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Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy(2008-08-06)CONTEXT: Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described. OBJECTIVE: To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006. INTERVENTIONS: Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine. MAIN OUTCOME MEASURES: Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed. RESULTS: The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7). CONCLUSION: In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.
Treatment failure and mortality factors in patients receiving second-line HIV therapy in resource-limited countries.(2010-07-21)CONTEXT: Long-term antiretroviral therapy (ART) use in resource-limited countries leads to increasing numbers of patients with HIV taking second-line therapy. Limited access to further therapeutic options makes essential the evaluation of second-line regimen efficacy in these settings. OBJECTIVES: To investigate failure rates in patients receiving second-line therapy and factors associated with failure and death. DESIGN, SETTING, AND PARTICIPANTS: Multicohort study of 632 patients > 14 years old receiving second-line therapy for more than 6 months in 27 ART programs in Africa and Asia between January 2001 and October 2008. MAIN OUTCOME MEASURES: Clinical, immunological, virological, and immunovirological failure (first diagnosed episode of immunological or virological failure) rates, and mortality after 6 months of second-line therapy use. Sensitivity analyses were performed using alternative CD4 cell count thresholds for immunological and immunovirological definitions of failure and for cohort attrition instead of death. RESULTS: The 632 patients provided 740.7 person-years of follow-up; 119 (18.8%) met World Health Organization failure criteria after a median 11.9 months following the start of second-line therapy (interquartile range [IQR], 8.7-17.0 months), and 34 (5.4%) died after a median 15.1 months (IQR, 11.9-25.7 months). Failure rates were lower in those who changed 2 nucleoside reverse transcriptase inhibitors (NRTIs) instead of 1 (179.2 vs 251.6 per 1000 person-years; incidence rate ratio [IRR], 0.64; 95% confidence interval [CI], 0.42-0.96), and higher in those with lowest adherence index (383.5 vs 176.0 per 1000 person-years; IRR, 3.14; 95% CI, 1.67-5.90 for < 80% vs > or = 95% [percentage adherent, as represented by percentage of appointments attended with no delay]). Failure rates increased with lower CD4 cell counts when second-line therapy was started, from 156.3 vs 96.2 per 1000 person-years; IRR, 1.59 (95% CI, 0.78-3.25) for 100 to 199/microL to 336.8 per 1000 person-years; IRR, 3.32 (95% CI, 1.81-6.08) for less than 50/microL vs 200/microL or higher; and decreased with time using second-line therapy, from 250.0 vs 123.2 per 1000 person-years; IRR, 1.90 (95% CI, 1.19-3.02) for 6 to 11 months to 212.0 per 1000 person-years; 1.71 (95% CI, 1.01-2.88) for 12 to 17 months vs 18 or more months. Mortality for those taking second-line therapy was lower in women (32.4 vs 68.3 per 1000 person-years; hazard ratio [HR], 0.45; 95% CI, 0.23-0.91); and higher in patients with treatment failure of any type (91.9 vs 28.1 per 1000 person-years; HR, 2.83; 95% CI, 1.38-5.80). Sensitivity analyses showed similar results. CONCLUSIONS: Among patients in Africa and Asia receiving second-line therapy for HIV, treatment failure was associated with low CD4 cell counts at second-line therapy start, use of suboptimal second-line regimens, and poor adherence. Mortality was associated with diagnosed treatment failure.