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

BackgroundDolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of virological failure (VF) with emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. MethodsWe performed a PubMed search using the term "Dolutegravir" last updated December 18, 2023, to estimate the prevalence of VF with emergent INSTI DRMs in clinical trials and cohorts of people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. ResultsOf 2131 records identified by search, 43 clinical trials, 39 cohorts, and six cross-sectional studies provided data across six clinical scenarios based upon ART history, virological status, and ARVs co-administered with DTG: (1) ART-naive PLWH receiving DTG plus two nucleoside reverse transcriptase inhibitors (NRTIs); (2) ART-naive PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on their previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.6% for scenario 3 and 2.9% for scenario 6. In the remaining four trial scenarios, prevalence of VF with emergent INSTI DRMs was [≤]0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, while cross-sectional studies yielded prevalence data lacking denominator details. ConclusionsIn clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess the risk of VF with emergent INSTI DRMs in PLWH receiving DTG in real-world settings. What is already known on this topicDolutegravir is known for its high resistance barrier, yet there remains a concern for virological failure and subsequent drug resistance in people living with HIV who begin first or second-line antiretroviral therapy with a dolutegravir-containing regimen. What this study addsThe prevalence of virological failure with the development of HIV mutations associated with reduced susceptibility to dolutegravir depends on a persons virological response to previous antiretroviral therapy, the presence of HIV replication at dolutegravir initiation, and the antiretroviral drugs co-administered with dolutegravir. In clinical trial settings, the prevalence of virological failure with emergent dolutegravir resistance was rare among people initiating therapy with a dolutegravir-containing regimen and was 1.6% over a period of one to two years among those who had previously experienced virological failure on an earlier treatment regimen. In the subset of persons with virological failure on a first-line dolutegravir-containing regimen, the prevalence of emergent dolutegravir resistance was 0.7%, whereas in the subset of persons with virological failure on a second-line dolutegravir-containing regimen, the prevalence of emergent dolutegravir resistance was 20.4%. How this study might affect research, practice, or policyIn people living with HIV with virological failure on a first-line dolutegravir-containing regimen, enhancing medication adherence may prove more beneficial than transitioning to an alternative treatment regimen. In cases of virological failure on a second-line dolutegravir-containing regimen, the potential for dolutegravir resistance suggests a need to investigate the role of genotypic resistance testing to inform treatment changes. Population-level surveillance for acquired dolutegravir resistance should take into account the antiretroviral treatment history and level of HIV replication prior to the initiation of dolutegravir-containing therapy.