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Breastfeeding is essential for child health and development in low-resource settings but carries a significant risk of transmission of HIV-1, especially in late stages of maternal disease. We aimed to assess the efficacy and safety of triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis in pregnant women infected with HIV. Pregnant women with WHO stage 1, 2, or 3 HIV-1 infection who had CD4 cell counts of 200–500 cells per μL were enrolled at five study sites in Burkina Faso, Kenya, and South Africa to start study treatment at 28–36 weeks' gestation. Women were randomly assigned (1:1) by a computer generated random sequence to either triple antiretroviral prophylaxis (a combination of 300 mg zidovudine, 150 mg lamivudine, and 400 mg lopinavir plus 100 mg ritonavir twice daily until cessation of breastfeeding to a maximum of 6·5 months post partum) or zidovudine and single-dose nevirapine (300 mg zidovudine twice daily until delivery and a dose of 600 mg zidovudine plus 200 mg nevirapine at the onset of labour and, after a protocol amendment in December, 2006, 1 week post-partum zidovudine 300 mg twice daily and lamivudine 150 mg twice daily). All infants received a 0·6 mL dose of nevirapine at birth and, from December, 2006, 4 mg/kg twice daily of zidovudine for 1 week after birth. Patients and investigators were not masked to treatment. The primary endpoints were HIV-free infant survival at 6 weeks and 12 months; HIV-free survival at 12 months in infants who were ever breastfed; AIDS-free survival in mothers at 18 months; and serious adverse events in mothers and babies. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, ISRCTN71468401. From June, 2005, to August, 2008, 882 women were enrolled, 824 of whom were randomised and gave birth to 805 singleton or first, liveborn infants. The cumulative rate of HIV transmission at 6 weeks was 3·3% (95% CI 1·9–5·6%) in the triple antiretroviral group compared with 5·0% (3·3–7·7%) in the zidovudine and single-dose nevirapine group, and at 12 months was 5·4% (3·6–8·1%) in the triple antiretroviral group compared with 9·5% (7·0–12·9%) in the zidovudine and single-dose nevirapine group (p=0·029). The cumulative rate of HIV transmission or death at 12 months was 10·2% (95% CI 7·6–13·6%) in the triple antiretroviral group compared with 16·0% (12·7–20·0%) in the zidovudine and single-dose nevirapine group (p=0·017). In infants whose mothers declared they intended to breastfeed, the cumulative rate of HIV transmission at 12 months was 5·6% (95% CI 3·4–8·9%) in the triple antiretroviral group compared with 10·7% (7·6–14·8%) in the zidovudine and single-dose nevirapine group (p=0·02). AIDS-free survival in mothers at 18 months will be reported in a different publication. The incidence of laboratory and clinical serious adverse events in both mothers and their babies was similar between groups. Triple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants. Revised WHO guidelines now recommend antiretroviral prophylaxis (either to the mother or to the baby) during breastfeeding if the mother is not already receiving antiretroviral treatment for her own health. Agence nationale de recherches sur le sida et les hépatites virales, Department for International Development, European and Developing Countries Clinical Trials Partnership, Thrasher Research Fund, Belgian Directorate General for International Cooperation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction.

Approximately 200,000 infants worldwide become infected with human immunodeficiency virus type 1 (HIV-1) annually through breast-feeding. In this randomized trial involving 2369 mother–infant pairs in Malawi, the use of either maternal antiretroviral therapy or infant nevirapine through the age of 6 months was found to significantly decrease the rate of maternal transmission of HIV-1 during breast-feeding. Approximately 200,000 infants worldwide become infected annually with human immunodeficiency virus type 1 (HIV-1) through breast-feeding. 1 , 2 Without treatment, half of these infants will die before their second birthday. 3 Although formula feeding decreases the risk of postnatal HIV transmission, it is associated with an increased rate of early death. 4 , 5 Thus, exclusive breast-feeding is recommended by the World Health Organization (WHO) for infants of HIV-1–positive women for the first 6 months of life in resource-limited settings. 6 The use of antiretroviral drugs during pregnancy, labor, and delivery effectively reduces intrauterine and intrapartum HIV-1 transmission. 7 , 8 However, without prophylaxis, an additional 9% . . .

