Transmission Rates in Consecutive Pregnancies Exposed to Single-Dose Nevirapine in Soweto, South Africa and Abidjan, Côte d'Ivoire

Martinson, Neil A MD, MPH*; Ekouevi, Didier K MD, PhD†; Dabis, Francois MD‡; Morris, Lynn PhD§; Lupodwana, Pumla MBBCh∥; Tonwe-Gold, Besigin MD, MSc¶; Dhlamini, Puleng RN∥; Becquet, Renaud PhD‡; Steyn, Jan G MSc∥; Leroy, Valériane MD, PhD‡; Viho, Ida MD, MPH¶; Gray, Glenda E MBBCh, FCPaeds(SA)∥; McIntyre, James A MBBCh, FRCOG∥

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 June 2007 - Volume 45 - Issue 2 - pp 206-209
doi: 10.1097/QAI.0b013e318050d652
Clinical Science: Brief Report

Background: Large numbers of women receive single-dose nevirapine (sdNVP) to prevent mother-to-child transmission (MTCT) of HIV; over time, an increasing proportion will return to prevention of MTCT programs for a second pregnancy. Because sdNVP selects resistance in a high percentage of women, we compared the effectiveness of sdNVP in preventing peripartum MTCT in successive pregnancies.

Methods: Prospective cohorts were recruited from MTCT programs in South Africa and Côte d'Ivoire. HIV-1-infected women and their infants exposed to sdNVP in 2 consecutive pregnancies-used alone or with zidovudine (ZDV) or ZDV plus lamivudine-were included.

Results: The median age of women at their initial exposure to sdNVP in Soweto (n = 120) and Abidjan (n = 41) was 26 (interquartile range [IQR]: 22-29) years and 28 (IQR: 24-31) years, respectively, and their median delivery interval was 21 (IQR: 15-29) months and 26 (IQR: 20-32) months, respectively. Transmission rates in Soweto and in Abidjan were 11.1% and 13.2% for the first pregnancy and 11.1% and 5.4% for the second pregnancy (P = 1.000 and P = 0.449 for Soweto and Abidjan, respectively, in unpaired analysis).

Conclusion: This analysis suggests that the effectiveness of sdNVP when used in successive pregnancies is probably not impaired, possibly because viral resistance selected by prior exposure to sdNVP may wane with time.

From the *School of Medicine, Johns Hopkins University, Baltimore, MD; †Agence Nationale de Recherches sur le SIDA (ANRS) Projet 1201/1202 Ditrame Plus, Abidjan, Côte d'Ivoire; ‡INSERM Unité 593, Institut de Santé Publique, Epidémiologie, et Développement, Université Victor Segalen, Bordeaux, France; §National Institute for Communicable Diseases, Johannesburg, South Africa; ∥Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; and ¶MTCT-Plus Initiative, ACONDA-VS-CI, Abidjan, Côte d'Ivoire.

Received for publication September 15, 2006; accepted February 22, 2007.

The primary sponsor of the Ditrame Plus project was the ANRS, grant agreements ANRS 1201 and 1202. The United States Agency for International Development and the President's Emergency Plan for AIDS Relief (grant numbers 674-0320-G-00-5053 and 674-A-00-05-00003-00) funded prevention of mother-to-child transmission and data collection in Soweto. D.K. Ekouevi is a fellow of the European and Developing Countries Clinical Trial Partnership, and R. Becquet is a fellow of SIDACTION.

Reprints: Neil Martinson, MD, MPH, Perinatal HIV Research Unit, PO Box 114, Diepkloof 1864, South Africa (e-mail: martinson@hivsa.com).

Article Outline

Single-dose nevirapine (sdNVP) administered to pregnant women at the onset of labor and to newborns soon after birth reduces rates of mother-to-child transmission (MTCT) of HIV-1.1,2 It is inexpensive, safe, and used extensively in resource-poor settings. The impact of prior exposure to sdNVP on its own effectiveness when used in a subsequent pregnancy has not yet been described but is an important issue, because many countries with high HIV prevalence have total fertility rates in excess of 4 births per woman.3 Additionally, maternal disease progression in the interdelivery period may contribute to higher MTCT rates in a second pregnancy. Because thousands of women receive sdNVP each year,4 it is likely that an increasing number of HIV-infected women have a second exposure to sdNVP during a subsequent pregnancy when their HIV disease has advanced. Recent demonstrations of enhanced potency of sdNVP in combination with antenatal and neonatal zidovudine (ZDV)5 and ZDV plus lamivudine (3TC)6 ensure the continued use of sdNVP. However, maternal resistance is detectable shortly after delivery,7-9 and persists months after exposure.10,11 Moreover, sensitive assays able to detect resistance at the level of <1% of viral populations show that most women develop resistant mutations after sdNVP12,13 and that these mutations also persist.11,14 These resistant mutations may have a negative impact on the response to subsequent nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing antiretroviral (ARV) therapy when started shortly after exposure.15,16

The objective of this study was to report peripartum transmission rates in women from Soweto, South Africa and from Abidjan, Côte d'Ivoire who were exposed to sdNVP alone or in combination with other ARVs in consecutive pregnancies.

