Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). CONCLUSIONS: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).

HIV-1 viral load and resistance in genital secretions in patients taking protease-inhibitor-based second-line therapy in Africa.

BACKGROUND: HIV is transmitted primarily through sexual intercourse, and the objective of this study was therefore to assess whether there is occult viral replication and resistance in genital secretions in patients on protease inhibitor (PI)-based second-line therapy. METHODS: HIV-infected adults taking ritonavir-boosted lopinavir with either two nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir or as monotherapy for 96 weeks, were enrolled at seven clinical sites in Uganda. Viral load (VL) was measured in cervico-vaginal secretions or semen and in a corresponding plasma sample. Genotypic resistance was assessed in genital secretion samples and plasma samples. Results were compared between compartments and with the plasma resistance profile at first-line failure. RESULTS: Of the 111 participants enrolled (91 female, 20 male), 16 (14%) and 30 (27%) had VL >1,000 and >40 copies/ml, respectively, in plasma; 3 (3%) and 23 (21%) had VL >1,000 copies/ml and >40 copies/ml, respectively, in genital secretions. There was 74% agreement between plasma and genital secretion VL classification above/below 40 copies/ml threshold (kappa-statistic =0.29; P=0.001). RT mutations (both NRTI and non-nucleoside reverse transcriptase inhibitor) were detected in genital secretions in four patients (similar profile to corresponding plasma sample at first-line failure) and PI mutations were detected in two (one polymorphism with no impact on resistance; one with high-level PI resistance). CONCLUSIONS: High level (>1,000 copies/ml) viral replication and development of new RT or PI resistance in the genital compartment were rare. The risks of transmission arising from resistance evolution in the genital compartment are likely to be low on PI-based second-line therapy.

Response to antiretroviral therapy of HIV type 1-infected children in urban and rural settings of Uganda.

From 2006 to 2011, a cohort study was conducted among 1000 children resident in urban and rural settings of Uganda to ascertain and compare the response to antiretroviral therapy (ART) among urban versus rural children and the factors associated with this response. Clinical, immunological, and virological parameters were ascertained at baseline and weeks 24, 48, 96, and 144 after ART initiation. Adherence to ART was assessed at enrollment by self-report (SR) and pill counts (PC). Overall, 499/948 (52.6%) children were resident in rural areas, 504/948 (53.1%) were male, and their mean age was 11.9±4.4 years (urban children) and 11.4±4.1 years (rural children). The urban children were more likely to switch to second-line ART at a rate of 39.9 per 1000 person-years (95% CI: 28.2-56.4) versus 14.9 per 1000 person-years (95% CI: 8.7-25.7), p=0.0038, develop any new WHO 3/4 events at 127/414 (30.7%) versus 108/466 (23.2%), p=0.012, and have a higher cumulative incidence of hospitalization of 54/449 (12.0%) versus 32/499 (6.4%), p=0.003, when compared to rural children. No differences were observed in mean changes in weight, height, CD4 count and percentage, and hemoglobin and viral load between urban and rural children. Adherence of ≥95% was observed in 88.2% of urban versus 91.3% of rural children by SR (p=0.130), and in 78.8% of urban versus 88.8% of rural children by PC (p<0.0001). In this study rural children had more favorable clinical outcomes and were more likely to adhere optimally to ART than urban children.