Published in the Bulletin of Experimental Treatments for AIDS Summer 1999 issue, by the San Francisco AIDS Foundation.

Summer 1999 Table of Contents

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News Briefs

By Liz Highleyman

In This Issue

This issue of BETA features articles on a broad range of current topics, including resistance testing ("Genotypic and Phenotypic Resistance Testing"), global reports on nutrition and HIV infection ("Nutrition and HIV Infection") and the perspectives on HIV of Jay A. Levy, MD, the preeminent virologist and HIV researcher. The article "Sexual Transmission of HIV in the Era of New Treatments" examines biological factors involved in the transmission of the virus and how these may be impacted by highly active antiretroviral therapy (HAART).

FDA Approves Reformulated Ritonavir (Norvir) Capsules

On June 30, Abbott Laboratories announced that their soft-gelatin capsule formulation of ritonavir had received Food and Drug Administration (FDA) approval. The new capsule has been tested for stability and will require refrigerated storage (between 36° and 46° F) until sold or distributed directly to persons for use. People with HIV who obtain the capsules are advised to store them in the refrigerator, although if the capsules will be used within 30 days and can be stored below 77° F, refrigeration is not necessary.

For those already taking the drug, the transition from liquid to soft-gel ritonavir is expected to be smooth. Ritonavir is approved for twice daily dosing and should be taken with food. It should not be taken with certain other drugs including some antihistamines and sedatives (see chart in this issue of BETA on page 52). For full prescribing information, see www.rxabbott.com/product/nor/norpi.htm.

AZT (Retrovir) Associated with Rapid Progression in Children

In the May 28, 1999 issue of AIDS, Maurizio de Martino and colleagues from the University of Florence, Italy, reported that HIV disease progression was rapid in infants whose mothers were treated with AZT during pregnancy. The study included 216 children who were infected by vertical (mother-to-child) transmission of HIV between 1992 and 1997; 38 of the mothers had received AZT monotherapy during pregnancy, while the rest had received no antiretroviral drugs. Results indicate that the children of the mothers who took AZT had a significantly lower three-year survival rate compared to children of the mother who received no drugs. The children of the AZT-treated mothers also had higher rates of severe immune suppression and clinical disease.

Activists Caution about Vitamin E in Amprenavir (Agenerase)

In June, AIDS treatment activists issued an alert that amprenavir, Glaxo Wellcome's recently approved protease inhibitor, contains d-alpha tocopherol, a form of vitamin E. D-alpha tocopherol is added to improve the bioavailability of the drug. Amprenavir contains the equivalent of 387 international units (IU) of vitamin E per gram, and a typical daily dose of the protease inhibitor adds up to 1,744 IU of the vitamin. Excess vitamin E can inhibit blood clotting. It is not expected that the use of amprenavir will lead to a vitamin E overdose, but doctors and people taking the drug should exercise caution when considering the use of blood-thinning agents or additional vitamin E supplementation.

HIV Persists in People Taking HAART

Two studies published in the May 27, 1999 issue of the New England Journal of Medicine indicate that HIV remains in the body despite HAART. While HAART eliminates most of the virus in the bloodstream, HIV can persist in latent CD4 T-cells. Likely HIV reservoirs include the brain, eyes, and testes, which are protected areas that are not easily reached by drugs.

One study, by Manohar Furtado and colleagues from Northwestern University Medical School, showed that new cells continue to be infected with HIV almost as fast as currently infected cells are killed off, even in persons taking prolonged HAART. According to Furtado, the results suggest that this represents "a serious impediment to the long-term goal of eradication." In the second study, by Lingi Zhang and colleagues from the Aaron Diamond AIDS Research Center in New York, genetic markers indicating replication-competent HIV could be detected in two of eight participants who had maintained unquantifiable blood viral load levels for two to three years. Zhang estimated that seven to ten years of HAART would be required to eliminate completely the reservoir of virus, but said it would be "difficult to maintain treatment for such a long time." In a related study published in the May 1999 issue of Nature Medicine, P. Finzi and colleagues examined the "decay rate" of inactive HIV in 34 persons on HAART with unquantifiable viral loads and estimated that complete virus eradication could take as long as 60 years.

