A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006)

OBJECTIVE: To determine the safety, pharmacokinetics, tolerance, antiretroviral activity, and infant HIV infection status after giving a single dose of nevirapine to HIV-1-infected pregnant women during labor and their newborns during the first week of life. DESIGN: An open label phase I/II study. SETTING: Tertiary care hospital, Kampala, Uganda. PATIENTS AND INTERVENTIONS: Nevirapine, 200 mg, was given as a single dose during labor to 21 HIV-1-infected pregnant Ugandan women. In cohort 1, eight infants did not receive nevirapine whereas in cohort 2, 13 infants received a single dose of nevirapine, 2 mg/kg, at 72 h of age. OUTCOMES: The number and type of adverse events; nevirapine concentrations in the plasma and breast milk; maternal plasma HIV-1 RNA copy number before and up to 6 weeks after delivery; and HIV-1 infection status of the infants were monitored. RESULTS: Nevirapine was well tolerated by women and infants; no serious adverse events that were related to nevirapine were observed. Median nevirapine concentration in the women at delivery was 1623 ng/ml (range 238-2356 ng/ml); median cord/maternal blood ratio of 0.75 (0.37-0.93). The median half-life in women was 61.3 h (27-90 h) and the transplacental nevirapine half-life in infants who did not receive a neonatal dose was 54 h. The median half-life after a single dose at 72 h in infants was 46.5 h. During the first week of life, the median colostrum/breast milk to maternal plasma nevirapine concentration was 60.5% (25-122%). The median nevirapine concentration in breast milk 1 week after delivery was 103 ng/ml (25-309 ng/ml). Plasma nevirapine concentrations were above 100 ng/ml in all infants from both cohorts tested at age 7 days. Maternal HIV-1 RNA levels decreased by a median of 1.3 logs at 1 week postpartum, and returned to baseline by 6 weeks postpartum. Detectable plasma HIV-1 RNA was observed in one out of 22 (4.5%) infants at birth; three out of 21 (14%) at 6 weeks; and four out of 21 (19%) at 6 months of age. CONCLUSION: The administration of a single dose of nevirapine to women during labor and to their newborns at 72 h was well tolerated and showed potent antiretroviral activity in the women at 1 week after dosing without rebound above baseline 6 weeks after a single dose. The nevirapine concentration was maintained above the target of 100 ng/ml in infants at age 7 days, even in those infants not receiving a neonatal dose. This regimen has promise as prophylaxis against intrapartum and early breast milk transmission in a breastfeeding population.     

Resistance after single-dose nevirapine prophylaxis emerges in a high proportion of Malawian newborns

The administration of single-dose nevirapine to women in labor and their infants can prevent HIV-1 mother-to-child transmission. We examined nevirapine resistance in infants who were HIV-1 infected despite single-dose nevirapine prophylaxis, including 18 Ugandan infants (HIVNET 012 trial, nine subtype A and nine subtype D) and 23 Malawian infants (NVAZ trial, all subtype C). Nevirapine resistance was more frequent in infants with subtype C than with subtypes A and D (87 versus 50%, P = 0.016).     

Impact of human immunodeficiency virus type 1 (hiv-1) subtype on women receiving single-dose nevirapine prophylaxis to prevent hiv-1 vertical transmission (hiv network for prevention trials 012 study)

In Uganda, the HIV Network for Prevention Trials (HIVNET) 012 study recently demonstrated that single-dose nevirapine (Nvp) prophylaxis is effective for preventing mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1). This exploratory study examines the relationship between HIV-1 subtype, MTCT, and the development of Nvp resistance (Nvp(R)) in women enrolled in HIVNET 012. For 102 women (32 whose infants were HIV-1 infected by age 6-8 weeks and 70 whose infants were uninfected), HIV-1 subtypes included 50 (49%) subtype A, 35 (34%) subtype D, 4 (4%) subtype C, 12 (12%) recombinant subtype, and 1 unclassified. There was no apparent difference in the rate of MTCT among women with subtype A versus D (adjusted odds ratio [OR], 1.24; 95% confidence interval [CI], 0.45-3.43). Nvp(R) mutations were detected more frequently at 6-8 weeks postpartum in women with subtype D than in women with subtype A (adjusted OR, 4.94; 95% CI, 1.21-20.22). Additional studies are needed to further define the relationship between HIV-1 subtype and Nvp(R) among women receiving Nvp prophylaxis.     

Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine

OBJECTIVE: To compare the effect of perinatal regimens of short-course nevirapine (HIVNET 012) and zidovudine [Thai-Centers for Disease Control and Prevention (CDC) regimen] on breast milk viral shedding and perinatal transmission during the first 6 weeks postpartum in a randomized clinical trial. DESIGN: Randomized clinical trial. METHODS: Pregnant HIV-1 seropositive women in Nairobi, Kenya who planned to breastfeed were randomized to HIVNET 012 or Thai-CDC regimens. Two to four breast milk samples were collected each week between delivery and 6 weeks postpartum. Breast milk HIV-1 RNA was quantified using the Gen-Probe TMA assay. Infants were tested for HIV-1 DNA at birth and 6 weeks. RESULTS: From March to October 2003, 76 women were enrolled and 795 breast milk samples were collected from 60 women who were randomized and followed after delivery. Between 3 and 21 days postpartum, nevirapine was associated with significantly greater suppression of breast milk log10 HIV-1 RNA: days 3 to 7 (1.98 versus 2.42, P = 0.1); days 8 to 14 (1.78 versus 2.48, P = 0.005); days 15 to 21 (1.90 versus 2.97, P = 0.003). At 6 weeks, the HIV-1 perinatal transmission rate was significantly lower among those who took nevirapine than zidovudine (6.8% versus 30.3%, P = 0.02). CONCLUSIONS: Compared to a peripartum zidovudine regimen, nevirapine was significantly more likely to decrease HIV-1 RNA in breast milk during the first week and through the third week postpartum following single-dose administration, and corresponded with decreased transmission risk at 6 weeks. Sustained breast milk HIV-1 suppression may contribute to the ability of nevirapine to decrease perinatal transmission of HIV-1.     

Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment

BACKGROUND: The magnitude of infant antiretroviral (ARV) exposure from breast milk is unknown. METHODS: We measured concentrations of nevirapine, lamivudine, and zidovudine in serum and whole breast milk from human immunodeficiency virus type 1 (HIV-1)-infected women in Botswana receiving ARV treatment and serum from their uninfected, breast-feeding infants. RESULTS: Twenty mother-infant pairs were enrolled. Maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 h after nevirapine ingestion). Median breast-milk concentrations of nevirapine, lamivudine, and zidovudine were 0.67, 3.34, and 3.21 times, respectively, those in maternal serum. The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the 50% inhibitory concentration and similar to peak concentrations after a single 2-mg/kg dose of nevirapine. The median infant serum concentration of lamivudine was 28 ng/mL, and the median infant serum concentration of zidovudine was 123 ng/mL, but infants were also receiving zidovudine prophylaxis. CONCLUSIONS: HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these ARVs, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion. Further study is needed to understand the impact of maternal ARV treatment on breast-feeding HIV-1 transmission, infant toxicity, and HIV-1 resistance mutations among infected infants.     

Universal nevirapine upon presentation in labor to prevent mother-to-child HIV transmission in high prevalence settings

OBJECTIVE: To assess the uptake of and adherence to nevirapine to prevent mother-to-child HIV transmission among women of unknown HIV serostatus presenting in labor. We also assessed preliminary efficacy of the approach. DESIGN: Women of unknown HIV serostatus presenting in labor were offered single-dose nevirapine in a prospective cohort study. Two additional contemporaneous comparison populations were also studied. METHODS: We measured uptake by counting the number of women that accepted enrollment when offered. We measured adherence with cord blood nevirapine assay. We measured preliminary efficacy with HIV DNA polymerase chain reaction of infant blood spots at 4-6 weeks of life. RESULTS: Of 1591 women approached in labor, 634 (40%) took up the intervention and received nevirapine, of whom 185 (29%) were HIV infected. Of 179 cord blood specimens from HIV-exposed infants that could be evaluated, 178 (99.4%) had nevirapine detected. This was higher than the 73 of 98 (74%) adherence rate observed in a comparison cohort in which women self-administered nevirapine before presenting to the labor ward (P < 0.001). Of 145 available infant specimens, 17 (11.7%) showed evidence of infection at 4-6 weeks, compared with 12 of 60 (20%) infants born immediately prior to study commencement whose HIV-infected mothers did not receive nevirapine (P < 0.05). CONCLUSIONS: Nevirapine without HIV testing upon presentation in labor was accepted by two-fifths of women. Because therapy is directly observed, adherence is nearly perfect. Labor ward dosing to enhance nevirapine coverage should be considered as an adjunct to antenatal nevirapine administration for prevention of mother-to-child transmission of HIV.     

