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AIDS:
Clinical Science

A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers

Gray, Glenda Ea; Urban, Michaelb; Chersich, Matthew Fa; Bolton, Carolyna; van Niekerk, Ronellea; Violari, Avya; Stevens, Wendyc; McIntyre, James Aa; for the PEP Study Group

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Author Information

From the aPerinatal HIV Research Unit

bCoronation Hospital Department of Pediatrics

cDepartment of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg South Africa.

*See Appendix for study members.

Received 9 November, 2004

Revised 8 April, 2005

Accepted 13 April, 2005

Correspondance to Dr G. Gray, Perinatal HIV Research Unit, University of the Witwatersrand, Chris Hani Baragwanath Hospital, PO Box 114, Diepkloof, Johannesburg 1864, South Africa. E-mail: gray@pixie.co.za

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Abstract

Background: Single-dose nevirapine (NVP) prophylaxis to mother and infant is widely used in resource-constrained settings for preventing mother-to-child transmission (MTCT) of HIV-1. Where women do not access antenatal care or HIV testing, postexposure prophylaxis to the infant may be an important preventative strategy.

Methods: This multicentre, randomized, open-label clinical trial (October 2000 to September 2002) in South Africa compared single-dose NVP with 6 weeks of zidovudine (ZDV), commenced within 24 h of delivery among 1051 infants whose mothers had no prior antiretroviral therapy. HIV-1 infection rates were ascertained at birth, and at 6 and 12 weeks of age. Kaplan–Meier survival methods were used to estimate HIV-1 infection rates in an intention-to-treat analysis.

Results: Overall, 6 week and 12 week MTCT probability was 12.8% [95% confidence interval (CI),10.5–15.0] and 16.3% (95% CI,13.4–19.2), respectively. At 12 weeks, among infants who were not infected at birth, 24 (7.9%) infections occurred in the NVP arm and 41 (13.1%) in the ZDV arm (log rank P = 0.06). Using multivariate analysis, factors associated with infection following birth were ZDV use [odds ratio (OR), 1.8; 95% CI,1.1–3.2; P = 0.032), maternal CD4 cell count < 500 × 106 cells/l (OR, 2.5; 95% CI,1.3–5.0; P = 0.007), maternal viral load > 50 000 copies/ml (OR, 3.6; 95% CI,2.0–6.2; P < 0.0001) and breastfeeding (OR, 2.2; 95% CI,1.3–3.8; P = 0.006).

Conclusion: A single-dose of NVP given to infants offers protection against HIV-1 infection and should be a strategy used in infants of mothers with untreated HIV infection.

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Introduction

In resource-constrained settings, current interventions to reduce mother-to-child transmission of HIV-1 (MTCT) target the peripartum period [1–4]. To date, the most widely used regimen is derived from the HIVNET 012 study, which demonstrated that a single-dose of nevirapine (NVP) given to the mother in labour and a dose administered to the infant soon after birth reduced transmission by half [5,6]. In regimens with an antenatal component, zidovudine (ZDV) is recommended from 28 weeks of gestation [7]. Adding single-dose NVP to antenatal ZDV regimens in Thailand [8] and Africa [9] has reduced transmission rates to levels seen previously only in the developed world, where triple antiretroviral regimens initiated prenatally have reduced MTCT rates to < 2% among women avoiding breastfeeding [10].

Postexposure prophylaxis [11] is based on the premise that administration of antiretroviral drugs soon after exposure will inhibit viral replication and dissemination, thus enabling the host defence mechanism to clear the inoculum [12,13]. The pathogenesis of transcutaneous, transmucosal, intrapartum and early postpartum infection with HIV has not been fully elucidated. Following intrapartum or early postpartum exposure, a ‘window of opportunity’ may exist in which antiretroviral treatment may prevent infection.

