RESUMO
The two-drug regimen dolutegravir plus lamivudine demonstrated durable efficacy for up to 3 years in phase III studies and a high barrier to resistance in treatment-naive and virologically suppressed people with HIV (PWH). This systematic literature review summarizes real-world evidence evaluating effectiveness and safety of dolutegravir plus lamivudine. We searched Ovid MEDLINE®, Embase®, PubMed, Cochrane library, and relevant international conference proceedings from 2013 to 2020. Qualitative synthesis of virologic suppression at Week 48, treatment-emergent resistance, discontinuation rates, and comorbidities was undertaken, with no statistical analyses conducted. Linked publications and potential for duplication in reporting of outcomes for cohorts and populations were identified, and the publication reporting the highest number of PWH receiving dolutegravir plus lamivudine was included in the analysis. Thirty-four studies reporting on cohorts of PWH not suspected to be linked or to include duplicate data receiving dolutegravir plus lamivudine were identified (N = 5017). Of 3744 virologically suppressed PWH who switched to dolutegravir plus lamivudine, 603 (16%) reported history of virologic failure. Nineteen studies included effectiveness data (n = 3558), four of which included data from treatment-naive PWH (n = 69). In studies with > 100 PWH, high rates of virologic suppression (Week 48, 97-100%) were maintained with dolutegravir plus lamivudine, with low rates of virologic failure (0-3.3 per 100 person-years of follow-up); one instance of emergent integrase strand transfer inhibitor resistance was reported in a complex treatment-experienced individual. Rates of discontinuation due to adverse events were low and consistent with previously observed trial data. Dolutegravir plus lamivudine minimally impacted renal function and had minimal impact on or improved lipid profiles and bone mineral density. This systematic review demonstrates that effectiveness and safety of dolutegravir plus lamivudine in clinical practice support data from randomized controlled trials with regard to high rates of virologic response, low rates of discontinuation, and a high barrier to resistance.
RESUMO
In HIV-1-infected patients, virological failure can occur as a consequence of the mutations that accumulate in the viral genome that allow replication to continue in the presence of antiretrovirals (ARVs). The development of treatment-emergent resistance to an ARV can limit a patient's options for future therapy, prompting the need for ARV regimens that are resilient to the emergence of resistance. The genetic barrier to resistance refers to the number of mutations in an ARV's therapeutic target that are required to confer a clinically meaningful loss of susceptibility to the drug. The emergence of resistance can be affected by pharmacological aspects of the ARV, including its structure, inhibitory quotient, therapeutic index, and pharmacokinetic characteristics. Dolutegravir (DTG) has demonstrated a high barrier to resistance, including when used in a two-drug regimen (2DR) with lamivudine (3TC). In the GEMINI-1 and GEMINI-2 studies, DTG +3TC was noninferior to DTG + emtricitabine/tenofovir disoproxil fumarate in treatment-naive participants, with similar proportions achieving HIV-1 RNA <50 copies/mL through 96 weeks. Furthermore, in the TANGO study, virological suppression was maintained at 48 weeks after switching to DTG +3TC from a tenofovir alafenamide (TAF)-based regimen compared with continuing a TAF-based regimen. Most other 2DRs with successful outcomes compared with three-drug regimens have been based on protease inhibitors (PIs); however, this class is associated with adverse metabolic effects and drug-drug interactions. In this review, we discuss the barrier to resistance in the context of a 2DR in which a boosted PI is replaced with DTG +3TC.