Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors

Background: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of antiretroviral therapy for HIV type-1 (HIV-1)-infected patients. Development of NNRTI resistance can lead to treatment failure and is conferred by the presence of specific resistance-associated mutations (RAMs) in the reverse transcriptase. In addition to the widely used list of NNRTI RAMs provided by the International AIDS Society-USA HIV-1 Drug Resistance Mutation Group, which were identified on the basis of clinical experience with the approved NNRTIs, a more comprehensive list of NNRTI RAMs is needed to guide the study of baseline and emerging resistance to new NNRTIs. Methods: We conducted an extensive review of the existing literature on NNRTI resistance, together with several in vitro and in vivo studies on the mechanism of HIV-1 resistance to approved NNRTIs and to NNRTIs formerly or currently in clinical development. Results: In total, 44 NNRTI RAMs were identified. These included V901, A98G, L100I, K101E/P/Q, K103H/N/S/T, V106A/I/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/ I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F. These NNRTI RAMs were observed, either alone or in combination with others, ranging in frequency from 0.02% to 56.96% in a panel of 101,679 NNRTI-resistant isolates submitted to Virco BVBA (Mechelen, Belgium) for routine clinical resistance testing. Phenotypical data from site-directed mutants helped to establish the contribution of each mutation to NNRTI resistance. Conclusions: The list of 44 NNRTI RAMs compiled in this study provides a comprehensive overview of mutations that play a role in HIV-1 NNRTI resistance and can be used to guide further in vitro and in vivo research on the mechanisms of HIV-1 NNRTI resistance.