Several studies have prompted treatment recommendations for postexposure prophylaxis. The Centers for Disease Control and Prevention (CDC) case–control study of occupational HIV infections found that healthcare workers who received ZDV treatment after exposure were 79% less likely [odds ratio (OR), 0.21] to acquire infection than those who did not receive treatment, independent of the other variables affecting the probability of transmission [11]. Further, data from the PACTG 076 study demonstrated that ZDV given to HIV-infected pregnant women from 14 weeks of pregnancy, continued intravenously in labour and given to the infant for 6 weeks could reduce MTCT transmission by 67% [14]. The efficacy of this regimen could not be explained purely on the basis of a reduction in maternal viral load. Experience with the PACTG 076 protocol demonstrates the prophylactic efficacy of antiretroviral therapy if ZDV is administered during pregnancy. It did not, however, address the issue of commencing therapy in the postpartum period to the infant.

Evidence supporting the role of postexposure prophylaxis in reducing HIV transmission among infants whose mothers did not access therapy during pregnancy or labour has been demonstrated in a prospective study in Malawi that investigated postpartum prophylaxis in newborns [15]. This study indicated that dual therapy with single-dose NVP and one week of ZDV given to the infant was superior to single-dose NVP alone. The overall transmission rate at 6–8 weeks of age in the group which received single-dose NVP and ZDV was 15.3% compared with 20.9% in the arm that received NVP alone.

Previously, a retrospective uncontrolled study by Wade et al. [16] demonstrated the use of ZDV prophylaxis in MTCT, even if only administered to the infant for 6 weeks. When ZDV was initiated within 48 h of delivery, the transmission rate was 9.3%, compared with 26.6% if no therapy was given. If ZDV was administered at longer than 48 h after delivery, the transmission rate was 18.4%.

Administration of single-dose NVP is associated with rapid emergence of NVP-resistant variants in both the mother and HIV-infected infants [17–21]. This may be associated with an increased risk of treatment failure among women who subsequently initiate NVP treatment [22]. Single-dose NVP given only to the infant would avoid the risk of maternal NVP resistance.

Postpartum prophylaxis of infants may be an important strategy to prevent MTCT in settings where women do not access antenatal care, are not offered HIV testing and counselling, where babies are born at home, or where health workers wish to avoid maternal NVP dosing. NVP is a potent inhibitor of HIV-1 replication, which, because of its long half-life in babies [23,24], may be as effective as longer therapy with ZDV.

The primary objective of this study was to compare postuterine HIV infection at week 12 in infants who were not infected at birth and were given either a single-dose of NVP or ZDV for 6 weeks [25]. Transmission data were collected up to 12 weeks of age. The secondary objective of this study was to assess how breastfeeding affected the efficacy of the two regimens.

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Methods

Participants

The trial was conducted in three hospitals in South Africa: Chris Hani Baragwanath Hospital (Soweto), Coronation Hospital (Johannesburg) and Mowbray Hospital (Cape Town) between October 2000 and September 2002. Women delivering without prior knowledge of their HIV status were offered postpartum voluntary counselling and rapid on-site testing (PP-VCT) within 24 h of delivery. Blood samples were tested with Determine HIV-1/2 tests (Abbott Laboratories, Abbott Park, Illinois, USA), and, if reactive, a second confirmatory test using the Uni-Gold HIV test (Trinity Biotech, Wicklow, Ireland) was performed. Women who tested negative with the initial Determine test were considered uninfected.

Eligible women testing HIV positive were offered enrolment. Infants were excluded if they were preterm weighing < 1200 g, requiring ventilation, unable to take oral medication or with congenital abnormalities. Ineligible infants or infants of mothers unwilling to participate were offered off-study single-dose NVP. Informed consent and randomization occurred within 24 h of delivery. Randomization was by using computer-generated random allocations; enrolled babies were sequentially assigned the next study number and allocation to the study arm was provided to study nurses in sequentially numbered non-transparent sealed envelopes that were only opened after informed consent was obtained.

At enrolment, after obtaining informed consent and randomization, blood samples were collected from infants for HIV-1 DNA polymerase chain reaction (PCR) and measurement of haemoglobin levels. Maternal blood was sent for HIV-1 RNA quantitative HIV testing (viral load) and CD4 cell counts.