In an editorial in the same issue of the New England Journal of Medicine, Roger Pomerantz, MD, of Thomas Jefferson University suggested that HIV treatment might follow a cancer chemotherapy model, with intensive HAART given as induction therapy, followed by maintenance therapy (possibly including interleukin 2 [IL-2] and hydroxyurea) focused on eliminating residual HIV.

HIV Rebounds During Drug Holidays

In May, a study sponsored by the National Institutes of Health (NIH) revealed that HIV replication begins again soon after HAART is discontinued. According to study author Richard Davey of the National Institute of Allergy and Infectious Diseases (NIAID), "Just within a matter of several weeks, a sizable amount of viral relapse is being seen."

In a related study, Richard Harrigan and colleagues from St. Paul's Hospital in Vancouver, Canada, reported in the May 28, 1999 issue of AIDS that HIV replication rebounded six to 15 days after the discontinuation of HAART in six persons with unquantifiable viral loads. The participants' viral load levels after stopping HAART reached or exceeded pre-treatment levels within 21 days.

These findings are a disappointment to those who had hoped that intermittent therapy alternating with "drug holidays" might keep HIV in check over the long term, or that taking a break from drugs might enhance the immune system's natural ability to fight the virus. However, more promising results presented by Veronica Miller of Goethe University in Frankfurt, Germany, suggest that in some people, drug holidays may cause drug-resistant strains of HIV to be replaced by more drug-sensitive virus.

More IL-2 Results

This past November, Anthony Fauci, MD, of NIAID reported at the annual meeting of the Infectious Disease Society of America that IL-2 could "flush out" latent HIV from CD4 cells, making the virus vulnerable to drug treatment.

Two recently published studies shed more light on the use of the cytokine. A study by Y. Levy and colleagues from the Hôpital Henri Mondor in Paris, published in the June 5, 1999 issue of the Lancet, showed that IL-2 led to an 80% increase in CD4 cells in 68% of participants receiving subcutaneous (under the skin) IL-2, and in 77% of participants receiving intravenous IL-2. The 94 participants were taking only AZT or ddI, not combination HAART. The researchers reported that subcutaneous administration was better tolerated than intravenous IL-2.

The study that Fauci reported on in November appeared in the June 1999 issue of Nature Medicine. Tae-Wook Chun and colleagues from NIAID compared 14 participants receiving HAART plus IL-2 to 12 participants receiving HAART alone. The researchers found that the number of latent CD4 cells decreased in those receiving IL-2, suggesting that the cytokine had activated these cells.

HAART May Help Rebuild the Immune System

A report in the May 1999 issue of the Proceedings of the National Academy of Sciences suggests that HAART may help rebuild immune systems damaged by HIV. Ashley Haase, MD, and colleagues from the University of Minnesota concluded that "even when pummeled by HIV for years, key elements of the immune system not only regenerate, but flourish" when HIV viral load is reduced by the use of potent antiretroviral therapy. The researchers found that the number of follicular dendritic cells, a type of immune system cell, increased in 20 participants with advanced HIV disease taking HAART.

Protease Inhibitors Effective against HIV Subtype C

In May, researchers from Stanford University Medical Center reported that protease inhibitor drugs were effective against HIV subtype C, the most prevalent subtype worldwide. The drugs were initially developed and tested against subtype B, which is most common in the U.S. and Western Europe. In a study conducted in Zimbabwe, five isolates of HIV subtype C were shown to be equally susceptible to protease inhibitors.

