Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission: Pediatric AIDS Clinical Trials Group (PACTG) protocol 185

Objectives

To determine if HIV hyperimmune globulin (HIVIG) given to HIV-positive pregnant women during the second and third trimester of pregnancy reduced the likelihood of maternal-fetal HIV transmission.

Background

Several studies have identified maternal, obstetrical, and infant characteristics associated with perinatal transmission of human immunodeficiency virus type 1 (HIV-1). However, these studies were conducted primarily before the widespread use of zidovudine for the prevention of perinatal transmission. Few studies have identified risk factors for transmission among HIV-1–infected women and infants who are receiving zidovudine, yet such information is critical to the development of new interventions to reduce the risk of perinatal transmission further.

Subjects

A total of 501 HIV-1–infected women who were 20 to 30 weeks pregnant, who had CD4+ lymphocyte counts of no more than 500 per cubic millimeter, and who were receiving zidovudine as prescribed by their physicians. Of these, 4 were lost to follow-up before delivery, resulting in a study population of 497 women. There were 505 live-born infants, including 9 sets of twins and 487 singletons, and 1 stillborn infant.

Design

The study was a multicenter, randomized, controlled phase 3 clinical trial conducted between October 1993 and March 1997 at 53 clinical sites in the contiguous United States and Puerto Rico. Study investigators evaluated whether prophylaxis with zidovudine combined with HIV-1 hyperimmune globulin (HIVIG) at a dose of 200 mg per kilogram of body weight administered intravenously to the women each month during pregnancy and once to the neonates at birth would lower the risk of perinatal HIV-1 transmission more than would zidovudine and intravenous infusions of immune globulin without HIV-1 antibody, at a dose of 200 mg per kilogram. Detailed information on antenatal and obstetrical variables was collected during the trial, and laboratory assays were performed at several points during the women's pregnancies to determine maternal plasma levels of HIV-1 RNA, viral titers in quantitative cultures of peripheral-blood mononuclear cells, CD4+ lymphocyte counts, and quantitative HIV-1 p24 antibody levels. This allowed evaluation of the independent contribution of potential risk factors for perinatal transmission of HIV-1 in a population of women and infants who received zidovudine.

Conclusions

The unexpectedly low transmission confirmed that zidovudine prophylaxis is highly effective, even for women with advanced HIV disease and prior zidovudine therapy, although it limited the study's ability to address whether passive immunization diminishes perinatal transmission (J Infect Dis 1999: 179: 567-75). There were no significant differences between the group that received HIV-1 hyperimmune globulin and the group that received intravenous immune globulin with respect to base-line maternal, obstetrical, and infant characteristics or rates of HIV-1 transmission. Since the rates of perinatal HIV-1 transmission and the clinical and laboratory characteristics were similar in the two groups, data for all women were combined in all subsequent analyses of risk factors. The maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women (NEJM 1999; 341:385-393).

Primary Outcome Paper

http://www.ncbi.nlm.nih.gov/pubmed/9952362

Publications

Stiehm ER, Lambert JS, Mofenson LM, Bethel J, Whitehouse J, Nugent R, Moye J Jr, Glenn Fowler M, Mathieson BJ, Reichelderfer P, Nemo GJ, Korelitz J, Meyer WA 3rd, Sapan CV, Jimenez E, Gandia J, Scott G, O'Sullivan MJ, Kovacs A, Stek A, Shearer WT, Hammill H. Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group protocol 185. J Infect Dis. 1999 179:567-75.

Lambert JS, Mofenson LM, Fletcher CV, Moye J Jr, Stiehm ER, Meyer WA 3rd, Nemo GJ, Mathieson BJ, Hirsch G, Sapan CV, Cummins LM, Jimenez E, O'Neill E, Kovacs A, Stek A. Safety and pharmacokinetics of hyperimmune anti-human immunodeficiency virus (HIV) immunoglobulin administered to HIV-infected pregnant women and their newborns. Pediatric AIDS Clinical Trials Group Protocol 185 Pharmacokinetic Study Group. J Infect Dis. 1997 175:283-91.

Mofenson LM, Lambert JS, Stiehm ER, Bethel J, Meyer WA 3rd, Whitehouse J, Moye J Jr, Reichelderfer P, Harris DR, Fowler MG, Mathieson BJ, Nemo GJ. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. 1999 341:385-93.

Lambert JS, Watts DH, Mofenson L, Stiehm ER, Harris DR, Bethel J, Whitehouse J, Jimenez E, Gandia J, Scott G, O'Sullivan MJ, Kovacs A, Stek A, Shearer WT, Hammill H, van Dyke R, Maupin R, Silio M, Fowler MG. Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team. AIDS. 2000 14:1389-99.

Watts DH, Lambert J, Stiehm ER, Harris DR, Bethel J, Mofenson L, Meyer WA 3rd, Mathieson B, Fowler MG, Nemo G; PACTG 185 Study Team. Progression of HIV disease among women following delivery. J Acquir Immune Defic Syndr. 2003 33:585-93.

Lambert JS, Harris DR, Stiehm ER, Moye J Jr, Fowler MG, Meyer WA 3rd, Bethel J, Mofenson LM. Performance characteristics of HIV-1 culture and HIV-1 DNA and RNA amplification assays for early diagnosis of perinatal HIV-1 infection. J Acquir Immune Defic Syndr. 2003 34:512-9.

Lambert JS, Moye J Jr, Plaeger SF, Stiehm ER, Bethel J, Mofenson LM, Mathieson B, Kagan J, Rosenblatt H, Paxton H, Suter H, Landay A. Association of selected phenotypic markers of lymphocyte activation and differentiation with perinatal human immunodeficiency virus transmission and infant infection. Clin Diagn Lab Immunol. 2005 12:622-31.

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