Enrolled women were counselled on infant feeding practices as in the South African infant feeding guidelines. Subsidized formula was provided for women who opted not to breastfeed. Women who decided to breastfeed were encouraged to breastfeed exclusive for 3–6 months. Women with CD4 cell counts < 200 × 106 cells/l were started on co-trimoxazole prophylaxis. Mother–infant pairs were followed up for 6 months or until 1 month after cessation of breastfeeding. Infants found to be HIV-1 infected received co-trimoxazole prophylaxis from 6 weeks of age.

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Trial design

The study was a multicentre, two-arm, randomized open-label trial of NVP compared with ZDV when administered postnatally to infants born to HIV-1-infected women who had not received antepartum or intrapartum antiretroviral therapy. Infants of women who had consented to participate were randomized to receive either a single oral dose of NVP (10 mg/ml oral suspension at a dose of 2 mg/kg) within 24 h of delivery or ZDV (10 mg/ml at a dose of 4 mg/kg administered 12-hourly for 6 weeks). Initial doses were administered by the study staff within 24 h of delivery.

A two group χ2 test with a 0.05 two-sided significance level would have 90% power to detect the difference between a 0.10 proportion (10%) of HIV-infected infants using ZDV, and a 0.19 proportion (19%) of HIV-infected infants using NVP (OR, 2.111) when the sample size in each group was 320. To allow for loss to follow-up, infant deaths, withdrawals and unavailable PCR results, 1051 infants were randomized to achieve the study groups needed.

Baseline sociodemographic information, medical and pregnancy history were recorded. Follow-up visits at day 10 and at weeks 6 and 12 for the infant included a clinical examination and a blood sample for HIV-1 diagnosis and haemoglobin estimation. Ongoing HIV-1 testing occurred in breastfed infants at 3-monthly intervals.

Serious adverse events were documented and the Ethics Committee and sponsors received biannual reports.

Standardized operating procedures for enrolment and data collection were used at all study sites. Staff training, site visits and ongoing external monitoring were conducted to ensure uniformity of the study across the sites.

A preliminary analysis of efficacy and safety was reviewed by an independent Data and Safety Monitoring Board in July 2002. A second meeting was held after all infants had been enrolled, where all new data was reviewed.

Approval for the study was given by the Gauteng Department of Health Provincial Review Committee, the University of the Witwatersrand Committee for Research on Human Subjects and the Mowbray Maternity Hospital Research Committee in Cape Town.

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Laboratory procedures

Laboratory testing was performed at Contract Laboratory Services in Johannesburg, which was certified by both internal and external quality assurance programmes. All blood specimens were collected in ethylenediaminetetraacetic acid-treated tubes, and whole blood was used for HIV-1 RNA (maternal) and DNA (infant) PCR. Infant samples were tested for HIV-1 DNA using the Roche Amplicor Monitor version 1.5 qualitative PCR assay (Roche Diagnostics, Basel, Switzerland).

Definite infant HIV-1 infection was defined as two consecutive blood samples tested positive for HIV-1 DNA by PCR. Infants who had one documented positive result and were then lost to follow-up were considered infected. Infants who tested positive at day 1 or before day 10 were considered to be infected in utero. Infants who tested negative at birth and positive at day 10 or more were considered to be infected postuterine (intrapartum or early postpartum). A child was considered to be uninfected when a week 6 or later result was negative in the absence of breastfeeding. In breastfed infants, retesting occurred 1 month after breastfeeding ceased. These infants were considered uninfected if this sample was negative.

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Statistical methods

Case report forms and laboratory results were checked for accuracy and completeness. Double data entry was performed using a Microsoft Access database. The datasets were merged using SAS version 8.2 (SAS Institute, Cary, North Carolina, USA) to detect data entry discrepancies. Edit checks were built into the Access database to ensure correction of data errors. A 100% quality control, in which the case report forms and database were cross-checked, was carried out on the following variables: HIV DNA results, treatment groups and infant feeding. Data analyses were performed using SAS version 8.2. Continuous baseline data were summarized using descriptive statistics. Student's t test was used for continuous baseline variable comparisons, with the exception of CD4 cell count and viral load, for which an analysis of variance (ANOVA) was used. Categorical baseline data were summarized using frequency tables and compared using the χ2 test, or Fisher's exact test where applicable.

