Paton NI, Musaazi J, Kityo C, et al. - For second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection, dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended by the World Health Organization. In view of the limited evidence for the efficacy of this regimen when NRTIs are predicted to have no activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine, researchers herein conducted a two-by-two factorial, open-label, noninferiority trial. They randomized patients in whom first-line therapy was failing (HIV-1 viral load, ≥ 1,000 copies per milliliter), to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients were administered lamivudine. Findings support the effectiveness of dolutegravir in combination with NRTIs in managing patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. They indicated noninferiority of tenofovir to zidovudine as second-line therapy.