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Efavirenz (EFV) and nevirapine (NVP), unlike nucleoside reverse transcriptase inhibitor drugs, do not inhibit mitochondrial (mt) polymerase gamma (Pol-γ), although EFV has been shown to induce mt depolarization (Δψmlow) in vitro at supratherapeutic concentrations. However, the capacity of nonnucleoside reverse transcriptase inhibitor drugs to induce mt toxicity in vivo remains undetermined.To determine the influence of EFV and NVP on peripheral lymphocyte mt transmembrane potential (Δψm) and apoptosis in HIV-1-infected patients treated with these nonnucleoside reverse transcriptase inhibitors.Thirty-two HIV-1-infected patients on highly active antiretroviral therapy (HAART) between 4 and 24 months (12 on EFV, 20 on NVP) and 16 HAART-naive HIV-1-infected patients were enrolled into this study. All participants were black South African patients. Spontaneous peripheral lymphocyte apoptosis and Δψmlow were measured ex vivo by flow cytometry for all patients.CD4 T-helper apoptosis for the EFV and NVP cohorts was 19.38% ± 2.62% and 23.35% ± 1.51% (mean ± SEM), respectively, whereas total lymphocyte Δψmlow was 27.25% ± 5.05% and 17.04% ± 2.98%, respectively. Both parameters for each cohort were significantly lower (P < 0.05) than that of the HAART-naive patients. The NVP cohort exhibited both a significant time-dependent increase in peripheral lymphocyte Δψmlow (P = 0.038) and correlation between T-helper apoptosis and Δψmlow (P = 0.0005). These trends were not observed in the EFV cohort.This study provides evidence that both EFV and NVP induce peripheral lymphocyte Δψmlow in HIV-1-infected patients on nonnucleoside reverse transcriptase inhibitor-based HAART, which in the case of NVP is sufficient to induce the apoptosis cascade.