A 95% confidence level (CI) was used and a P value of 0.05 was considered to be statistically significant; all statistical tests were two-tailed. Data were collected up to 12 weeks of age (time window defined as 70–100 days), based on scheduled visits. An intention-to-treat analysis was performed.

Kaplan–Meier survival analysis was performed to determine and compare HIV-1 transmission rates, using the log rank test. The HIV-free survival time for infants infected within the 12-week period was defined as the date of birth to the date of the first positive PCR result; for infants not infected within the 12-week period, the HIV-free survival time was defined as the date of birth to the date of the last negative PCR result. Survival time was censored when the survival time was greater than 100 days.

The 95% CI values for this estimate were calculated based on the normal distribution and the 95% CI for the log of the relative risk (RR). The 95% CI for the estimate was calculated as the range between (1 − upper bound anti-log 95% CI for RR) and (1 − lower bound anti-log 95% CI for RR).

Infant feeding at week 12 was classified as either exclusive formula feeding or as ‘breast milk exposure’. The latter group included exclusively breast feeders, mixed feeders and ever breast feeders. Infants were classified into one of these two groups by taking the feeding practices into account at all visits. Infants who were formula fed from randomization or who were exposed to < 2 days of breast milk were classified as exclusive formula fed.

Risk factors included in the logistic regression model for predicting transmission in utero and at week 12 (only postuterine infection at week 12) were treatment, infant feeding exposure, mode of delivery, maternal viral load and CD4 cell count, and time to study drug ingestion.

Deaths with unknown ‘date of death’ and serious adverse events with unknown ‘start date’ were included in the 12-week analyses.

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Results

From October 2000 to September 2002, approximately 12 000 women delivered without HIV results and were offered PP-VCT. Of these 5634 (49.5%) accepted PP-VCT; 1530 (27.2%) were found to be HIV positive and 1051 infants (68.7%) were randomized into the study: 533 in the ZDV arm and 518 in the NVP arm (Fig. 1).

Fig. 1
Fig. 1
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The maternal demographic data were comparable in both groups (Table 1). At enrolment, the median total CD4 cell count was 467 × 106 cells/l and the median plasma viral load was 21 800 copies/ml. Mean time of drug ingestion were similar in both groups. There was no difference in birthweight, gender or feeding practices between the groups (Table 1).

Table 1
Table 1
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Primary endpoint: efficacy

A total of 718 infants had evaluable results at week 12 and loss to follow-up was similar in both groups (Fig. 1). At birth, HIV PCR positivity was observed in 7.0% of the NVP-treated infants and 5.8% of the ZDV-treated infants (log rank test, P = 0.5). Cumulative HIV-1 transmission rates by Kaplan–Meier estimates at 6 weeks were 11.9% in the NVP arm and 13.6% in the ZDV arm (log rank test, P = 0.6). At 12 weeks, the cumulative infection rate in the NVP arm was 14.3% and in the ZDV arm was 18.1% (log rank test, P = 0.4). In infants uninfected at birth, the postuterine MTCT probabilities at week 6 in the NVP and the ZDV groups were 5.3% and 8.2%, respectively. At week 12, the postuterine MTCT probabilities in the NVP and the ZDV groups were 7.9% and 13.1%, respectively (log rank test, P = 0.06). In multivariate analysis, at 12 weeks, ZDV use was less protective (OR, 1.8; 95% CI,1.1–3.2) (Tables 2 and 3).

Table 2
Table 2
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Table 3
Table 3
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Primary endpoint: safety

The rate of serious adverse events were similar in both arms (118 in the ZDV arm and 94 in the NVP arm; P = 0.56), were deemed to be unrelated to study medication and were mostly caused by infections such as pneumonia (22 in the ZDV arm and 18 in the NVP arm; ZDV; P = 0.75) and gastroenteritis (20 in the ZDV arm and 15 in the NVP arm; P = 0.91). Birth-related conditions (14 in the ZDV arm and 6 in the NVP arm; P = 0.15), physiological jaundice (10 in the ZDV arm and 5 in the NVP arm; P = 0.26) and neonatal septicaemia (7 in the ZDV arm and 13 in the NVP arm; P = 0.09) were the next most frequent serious adverse events.

