New ACTG 076 Analysis Emphasizes Importance of Offering AZT Therapyto All HIV-Infected Pregnant Women

National Institute of Allergy and, Infectious DiseasesEMBARGOED FOR RELEASE, Wednesday, Nov. 27, 1996, 5:00 PM Eastern Time, Greg Folkers, [email protected]

Transmission of HIV from a pregnant woman to her infant can occur when a woman has little or no detectable HIV in her blood and a relatively intact immune system, according to a new report by researchers supported by the National Institutes of Health (NIH).

However, in the study a specific regimen of the drug zidovudine (AZT) reduced the risk of perinatal transmission, regardless of a woman's viral load or CD4+ T cell count. Therefore, researchers urge caregivers to offer AZT therapy to all pregnant HIV-infected women, regardless of their stage of disease.

"HIV transmission to the infant is most likely to occur when a woman has large quantities of virus in her bloodstream, but there appears to be no absolute threshold of maternal viral load below which HIV is not transmitted from mother to infant, nor a 'safe' maternal CD4+ T cell level above which transmission never occurs," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID).

"These new data underscore the importance of following the Public Health Service recommendations to offer therapy to all HIV-infected women and their babies, including women who have high CD4+ T cell counts and those with low viral load," says Jack Killen, M.D., director of NIAID's Division of AIDS.

Rhoda S. Sperling, M.D., associate professor of obstetrics, gynecology and reproductive science at Mount Sinai School of Medicine in New York, and her colleagues report the new findings in the Nov. 28 issue of The New England Journal of Medicine.

The researchers found that the reduction in perinatal transmission after AZT treatment could only partially be explained by the drug's effect of reducing HIV in a mother's bloodstream.

"The benefits of AZT in reducing perinatal transmission appear to be due in part to mechanisms other than decreasing the amount of HIV in a woman's plasma," says Dr. Sperling. "Even when antiretroviral drugs with a greater impact on reducing viral load are indicated for the health of a pregnant HIV-infected women, she and her physician should strongly consider incorporating AZT into her treatment regimen, and should continue AZT during delivery and to the newborn, according to the ACTG 076 protocol."

"Further research is needed into the mechanisms whereby AZT reduces perinatal HIV transmission, as well as into the risk factors for transmission at all levels of maternal viral load," she adds.

A related editorial by Catherine M. Wilfert, M.D., of Duke University Medical Center appears in the same issue. Dr. Sperling and Dr. Wilfert are investigators within the Pediatric AIDS Clinical Trials Group, a nationwide network of clinical trials sites sponsored by NIAID and the National Institute of Child Health and Human Development (NICHD).

The current article is the second publication from a randomized, double-blind clinical trial known as ACTG 076. The study enrolled 477 pregnant, HIV-infected women between April 1991 and December 1993, and assessed the safety and efficacy of AZT in reducing the risk of maternal-infant transmission. Women enrolled in the study had CD4+ T cell counts greater than 200 cells/mm3 of blood at study entry. They received AZT beginning in the second or third trimester of pregnancy and during labor and delivery; their newborns received the drug for the first six weeks of life.

The first publication from ACTG 076 analyzed data from 363 mother-infant pairs in which at least one culture of the infant's blood had been performed, and demonstrated that the AZT regimen reduced mother-to-infant transmission by approximately two-thirds, with minimal short-term toxic effects (see The New England Journal of Medicine, 11/03/94).

The current analysis of ACTG 076 data included 402 mother-infant pairs in which the HIV infection status of the infant was definitively known at 18 months of age. Among the mother-infant pairs, 198 had been assigned to receive AZT during the study and 204 had been assigned to the placebo group. Fifteen infants in the AZT group (7.6 percent) were HIV-infected; in the placebo group, 46 infants (22.6 percent) were HIV-infected.

The investigators tested stored samples of maternal blood collected when women entered the study and when they delivered their infants. For their analyses, the researchers used two sensitive assays not available at the start of ACTG 076, the branched DNA assay and a reverse transcription PCR assay. Each of these assays is used to measure levels of HIV's genetic material -- HIV RNA -- in a person's bloodstream. These levels of virus are also referred to as a person's "viral burden" or "viral load." In addition, the researchers cultured the mothers' blood samples for the presence of HIV.

In both the AZT and placebo groups, perinatal transmission occurred within a wide range of maternal HIV RNA levels, including instances when women had undetectable levels of HIV in their bloodstreams as well as when women had viral loads greater than 100,000 RNA copies per milliliter of blood.

In the placebo group, a high maternal viral load at study entry or at delivery, or a positive blood culture, was associated with an increased risk of transmission. Among the quarter of women with the highest viral loads, the rate of transmission was more than 40 percent. The investigators also found that transmission was more likely when a woman not receiving AZT had a low CD4+ T cell count. However, even among 119 untreated mothers with CD4+ T cell counts above 500/mm3, the transmission rate was 21 percent.

In the treatment group, AZT therapy reduced median maternal HIV RNA levels 1.7-fold between study entry and delivery. This modest change, however could not account for the substantially reduced transmission rate in the AZT group, a benefit that was observed regardless of maternal viral load and CD4+ counts.

Background

Following the dissemination of ACTG 076 study results in 1994, the Public Health Service published guidelines for the use of AZT to prevent perinatal HIV transmission and for HIV counseling and voluntary testing for pregnant women. Other organizations in the public and private sector also launched campaigns to translate the ACTG 076 findings into prevention programs.

These efforts have been successful, according to a number of recent studies. For example, in a national study conducted by the U.S. Centers for Disease Control and Prevention (CDC), rates of HIV infection among infants born to HIV-infected women dropped from 21 percent before the 1994 PHS guidelines to 11 percent in 1995.

New data indicate that perinatal prevention efforts also have dramatically reduced AIDS cases in children. On Nov. 21, 1996, CDC released in the Morbidity and Mortality Weekly Report (MMWR) information that documents a substantial reduction in perinatally acquired AIDS cases. These new data confirm what earlier research had indicated -- that routine and universal counseling and voluntary testing, combined with AZT therapy is highly effective in preventing the perinatal transmission of HIV.

"The demonstration that AZT reduces perinatal HIV transmission is clearly one of the most significant research advances to date in the fight against HIV and AIDS, and has opened the door to major prevention efforts that have reduced the number of new cases of pediatric HIV infection," says Dr. Fauci.

By late 1995, more than 1.5 million children worldwide had been infected with HIV, a figure that may grow to 10 million by the year 2000, according to the World Health Organization. More than 90 percent of children with HIV infections contracted the virus from their HIV-infected mothers. In the United States, 7,472 cases of AIDS among children younger than 13 years had been reported to the CDC as of Sept. 30, 1996. HIV infection ranks seventh among leading causes of death for children aged one to 14 years. In many cities in the eastern United States, HIV disease is the leading cause of death among children ages two to five.

NIAID and NICHD are components of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, asthma and allergies. NICHD conducts and supports laboratory, clinical and epidemiological research on the reproductive, neurobiologic, developmental, social and behavioral processes that determine and maintain the health of children, adults, families and populations. NIH is an agency of the Public Health Service, U.S. Department of Health and Human Services.

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