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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 . . .

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% . . .

The prevention of mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding is a unique opportunity to curtail the AIDS epidemic. In this trial in Malawi, 3016 infants without HIV-1 infection who were born to infected mothers were randomly assigned to receive a single dose of nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus extended daily prophylaxis with nevirapine or with nevirapine plus zidovudine until the age of 14 weeks. Extended prophylaxis significantly decreased the rate of HIV-1 transmission (10.6%, 5.2%, and 6.4%, respectively) at 9 months. In this trial in Malawi, infants without HIV-1 infection who were born to infected mothers were randomly assigned to receive a single dose of nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus extended daily prophylaxis until the age of 14 weeks. Extended prophylaxis significantly decreased the rate of HIV-1 transmission at 9 months. In sub-Saharan Africa, where breast-feeding is critical for infant survival, postnatal transmission of human immunodeficiency virus type 1 (HIV-1) occurs in up to 16% of untreated infants when breast-feeding continues into the second year of life. 1 Although effective interventions have been identified to reduce in utero and intrapartum transmission of HIV-1 in resource-limited countries, 2 breast-feeding attenuates the efficacy of such methods. 3 , 4 Thus, a major concern in developing countries is HIV-1 transmission through breast milk. 5 To optimize the survival of infants who are born to mothers with HIV-1 infection, interventions that allow safe breast-feeding during the first 6 months of . . .

The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log 10 decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. Treatment failure occurred in 96 (43·6%) of 220 patients assigned nevirapine once daily, 169 (43·7%) of 387 assigned nevirapine twice daily, 151 (37·8%) of 400 assigned efavirenz, and 111 (53·1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5·9% (95% CI −0·9 to 12·8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0·193) or the increases in CD4-positive cells (p=0·800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

Background Few studies have assessed metabolic and body composition alterations in perinatally HIV-infected African children on antiretroviral therapy (ART). We compared metabolic profiles and regional fat of children on ritonavir-boosted lopinavir (lopinavir/ritonavir), lamivudine and stavudine to those switched to nevirapine, lamivudine and stavudine. Methods This study evaluated metabolic and body composition outcomes in 156 HIV-infected children completing a randomised trial that assessed the continued use of lopinavir/ritonavir-based ART or switch to nevirapine-based ART in Johannesburg, South Africa (2005–2010). Fasting total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides total and regional body fat (BF) were measured. A clinical assessment for lipodystrophy (LD) was conducted. Results 156 children (mean age 5.1±0.8 years, mean duration of treatment 4.2±0.7 years, mean time since randomisation 3.4±0.7 years) were enrolled. 85 were randomised to the lopinavir/ritonavir group and 71 to the nevirapine group. The lopinavir/ritonavir group had lower mean HDL (1.3±0.4 vs 1.5±0.4 mmol/l, p<0.001) and higher mean TC (4.4±1.0 vs 4.1±0.8 mmol/l, p=0.097), LDL (2.6±0.9 vs 2.3±0.7 mmol/l, p=0.018) and triglycerides (1.1±0.4 vs 0.8±0.3 mmol/l, p<0.001). The lopinavir/ritonavir group had more total BF by mean skinfold sum (43±11.1 vs 39±10.1 mm, p=0.031) and BF% by bioelectrical impedance analysis (17.0±7.0 vs 14.1±8.0%, p=0.022). Thirteen (8.4%) met criteria for LD. Conclusions Unfavourable alterations in lipid profile and triglycerides, and differences in fat are detectable in young HIV-infected South African children receiving lopinavir/ritonavir-based regimens versus those switched to nevirapine-based regimens. Interventions to mitigate these alterations are warranted to reduce long-term cardiovascular disease risk.

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. Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)—infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors. Methods. An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ 3 /4RH 3 ; [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide / 4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed. Results. A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm 3 , and a median viral load of 310 000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P =.024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P =.058). Conclusions. Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death. Clinical Trials Registration. NCT00332306.

Associations have been reported between an MDR1 variant and responses to nonnucleoside reverse-transcriptase inhibitors. We explored associations between MDR1, CYP2B6, and CYP3A polymorphisms and nevirapine hepatotoxicity. Among participants in a randomized study in South Africa (FTC-302), MDR1 3435C→;T was significantly associated with decreased risk of hepatotoxicity (risk ratio, 0.30; P = .016).

Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART. In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF. Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm(3). ClinicalTrials.gov NCT00089505.