Federal Treatment Guidelines Updated

In May, the federal government once again released updated Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. The revised guidelines include information on the use of abacavir (Ziagen) in combination regimens and the use of hydroxyurea, as well as a comprehensive table of interactions between antiretrovirals and other drugs. Abacavir-containing, protease-sparing combinations are recommended as "alternative" rather than "preferred" regimens at this time. Information about amprenavir and about rates of HIV disease progression in women are expected to be included in a future revision. The most recent guidelines can be found online at www.hivatis.org/trtgdlns.html.

Stress Hastens Development of AIDS

Researchers recently reported that HIV disease progression is accelerated by stress and lack of social support. Jane Leserman, PhD, and colleagues from the University of North Carolina School of Medicine studied 82 HIV positive men over the course of five and a half years. Men who had more than average stress or less than average social support progressed to AIDS two to three times faster than men with less than average stress or more than average support. According to Leserman, the research shows that "for every increase in cumulative average stressful life events-equivalent to one severe stressor or two moderate stressors-the risk of AIDS was doubled." The research was published in the June 1999 issue of Psychosomatic Medicine.

Nef-Deleted HIV Still Progresses

In June, Australian researchers reported that a group of persons infected with an attenuated (weakened) strain of HIV appeared to be experiencing disease progression and immune system damage. The group, known as the Sydney Blood Bank Cohort, includes a blood donor and eight people who were infected before 1985 via transfusions of his blood. All were infected with the same strain of HIV, which lacks a functioning nef gene. For several years the cohort appeared free of disease progression. However, the latest report on the cohort, which appeared in the June 3, 1999 issue of the New England Journal of Medicine, indicates that three persons (the original blood donor and two recipients) have developed signs of progression, including detectable viral loads and declining CD4 cell counts. Three other cohort members show no signs of virological or immunological progression. The findings are a disappointment to those who had hoped that an attenuated strain of HIV might be used as a safe AIDS treatment vaccine. In an editorial in the same issue, vaccine researchers Kathleen Collins, MD, and Gary Nabel, MD, said the current report "adds to the evidence...that attenuated viruses as vaccines are going to be more complicated than we had originally expected."

Gynecological Problems Common in Women with HIV

In April, Howard Minkoff and colleagues from Maimonides Medical Center in New York reported in the American Journal of Obstetrics and Gynecology that women with HIV have higher rates of gynecological disorders than HIV negative women do. These disorders include sexually transmitted diseases (STDs) such as human papillomavirus (HPV) and syphilis; fungal infections such as candidiasis; menstrual problems such as amenorrhea; and abnormal Pap smears. About two-thirds of the HIV-infected women studied had at least one gynecological disorder, while about one-third had more than one. Rates of candidiasis, herpes simplex, and cytomegalovirus (CMV) infection were highest in women with low CD4 cell counts.

Researchers from the Women's Interagency HIV Study (WIHS) obtained similar results. WIHS involved 2,058 HIV positive and 567 HIV negative women at 23 U.S. sites. Ruth Greenblatt and colleagues from the University of California at San Francisco (UCSF) found that rates of all STDs except bacterial vaginosis and chlamydia were higher in HIV positive than in HIV negative women. The researchers also found that STD symptoms grew worse as CD4 cell counts declined. Both research teams recommend that HIV positive women receive careful and regular medical evaluations to detect gynecological conditions.

Anal Pap Smears Recommended for Gay Men with HIV

Researchers reported in the May 19, 1999 issue of the Journal of the American Medical Association that anal Pap smears can reduce the risk of cancer in men who engage in receptive anal sex. Pap smears have greatly reduced the rate of deaths due to cervical cancer in women, and the new research suggests that they also may be a cost-effective way to detect precancerous changes and early anal squamous cell (a cell found in the skin and mucosal membranes) cancer in HIV positive men; both anal and cervical cancer are associated with HPV infection. According to author Joel Palefsky, MD, of UCSF, "Unlike other cancers in HIV positive men, this cancer is potentially preventable." The researchers recommend annual Pap smear screening of gay and bisexual men in order to catch the disease at its earliest, most treatable stages. The rate of anal cancer is 0.8 per 100,000 in the population as a whole, but 35 per 100,000 among HIV negative gay and bisexual men, and about 70 per 100,000 among HIV positive men who have sex with men.

