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Background: Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring.Methods and Findings: In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI -3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post-week 24 was spent with persistent low-level viraemia (80-5,000 copies/ml) and 10% with VL rebound ≥5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound ≥5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years' rebound. Nineteen out of 48 (40%) VLs 1,000-5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs ≥5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes.Conclusions: In this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring.Trial Registration: ISRCTN Registry, ISRCTN24791884. [ABSTRACT FROM AUTHOR]

Objectives To confirm whether 7 days of phenytoin, an enzyme inducer, would decrease the elimination half-life of single-dose nevirapine and to investigate its effect on the development of nevirapine resistance in pregnant, HIV-infected women. Methods In a pharmacokinetic pilot trial (NCT01187719), HIV-infected, antiretroviral (ARV)-naive pregnant women ≥18 years old from Zambia and Tanzania and with CD4 cell counts >350 cells/mm3 were randomized 1 : 1 to a control (zidovudine pre-delivery, single-dose nevirapine/zidovudine/lamivudine at delivery and zidovudine/lamivudine for 7 days post-delivery) or an intervention (control plus 184 mg of phenytoin once daily for 7 days post-delivery) group. Primary endpoints were the pharmacokinetics of and resistance to nevirapine. Results Thirty-five and 37 women were allocated to the control and intervention groups, with median (IQR) ages of 27 (23–31) and 27 (23–33) years, respectively. Twenty-three and 23 women had detectable nevirapine levels at delivery and subsequent samples in the control and the intervention groups, respectively. Geometric mean (GM) (95% CI) plasma levels of nevirapine at delivery were 1.02 (0.58–1.78) mg/L and 1.14 (0.70–1.86) mg/L in the control and intervention groups, respectively (P = 0.76). One week after delivery, 0/23 (0%) and 15/22 (68%) control and intervention mothers, respectively, had undetectable levels of nevirapine (<0.05 mg/L; P<0.001). One week later, the figures were 10/21 (48%) and 18/19 (95%) mothers, respectively (P = 0.002). The GM (95% CI) half-life of nevirapine was 63.2 (52.8–75.7) versus 25.5 (21.6–30.1) h in the control group versus the intervention group (P < 0.001). New nevirapine mutations were found in 0/20 (0%) intervention-group mothers versus 1/21 (5%) control-group mothers. Overall, there was no difference in adverse events reported between the control and intervention arms (P > 0.28). Conclusions Adding 7 days of an enzyme inducer to single-dose nevirapine to prevent mother-to-child transmission of HIV significantly reduced subtherapeutic nevirapine levels by shortening the half-life of nevirapine. As prolonged subtherapeutic nevirapine dosage leads to the emergence of resistance, single-dose nevirapine could be used with phenytoin as an alternative if other ARVs were unavailable. [ABSTRACT FROM PUBLISHER]

In the CHAP randomized placebo-controlled trial of cotrimoxazole prophylaxis in HIV-infected Zambian children conducted between 2001 and 2003, cotrimoxazole was associated with significant mortality reductions. In a secondary analysis we used Cox regression models to estimate the association between adherence measured by bottle weights and caregiver report and subsequent mortality in children surviving >28 days ( n = 496, 153 deaths). Adherence was high and similar in both cotrimoxazole and placebo groups; adherence from bottle weights was 100% at 71% of visits, while caregivers reported 100% adherence at 79% of visits. Every 10% lower adherence to cotrimoxazole or placebo measured by bottle weights was associated with a 10–11% increase in mortality risk. Effects remained after adjustment for baseline predictors of survival and for current and recent change in primary caregiver. Caregiver-reported adherence was not associated with survival. The association between bottle-weight adherence to placebo and survival is likely capturing unmeasured caregiver effects, whose identification will be essential for quantifying the impact of antiretroviral therapy (ART) adherence on clinical outcomes in children. [ABSTRACT FROM AUTHOR]