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METHODS

We followed up women recruited at 2 African sites who had been exposed to sdNVP on 2 occasions in subsequent pregnancies. At the time of the study, highly active ARV therapy was not widely available for pregnant women at either site.

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Soweto

In Soweto, from June 2003 to April 2005, 120 pregnant women attending the MTCT program a second time were identified at antenatal clinics and, after providing informed consent, were enrolled into a larger study of MTCT, which was approved by the local university's Ethics Committee. Eligibility criteria included written evidence that sdNVP had been dispensed to a woman during the previous pregnancy, with maternal self-reports of taking a tablet of NVP at the onset of labor and of not breast-feeding the previous infant. The HIV Network for Prevention Trials (HIVNET) 012 sdNVP regimen1,2 was used in Soweto for the duration of this study. Two study visits were scheduled; at baseline, when CD4 cell counts and HIV plasma viral loads were ascertained, and 6 weeks postpartum, when the HIV status of the infant was assessed using the Amplicor HIV-1 qualitative assay, version 1.5 (Roche Diagnostics, Basel, Switzerland). The HIV status of the previous child was ascertained in the same manner if the child was <18 months of age or by HIV enzyme-linked immunoassay (ELISA) if the child was ≥18 months of age at the time of testing.

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Abidjan

In Abidjan, 41 women were included and followed up in the Agence Nationale de Recherches sur le SIDA (ANRS) Ditrame Plus Study6 in Abobo and Yopougon, the most densely populated districts of the city. This open-label interventional cohort enrolled between March 2001 and July 2003 with approval from the National Health Sciences Ethical Committee in Côte d'Ivoire and from the ANRS in France. Women received a short peripartum course of ZDV plus sdNVP or ZDV plus 3TC with sdNVP. Neonates received ZDV syrup (2 mg/kg every 6 hours) for 7 days and sdNVP (2 mg/kg) 3 days after birth. For the second pregnancy, the same women were followed up in a prospective cohort study of HIV-infected pregnant women within the MTCT-Plus Initiative. At that time, they received one of the MTCT regimens evaluated in the Ditrame Plus project. Pediatric HIV status was assessed using a validated real-time HIV RNA polymerase chain reaction (PCR) technique performed at the Centre de Diagnostic et de Recherche sur le Sida (CeDReS) laboratory on infants' plasma samples at 4 weeks and confirmed at 6 weeks if positive.17 Alternatives to prolonged and predominant breast-feeding were promoted.

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Statistical Analysis

Peripartum transmission rates and 95% confidence intervals (CIs) are reported for both study pregnancies by site. Three analyses were performed: the first included all infants who were HIV tested from both pregnancies (unpaired observations and Pearson χ2 test); the second was restricted to participants from whom both children were tested for HIV (paired observations and McNemar χ2 test); and the third included those children who were stillborn or died before being tested for HIV in either pregnancy and were assumed to be infected with HIV (unpaired observations).

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RESULTS

HIV test results were available for 90 infants from the first pregnancy and for 108 from the second pregnancy of 120 pregnant women recruited in Soweto. In Abidjan, 41 women were recruited, and 38 infants from the first pregnancy and 37 from the second pregnancy had an HIV diagnosis. Baseline characteristics of all women are reported in Table 1. Transmission rates using all available children's HIV results in the first pregnancy exposed to sdNVP were 11.1% (10 of 90 children, 95% CI: 5.5% to 19.5%) and 13.2% (5 of 38 children, 95% CI: 4.4% to 28.1%) in Soweto and Abidjan, respectively; for the second pregnancy, transmission rates were 11.1% (12 of 108 children, 95% CI: 5.9% to 18.6%) and 5.4% (2 of 37 children, 95% CI: 0.6% to 18.2%) in Soweto and Abidjan, respectively (P = 1.000 and P = 0.625 in unpaired analysis).

