Journal Watch

Date: March 1, 1996
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

HIV-infected men who maintain their weight prior to an AIDS diagnosis live longer than men who lose too many pounds, according to a recent report from the NIAID-supported Multicenter AIDS Cohort Study (MACS).

In the study, 962 HIV-infected men were examined twice a year for up to 8.5 years. Those who maintained their weight lived for a median of 1.48 years after being diagnosed with AIDS, while those who lost more than 10 percent of their body weight three to nine months before developing AIDS lived for a median of 1.05 years following an AIDS diagnosis.

Previously, severe weight loss in patients with AIDS has been shown to predict early death. The new research extends these findings by demonstrating that even moderate weight loss before AIDS also may result in shorter survival. Neil Graham, M.D., of The Johns Hopkins School of Hygiene and Public Health and his colleagues reported their findings in the November 1995 Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology.

The new research underscores the need to assess the potential survival benefits of therapies that reduce HIV-related weight loss, the authors write. Therapies currently under study by NIAID-supported investigators and others include growth hormones, appetite enhancers and agents that suppress tumor necrosis factor (an immune system protein that contributes to weight loss in HIV-infected people).

The MACS is one of the largest prospective HIV studies in the world. More than 5,000 homosexual and bisexual men were enrolled into the MACS between 1983 and 1991 at sites in Baltimore, Los Angeles, Pittsburgh and Chicago. Each volunteer is seen every three to six months for an assessment of their virologic, immunologic, clinical, behavioral and neurological status.

Two-Drug Treatment Effective Against Recurrent CMV Retinitis

For HIV-infected patients with repeated episodes of cytomegalovirus (CMV) retinitis, daily intravenous administration of both foscarnet and ganciclovir is more effective than either drug alone, according to a randomized study of 279 patients sponsored by the National Eye Institute, NIAID and the National Center for Research Resources.

Among patients who received both drugs, CMV retinitis was controlled for about four months on average, while those treated with either foscarnet or ganciclovir alone suffered recurrences in one to two months on average. The combination treatment was associated with the smallest reduction in a patient's field of vision, but visual acuity was preserved equally well in all patients receiving the drug regimens tested.

Combination therapy was much better than treatment with either foscarnet or ganciclovir alone in controlling the progression of CMV retinitis," says study chairman Douglas A. Jabs, M.D., of The Johns Hopkins University School of Medicine. "However, combination therapy was more inconvenient, required two infusions, and will be more expensive. But for those patients who have suffered a relapse of their retinitis and can tolerate combination therapy, its improved control of the disease offers distinct advantages."

Dr. Jabs and his colleagues reported their findings in the January issue of Archives of Ophthalmology.

3TC Treatment May Slow HIV Mutations, Development of Drug Resistance

In HIV-infected patients treated with the drug 3TC (lamivudine), the virus develops a specific mutation (M184V) that confers resistance to 3TC but also decreases the rate at which subsequent mutations develop, according to NIAID grantee Vinayaka R. Prasad, Ph.D., of the Albert Einstein College of Medicine and his colleagues. The finding has possible implications for therapy because HIV's high mutation rate ordinarily allows the virus to evade the immune system and become resistant to drugs.

The research represents a collaborative effort between the groups of Dr. Prasad and Mark Wainberg, Ph.D., of the McGill AIDS Center, Montreal, Canada.

"We can now imagine a combination therapy that would involve first administering 3TC and then waiting until all the viruses have developed this mutation," says Dr. Prasad. "Then, once the virus's ability to mutate further was held in check, we could add a second drug directed against another viral component. In such a scenario, the viral population would not only be sensitive to the second drug, but less likely to become resistant to it as well."

As reported in the March 1, 1996 Science, Dr. Prasad and his colleagues observed that the M184V mutation in reverse transcriptase, in addition to causing resistance to 3TC, also increases the "fidelity" or accuracy of reverse transcriptase, thereby diminishing genetic diversification. An advantage of the slowed genetic variation could be a reduced rate at which immunological escape variants would arise.

"The benefits of a slowed rate of variation of HIV may be tremendous in terms of the immune system's ability to suppress HIV," says Dr. Prasad.

In cell culture experiments, the researchers found that HIV with the M184V mutation, unlike wild-type HIV, did not develop drug resistance in the presence of AZT, d4T, nevirapine, delavirdine or saquinavir. Further experiments will determine the relevance of this observation for care of HIV-infected individuals.

Miscarriage More Likely in HIV-Infected Women

HIV-infected women are three times more likely to experience a miscarriage than healthy women, according to a report by NIAID-supported researchers in the December 1995 Journal of Infectious Diseases.

William T. Shearer, M.D., and his colleagues at Baylor College of Medicine followed 124 HIV-infected women from the time they learned of their pregnancy. More than 11 percent of these women had miscarriages, compared to a typical rate of less than 3 percent for non-HIV-infected pregnant women.

