The current recommended first-line therapy for HIV-1 infected patients is a second generation integrase (IN) strand transfer inhibitor (INSTI), either Dolutegravir (DTG) or Bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by first-generation INSTIs. BIC has not been reported to select for resistance in treatment-naïve patients and DTG has selected for a small number of resistant viruses in treatment-naïve patients. However, some patients who had viruses with substitutions selected by first-generation INSTIs responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI Cabotegravir (CAB), which is in late stage clinical trials, has been shown to select for novel resistant mutants in vitro Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.
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