News Briefs

Liz Highleyman

In This Issue

This issue of BETA focuses on adherence to anti-HIV therapy, with a transcript of Margaret Chesney's talk at the 12th World AIDS Conference in June 1998, and an interview with William Holzemer of the Department of Community Health Systems at the University of California at San Francisco School of Nursing. We also feature articles on body fat redistribution, mother-to-child HIV transmission, and whether it is safe for people on HAART to stop prophylaxis for opportunistic infections. Finally, the issue includes highlights from three recent conferences: the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, the 4th International Congress on Drug Therapy in HIV Infection, and the 36th Infectious Disease Society of America Annual Meeting.

Government Updates HIV Treatment Guidelines

On December 1, the federal Department of Health and Human Services (DHHS) updated its Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Among the major changes was the addition of the newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva) as a "preferred" component of combination anti-HIV therapy; efavirenz is the first non-protease inhibitor drug to be included as a preferred agent. The other approved NNRTIs, nevirapine and delavirdine, were included as an "alternative" recommendation. More information was added about adverse effects of anti-HIV drugs and about drug resistance testing. The Panel on Clinical Practices for Treatment of HIV Infection also affirmed that the goal of anti-HIV therapy should be achievement of a viral load below 50 copies/mL using the most sensitive viral load tests. The full guidelines are available on the web at www.hivatis.org/trtgdlns.html.

CDC Updates TB Treatment Guidelines for People with HIV

In October, the Centers for Disease Control and Prevention (CDC) released its Prevention and Treatment of Tuberculosis among Patients Infected with Human Immunodeficiency Virus: Principles of Therapy and Revised Recommendations. The updated guidelines include recommendations for prevention and treatment of tuberculosis (TB) in people taking combination anti-HIV therapy. These guidelines are important because some anti-TB drugs can interact with certain anti-HIV drugs, notably the protease inhibitors and NNRTIs.

The revised guidelines include three options for treatment of TB in persons taking anti-HIV therapy. The first involves substituting rifabutin for rifampin in a combination anti-TB regimen, and adjusting doses of protease inhibitors and NNRTIs; the second option excludes all rifamycin drugs (e.g., rifampin, rifabutin); and the third option is for people whose anti-HIV regimen does not include any protease inhibitors or NNRTIs. The guidelines do not recommend that people with HIV stop potent anti-HIV therapy in order to begin anti-TB treatment.

The guidelines appeared in the October 16, 1998 Morbidity and Mortality Weekly Report, Recommendations and Reports, Volume 47, #20.

FDA Approves Abacavir

On December 18, 1998, the U.S. Food and Drug Administration (FDA) approved Glaxo Wellcome's new nucleoside analog drug abacavir (brand name Ziagen, formerly 1592) for use in combination anti-HIV regimens for adults and children. Glaxo priced the drug at $3,540 per year wholesale, with a 15% discount for AIDS Drug Assistance Programs (ADAPs); California's ADAP has already added abacavir.

Early clinical trial results up to 24 weeks indicate that abacavir is effective in suppressing HIV replication when used with other antiretroviral drugs. Responses are better in people who have not previously taken nucleoside analogs. Preliminary data suggest that a "protease-sparing" regimen of abacavir plus AZT/3TC may be an effective treatment option for some people. The drug is taken twice daily, one 300 mg tablet per dose, with no food or water restrictions.

Abacavir is generally well-tolerated, with the most common side effects being headache, nausea, vomiting, diarrhea, and malaise. However, the drug can cause a severe hypersensitivity (allergic) reaction in 3-5% of those who use it. People who experience increasing nausea, abdominal pain, fever, fatigue, and/or skin rash within six weeks after starting abacavir should contact their doctor immediately. Once such people stop taking abacavir, they should not restart the drug, since doing so may result in a life-threatening reaction.

3TC and Rebetron Approved for Hepatitis Treatment

In October, an FDA panel unanimously recommended the approval of 3TC (Epivir HBV) for the treatment of chronic hepatitis B. 3TC is a nucleoside analog reverse transcriptase inhibitor that is also used to treat HIV disease; the dose used to treat hepatitis B is one-third lower than that for HIV infection.

In related news, the FDA approved Rebetron for the treatment of chronic hepatitis C in people with no prior use of alpha interferon treatment; the drug was previously approved only for those whose alpha interferon monotherapy had failed. Rebetron is a combination of the antiviral drug ribavirin and interferon-alpha-2B, an immune modulator.

Also in October, the CDC revised and expanded its Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease. The guidelines appeared in the October 16, 1998 Morbidity and Mortality Weekly Report, Recommendations and Reports, Volume 47, #19.