Table 2 presents the cross-tabulation of HIV status in infants of first- and second-study pregnancies, restricted to the group in which the first and second infants were tested for HIV. Transmission rates in this paired analysis were 10.2% (9 of 88 children, 95% CI: 4.8% to 18.5%) in Soweto in both pregnancies and 8.8% (3 of 34 children, 95% CI: 1.8% to 23.7%) in Abidjan in the first pregnancy and 2.9% (1 of 34 children, 95% CI: 0.1% to 15.3%) in the second pregnancy (P = 1.000 and P = 0.625 in Soweto and Abidjan, respectively).

In the worst-case scenario (including stillbirths and infant deaths as HIV infected) and using all available HIV test results (unpaired analysis), transmission rates in Soweto and Abidjan were 22.7% (23 of 101 children, 95% CI: 15.0% to 32.2%) and 19.5% (8 of 41 children, 95% CI: 8.8% to 34.9%), respectively, after the initial exposure and 10.7% (11 of 103 children, 95% CI: 5.4% to 18.3%) and 14.6% (6 of 41 children, 95% CI: 5.6% to 29.2%), respectively, after the second exposure to sdNVP (P = 1.000 and P = 0.625 in Soweto and Abidjan, respectively).

In Abidjan, 34 HIV-infected pregnant women received sdNVP with short-course AZT and 3TC in their second pregnancy; among these, 2 transmitted HIV to their infants. Also, 16 of the 34 received sdNVP with AZT plus 3TC in both pregnancies, and 1 woman transmitted HIV to her second infant. Of all women from both sites with an interdelivery time of <12 months, 4 (28.6%) of 14 transmitted HIV to their infants compared with 10 (7.7%) of 130 whose interdelivery duration was ≥12 months (P = 0.0321, unpaired χ2 test).

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DISCUSSION

This report comparing HIV transmission rates when sdNVP is used alone or in combination in consecutive pregnancies suggests that vertical peripartum transmission rates did not increase at both study sites despite progression of HIV disease in the interdelivery period and despite the assumed presence of resistance mutations selected by prior sdNVP. Of course, this observational study is limited in the conclusions that can be drawn by the small sample size and by differences in sdNVP-containing MTCT regimens, because the addition of a short postpartum course of AZT plus 3TC to sdNVP has been shown to reduce selection of maternal and infant NNRTI resistance markedly.18,19 Furthermore, determination of the HIV status was performed at an older age for the first child, possibly also resulting in bias. To be eligible for the study in Soweto, however, first-born infants had to be exclusively formula fed, and in Abidjan, no postnatal transmissions were observed among the first infants. Thus, we hypothesize that our results reflect peripartum transmission rates. Our study allowed comparison of matched samples (the same women in the first and second pregnancies), but we could not control for variables affecting transmission that could have changed between deliveries. These include HIV disease progression (lower CD4 cell counts and higher viral loads), breast-feeding practices, and mode and duration of delivery.

In support of our findings, both sites report similar results, the transmission rates we report after a second exposure to sdNVP are comparable to those reported previously for first-time exposure to sdNVP,1,20,21 and results are maintained when all children who died before HIV testing were considered to be infected with HIV. In addition, an unpublished report from Kampala, Uganda comparing transmission rates in second pregnancies between sdNVP-naive and -exposed women22 showed that transmission after a second exposure was not significantly higher than that in women attending the MTCT program for the first time. Finally, although we report lower transmission rates, our results are similar to those of women studied in New York prior to ARVs becoming available in that women seldom transmitted HIV in consecutive pregnancies.23 We do not report resistance data, but in Lusaka, Zambia, resistance was found in 7 of 15 women after sdNVP using sdNVP in consecutive pregnancies.24 Although significant proportions of women still have resistance detectable in minority populations 12 months after sdNVP,11 we postulate that the time elapsed between labor (and exposure to sdNVP) may allow NVP-resistant populations selected by the prior dose to wane and suggest this as a reason why transmission rates do not increase after a subsequent pregnancy. Additionally, higher transmission rates found in women whose interdelivery time was <12 months compared with those with times of ≥12 months and findings from another study, which showed that fewer women failed ARV therapy if they were initiated at least 6 months after their exposure to sdNVP,16 support this.

More research is needed that elucidates effectiveness of sdNVP-containing MTCT regimens under a variety of conditions, particularly in settings where sdNVP is the mainstay of MTCT programs.

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Acknowledgments

The authors thank the women and their children who participated; Lynette Modise (Soweto); and Dr. Adrian Puren, Sarah Cohen, and staff at the National Institute for Communicable Diseases (NICD). This study was made possible by the generous support of the American people through USAID. The contents do not necessarily reflect the views of USAID or the United States Government.

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Keywords:

Africa; mother-to-child transmission; nevirapine; nonnucleoside reverse transcriptase inhibitor; resistance; second pregnancy

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