Prevention of mother-to-child transmission of HIV-1 using antiretroviral drugs in Dar Es Salaam, Tanzania

Abstract: This thesis describes studies of prevention of mother-to-child transmission (MTCT) of HIV-1 in breast-feeding populations in sub-Saharan Africa by perinatal and postnatal prophylactic antiretroviral therapy (ART) of mothers and infants. The acceptability of HIV counseling and testing in pregnant women and the mortality among HIV-1-infected women during 2 years after delivery was also studied. Three short course regimens of zidovudine (ZDV)+lamivudine (3TC) prophylaxis were evaluated for their efficacy to prevent MTCT of HIV in HIV-1-infected pregnant women in Uganda, Tanzania, and South Africa (the Petra trial). In group A treatment was given antepartum for 2 weeks, intrapartum and postpartum for 7 days to mother and infant. In group B the treatment started intrapartum and continued as in group A. In group C the treatment was given intrapartum only. At 6 weeks after birth the HIV transmission rates were 5.7%, 8.9%, 14.2% and 15.3% in groups A, B, C, and the placebo group, respectively and the relative risks (RR) for transmission in the treatment groups compared to placebo were 0.37, 0.58 and 0.93 respectively. The combined HIV-1 infection or death rates at 6 weeks were 7.0%, 11.6%, 17.5% and 18.1% in groups A, B, C, and the placebo group, respectively and the RR for HIV infection or death compared to placebo were 0.39, 0.64 and 0.97, respectively. After 18 months of follow up the transmission rates were 14.9% (95%CI 9.4-22.8), 18.1% (12.1-26.2), 20.0% (12.9-30.1) and 22.2% (15.9-30.2) for groups A, B, C and the placebo group respectively (Turnbull analysis). Arm A and B were effective in preventing HIV transmission at 6 weeks after birth but the preventive effect had diminished considerably at 18 months because of continued breastfeeding. The implication of this finding is that extended prophylaxis is necessary to reduce postnatal transmission in breast-feeding populations. Two studies evaluated prevention of postnatal MTCT of HIV-1 through breast milk by extended antiretroviral (ARV) prophylaxis to the infant (the Mitra study) or the mother (the Mitra Plus study) during breast-feeding in Dar es Salaam, Tanzania. In the Mitra study mothers received the Petra arm A regimen and infants 3TC for 6 months. In the Mitra Plus study mothers received highly active ART (HAART) (ZDV+3TC+nevirapine or nelfinavir) irrespective of their stage of infection starting at 34 weeks gestation. Treatment was stopped at 6 months after delivery except in women who needed HAART for their own health. There were 398 infants included in the transmission analysis in the Mitra study and 441 infants in the Mitra Plus study. Cumulative HIV transmission rates determined by Kaplan-Meier survival analysis were 3.8% (95% CI 2.0-5.6) and 4.1% (95% CI 2.2-6.0) at 6 weeks and 4.9% (95% CI 2.7-7.1) and 5.0% (95% CI 2.9-7.1) at 6 months in the Mitra and the Mitra Plus studies, respectively. The cumulative risk of HIV infection between 6 weeks and 6 months was 1.2% and 1% in the Mitra and the Mitra Plus studies, respectively. At 18 months the cumulative transmission was 6.0% (95% CI 3.7-8.3) in the Mitra Plus study. Cox regression analysis showed that the transmission of HIV-1 up to 6 months was about 50% lower in the Mitra and Mitra Plus studies than in the breast-feeding women in group A of the Petra trial (p?0.001). These results showed that infant and maternal ARV prophylaxis for 6 months during breast-feeding resulted in similar low transmission rates at 6 months. A study to determine the acceptability of HIV counseling and testing and participation in a PMTCT intervention was performed at the Dar es Salaam site of the Petra trial. HIV counseling and testing was offered to 10 010 pregnant women of whom 7647 (76.4%) agreed to be tested and 1050 (13.7%) were HIV-1 seropositive. Sixty-eight percent returned to receive results. Only 16.7% of the 288 enrolled HIV-1 seropositive women disclosed their positive HIV serostatus to their sexual partners. Reasons for not disclosing the HIV status were fear of stigma, divorce and violence. Sixty percent (29 of 48) of the informed sexual male partners agreed to HIV testing and 69% (20 of 29) were HIV seropositive. In the Mitra study, out of 10 179 pregnant women counseled 92% accepted rapid HIV testing and 93.6% received their results. In the Mitra Plus study, out of 14 255 pregnant women counseled 95.7% accepted rapid HIV testing and 98.9% received their results. The Petra, Mitra and Mitra Plus studies showed that the proportion of women accepting HIV testing and receiving their test results was high and higher in the last two studies in which the rapid HIV testing strategy was used. A secondary analysis of the Petra cohort at the Dar es Salaam site was performed to determine the mortality of the HIV-1-infected women during 24 months of follow up after delivery in relation to their CD4 cell count and viral load at enrolment. About 14.5% of the women had CD4 cell counts <200/?L at enrolment and would have benefited from ART for their own health. However, ART was not available in Tanzania at the time of the study. The mortality was 29.9% in women with CD4 cell counts <200/?L and 15% in women with viral load >100 000 copies/mL. The mortality in women with 200-499 CD4 cells/?L was similar to that in women with >500 CD4 cells/?L (3.3% and 2.9%, respectively). In the multivariate analysis low CD4 cell counts and high viral load were both independent risk factors for mortality (p<0.001 and p=0.004, respectively).