In this randomized trial involving neonates whose HIV-infected mothers did not receive antenatal antiretroviral therapy (ART), combination ART significantly reduced intrapartum HIV infection, as compared with monotherapy. Three-drug ART had more side effects than two-drug ART. Randomized, controlled studies of postexposure prophylaxis in infants born to late-presenting women with human immunodeficiency virus (HIV) infection who did not receive antiretroviral therapy (ART) in pregnancy have been performed in breast-fed populations 1 – 5 but not in non–breast-fed populations of higher-income countries. Observational studies have shown reduced transmission when zidovudine therapy was initiated within 48 hours after birth and continued for 6 weeks in neonates born to untreated mothers with HIV type 1 (HIV-1) infection, 6 , 7 although transmission rates in this scenario remain as high as 12 to 26%. 6 – 8 In a randomized South African trial of infants born to . . .

In this study of 288 HIV-infected children conducted in Africa and India, an antiretroviral regimen based on ritonavir-boosted lopinavir was found to be more effective and had a more acceptable safety profile than a nevirapine-based regimen. New antiretroviral drugs and drug classes have markedly advanced the treatment of human immunodeficiency virus (HIV) infection in children. In resource-limited settings, where most HIV-infected children live, therapeutic options are restricted by financial and logistic constraints. Nevirapine is an important component of long-term therapy because it is stable at high temperatures, available in fixed-dose combinations, and relatively inexpensive, and its use is based on extensive experience and an acceptable safety profile in the pediatric population. Often, it is the only option available for infants and children. Randomized studies have shown that regimens incorporating ritonavir-boosted lopinavir (both protease inhibitors) are superior . . .

This double-blind, randomized trial in Botswana compared two highly active antiretroviral regimens in HIV-1−infected pregnant women (CD4+ count, ≥200) from pregnancy through 6 months post partum (when breast-feeding ceased). Both regimens were highly effective in suppressing the maternal HIV-1 viral load as well as mother-to-child transmission, with an overall transmission rate of 1.1%. Highly active antiretroviral therapy (HAART) used to prevent in utero and intrapartum mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) is among the most successful public health interventions of the HIV era. 1 , 2 However, the use of HAART in mothers to prevent mother-to-child transmission through breast-feeding in areas of the world where replacement feeding is neither safe nor feasible remains an unproven strategy. 1 , 3 We compared different HAART regimens used in pregnancy and during breast-feeding to determine whether the regimens differ with respect to virologic suppression during pregnancy and breast-feeding, pregnancy outcomes, and toxic effects in mothers and infants. . . .

HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per μL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per μL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1·18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85–88) in the CDM group and 90% (88–91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4·9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6·94 [95% CI 6·33–7·60] vs 5·24 [4·72–5·81] per 100 person-years; absolute difference 1·70 per 100 person-years [0·87–2·54]; HR 1·31 [1·14–1·51]; p=0·0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1·12 [0·94–1·32]; p=0·19), with anaemia the most common (76 vs 61 cases). ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Background. To our knowledge, to date, no prospective, randomized, clinical trial has compared standard doses of efavirenz- and nevirapine-based antiretroviral therapy among patients with concurrent human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis (TB) who are receiving rifampicin. Methods. Rifampicin recipients with concurrent HIV-1 infection and TB were randomized to receive antiretroviral therapy that included either efavirenz (600 mg per day) or nevirapine (400 mg per day). Efavirenz and nevirapine concentrations at 12 h after dosing (C12) were monitored at weeks 6 and 12. CD4+ cell counts and HIV-1 RNA levels were assessed every 12 weeks. Results. One hundred forty-two patients were randomized into 2 groups equally. The mean body weight of patients was 53 kg, the mean CD4+ cell count was 65 cells/mm3, and the median HIV-1 RNA level was 5.8 log10 copies/mL. At weeks 6 and 12, the mean C12 of efavirenz (± standard deviation) were 4.27±4.49 and 3.54±3.78 mg/L, respectively, and those for nevirapine were 5.59±3.48 and 5.6±2.65 mg/L, respectively. Interpatient variability in the efavirenz group was 2.3-fold greater than that in the nevirapine group (coefficient of variation, 107% vs. 47%). At week 12, 3.1% of patients in the efavirenz group and 21.3% in the nevirapine group had C12 values that were less than the recommended minimum concentrations (odds ratio, 8.396; 95% confidence interval, 1.808–38.993; P=.002). Intention-to-treat analysis revealed that 73.2% and 71.8% of patients in the efavirenz and nevirapine groups, respectively, achieved HIV-1 RNA levels <50 copies/mL at week 48, with respective mean CD4+ cell counts of 274 and 252 cells/mm3 (P>.05). Multivariate analysis revealed that patients with low C12 values and those with a body weight <55 kg were 3.6 and 2.4 times more likely, respectively, to develop all-cause treatment failure (P<.05). Conclusions. Antiretroviral therapy regimens containing efavirenz (600 mg per day) were less compromised by concomitant use of rifampicin than were those that contained nevirapine (400 mg per day) in patients with concurrent HIV-1 infection and TB. Low drug exposure and low body weight are important predictive factors for treatment failure. Trial registration. ClinicalTrials.gov identifier: NCT00483054.

