Does giving AZT to pregnant women with HIV decrease transmission? 

Connor EM et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331: 1173-80.

 

Take Home Message: Zidovudine given to pregnant women antepartum, intrapartum and given to the newborn reduced the risk of perinatal HIV transmission by approximately two-thirds.

Highlights:  The vertical transmission of HIV from mother to baby is the primary way by which children become infected. To study the effects of perinatal antiretroviral use on vertical transmission, Connor et al., with the Pediatric Aids Clinical Trials Group Protocol 076 Study Group, published this study in 1994.[i]  They randomized pregnant women with HIV to receive zidovudine (AZT) or placebo at multiple centers in the United States and France.  Women in the zidovudine group received the medication antepartum and intrapartum, and their infants received it for 6 weeks.  As estimated by Kaplan-Meier analysis, 8.3% of infants in the zidovudine group and 25.5% of infants in the placebo group were infected with HIV at 18 months – a relative risk reduction of 67.5%. In fact, the Data and Safety Monitoring Board recommended the discontinuation of the study and that all patients be offered zidovudine. The only side effect attributable to zidovudine was anemia in the infants. This study has had important implications on the management of pregnant women with HIV and their infants and has formed the basis for the standard of care in the management of pregnant women with HIV and their neonates.

The Nitty-Gritty:

  • Design:

    • Multicenter, randomized, double-blind, placebo-controlled trial

    • N= 409

      • Zidovudine group (n=205)

      • Placebo group (n=204)

    • Setting: multiple centers in the United States and France

    • Enrollment: 1991-1993

    • Primary outcome: HIV infection of newborn

    • Analysis: intention-to-treat

  • Population:

    • Inclusion Criteria:

      • Pregnant, HIV-infected women

      • 14 to 34 weeks’ gestation

      • CD4+ T-lymphocyte counts >200 cells/mm3

      • No indication for antiretroviral therapy  

      • Laboratory criteria

        • Hemoglobin >8g/dl

        • Absolute neutrophil count >1,000 cells/mm3

        • Platelets >100,000 cells/mm3

        • Serum ALT <2.5 times upper limit of normal

        • Serum creatinine concentration <1.5 mg/dl or 8 hour urinary creatinine clearance >70 ml/min

    • Exclusion Criteria

      • Ultrasound findings including:

        • Life-threatening fetal anomaly

        • Anomaly that might increase fetal concentration of zidovudine or its metabolites

        • Oligohydraminos in the second trimester

        • Unexplained polyhydramnios in the third trimester

        • Fetal hydrops, ascites, or other evidence of fetal anemia

      • Women who had received any antiretroviral treatment during this pregnancy

      • Women who had received immunotherapy, anti-HIV vaccines, cytolytic chemotherapeutic agents or radiotherapy

    • Baseline Characteristics – from both groups combined, no significant differences between groups

      • Mothers

        • Median age at entry: 25 years

        • Race: White 19%, Black 51%, Hispanic 29%

        • History of injection drug use: 16%

        • Median CD4 count at entry: 550 cells/mm3

        • Median gestational age at entry: 26 weeks

        • Zidovudine before current pregnancy: 4%

        • Other sexually transmitted disease: 12% syphilis

      • Infants

        • Median gestational age: 39 weeks

        • Median birth weight: 3160 grams

      • Delivery

        • Mode of delivery: Vaginal 73%

        • Premature rupture of membranes: 2%

        • Abruptio placentae: 3%

        • Fetal scalp sampling: 1%

        • Fetal scalp electrodes: 5%

  • Intervention:

    • Women were randomly assigned to receive either zidovudine or placebo

    • Zidovudine regimen: antepartum zidovudine (100 mg PO 5 times daily), intrapartum zidovudine (2 mg/kg IV for 1 hour followed by 1 mg/kg per hour until delivery), plus zidovudine for the newborn (2mg/kg PO every 6 hours for 6 weeks)

    • Infants evaluated at birth and periodically until 78 weeks of age. HIV cultures of peripheral-blood mononuclear cells were performed at birth, at 12 and 78 weeks of life. HIV serologic testing (enzyme immunoassay and a Western blot assay) was performed at 72 and 78 weeks

    • Infants with at least one positive HIV culture were classified as HIV infected

  • Outcomes: comparisons are zidovudine group vs. placebo

    • Primary outcome: based on evaluation of 363 births for which HIV status known: 180 infants in zidovudine group and 183 infants in placebo group

      • Number of infants infected with HIV: 13 vs. 40

      • Proportions of infants infected at 18 months (as estimated by Kaplan-Meier analysis): 8.3% (95% CI 3.9-12.8%) vs. 25.5% (95% CI 18.4-32.5%)  (P=0.00006; 67.5% relative risk reduction; 95% CI 40.7 to 82.1%)

  • Adverse Effects

    • Hemoglobin concentration of infants in zidovudine group was significantly lower at birth than that of infants in placebo group

  • Criticisms

    • The zidovudine regimen is not practical or afforadable in developing countries. [ii][iii]

 

[i] Connor EM et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331: 1173-80.

[ii] Rogers MF and Jaffe HW. Reducing the risk of maternal-infant transmission of HIV: a door is opened. N Engl J Med 1994; 331:1222-1223.

[iii] Mtimavalye L et al. Maternal-infant transmission of HIV-1. N Engl J Med1995; 332:890-1.