Quantifying the treatment efficacy of reverse transcriptase inhibitors: new analyses of clinical data based on within-host modeling

BACKGROUND: Current measures of the clinical efficacy of antiretroviral therapy (ART) in the treatment of HIV include the change in HIV RNA in the plasma and the gain in CD4 cells. METHODS: We propose new measures for evaluating the efficacy of treatment that is based upon combinations of non-nucleoside and nucleoside reverse transcriptase inhibitors. Our efficacy measures are: the CD4 gain per virion eliminated, the potential of CD4 count restoration and the viral reproduction number (R(0)). These efficacy measures are based upon a theoretical understanding of the impact of treatment on both viral dynamics and the immune reconstitution. Patient data were obtained from longitudinal HIV clinical cohorts. RESULTS: We found that the CD4 cell gain per virion eliminated ranged from 10(-2 )to 600 CD4 cells/virion, the potential of CD4 count restoration ranged from 60 to 1520 CD4 cells/μl, and the basic reproduction number was reduced from an average of 5.1 before therapy to an average of 1.2 after one year of therapy. There was substantial heterogeneity in these efficacy measures among patients with detectable viral replication. We found that many patients who achieved viral suppression did not have high CD4 cell recovery profiles. Our efficacy measures also enabled us to identify a subgroup of patients who were not virally suppressed but had the potential to reach a high CD4 count and/or achieve viral suppression if they had been switched to a more potent regimen. CONCLUSION: We show that our new efficacy measures are useful for analyzing the long-term treatment efficacy of combination reverse transcriptase inhibitors and argue that achieving a low R(0 )does not imply achieving viral suppression.