Elsevier

The Lancet

Volume 359, Issue 9313, 6 April 2002, Pages 1178-1186
The Lancet

Articles
Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(02)08214-4Get rights and content

Summary

Background

Large reductions in transmission of HIV-1 from mother to child have been achieved in more-developed countries due to the use of antiretrovirals. Short-course regimens, suitable for resource-poor countries, have also been shown to significantly reduce peripartum HIV-1 transmission. We assessed the efficacy of short-course regimens with zidovudine and lamivudine in a predominantly breastfeeding population.

Methods

We did a randomised, double-blind, placebo-controlled trial in South Africa, Uganda, and Tanzania. Between June, 1996, and January, 2000, HIV-1-infected mothers were randomised to one of four regimens: A, zidovudine plus lamivudine starting at 36 weeks' gestation, followed by oral intrapartum dosing and by 7 days' postpartum dosing of mothers and infants; B, as regimen A, but without the prepartum component; C, intrapartum zidovudine and lamivudine only; or placebo. From Feb 18, 1998, onward, women were only randomised to one of the active treatment groups. Primary outcomes were HIV-1 infection and child mortality at week 6 and month 18 after birth. Analysis was by intention to treat of those randomised before Feb 18, 1998.

Findings

1797 HIV-1-infected women were identified. Week 6 HIV-1 transmission rates were 5·7% for group A, 8·9% for group B, 14·2% for group C, and 15·3% for the placebo group. Respective relative risks for HIV-1 transmission in the treatment groups compared with placebo were 0·37 (95% Cl 0·21–0·65), 0·58 (0·36–0·94), and 0·93 (0·62–1·40). For the combined endpoint of HIV-1 infection and infant mortality at week 6 rates were 7·0%, 11·6%, 17·5%, and 18·1%, respectively, with relative risks of 0·39 (0·24–0·64), 0·64 (0·42–0·97), and 0·97 (0·68–1·38). 1081 (74%) of the women analysed initiated breastfeeding. Based on an interval-censored survival analysis, HIV-1 infection rates at month 18 were 15% (95% Cl 9–23), 18% (12–26), 20% (13–30) and 22% (16–30), respectively.

Interpretation

Although at week 6 after birth, regimens A and B were effective in reducing HIV-1 transmission, benefits have diminished considerably after 18 months of follow-up. Introduction of short-course regimens to prevent mother-to-child transmission of HIV-1 in less-developed countries should be accompanied by interventions to minimise the risk of subsequent transmission via breastfeeding.

Introduction

In 1994, the Pediatric AIDS Clinical Trials Group 076 (PACTG 076) study, done in the USA and France, found that a complex regimen of the antiretroviral agent zidovudine, given to HIV-1-infected women during pregnancy, labour, and then to the neonate for 6 weeks, reduced mother-to-child transmission of HIV-1 by two-thirds.1 Large reductions in transmission have since then been achieved by the wide-scale introduction of antiretroviral regimens in the more-developed world.2, 3 Additionally, elective caesarean section reduces transmission rates.4, 5, 6

Most cases of HIV-1 transmission from mother-to-child, however, arise in the less-developed world. More than 500 000 children become infected with HIV-1 annually. Most of them acquire the virus from their mothers and most of them live in Africa.7

Antiretroviral interventions that were so successful at reducing mother-to-child transmission of HIV-1 in the more-developed world were found to be too complex and too costly for large-scale application in less-developed countries. Therefore, a number of studies were done to investigate whether simplified short-course antiretroviral regimens, targeted around the time of delivery, could be beneficial in less-developed countries. The rationale for targeting the perinatal period was that it was estimated that, in the absence of breastfeeding, up to 70% of mother-to-child transmissions of HIV-1 arise during labour and delivery.8, 9, 10 Several studies from Thailand and Africa, and observational data from the USA, showed the efficacy of short-course zidovudine or nevirapine monotherapy in reducing perinatal transmission of HIV-1.11, 12, 13, 14, 15

Instead of antiretroviral monotherapy, we used three different regimens of zidovudine and lamivudine (3TC) combination therapy in this study: the first targeting the prepartum, intrapartum, and postpartum period, the second the intrapartum and postpartum period, and the third the intrapartum period only. Lamivudine was added to zidovudine to increase antiviral potency.16 Lamivudine has an excellent safety profile,17 exerts rapid antiviral activity,18 crosses the placenta efficiently, and has shown promise in a small pilot study either alone or when co-administered with zidovudine in HIV-1-infected pregnant women and their offspring.19 We report on the efficacy of the trial regimens in reducing HIV-1 transmission in a predominantly breastfeeding group of women at 6 weeks after birth and after 18 months.

Section snippets

Participants

The trial was done in five sites in three countries: two large public hospitals in South Africa (Chris Hani Baragwanath Hospital in Johannesburg and King Edward VII Hospital in Durban); one large public hospital in Tanzania (Muhimbili General Hospital in Dar es Salaam); one large public hospital in Uganda (Mulago Hospital in Kampala); and one semi-private missionary hospital in Uganda (St Francis Hospital in Nsambya, Kampala).

All pregnant women attending prenatal clinics in the five sites were

Results

We screened 23 273 women, of whom 4640 (20%) tested HIV-1 seropositive. Of these women, 1797 (39%) enrolled in the Petra trial, of whom 43 were excluded from the analysis due to seronegativity,2 default,21 or replacement of placebo trial drug after the discontinuation of the placebo group20 (table 1, figure 1). Of the remaining 1754 pregnant women, 1457 were randomised to one of the four treatment groups. After Feb 18, 1998, 297 women were randomised to one of the three intervention groups.

Discussion

Three studies, done in Thailand, Cote d'Ivoire, and Cöte d'Ivoire plus Burkina Faso, showed that short-course prepartum oral regimens of zidovudine were able to reduce mother-to-child transmission of HIV-1 by 40–50%.11, 12, 13 Regimen A in our trial resulted in a 63% reduction in HIV-1 transmission and a 61% reduction in HIV-1 transmission and mortality at 6 weeks after birth. Although one should be cautious in making cross-study comparisons, these figures represent the highest relative

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