Sensitive drug-resistance assays reveal long-term persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some women and infants after the administration of single-dose NVP: HIVNET 012

BACKGROUND: The HIV Network for Prevention Trials (HIVNET) 012 trial showed that NVP resistance (NVPR) emerged in some women and children after the administration of single-dose nevirapine (SD-NVP). We tested whether K103N-containing human immunodeficiency virus (HIV)-1 variants persisted in women and infants 1 year or more after the administration of SD-NVP. METHODS: We analyzed samples from 9 women and 5 infants in HIVNET 012 who had NVPR 6-8 weeks after the administration of SD-NVP. Samples were analyzed with the ViroSeq system and with 2 sensitive resistance assays, LigAmp and TyHRT. RESULTS: ViroSeq detected the K103N mutation in 8 of 9 women and in 2 of 5 infants. LigAmp detected the K103N mutation at low levels in 8 of 9 women and in 4 of 5 infants. K103N was not detected by ViroSeq 12-24 months after the administration of SD-NVP but was detected by LigAmp in 3 of 9 women and in 1 of 5 infants. K103N was also detected in those samples by use of the TyHRT assay. CONCLUSIONS: K103N-containing variants persist in some women and infants for 1 year or more after the administration of SD-NVP. Sensitive resistance assays may provide new insight into the impact of antiretroviral drug exposure on HIV-1 evolution.     

A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk

OBJECTIVE: To evaluate the safety, tolerability, and trough levels of three pre-exposure prophylaxis regimens of nevirapine among HIV-1-uninfected subjects at high risk for HIV-1 infection. METHODS: A phase I/II trial (HIVHOP 101) in which 33 such uninfected subjects received a 200 mg tablet of nevirapine once weekly (cohort A, n = 12), twice weekly (cohort B, n = 12), or every other day (cohort C, n = 9) for 12 weeks. Clinical signs/symptoms, laboratory parameters, and nevirapine trough levels were assessed at entry and at 1, 2, 4, 6, 9, and 12 weeks, with a follow-up sample at 16 weeks. RESULTS: No subject experienced clinical symptoms attributed to nevirapine, including rash. There were no significant changes in liver enzyme levels from baseline to week 12 in the three cohorts, except for glutamyl transpeptidase in cohort B. Median nevirapine trough levels at weeks 1 and 12 were 119 ng/ml (range, < 25-205) and 135 ng/ml (range, < 25-1065), respectively, for cohort A, 569 ng/ml (range, 135-2641) and 431 ng/ml (range, 42-2454) for cohort B, and 1942 ng/ml (range, 1214-2482) and 943 ng/ml (range, 262-5281) for cohort C. No subject became HIV-1 antibody positive by week 16. CONCLUSIONS: A single dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was safely tolerated by the subjects in this small study, and resulted in nevirapine levels well above the IC (inhibitory concentration of 50%: 10 ng/ml) over the 12-week period in nearly all evaluable subjects. (50)     

Low efficacy of nevirapine (HIVNET012) in preventing perinatal HIV-1 transmission in a real-life situation

Since 2001, the unrestricted use of HIVNET012 has been recommended for the prevention of mother-to-child transmission in low-resource settings, despite the lack of validated efficacy data outside research settings. We implemented the nevirapine regimen in a real-life situation in Kenya. The perinatal HIV-1 transmission rate at 14 weeks was 18.1%, similar to the 21.7% before the intervention. These data call for further evaluation of the simple nevirapine regimen in field conditions, and underline the need for alter-native strategies.     

Timing of maternal and neonatal dosing of nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024

OBJECTIVE: Despite a growing emphasis worldwide on complex and potent antiretroviral drug regimens for the prevention of mother-to-child transmission of HIV-1 (MTCT), two-dose nevirapine (NVP) prophylaxis remains an important choice in many settings. We analyzed data from a multicenter clinical trial to determine whether timing of maternal or infant NVP was associated with MTCT between delivery and 6 weeks of age (intrapartum/early postnatal transmission; I/EP). METHODS: HIVNET 024 was a placebo-controlled, double-blind trial of empiric antibiotics to reduce chorioamnionitis-associated MTCT. This secondary analysis used data collected in the original randomized trial. Enrolled women were instructed to self-administer NVP at labor onset; infants were to receive a dose within 72 h of birth. RESULTS: Data regarding 1491 mother-infant pairs were analyzed. The overall I/EP HIV-1 transmission rate was 8.1% at 6 weeks. Almost all women (93%) ingested NVP within 24 h of delivery; 90% of infants were given NVP within 48 h after delivery. Variations in mother or infant dose timing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women ingesting NVP or= 4 h). CONCLUSION: Variations in the timing of maternal and infant NVP doses (within reasonable proximity to delivery) do not appear to affect the risk of MTCT.     