The investigators detected HIV in the tissues of 60 percent of the spontaneously aborted fetuses. In contrast, approximately 10 to 30 percent of infants born to HIV-infected women with full-term pregnancies are HIV-infected.

In the pregnancies that ended in miscarriage, researchers observed significant damage to the thymus glands of the HIV-infected fetuses. The thymus is central to the development of an infant's immune system.

The researchers suggest four possible factors that alone or in combination contribute to fetal demise in HIV-infected women:

  • Direct toxic effects of HIV on the fetus
  • Fetal thymic dysfunction
  • Placental changes
  • Elevated uterine levels of the inflammatory cytokines IL-4, IL-6 and TNF.

"All of this is significant," says Dr. Shearer, who is the principal investigator of the Pediatric AIDS Clinical Trials Unit at Texas Children's Hospital in Houston. "If inflammatory cytokines are involved in the miscarriages, we may be able to develop drug therapies that lower levels of these cytokines."

Blacks, Hispanics Not at Increased Risk for AZT Side Effects

Black and Hispanic patients with HIV are not more likely than white HIV-infected patients to suffer AZT-related side effects, according to a new analysis of data from two large NIAID-supported studies of AZT monotherapy.

Mark Jacobson, M.D., of the University of California, San Francisco/San Francisco General Hospital and his colleagues reviewed the records of 1,801 white/non-Hispanic, 195 black and 214 Hispanic patients who participated in ACTG 016 and ACTG 019.

The investigators' analyses, reported in the January 1996 Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, revealed only minor differences between the three ethnic groups in subjective AZT intolerance. The differences were not clinically important, the investigators concluded.

Several studies have shown that black and Hispanic patients with HIV disease are more likely than white patients to do poorly because of delayed treatment. Because of this disparity, education about the relative risks of side effects for patients of different ethnic/racial origin is needed to ensure uniform access to appropriate drug therapy for HIV disease, the authors write.

"Because AZT is a part of many current anti-HIV treatment regimens, this study has important implications for primary care providers in helping patients make informed choices about treatment options," says Jack Killen, M.D., director of NIAID's Division of AIDS.

AZT Reduces HIV Risk Following Needle Sticks

Post-exposure prophylaxis with AZT decreased by an estimated 79 percent the risk of HIV infection in healthcare workers exposed to infected blood, according to a retrospective case-control study reported by the Centers for Disease Control and Prevention. The study appears in the Dec. 22, 1995 Morbidity and Mortality Weekly Report.

The researchers determined that the risk of HIV transmission from an HIV-infected patient to a healthcare worker was greatest when the worker suffered an injury that was deep; that was caused by a device visibly contaminated with a patient's blood; or involved a needle inserted directly into the worker's vein or artery.

The investigators also found an elevated risk for healthcare workers exposed to the blood of patients with terminal illness, perhaps reflecting the large amount of virus generally found in a patient's blood late in the course of HIV disease.

The Public Health Service is evaluating these findings and other available information in assessing the need for revisions of current recommendations regarding post-exposure use of antiretroviral agents.

Putative KS Virus Grown in Laboratory

A herpesvirus thought to cause Kaposi's sarcoma (KS) has been grown for the first time in the laboratory, an advance that may facilitate the development of new diagnostic tests and specific antiviral treatments for the virus.

KS is commonly seen in homosexual men with HIV disease, and less frequently in other HIV-infected people and in individuals taking immunosuppressive drugs. KS also occurs among many African populations, with or without HIV, and among elderly men from the Mediterranean region. The disease is characterized by purplish, sometimes disfiguring lesions that can occur on the skin and many body organs.

Researchers at the University of California, San Francisco, grew the virus, known as Kaposi's sarcoma-associated herpes virus (KSHV), in a special cell line derived from a rare lymph system cancer.

The investigators, led by Don Ganem, M.D., and supported by the Howard Hughes Medical Institute, NIAID and the National Cancer Institute, report their findings in the March 1995 Nature Medicine. In the same article, the researchers present the first published photographs of the virus.

Other investigators, including NIAID grantee Gary Nabel, M.D., Ph.D., of the University of Michigan, also have grown KSHV to high titers in cell cultures, as discussed at a recent Keystone Symposium on HIV pathogenesis.

KSHV, the eighth herpesvirus linked to human disease, was first described in 1994 (see Science 266: 1865-1869) after growing epidemiologic evidence led many to conclude that KS had an infectious etiology.

Although the role of KSHV in KS is still being debated, "the circumstantial evidence implicating this herpesvirus in Kaposi's sarcoma is strong," says Dr. Ganem. "During the past year it has become clear that KSHV DNA appears in KS tumors far more often than in normal tissue, and that it also occurs at a higher rate in individuals with AIDS compared with those without AIDS. Furthermore, AIDS patients exhibiting genetic evidence of KSHV infection are more likely to later develop KS than those who appear uninfected by KSHV."

--Greg Folkers