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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.

In this randomized, controlled trial in Africa and India, combination antiretroviral therapy was more effective than standard therapy in preventing mother-to-child transmission of HIV but was associated with increased toxic effects. Antiretroviral regimens used for the prevention of mother-to-child transmission of the human immunodeficiency virus (HIV) have evolved from the first successful trial that used zidovudine single-drug prophylaxis in 1994 to current triple-drug regimens. 1 , 2 Although there are clear benefits of combination antiretroviral therapy (ART) for the mother and infant, these do not come without risks; some studies have shown higher rates of adverse pregnancy outcomes with maternal ART than with regimens containing fewer antiretroviral agents. 3 – 5 The Promoting Maternal and Infant Survival Everywhere (PROMISE) trial compared the relative efficacy and safety of various proven antiretroviral strategies for the prevention of . . .

Problems associated with lifelong antiretroviral therapy, such as need for strict adherence, drug-related toxic effects, difficulties with treatment schedules, and cost, mean that simplification strategies should be sought. We aimed to explore the efficacy and safety of dual treatment with atazanavir–ritonavir plus lamivudine as an option to switch to from standard combination antiretroviral therapy in patients with an HIV-1 infection who are virologically suppressed. In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years and older with chronic HIV-1 infection and no previous treatment failure or resistance, and with HIV-1 RNA of less than 50 copies per mL for at least 6 months, negative hepatitis B virus surface antigen, and good general health, from 30 hospitals in Spain. Exclusion criteria were switch in antiretroviral therapy during the previous 4 months, previous virological failure, pregnancy or breastfeeding, Gilbert's syndrome, use of contraindicated drugs, grade 4 laboratory abnormalities, and previous intolerance to any of the study drugs. We randomly assigned patients (1:1; stratified by active hepatitis C virus infection and previous treatment; computer-generated random number sequence) to dual treatment with oral atazanavir (300 mg once daily) and ritonavir (100 mg once daily) plus lamivudine (300 mg once daily) or triple treatment with oral atazanavir (300 mg once daily) and ritonavir (100 mg once daily) plus two nucleos(t)ide reverse transcriptase inhibitors at the discretion of the investigators. The primary endpoint was virological response, defined as HIV-1 RNA of less than 50 copies per mL at week 48, in the per-protocol population, with a non-inferiority margin of 12%. We included patients who received at least one dose of the study drug in the safety analysis. This study is registered at ClinicalTrials.gov, number NCT01307488. Between Sept 29, 2011, and May 2, 2013, we randomly assigned 286 patients (143 [50%] to each group). At week 48 in the per-protocol population, 112 (84%) of 133 patients had virological response in the dual-treatment group versus 105 (78%) of 135 in the triple-treatment group (difference 6% [95% CI −5 to 16%), showing non-inferiority at the prespecified level. 14 (5%) patients developed severe adverse events (dual treatment six [4%]; triple treatment eight [6%]), none of which we deemed related to the study drug. Grade 3–4 adverse events were similar between groups (dual treatment 77 [55%] of 140; triple treatment 78 [55%] of 141). Treatment discontinuations were less frequent in the dual-treatment group (three [2%]) than in the triple-treatment group (ten [7%]; p=0·047). In our trial, dual treatment was effective, safe, and non-inferior to triple treatment in patients with an HIV-1 infection who are virologically suppressed who switch antiretroviral therapy because of toxic effects, intolerance, or simplification. This combination has the potential to suppress some of the long-term toxic effects associated with nucleos(t)ide reverse transcriptase inhibitors, preserve future treatment options, and reduce the cost of antiretroviral therapy. Bristol Myers-Squibb and Fundación SEIMC-GESIDA.

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 randomized, open-label trial compared two regimens for the initial treatment of human immunodeficiency virus (HIV) infection: tenofovir disoproxil fumarate and emtricitabine plus efavirenz or a fixed dose of zidovudine and lamivudine plus efavirenz. Through week 48, the first regimen was superior in terms of viral suppression, CD4-cell response, and adverse events leading to discontinuation of the medication. As this trial continues, it will be important to assess any differences in long-term toxic effects, especially with regard to lipoatrophy and hyperlipidemia. For the initial treatment of HIV, a regimen of tenofovir and emtricitabine plus efavirenz was superior in terms of viral suppression, CD4-cell response, and adverse events through week 48. Highly active antiretroviral therapy has fundamentally altered the course of human immunodeficiency virus (HIV) infection by making it possible to suppress the plasma viral load below the limit of detection and to increase the number of CD4 cells. 1 The cornerstone of durable suppression of HIV replication is maintenance of a potent and tolerable regimen to which the patient can adhere. Adherence is necessary to prevent the emergence and replication of drug-resistant strains of the virus. 2 Current guidelines for the management of HIV infection recommend the use of zidovudine or tenofovir disoproxil fumarate (DF) with lamivudine or emtricitabine as preferred nucleoside . . .

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% . . .

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.

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. . . .

Background. Antiretroviral (ARV) regimens during pregnancy are highly effective in preventing mother-to-child transmission of human immunodeficiency virus (HIV). Congenital heart defects (CHDs) and anomalies in cardiac function have been reported in zidovudine (ZDV)–exposed uninfected children. We explored these associations in a large observational cohort and a randomized clinical trial. Methods. Since 1986, the French Perinatal Cohort prospectively enrolled all HIV-infected women in 90 centers and collected follow-up on their children through 2 years of age. All CHDs were reviewed by a specialist blinded to exposures. Additionally, in a randomized trial (PRIMEVA ANRS 135) of 2 ARV regimens during pregnancy, 1 of which was without nucleoside reverse transcriptase inhibitors, infants had a specific follow-up including echocardiography at 1 month and 12 months. Results. Among 12 888 children included, ZDV exposure in the first trimester was significantly associated with CHD (1.5% vs 0.7%; adjusted odds ratio, 2.2 [95% confidence interval, 1.3–3.7]; P < .001). This association was significant for ventricular septal defects (1.1% vs 0.6%; P = .001) and other CHDs (0.31% vs 0.11%; P = .02). In the randomized trial, among 50 infants, girls (but not boys) exposed in utero to ZDV/lamivudine/ritonavir-boosted lopinavir (LPV/r) had a higher left ventricular shortening fraction at 1 month (40% vs 36%; P = .008), and an increased posterior wall thickness at 1 year (5.4 mm vs 4.4 mm; P = .01) than the LPV/r group. Conclusions. This study confirms a specific association between in utero exposure to ZDV and CHDs, and a longlasting postnatal myocardial remodeling in girls. A potential common mechanism, including the involvement of mitochondrial dysfunction, must be explored, and long-term consequences on cardiac function warrant specific attention. Clinical Trials Registration. NCT00424814.