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012)

OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) mutations faded from detection within 12-24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.     

Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial

A study was conducted to assess the safety and efficacy of short-course nevirapine compared with zidovudine given to women during labor and to neonates during the first week of life. 626 HIV-1 infected pregnant women attending the antenatal clinic from November 1997 to April 1999 at Mulago Hospital in Kampala, Uganda, were randomly given nevirapine or zidovudine. Infants were tested for HIV-1 infection at birth, at 6-8 weeks, and at 14-16 weeks. Findings revealed that the estimated risk of HIV-1 transmission in the zidovudine and nevirapine groups was 10.4% and 8.2%, respectively, at birth; 21.3% and 11.9%, by 6-8 weeks; and 25.1% and 13.1%, by 14-16 weeks. There was a 47% relative efficacy rate of the nevirapine regimen at 14-16 weeks compared to zidovudine. Based on the findings, nevirapine lowers the risk of HIV-1 transmission by nearly 50% during the first 14-16 weeks of life in breast-fed infants.     

Nevirapine (NVP) resistance in women with HIV-1 subtype C, compared with subtypes A and D, after the administration of single-dose NVP

OBJECTIVE: In the Human Immunodeficiency Virus (HIV) Network for Prevention Trials (HIVNET) 012 trial in Uganda, 6-8 weeks after single-dose nevirapine (SD-NVP), NVP resistance mutations were detected at a higher rate in women with HIV-1 subtype D than in women with subtype A. Here, we evaluate the rate of NVP resistance mutations in women with subtype C. METHODS: NVP resistance mutations were detected using the ViroSeq HIV-1 Genotyping System. RESULTS: The portion of women with any NVP resistance mutation was higher in those with subtype C (45/65 [69.2%] in the NVP and zidovudine trial, Malawi) than in those in the HIVNET 012 trial with either subtype A (28/144 [19.4%]; P<.0001) or subtype D (35/97 [36.1%]; P<.0001). In a multivariate model, subtype (C vs. A: odds ratio [OR], 8.73 [95% confidence interval {CI}, 4.29-17.76]; C vs. D: OR, 3.38 [95% CI, 1.65-6.93]) and viral load at delivery (OR, 2.35 [95% CI, 1.62-3.40]) independently predicted NVP resistance mutations, but maternal age, parity, and time between SD-NVP and the 6-8-week visit did not. CONCLUSIONS: The rate of NVP resistance mutations after SD-NVP was significantly higher in women with HIV-1 subtype C than in women with subtype A or D. Studies are needed to assess the clinical significance of this finding.     

Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir

OBJECTIVE: Although most uninfected infants born to women infected with HIV-1 show no clinical evidence of mitochondrial compromise, mitochondrial dysfunction has been reported in children born to women receiving zidovudine and/or lamivudine during pregnancy. In this pilot study we examined mitochondrial integrity in HIV-1-uninfected infants born to HIV-1-infected women receiving Combivir during pregnancy. DESIGN:: Samples of umbilical cord and cord blood were obtained from HIV-1-uninfected infants born to either HIV-1-infected women receiving Combivir therapy during pregnancy (n = 10) or HIV-1-uninfected women (n = 9). METHODS: Mitochondrial morphological integrity was examined in umbilical cords (n = 16) by electron microscopy and mtDNA quantity was determined in DNA from cord blood (n = 18) and umbilical cord (n = 18) by PCR-chemiluminescence immunoassay detection. RESULTS: In umbilical cords from six of nine infants born to HIV-1-infected mothers taking Combivir moderate to severe mitochondrial morphological damage was observed (P = 0.011), while none of seven unexposed infants showed similar damage. Compared to unexposed infants, statistically significant mtDNA depletion was observed in umbilical cord (P = 0.006) and cord blood (P = 0.003) from drug-exposed infants. CONCLUSIONS: A cohort of HIV-1-uninfected Combivir-exposed infants with no clinical symptoms showed morphological and molecular evidence of mitochondrial damage.     