Levy Questions Early Treatment

In the September 9, 1998 issue of The Lancet, Jay Levy, MD, of the University of California at San Francisco questioned the value of early treatment for HIV disease. Levy noted that many anti-HIV drugs have adverse side effects, that regimens are difficult to adhere to, and that the virus is likely to develop resistance if drugs are taken for an extended period of time. He also expressed concern that treatment that begins too early might negatively impact a person's natural immune response, including CD8 cell activity. Levy suggests that treatment should begin when people show clinical symptoms of HIV disease, or when their CD4 T-cell counts fall below 400 cells/mm³ and their viral load is above 30,000 copies/mL on two separate tests. According to Levy, "treatment with antiviral drugs starts the clock ticking too soon, limiting future options and making therapy a necessity for the lifetime for the person." He goes on to ask, "Would we not serve infected people better by reserving certain therapies and administering them at a time when their use is clearly required?" Levy's concerns apply to person who have had HIV for several months or years, not to those with primary or acute HIV infection.

In a response in the December 12, 1998 issue of the journal, Anthony Fauci, MD, John Bartlett, MD, and Eric Goosby, MD, acknowledged Levy's call for caution, but noted that the federal HIV treatment guidelines are intended to be flexible, and should not be interpreted as hard and fast rules for all people with HIV.

IL-2 Flushes Out HIV

In late November, Anthony Fauci, MD, of the National Institute for Allergy and Infectious Diseases (NIAID) made headlines when he announced at the annual meeting of the Infectious Disease Society of America that HIV could not be found in three persons taking a four-drug combination anti-HIV regimen that included three antiretroviral drugs plus high-dose interleukin-2 (IL-2). IL-2 is a cytokine (chemical messenger) that stimulates immune system cells. Resting CD4 cells are a reservoir for latent HIV. IL-2 activates or "flushes out" these cells, so that the HIV they contain is exposed to antiretroviral drugs.

Fourteen patients were treated with the four-drug combination. The researchers examined 10-20 million latent (resting) CD4 cells taken from the participants' blood. Six participants had no evidence of replicating HIV in their CD4 cells. After a more thorough examination of more than 300 million CD4 cells, no evidence of HIV was found in three participants. A lymph node of one participant was also examined, again yielding no trace of replication-competent HIV.

According to Fauci, "Adding interleukins...to the existing three-drug combination to treat AIDS patients totally eliminates the HIV virus from CD4 cells that circulate in the blood." HIV may remain in reservoirs elsewhere in the bodies of these people, for example the brain, gut, or testes. The researchers next plan to take some of the participants off their anti-HIV drug regimens to see if the virus reappears. Fauci cautioned that the results do not indicate a cure, and added that, "It's conceivable that we'll take these people off their drugs and the virus will come roaring back from a reservoir we didn't find." For more details, see "Highlights from Recent Conferences."

Thymus Remains Functional in Adults

In other news from NIAID, researchers reported that the thymus gland appears to remain functional in adults, suggesting that some restoration of the immune system is possible. The report appeared in the December 17, 1998 issue of Nature. The thymus is a gland in the upper chest where new CD4 T-cells learn to recognize invading organisms. The gland shrinks after early childhood, and has been thought to be non-functional in adults. The new research indicates that the thymus continues to produce new CD4 cells once HIV infection is suppressed by anti-HIV therapy. According to Fauci, "This is a very promising finding because it confirms that the thymus is active in adults and potentially can partially reconstitute an HIV-infected individual's T-cells after his or her viral load has been driven down by highly active antiretroviral therapy."

Induction/Maintenance Therapy Unsuccessful

Two recent studies examined at the possibility of using an aggressive initial treatment regimen (induction) followed by less aggressive treatment over the long term (maintenance). The induction/maintenance model is successfully used for cancer treatment. In the case of HIV, however, researchers found that people did better when they stayed on an aggressive combination regimen. The AIDS Clinical Trials Group (ACTG) Study 343 Team and the French Trilege Study Team reported in the October 29, 1998 issue of the New England Journal of Medicine that continued triple-drug therapy with indinavir/3TC/AZT maintains viral suppression better than indinavir monotherapy, indinavir/AZT, or AZT/3TC. The research teams concluded that sustained three-drug therapy is more effective in maintaining an undetectable viral load than monotherapy or two-drug therapy. According to Fauci, "Patients who have responded well to intensive antiretroviral therapy, as evidenced by prolonged suppression of HIV viral load, should continue with their current treatment regimen."

Viral Load Tests May Understate HIV Disease in Women

Researchers have found that viral load test results may mean different things for men and women. A research team from the Johns Hopkins School of Hygiene and Public Health discovered that women at a given stage of HIV disease tended to have lower viral load measurements than men, even if the women's immune systems had sustained the same amount of damage. The report appeared in the November 6, 1998 issue of The Lancet.