Panel Recommends Suspension of Remune Trials

In May, a Data Safety Monitoring Board recommended ending phase III trials of Remune, also known as the Salk vaccine, after no significant differences were found between groups receiving Remune and groups receiving a placebo. Remune is an AIDS treatment vaccine that is intended to boost the immune system and reduce illness in people already infected with HIV. Immune Response Corporation and Agouron Pharmaceuticals, the makers of Remune, suggested that the lack of results was due to the fact that many subjects had begun HAART after the Remune trial began, which tended to mask any beneficial effects of the vaccine. Because HAART has reduced clinical endpoints (opportunistic infections [OIs] and deaths) to such a low level, Immune Response and Agouron plan to focus on studies that instead will look at surrogate markers, such as CD4 cell counts and HIV viral loads.

New Nonoccupational PEP Registry

On June 7, the Centers for Disease Control and Prevention (CDC) announced the opening of the National Nonoccupational HIV Postexposure Prophylaxis (PEP) Registry. The purpose of the registry is to monitor the incidence of HIV exposure due to sexual contact and injection drug use, and to see whether PEP appears effective in preventing infection. The registry will collect data regarding the type of exposure, whether or not the recently exposed person chose to use PEP, and, if so, which drugs were used. The registry is anonymous, and no identifying information will be collected. The new registry joins an existing registry for occupational HIV exposures such as accidental needlesticks.

Senate Approves Medicaid for Working Disabled

On June 16, the Senate unanimously passed the Work Incentives Improvement Act, which would extend Medicaid coverage for working persons with disabilities. The legislation would allow low-income disabled people to retain their Medicaid coverage for up to ten years when they take a job, and would allow those with higher incomes to buy into Medicaid on a sliding-scale basis. Currently many people lose their Medicaid coverage when they take a job, even if the job does not provide adequate health-care coverage. The legislation also includes a demonstration project offering Medicaid coverage to people with HIV and other illnesses whose disability is not currently considered advanced enough to qualify for benefits. The new program is expected to cost $800 million over five years. The House version of the bill is currently under consideration as legislators debate how to fund the measure.

MMWR Reports OI Declines

In the April 16, 1999 issue of Morbidity and Mortality Weekly Report (MMWR), the CDC reported that rates of 15 OIs have declined significantly from 1992 to 1997. Data was compiled from the Adult/Adolescent Spectrum of HIV Disease (ASD) surveillance project, which collects data from 11 U.S. cities. Over the five-year period, OIs were diagnosed in 12,984 people with HIV. Men, who made up 82% of the survey, were more likely to have Kaposi's sarcoma (KS), cryptococcosis, and CMV disease. Women, who made up 18% of the survey, were more likely to have esophageal candidiasis, recurrent pneumonia, tuberculosis, and herpes. Although HAART has reduced OI rates substantially (see BETA, January 1999), the CDC stated that OIs are still occurring, especially when people access health care late in the course of HIV disease, develop drug-resistant HIV, adhere poorly to treatment, or do not receive prophylaxis (preventive treatment) for specific OIs.

AIDS Hospitalizations Drop

New data from the CDC's National Center for Health Statistics indicate that hospitalization rates for people with HIV disease and AIDS in the U.S. have decreased. In 1997 there were 71,000 fewer hospitalizations of people with HIV compared to 1995, a drop of 30%. In addition, HIV positive persons who were hospitalized in 1997 stayed for shorter periods of time, resulting in a 40% decrease in total inpatient days. In the western U.S., the decline in hospital visits by people with HIV reached 60%.

Liz Highleyman is a freelance writer based in San Francisco and a former member of the BETA editorial staff.

Page last updated 5 October 1999