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

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.

Risk of Emergent Dolutegravir Resistance Mutations In People Living With HIV: A Rapid Scoping Review

“…One cross-sectional study from Brazil reported that among 113 previously ART-naïve PLWH with confirmed VF while receiving DTG plus tenofovir disoproxil fumarate (TDF)/3TC, seven (6.2%) individuals had major INSTI DRMs [42] (Supplementary Table 1). However, the size of the population receiving DTG plus TDF/3TC and the total number with VF was not reported in this study.…”

“…Cross-sectional studies in which GRT is performed in persons with confirmed VF on a DTG-containing regimen provide an alternate mechanism for assessing the risk of emergent DTG resistance. We described six such studies including one from Brazil of 113 PLWH with confirmed VF on a first-line regimen of DTG plus two NRTIs [42] and five from Sub-Saharan Africa. The studies from Sub-Saharan Africa included approximately 214 individuals most of whom had prior ART experience before initiating DTG treatment [72][73][74][75][76].…”

Dolutegravir resistance in sub-Saharan Africa: should resource-limited settings be concerned for future treatment?

“…The deleterious effect of the mutation tends to differ between subtypes, and has been shown to be higher in subtype C than in subtype B (47,48). Nevertheless, in vivo selection of R263K has been observed in subtypes C, D, CRF02_AG, and B (21,(49)(50)(51)(52)(53). Furthermore, some studies suggest that R263K mutations may protect against further selection of resistance mutations within the integrase region (46,54,55) and in the reverse transcriptase region (48).…”