Of these serious adverse events, 17 (18.1%) in the NVP arm and 36 (30.5%) in the ZDV arm were related to HIV (P = 0.84). There were 165 (15.7%) instances of hospitalization: 73 (14.1%) in the NVP arm, 92 (17.3%) in the ZDV arm (P = 0.44).

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Primary endpoint: infant mortality

Twenty-four infants (3.4%) died before 100 days (13 in the ZDV arm and 11 in the NVP arm; log -rank test, P = 0.8). Five (20.8%) died from respiratory infections, three (12.5%) from gastroenteritis, four (16.7%) from birth-related conditions and 12 (50.0%) from other causes, such as meningitis and septicaemia. Nine (37.5%) infants had negative PCR results; two (8.3%) infants died before day 1 blood was taken and 13 (54.2%) infants were PCR positive. No deaths were attributed to study medication. Four (2.2%) breastfed infants died before 12 weeks of age and 19 (3.8%) formula-fed infants. There was no increased mortality in the formula-fed group (log rank test, P = 0.2).

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Secondary endpoint: effect of breastfeeding

Overall, when comparing breastfed with formula-fed infants in the treatment arms (Table 2), the additional infection rate at 12 weeks was 14.8% in the breastfed group compared with 9.4% in the formula-fed group (log rank test, P = 0.007) Comparing infant feeding within treatment arms, the additional infection rate in the breastfed infants in the ZDV-treated infants was 20.6% compared with 11.1% (log rank test, P = 0.004) in those infants who were not breastfed. The additional infection rate in the breastfed infants in the NVP arm was 9.9% compared with 7.3% (log rank test: P = 0.3) in the non-breastfed group (Table 2).

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Additional analyses

Table 4 shows that maternal viral load, CD4 cell counts, breastfeeding and randomization to ZDV were independently associated with an increased risk of infection between day 10 and day 100. A maternal CD4 cell count < 500 × 106 cells/l was associated with a twofold increase in transmission (multivariate OR, 2.5; 95% CI, 1.3–5.0); a maternal viral load of > 50 000 copies/ml led to a more than threefold increased risk of infection (multivariate OR, 3.6; 95% CI, 2.0–6.2). Breastmilk exposure (multivariate OR, 2.2; 95% CI, 1.3–3.8) was also identified as a significant risk for transmission at week 12.

Table 4
Table 4
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Discussion

A postexposure prophylaxis regimen of single-dose NVP given to infants whose mothers had received no prior antiretroviral therapy was as least as good as 6 weeks of ZDV in reducing MTCT. Compared with 6 weeks of ZDV therapy, single-dose NVP is easier to implement, is likely to be more cost-effective and adherence would be easier to ensure. Further, in multivariate analysis, the ZDV regimen did not appear to be as effective as single-dose NVP in reducing postnatal transmission.

Although directly comparing trials is difficult, the transmission rate seen in our single-dose NVP arm at 6 weeks (11.9%; 95% CI, 8.8–15.0) of age is comparable to the transmission rate seen in HIVNET 012 (11.8%; 95% CI, 8.2–15.5) [5,6], where both mother and infant received NVP, and to the transmission rate at 6–8 weeks (15.3%) seen in infants who received single-dose NVP in addition to 1 week ZDV in the Malawi study [15]. At 12 weeks of age, the transmission rate seen in our single-dose NVP arm (14.3%) was similar to the transmission rate (13.1%) seen in HIVNET 012 at 14–16 weeks of age. There are no data available on transmission at 12 weeks from the Malawi study.

As in other studies [26–29], we demonstrated an increase risk of transmission with maternal CD4 cell counts < 500 × 106 cells/l and plasma HIV-1 RNA levels > 50 000 copies/ml. Our findings, showing the association of maternal viral load with transmission, are consistent with those of Dickover et al. [26], who demonstrated that mothers who transmitted infection to their offspring were more likely to have plasma HIV-1 RNA levels > 50 000 copies/ml at delivery.

