Clinical Impact of Virological Failure and Resistance Analysis Definitions used in Pivotal Clinical Trials of Initial Antiretroviral Treatment: A Systematic Review

There are no standardized criteria to characterize confirmed protocol-defined virological failure (PDVF) nor the inclusion criteria for the resistance analysis population (RAP) in Phase III randomized clinical trials (RCTs) of initial antiretroviral therapy (ART). We assessed the clinical impact of mismatching between virological non-response (HIV-1 RNA ≥50 copies/mL), confirmed PDVF (48 weeks), and RAP definition in studies with the newest first-line ART. A systematic review of all Phase III RCTs was performed, including preferred once-daily ART (EACS European AIDS guidelines) or recently approved by the US Food and Drug Administration. We identified 16 treatment arms (14 RCTs) with 6175 participants treated with dolutegravir, bictegravir, elvitegravir/cobicistat, raltegravir, darunavir/cobicistat, rilpivirine, or doravirine. Plasma HIV-1 RNA thresholds for PDVF or RAP ranged from 40 to 50, 200, 400, and 500 copies/mL. This led to discrepancies between trials regarding the participants defined as virological non-responders, PDVF, or included in RAP. Overall, 85/296 (29%) patients with PDVF were not genotyped. There was a linear correlation between the threshold of HIV RNA chosen to perform genotyping and rates of participants with PDVF but not genotyped. Only eight treatment arms genotyped all participants with PDVF. Most of the remaining eight arms genotyped roughly < 50% of those with PDVF. In summary, the absence of standardized definitions of VF and criteria for resistance testing in pivotal Phase III RCTs of the first-line ART leads to the possibility of underreporting of resistance mutations when genotypes are only performed at higher viral load cutoffs. Stringent homogeneous criteria should be defined to ensure that all participants with PDVF (e.g., confirmed HIV RNA ≥ 50 copies/mL and the second > 200 copies/mL) undergo genotyping.