Dolutegravir-Associated Resistance Mutations after first-line treatment failure in Brazil

Abstract

Abstract Background: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine, with dolutegravir (TL+D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. Methods: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL+D in the Brazilian public health system before December 31, 2018. Results: 113 individuals were included in the analysis. Major INRAMs were detected in six patients (5.31%), four with R263K, one with G118R, one with E138A. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. 16(14.2%) additional individuals presented minor INRAMs, and three (2.7%) patients had both major and minor INRAMS. 13 (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The polymorphic integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients respectively. Mutations not related to TL+D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. Conclusions: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL+D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.