Grinsztejn B, Hughes MD, Ritz J, et al. - Use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to enhance adherence in individuals presenting with second-line viral failure were evaluated via performing A5288, a phase 4, third-line antiretroviral therapy (ART) strategy study, at 19 urban sites in ten countries. Participants comprised 545 adults with confirmed plasma HIV-1 RNA (viral load) of 1,000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. Based on ART history and real-time drug resistance genotypes, participants were allotted to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Overall, viral suppression at week 48 was achieved in 349 (64%) participants, with proportions varying from 125/287 (44%) in cohort A to 65/74 (88%) in cohort B1, 63/72 (88%) in B2, eight/eight (100%) in B3, 63/70 (90%) in C, and 25/34 (74%) in D. Findings support the possibility for appropriate allocation of more costly antiretrovirals to those with greater levels of HIV drug resistance via targeted real-time genotyping to select third-line ART.