The study found that women with a similar number of CD4 cells as men had viral load levels about 50% lower, and that women with the same viral load measurements as men had a 60% greater chance of developing AIDS. The results imply that reliance on viral load tests may lead physicians to assume that women with HIV are healthier than they are. David Vlahov, PhD, of Johns Hopkins, suggested that women have a lower "viral set point" than men and should begin anti-HIV treatment at lower viral load levels. However, other researchers believe that it is premature to change current treatment recommendations for women.

AZT During or After Delivery Prevents Infant HIV Infection

Results reported at the 12th World AIDS Conference last summer confirmed that a short course of AZT could help prevent HIV transmission from mothers to their babies. Now, new research published in the November 12, 1998 issue of the New England Journal of Medicine shows that even less AZT is still effective. Researchers from the New York State Department of Health found that giving AZT during delivery or within 48 hours after birth lowered transmission to newborns by more than half. HIV transmission rates were 6.1% for infants whose AZT treatment started before birth, 10% for infants whose treatment started during delivery, 9.3% for infants treated within 48 hours after birth, and 18.4% for those treated after 48 hours; this compared to a transmission rate of 26.6% for infants that did not receive AZT at all. The results suggest that infants of women who do not receive prenatal care -- including those in developing countries -- may still benefit from later AZT preventive therapy. For more details, see "Strategies for Preventing Late-Term Vertical HIV Transmission."

HIV Remains in Semen

Researchers reported in the December 17, 1998 issue of the New England Journal of Medicine that they had been able to detect HIV DNA in the semen of HIV positive men taking HAART. Because HAART can lower viral load to undetectable levels in the blood plasma, many had hoped that similar viral load decreases would be seen in the semen. The researchers, from Thomas Jefferson University in Philadelphia, found proviral DNA (DNA integrated into the host cell chromosome) in four of seven men who were taking antiretroviral therapy and had undetectable blood viral loads; in two of these men, the HIV was able to replicate. Similarly, researchers from Brown University found that HIV genetic material could still be detected in the genital secretions of 3% of HIV positive women who were taking HAART and had undetectable blood viral loads.

In related news, researchers from North Carolina and Switzerland reported in the October 22, 1998 issue of AIDS that HIV can mutate into different strains in different compartments of the body, such as the blood plasma and semen. The results suggest that antiretroviral drugs are not able to adequately suppress HIV in certain parts of the body such as the genital tract; the brain and the retina are other possible HIV reservoir sites.

The results have implications for HIV prevention, and suggest that people with HIV may still be able to transmit the virus even if they have an undetectable blood viral load.

Reverse Transcriptase Structure Uncovered

Researchers from Harvard University reported in the November 27, 1998 issue of Science that they had uncovered the structure of HIV's reverse transcriptase (RT) enzyme. The RT enzyme is made up of two chains arranged in a configuration that is often referred to as "hand-shaped," having "finger," a "thumb," and a "palm." RT allows retroviruses like HIV to translate their genetic material from RNA into DNA; the new DNA is then inserted into the chromosome of the host cell, allowing the virus to replicate. Drugs that block the RT enzyme inhibit HIV reproduction. However, mutations to the viral gene that produces RT can make HIV resistant to these drugs. The Harvard researchers found that mutations that confer resistance to AZT affect different parts of the RT structure than mutations that confer resistance to drugs like ddI and ddC. The new information about the enzyme's structure may help scientists to better control the development of drug-resistant HIV.

U.S. AIDS Death Rate Decreases by Nearly Half

In October, the CDC's National Center for Health Statistics announced that the rate of deaths due to AIDS in the U.S. decreased by 47% in 1997. There were 16,865 AIDS deaths in 1997 (or 5.9 deaths per 100,000 persons), down from 31,130 in 1996. The decrease caused AIDS to fall from the eight leading cause of death in 1996 to the fourteenth in 1997; for adults age 25-44, AIDS fell from the first leading cause of death in 1995 to the fifth in 1997. The decrease was attributed to potent new anti-HIV drugs and government programs to provide access to them. Robert Schooley, MD, of the ACTG stated, "I would challenge anybody to come up with any single disease that has had such a dramatic change in mortality in such a short period of time." However, the decrease in deaths has not been uniform across different subpopulations.

Despite the good news about decreased AIDS deaths, the overall incidence rate of new HIV infections appears to be holding steady (although it is decreasing for some groups, such as gay and bisexual men, and increasing for others, such as heterosexual injection drug users), indicating that there is a growing number of people living with HIV.

Liz Highleyman is Acting Editor of BETA.

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