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. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. 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 One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (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 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.

Prevalence 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 S1 ). 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 [ 70 , 71 , 72 , 73 , 74 ].…”

Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review

“…Following the review of their titles and abstracts, 232 publications were submitted for full-text review. Following full-text review, 36 publications were found to have reports of INSTI-naïve PLWH who developed one or more INSTI-associated DRMs while receiving DTG [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], and 21 publications contained in vitro susceptibility results performed using the PhenoSense assay [ 32 , 33 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , ...…”

Strengthening and enhancing national antiretroviral drug resistance surveillance in Zimbabwe—A country that has reached UNAIDS 95-95-95 amongst adults

“…As ART and PrEP expand, HIVDR emergence is likely, to jeopardize HIV/AIDS eradication efforts. Dolutegravir (DTG), though known for its high genetic resistance barrier, has shown resistance elsewhere, particularly among ART-experienced individuals ( 23 ). While a recent Zimbabwe study found no DTG resistance among ART-naïve individuals ( 24 ), surveillance and monitoring of HIVDR among DTG users is crucial due to its widespread use and potential future treatment limitations ( 25 , 26 ).…”