Novel Method To Assess Antiretroviral Target Trough Concentrations UsingIn VitroSusceptibility Data

Abstract

Durable suppression of HIV-1 replication requires the establishment of antiretroviral drug concentrations that exceed the susceptibility of the virus strain(s) infecting the patient. Minimum plasma drug concentrations (C_trough) are correlated with response, but determination of targetC_troughvalues is hindered by a paucity ofin vivoconcentration-response data. In the absence of these data,in vitrosusceptibility measurements, adjusted for serum protein binding, can provide estimations of suppressivein vivodrug concentrations. We derived serum protein binding correction factors (PBCF) for protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and an integrase inhibitor by measuring the effect of a range of human serum concentrations onin vitrodrug susceptibility measured with the PhenoSense HIV assay. PBCFs corresponding to 100% HS were extrapolated using linear regression and ranged from 1.4 for nevirapine to 77 for nelfinavir. Using the mean 95% inhibitory concentration (IC₉₅) for ≥1,200 drug-susceptible viruses, we calculated protein-bound IC₉₅(PBIC₉₅) values. PBIC₉₅values were concordant with the minimum effectiveC_troughvalues that were established in well-designed pharmacodynamic studies (e.g., indinavir, saquinavir, and amprenavir). In other cases, the PBIC₉₅values were notably lower (e.g., darunavir, efavirenz, and nevirapine) or higher (nelfinavir and etravirine) than existing target recommendations. The establishment of PBIC₉₅values as described here provides a convenient and standardized approach for estimation of the minimum drug exposure that is required to maintain viral suppression and prevent the emergence of drug-resistant variants, particularly whenin vivoconcentration-response relationships are lacking.