Interpretation of resistance data from randomized trials of first-line antiretroviral treatment

There are four key differences between HIV clinical trials in the analysis of HIV drug resistance: (i) baseline resistance testing used versus not used for patient inclusion; (ii) using HIV RNA cutoff levels of ≥ 50 versus ≥ 400 copies/ml to define virologic failure; (iii) testing versus not testing drug resistance in patients who discontinue treatment; (iv) analyzing drug resistance based on intent-to-treat analysis versus the subset of patients with samples genotyped. In this review we illustrate the importance of these issues, using data from 17 clinical trials of first-line nonnucleoside reverse transcriptase inhibitor-based treatment reported in the past 10 years. We also analyzed the data from the efavirenz arm of the SENSE trial, using all the different methods to show the range of results that can be obtained using different methods of analysis. Detection of treatment-emergent nucleoside/nonnucleoside reverse transcriptase inhibitor resistance differs significantly between clinical trials of the same first-line treatment (two nucleoside reverse transcriptase inhibitors/efavirenz), depending on the methods used for testing and analysis. Several clinical trials may have underestimated the prevalence of treatment-emergent drug resistance, by (i) not testing virologic failures with HIV RNA 50-400 copies/ml or (ii) not testing patients after discontinuation of treatment.