Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy

Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (C-min) and total drug exposure over 24 hr (AUC(24)) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the C-min and AUC(24) below which the risk of virologic failure increased. The relation between C-min and AUC(24) with virologic failure (never a plasma viral load [pVL] <50 copies/ml or a rebound to two consecutive pVL >50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a C-min <3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC(24). The risk of virologic failure with EFV (n = 312) was significantly increased at a C-min <1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC(24) <40 mg.hr.L-1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between C-min and AUC(24) with virologic failure statistically nonsignificant. The sensitivity of the C-min values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the C-min value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).