In countries with a high incidence of HIV and tuberculosis co-infection, nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs. We aimed to compare efficacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in co-infected patients. We did a multicentre, open-label, randomised, non-inferiority trial at three health centres in Maputo, Mozambique. We enrolled adults (≥18 years) with tuberculosis and previously untreated HIV infection (CD4 cell counts <250 cells per μL) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal. 4–6 weeks after the start of tuberculosis treatment, we randomly allocated patients (1:1) with central randomisation, block sizes of two to six, and stratified by site and CD4 cell count to nevirapine (200 mg twice daily) or efavirenz (600 mg once daily), plus lamivudine and stavudine. The primary endpoint was virological suppression at 48 weeks (HIV-1 RNA <50 copies per mL) in all patients who received at least one dose of study drug (intention-to-treat population); death and loss to follow-up were recorded as treatment failure. The non-inferiority margin for the difference of efficacy was 10%. We assessed efficacy in intention-to-treat and per-protocol populations and safety in all patients who received study drug. This study is registered with ClinicalTrials.gov, number NCT00495326. Between October, 2007, and March, 2010, we enrolled 285 patients into each group. 242 (85%) patients in the nevirapine group and 233 (82%) patients in the efavirenz group completed follow-up. In the intention-to-treat population, 184 patients (64·6%, 95% CI 58·7–70·1) allocated nevirapine achieved virological suppression at week 48, as did 199 patients (69·8%, 64·1–75·1) allocated efavirenz (one-sided 95% CI of the difference of efficacy 11·7%). In the per-protocol population, 170 (70·0%, 63·8–75·7) of 243 patients allocated nevirapine achieved virological suppression at week 48, as did 194 (78·9%, 73·2–83·8) of 246 patients allocated efavirenz (one-sided 95% CI 15·4%). The median CD4 cell count at randomisation was 89 cells per μL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine. 20 patients allocated nevirapine (7%) had grade 3–4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz (6%). Three patients had severe rash after receipt of nevirapine (1%) but no patients did after receipt of efavirenz. 18 patients in the nevirapine group died, as did 17 patients in the efavirenz group. Although non-inferiority of the nevirapine-regimen was not shown, nevirapine at full dose could be a safe, acceptable alternative for patients unable to tolerate efavirenz. French Research Agency for HIV/AIDS and hepatitis (ANRS).

Background. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. Methods. Human immunodeficiency virus (HIV)–infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. Results. As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3–6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37–2.65) but not death alone (aHR, 1.65; 95% CI, .72–3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. Conclusions. These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. Clinical Trials Registration. NCT00307151.

Background India has among the highest rates of infant malnutrition. Few studies investigating the growth patterns of HIV-exposed infants in India or the impact of timing of HIV infection on growth in settings such as India exist. Methods We used data from the Six Week Extended Nevirapine (SWEN) trial to compare the growth patterns of HIV-infected and HIV-exposed but uninfected infants accounting for timing of HIV infection, and to identify risk factors for stunting, underweight and wasting. Growth and timing of HIV infection were assessed at weeks 1, 2, 4, 6, 10, 14 weeks and 6, 9, 12 months of life. Random effects multivariable logistic regression method was used to assess factors associated with stunting, underweight and wasting. Results Among 737 HIV-exposed infants, 93 (13%) were HIV-infected by 12 months of age. Among HIV-infected and uninfected infants, baseline prevalence of stunting (48% vs. 46%), underweight (27% vs. 26%) and wasting (7% vs. 11%) was similar (p>0.29), but by 12 months stunting and underweight, but not wasting, were significantly higher in HIV-infected infants (80% vs. 56%, 52% vs. 29%, p< 0.0001; 5% vs. 6%, p=0.65, respectively). These differences rapidly manifested within 4–6 weeks of birth. Infants infected in utero had the worst growth outcomes during the follow-up period. SWEN was associated with non-significant reductions in stunting and underweight among HIV-infected infants and significantly less wasting in HIV-uninfected infants. In multivariate analysis, maternal CD4 < 250, infant HIV status, less breastfeeding, low birth weight, non-vaginal delivery, and infant gestational age were significant risk factors for underweight and stunting. Conclusion Baseline stunting and underweight was high in both HIV-infected and uninfected infants; growth indices diverged early and were impacted by timing of infection and SWEN prophylaxis. Early growth monitoring of all HIV-exposed infants is an important low-cost strategy for improving health and survival outcomes of these infants. Trial Registration NCT00061321