ACTG Protocol 185 Enrollment Halted

March 26, 1997

Enrollment has been stopped in a clinical trial of mother to child HIV transmission, Pediatric ACTG Protocol 185, due to a welcome but unexpectedly low rate of infant infection which made comparison of the standard and experimental treatments impossible. Pediatric ACTG Protocol 185 was a randomized, controlled clinical trial designed to test whether HIVIG (an immune globulin containing high levels of antibodies to HIV) reduced transmission of HIV from infected pregnant women to their infants when added to the standard AZT-based preventive treatment regimen. The comparison group received AZT and standard intravenous immunoglobulin (IVIG) that does not contain HIV antibodies.

Although enrollment will be stopped, the trial will continue with the standard AZT treatment and followup of mothers and children, it was announced by the study's sponsors, the National Heart, Lung and Blood Institute; the National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases.

The trial allowed enrollment of HIV-infected women with more advanced disease and lower CD4+ T cell count than had Pediatric ACTG Protocol 076, the 1994 clinical trial that demonstrated that AZT decreases mother-to-child HIV transmission by two-thirds. The Pediatric ACTG Protocol 185 trial enrolled HIV-infected pregnant women with CD4+ T cell count less than or equal to 500/mm3 who were receiving AZT during pregnancy for medical indications. Women could receive other nucleoside antiretroviral agents, if required, for their own health. It was anticipated that transmission from mother to child in a population of women with advanced disease, even when receiving AZT, would be significantly higher than that observed in women with less severe disease receiving AZT (in Pediatric ACTG Protocol 076, the transmission rate was 7.6% from AZT-receiving women).

On March 21, 1997, the study's independent Data and Safety Monitoring Board (DSMB) reviewed results from the first of four planned efficacy analyses. The protocol opened on October 13, 1993. By December 23, 1996, the date on which the study database was closed for the first efficacy analysis, 445 women had enrolled, 394 had delivered 402 liveborn infants, and one or more diagnostic HIV test results were available in 379 infants.

The estimated overall rate of mother-to-infant HIV transmission was an unexpectedly low 4.8%, and did not differ between HIVIG and IVIG recipients (4.7% versus 4.8%, respectively). The transmission rates were well below the anticipated transmission rate on which the study was originally designed. The DSMB determined that it would require a substantial increase (more than a doubling) in the number of women enrolled into the study to meet the initial guidelines of this study. Given the unexpectedly low rates of transmission and the low ability to detect a treatment difference under the current study design, the DSMB recommended that further enrollment into the study be discontinued and that all patients currently on study continue follow-up according to the protocol, without further administration of HIVIG or IVIG immunoglobulin.

The preliminary results of Pediatric ACTG Protocol 185 provide important information regarding the efficacy of AZT for reducing mother-to-child HIV transmission. Although the study will not be able to answer the question of whether HIVIG is effective in reducing perinatal HIV transmission, the results not only confirm the effectiveness of AZT in preventing such transmission, but extend this effectiveness to women with more advanced disease and previous AZT use. In Pediatric ACTG Protocol 076, all women had CD4+ T cell counts greater than or equal to 200/mm3 and only 5% had received any AZT prior to the current pregnancy. In contrast, in Pediatric ACTG Protocol 185, 23% had baseline CD4+ T cell count less than 200/mm3 and 21% of women had received AZT prior to as well as during the current pregnancy.

The preliminary results from Pediatric ACTG Protocol 185 are consistent with accumulating information from other studies in the United States. For example, in North Carolina, mother-to-child transmission rates have decreased from 21% in 1993 to 6% in 1996 with use of AZT; in New York City, rates have similarly decreased to 5% for infected women who have received the antenatal, intrapartum and newborn AZT regimen. Additionally, in France, transmission rates have decreased from 14% prior to the use of AZT to 5% in women receiving AZT.

The Pediatric ACTG Protocol 185 results provide important strong additional support to the existing Public Health Service recommendations that all pregnant women enter prenatal care early and be offered HIV testing. All HIV-infected pregnant women should be offered the Pediatric ACTG Protocol 076 regimen of antenatal, intrapartum and newborn AZT for the purpose of reducing transmission risk, and the now standard AZT regimen for reduction of perinatal transmission should be part of whatever treatment an infected woman receives during pregnancy for her own health.

No short-term serious side effects in either women or infants were observed in either Pediatric ACTG Protocol 185 or 076. However, information on long-term safety of antiretroviral drugs in pregnancy is lacking. Long-term follow-up is recommended for all infants exposed to antiretroviral treatments in utero or as newborns, and is being provided for infants born in Pediatric ACTG perinatal clinical trials through other protocols in the Pediatric ACTG.

Because almost all HIV-infected women in the United States will be receiving antiretroviral therapy during pregnancy, it will not be possible to address the role of HIVIG in reducing perinatal transmission in a timely fashion. However, in areas of the world in which HIVIG may be a more practical option, it is possible that this question could be addressed. It is still unknown whether passive immunization by administration of immunoglobulin may provide some benefit in reducing perinatal transmission. Therefore, further study in appropriate settings is warranted.

Glaxo Wellcome provided AZT for the study. IVIG was acquired from Bayer Pharmaceuticals, West Haven, Connecticut, and HIVIG was acquired from NABI, Boca Raton, Florida.

Mother-to-child transmission of HIV accounts for the vast majority of HIV infection in infants and children worldwide. As of December 1996, 7,629 cases of pediatric AIDS have been reported in the U.S.; of these children, 4,406 have died. AIDS is currently the seventh leading cause of death in the U.S. for children between one and fourteen years of age; in New York State, it is the leading cause of death for African-American children between one to four years old and second leading cause of death for Hispanic children of the same age. It is estimated that in addition to those children living with AIDS, there are approximately 10,000 other children infected with HIV who have not yet developed AIDS. Furthermore, approximately 7,000 infants are born to HIV-infected women each year in the United States. While not all infants born to infected women become infected, the overall transmission rate in the U.S. is approximately 23% without AZT treatment. Pediatric ACTG Protocols 076 and 185 have demonstrated that it is now possible to dramatically reduce the risk of HIV transmission to the infants born to these women.

NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

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