Nonnucleoside Reverse Transcriptase Inhibitor Concentrations During Treatment Interruptions and the Emergence of Resistance: A Substudy of the ISS-PART Trial

Emergence of resistance is one of the drawbacks associated with treatment interruptions (TI), especially when regimens include nonnucleoside reverse transcriptase inhibitors (NNRTIs), because of their long half-life. ISS-PART was a randomized trial comparing a continuous treatment arm with a TI arm in which 136 patients underwent five treatment interruptions, each followed by 3 months of therapy, over 2 years. To minimize the potential risk of developing resistance, patients on NNRTIs were requested, at each TI, to interrupt nevirapine (NVP) or efavirenz (EFV) 3 or 6 days before the other drugs, respectively. To determine if a difference in drug levels existed during TIs between patients with and without resistance we compared NNRTI concentrations in the 12 patients (6 on NVP and 6 on EFV) who developed NNRTI mutations during TIs with those of 20 patients (10 on NVP and 10 on EFV) who retained a wild-type virus. Genotypic resistance and drug concentrations were analyzed on plasma samples collected 15 days after each drug interruption. Overall, EFV was quantifiable in 28% (16/57) and NVP in 22.9% (14/61) of evaluable samples collected during TIs, with no difference between patients with and without mutations. Median EFV or NVP concentrations at each TI were not significantly different between patients with and without mutations. Although the staggered stop strategy was not completely effective in preventing exposure to suboptimal levels, no evident correlation was found between NNRTI concentrations and the emergence of resistance, suggesting that other factors (such as the presence of drug-resistant minority variants) could also play an important role in these patients.