A limitation of our study is that 20% of infants were lost to follow-up. This group of infants had similar baseline characteristics to the overall study group and all known characteristics of this group were similar to other study participants (Table 1). Attempts to minimize follow-up loss included three or more home visits to trace non-attending participants. Any information regarding ill-health or mortality obtained from the given address was used. Although our dropout rate is concerning, many published studies report similar rates (e.g. 20% as seen in the Nairobi [30] and SAINT studies [31]).

Despite proven efficacious and cost-effective interventions for prevention of MTCT [2–6,32], these interventions have only been implemented on a very small scale. In some settings where these interventions are available, uptake has been low or variable [33,34]. For these reasons, an intervention that targets infants may be an additional important strategy in resource-constrained settings. In richer parts of the world, infants of mothers delivering without prenatal care account for a large proportion of infections and, as optimal care of this group has not been fully elucidated, the results of this trial may also be relevant to these women [35].

In countries with a high HIV burden, universal NVP therapy to all newborns could be considered, particularly where HIV testing and counselling is not available [31,36]. This could be viewed as analogous to the universal use of tetracycline eye ointment in newborns for preventing ophthalmia neonatorum. Further research on the effectiveness of this approach is needed.

So far, almost all programmes to prevent MTCT in resource-constrained settings have concentrated on antenatal VCT. PP-VCT has been shown to be feasible and advantageous to programmes that aim to prevent HIV infection in infants [37]. For women who have not accessed antenatal care, PP-VCT, infant-feeding counselling and single-dose NVP could be considered as part of essential care. In areas with high HIV incidence rates, women testing negative during antenatal care may benefit from retesting after delivery.

There is concern that single-dose NVP for prevention of MTCT could result in the selection of drug resistance that would limit future therapeutic options. Several studies have demonstrated that drug-resistance mutations were present in maternal and infant viral sequences following NVP exposure for prevention of MTCT [17–21]. Limited evidence suggests that women exposed to single-dose NVP have a poorer response to subsequent therapy based on non-nucleoside reverse transcriptase inhibitors [22]. Preliminary data from our study suggest that in HIV-infected infants exposed to single-dose NVP have a lower frequency of resistance compared with those in HIVNET 012 [38].

Although breastfeeding rates were low, multivariate analysis demonstrates that, by 12 weeks of age, breastfeeding was associated with an increased risk of transmission (OR, 2.2; 95% CI, 1.3–3.8). Investigating alternatives to breastfeeding, or minimizing breastmilk transmission, remain important strategies in preventing MTCT.

Our data demonstrate that a single postpartum dose of NVP administered to infants is a valid additional intervention for prevention of MTCT. As access to antiretroviral therapy becomes a reality in countries heavily affected by HIV, attempts should be made to preserve the efficacy of NVP for the treatment and care of women. Postexposure prophylaxis to infants provides a valuable alternative.

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Acknowledgements

The authors would like to acknowledge Professor Herman Schoeman for his input on the statistical analysis; Professor Louise Kuhn for her helpful advice on both the analysis and interpretation of our data, as well as her input into the manuscript and Professor Marie-Louise Newell for her valuable insight into our analysis and for her input into the manuscript.

Sponsorship: This study was funded by a grant from the Bristol-Myers Squibb Secure the Future Programme (RES 057–02) and by additional funding from the US Agency for International Development (USAID: 674–0320–G-00–5053) under the terms of Award No 674-0320-G-00-5053.

Note: The opinions expressed herein are those of the authors and do not necessary reflect the views of the US Agency for International Development.

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Appendix

Members of the PEP Study Group: Boris Jivkov, Lucy Connell, Deidre Josipovic, Lorna Jenkins, Eileen Botha, Busi Saba, Pascort Khela, Miriam Kunene, Gloria Tshabalala, Manko Ngakane, Doreen Schultz, Michael Duvenhage (Baragwanath Hospital); Lucia Thomas, Edith Ramorokana (Coronation Hospital); and Mitch Besser (Mowbray Hospital).

Keywords:

Africa; mother-to-child transmission; zidovudine; nevirapine; postexposure prophylaxis; breastfeeding; infant HIV-1 infection

© 2005 Lippincott Williams & Wilkins, Inc.

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