a third case has since occurred. The report was published in the May 2 issue of The Lancet. The men were 26 and 37 years old. They saw their doctors after experiencing angina, or chest pain caused by reduced flow of blood to the heart muscle. Both men were found to have occlusions that blocked the arteries supplying their hearts. The older man also had severe atherosclerosis ("hardening of the arteries") and developed a "buffalo hump" (fat accumulation at the base of the neck). Henry subsequently conducted a chart review that revealed that 33% of 124 people taking protease inhibitors had blood fat levels high enough to require treatment. Coronary artery disease has long been associated with high levels of blood fats such as cholesterol, but it usually occurs in older people and develops slowly over many years.

Viagra and Poppers Don't Mix

In April, Pfizer warned AIDS treatment advocates and physicians that its new blockbuster drug Viagra (generic name sildenafil) may lead to dangerous rapid drops in blood pressure when taken with inhalant drugs including amyl and isobutyl nitrite ("poppers"). Viagra is used to treat male erectile dysfunction. Poppers are used recreationally as a sexual enhancer. Both work by dilating blood vessels. Studies have shown that when Viagra is taken with nitroglycerin -- a chemical cousin of poppers that is used to relieve angina pain -- both systolic and diastolic blood pressure decreased. The package insert for Viagra advises against taking the drug with nitrates or nitric oxide donor agents. Blood vessel dilation and the resulting low blood pressure may lead to headache, dizziness, fainting, stroke and heart attack. FDA is investigating several deaths in men taking Viagra that may be associated with drug interactions.

In related news, several activist groups have expressed concern about using Viagra with protease inhibitors, certain antibiotics (e.g., erythromycin) and certain antifungal medications (e.g., ketoconazole). Because the drugs are metabolized by the same CP450 enzyme pathway in the liver, it is possible that Viagra may lower the effectiveness of protease inhibitors, or that protease inhibitors could increase the side effects of Viagra. Pfizer holds that the combinations are not dangerous, but that people using enzyme-inhibiting drugs should consider starting with lower doses of Viagra. Further testing of drug interactions with Viagra is ongoing.

Updated Federal HIV Treatment Guidelines

This spring the federal government updated its Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Among the changes are the addition of the new soft-gel formulation of saquinavir (Fortovase) as a recommended component of combination antiretroviral therapy and the acknowledgement of the benefit of reducing HIV viral load to below 500 copies/mL. For more details, see the Advocacy section and Research Notes. The updated adult and adolescent guidelines appeared in the April 24 issue of Morbidity and Mortality Weekly Report. Updated Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection appeared in the April 17 issue. Both sets of guidelines are available on the web at www.hivatis.org/trtgdlns.html.

New Occupational Exposure Guidelines for Healthcare Workers

The May 15 issue of Morbidity and Mortality Weekly Report published updated Public Health Service Guidelines for the Management of Health-Care Worker Exposures to HIV and Recommendations for Postexposure Prophylaxis. This report consolidates previous guidelines and provides new recommendations regarding post-exposure prevention (PEP) of HIV disease following needlestick injuries and other occupational exposures to blood or body fluids containing the virus. The guidelines are available on the CDC's website at www.cdc.gov/epo/mmwr/mmwr_rr.html or by calling the National AIDS Clearinghouse at 800-458-5231.

HIV Can Resist Most Drugs

A new study by researchers at Stanford University Medical Center indicates that HIV can develop simultaneous resistance to almost all anti-HIV drugs. Robert Shafer, MD, and colleagues analyzed samples of HIV from 4 people who had been treated previously with several antiretroviral drugs. Using genotypic and phenotypic resistance tests, the researchers found that the patients' HIV strains had lost their susceptibility to 10 of the 11 currently appproved anti-HIV drugs -- all but nevirapine (Viramune). The strains also remained vulnerable to 2 new, not-yet-approved drugs, efavirenz (Sustiva) and adefovir. The HIV samples showed evidence of 8 genetic mutations that confer resistance to reverse transcriptase inhibitor drugs and 7 that confer resistance to protease inhibitors. The patients studied by Shafer have had AIDS for 4-9 years. A follow-up study found that 20% of people with HIV/AIDS in the San Francisco Bay Area have virus that is resistant to most anti-HIV drugs. Prior to the "protease inhibitor era," anti-HIV drugs were often started one at a time. Shafer said that patients who have begun treatment more recently with potent combination anti-HIV regimens are less likely to develop resistance. The report was published in the June 1, 1998 issue of Annals of Internal Medicine.

New Adherence Study Results

A recent survey of people with HIV showed that over 40% do not always take their medications as directed, including a quarter who had failed to take drugs as directed the day before they were surveyed. The telephone survey of 665 HIV positive people was sponsored by Dupont Merck, maker of the new anti-HIV drug efavirenz. The 100 physicians who were also surveyed estimated that over 50% of their patients do not take medicines as directed. The doctors also estimated that 6% of prescriptions they write for anti-HIV drugs are never filled. Nearly a quarter of patients reported taking "drug holidays," the length of which increased as people took drug regimens for longer periods. Not taking drugs as prescribed -- even for a short time -- can lead to the development of drug-resistant HIV. According to Joel Gallant, MD, of Johns Hopkins University, "Once resistant strains of HIV are present, the patient's treatment options are narrowed and sometimes entirely exhausted." Both patients and doctors suggested that simpler regimens with fewer daily doses would improve adherence. The results of the survey appear in the May 1998 issue of the Journal of the International Association of Physicians in AIDS Care.