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

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 x 10(6) 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.     

Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1

We analyzed the development of nevirapine (NVP) resistance in human immunodeficiency virus type 1 (HIV-1)-infected Malawian infants who received regimens containing single-dose NVP (SD-NVP) for the prevention of mother-to-child transmission (MTCT) of HIV-1. All infants received SD-NVP, and some randomly received zidovudine (ZDV) as well. Mothers did or did not receive SD-NVP on the basis of when they arrived at the hospital for delivery. In infants 6-8 weeks of age, NVP resistance was less frequent when infants had received SD-NVP plus ZDV and mothers had not received SD-NVP than when infants had received SD-NVP alone and mothers had received SD-NVP (4/15 [27%] vs. 20/23 [87%]; P < .001). The risk of MTCT of HIV-1 was comparable with these regimens. Infant-only prophylaxis also eliminates the development of NVP resistance in mothers.     

Transplacental passage of protease inhibitors at delivery

OBJECTIVE: Although combinations of different antiretroviral drugs are increasingly used by pregnant HIV-1-infected women, few human data are available to evaluate in utero protease inhibitors (PI) exposure. The aim of this study was to assess the extent of transplacental passage of PI at delivery. METHODS: Pregnant women treated with antiretroviral drugs including PI and/or nevirapine were eligible for the study. Placental transfer was determined by comparison of drug concentrations in blood samples simultaneously collected from a peripheral maternal vein and the umbilical cord at delivery. Drug levels were determined by high-performance liquid chromatography. RESULTS: Thirteen maternal-cord blood sample pairs were evaluable for transplacental passage determination (nine nelfinavir, two ritonavir, one saquinavir, one lopinavir, two nevirapine). Median cord and maternal drug concentrations, respectively, were nelfinavir < 250 and 1110 ng/ml; ritonavir < 250 and 1113 ng/ml; saquinavir < 100 and 350 ng/ml; lopinavir < 250 and 3105 ng/ml and nevirapine 2072 and 2546 ng/ml. The cord-to-maternal blood ratio was extremely low for all PI. CONCLUSION: PI do not cross the placenta to an appreciable extent and consequently cannot be expected to exert a direct antiviral activity in utero during the whole dosing interval. Limited transfer may result from their high degree of plasma protein binding and their backwards transport through P-glycoprotein, largely expressed in the placenta. In contrast, nevirapine readily crosses the placental barrier. Such considerations may support treatment decisions in pregnant women.     

A phase III clinical trial of antibiotics to reduce chorioamnionitis-related perinatal HIV-1 transmission

OBJECTIVE: A multisite study was conducted in Africa to assess the efficacy of antibiotics to reduce mother-to-child transmission (MTCT) of HIV-1. DESIGN: A randomized, double-blinded, placebo-controlled, phase III clinical trial. METHODS: HIV-1-infected women were randomly assigned at 20-24 weeks' gestation to receive either antibiotics (metronidazole plus erythromycin antenatally and metronidazole plus ampicillin intrapartum) or placebo. Maternal study procedures were performed at 20-24, 26-30, and 36 weeks antenatally, and at labor/delivery. Infants were seen at birth, 4-6 weeks, and 3, 6, 9 and 12 months. The primary efficacy endpoints were overall infant HIV-1 infection and HIV-1-free survival at 4-6 weeks. All women and infants received single-dose nevirapine prophylaxis in this study. RESULTS: A total of 1510 live-born infants were included in the primary analysis. The proportions of HIV-1-infected infants at birth were similar (antibiotics 7.1%; placebo 8.3%; P = 0.41). Likewise, there were no statistically significant differences at 4-6 weeks in the overall risk of MTCT of HIV-1 (antibiotics 16.2%; placebo 15.8%; P = 0.89) or HIV-1-free survival (79.4% in each study arm). Post-randomization, the proportion of women with bacterial vaginosis at the second antenatal visit was significantly lower in the antibiotics arm compared with the placebo arm (23.8 versus 39.7%; P < 0.001), but the frequency of histological chorioamnionitis was not different (antibiotics 36.9%; placebo 39.7%; P = 0.30). Adverse events in mothers and their infants did not differ by randomization arm. CONCLUSION: This simple antepartum and peripartum antibiotic regimen did not reduce the risk of MTCT of HIV-1.