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To assess the association between adherence to antiretroviral therapy and the presence of class-specific antiretroviral medication resistance.Secondary analysis of prospective clinical trial data.Participants randomized to the protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) strategies of the Community Programs for Clinical Research on AIDS (CPCRA) Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study were included. Adherence was measured by 7-day self-report. Virological failure was defined as an HIV-RNA more than 1000 at or after 4 months. The association between cumulative adherence and the development of class-specific genotypic resistance was assessed by Cox regression analysis.Included were 457 and 446 antiretroviral-naive participants on the protease inhibitor and NNRTI strategies, respectively. The median time to initial virological failure in the protease inhibitor strategy was 1.2 years; 135 (30%) individuals failed with resistance. The median time to initial virological failure in the NNRTI strategy was 3.0 years; 127 (28%) failed with resistance. No association was found between cumulative adherence and protease inhibitor resistance [hazard ratio 1.1, 95% confidence interval (CI) 0.9-1.4 per 10% lower adherence]. However, lower cumulative adherence was associated with an increased risk of NNRTI resistance at initial virological failure (hazard ratio 1.2, 95% CI 1.1-1.3 per 10% lower adherence). In both strategies, lower cumulative adherence was associated with an increased risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance at initial virological failure.Adherence-resistance relationships are class-specific. For NRTIs and NNRTIs, initial virological failure with resistance is more likely at lower levels of cumulative adherence.

Objectives—To investigate the occurrence of differential adherence to components of combination antiretroviral therapy and assess its predictors and association with virological failure and antiretroviral medication resistance. Design—A secondary analysis of prospective clinical trial data. Methods—The Flexible Initial Retrovirus Suppressive Therapies study (Community Programs for Clinical Research on AIDS 058) was a randomized trial comparing non-nucleoside reverse transcriptase inhibitor (NNRTI) versus protease inhibitor (PI) versus NNRTI plus PI-based (threeclass) antiretroviral therapy in treatment-naive HIV-1-infected individuals. Adherence was assessed at months 1 and 4, and then every 4 months. Differential adherence, defined as any difference in selfreported level of adherence to individual antiretroviral medications at the same timepoint, was evaluated as a binary time-updated variable in multivariate Cox regression analyses of time to initial virological failure (HIV-RNA >1000 copies/ml) and initial virological failure with genotypic antiretroviral resistance. Results—Differential adherence was reported at least once by 403 of 1379 participants (29%), over 60 months median follow-up. Differential adherence was more commonly reported by participants randomly assigned to the three-class strategy (35%) than the NNRTI (28%) or PI (25%) strategies (P = 0.005), but was not associated with demographic or baseline disease-specific factors. Of those reporting differential adherence, 146 (36%) reported it before initial virological failure. These participants had an increased risk of initial virological failure and initial virological failure with antiretroviral resistance compared with participants without differential adherence before initial virological failure. Conclusion—Differential adherence was commonly reported and was associated with an increased risk of initial virological failure and initial virological failure with antiretroviral resistance.