Foscarnet Has Anti-HIV Activity

Foscarnet (Foscavir) is best known as a treatment for cytomegalovirus (CMV) retinitis. Earlier research had shown that patients receiving foscarnet for CMV infection lived longer than those receiving ganciclovir, leading researchers to suspect that foscarnet might have an anti-HIV effect. Now, 2 recent European studies have confirmed that foscarnet reduces HIV viral load. The first study, from France, looked at 17 people with both HIV and another condition such as CMV, herpes simplex, varicella-zoster virus or Kaposi's sarcoma; the patients were taking combination anti-HIV therapy in addition to foscarnet. The second study, from Sweden, evaluated 10 people with HIV but not CMV who were treated with foscarnet. In both studies, HIV viral load was decreased during foscarnet treatment, but increased again when the drug was stopped. Both research teams believe that the anti-HIV effect was due to foscarnet's inhibition of the HIV reverse transcriptase enzyme. The 2 reports were published in the May 1, 1998 issue of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology.

Early HIV Infection May Target Gut

Recent research indicates that HIV may target the gastrointestinal tract early in the course of infection. Tests done on macaque monkeys at Harvard's New England Primate Research Center showed that simian immunodeficiency virus (SIV), a monkey virus related to HIV, destroys immune cells -- including CD4 T-cells -- in the lining of the gut before it attacks immune cells in the blood and lymph nodes. After the monkeys were injected with SIV, researchers found that within a few days the virus had wiped out CD4 cells in the animals' intestines, well before CD4 cell destruction was seen in the blood, lymph nodes or spleen. Most HIV studies to date have focused on the blood and lymph nodes, although the majority of the lymphoid (immune system) tissue in the body is in the gastrointestinal tract. Researchers suggest that the new findings may have implications for HIV vaccine development. The report appeared in the April 17, 1998 issue of Science.

Gene Mutation Links Plague and HIV

Researchers at the National Cancer Institute have suggested that a genetic mutation which protects some people from HIV infection may have arisen as a defense against the bubonic plague, or Black Death. The CCR5-delta 32 mutation leads to the expression of defective co-receptors on the surface of immune cells called macrophages. These defective co-receptors do not allow HIV to enter the cell. About 10% of white Europeans, but few Africans or Asians, have the CCR5 mutation; it is most common in Sweden. By looking at the population distribution and the mutation rate of other genes, researchers estimated that the CCR5 mutation originated 700 years ago in Northern Europe -- a time when the plague was wiping out a large proportion of the local population. Like HIV, the bacteria that causes bubonic plague (Yersinia pestis) attacks macrophages; it may be that the CCR5 mutation evolved to protect these cells from infection.

California Adds Funds, Drugs to ADAP

In May, California governor Pete Wilson released his new budget which would increase funding for the state's AIDS Drug Assistance Program (ADAP) by $31.7 million. In reviewing the ADAP budget, the state legislature proposed increasing the governor's funding level by $4.2 million, bringing the total California ADAP budget to $126.2 million. The new funds should help ensure access to the program and allow for the addition of more drugs to the ADAP formulary (for the complete formulary, see Drugs Covered by the California ADAP). Hydroxyurea, an anti-cancer drug that was recently shown to produce a sustained reduction in viral load when used in combination with ddI and d4T (see Research Notes, BETA, April 1998) was recently added. The ADAP Medical Advisory Committee has recommended adding several other drugs including oxandrolone, paclitaxel, antidepressants and anti-diarrhea drugs.

New FDA Director Nominated

On June 24, President Clinton nominated Jane E. Henney as the new commissioner of the FDA. From 1992 to1994, Henney served as deputy commissioner under David A. Kessler. Henney, a physician and cancer researcher, is currently Vice President for Health Sciences at the University of New Mexico; she previously worked at the National Cancer Institute. Before her term as head of FDA begins, Henney's nomination must be approved by the Senate.

New Federal AIDS Research Director Named

On May 18, Neal Nathanson, MD, was appointed as the new director of the Office of AIDS Research (OAR) at the National Institutes of Health (NIH). Nathanson is an expert in viral pathogenesis and also has experience in epidemiology and public health. He has worked at the Centers for Disease Control and Prevention, the Johns Hopkins School of Hygiene and Public Health, and the University of Pennsylvania Medical Center. Nathanson is a member of the NIH AIDS Vaccine Research Committee. The OAR coordinates federally-funded HIV/AIDS research.

Needle Exchange Funding Denied

On April 20, Department of Health and Human Services Secretary Donna Shalala announced that the scientific literature shows that needle exchange programs reduce HIV transmission and do not encourage the use of injection drugs. At the same time, the Administration stated that it would not allow federal funds to be used for needle exchange programs. Shalala urged cities and states to fund needle exchange programs with local or private resources. Soon after Shalala's announcement, the U.S. House of Representatives passed legislation that permanently bars federal funding for needle exchange programs; the U.S. Senate has added a similar provision as an amendment to another bill. Previously the decision had been in the hands of the Administration.

CDC: HIV Infection Rate Holds Steady

The Centers for Disease Control and Prevention reported in April that HIV continues to spread, even though the rate of new AIDS cases and deaths has declined. The drop in AIDS cases is due to new combination anti-HIV drug regimens that prevent many people with HIV from developing AIDS. However, new HIV infections continue to occur at a steady rate. In 1996, AIDS deaths declined by 21%, while new HIV infections decreased by just 2% from 1995 to 1996. Nationwide, the HIV incidence rate among women increased by 3%, while the rate for men decreased by 3%.

Page last updated 9 July 1998