Long-Term Virologic Outcomes of Dolutegravir-Based Regimens in Treatment-Naive Adults

Abstract

Dolutegravir-based regimens have become the dominant first-line antiretroviral therapy worldwide, but the evidence supporting that shift is spread across more than a decade of independently conducted trials and cohorts. This article synthesizes the literature on long-term virologic outcomes of dolutegravir-based regimens in treatment-naive adults, tracing the pharmacological basis for dolutegravir's high genetic barrier to resistance through the pivotal phase 3 trials (SINGLE, SPRING-2, and FLAMINGO) that established its superiority or non-inferiority against efavirenz-, raltegravir-, and darunavir-based comparators, the ADVANCE and NAMSAL trials that extended this evidence to high-burden, resource-limited settings, and the GEMINI trials demonstrating that a simplified two-drug dolutegravir-lamivudine regimen preserves virologic durability through 96 weeks. We give particular attention to the resistance and cohort literature specific to integrase-inhibitor-naive, first-line initiation, which finds treatment-emergent resistance to be rare even among the minority of dolutegravir recipients who experience virologic failure, and to the special-population evidence on pregnancy safety, weight and metabolic change, and tuberculosis coinfection that has shaped how dolutegravir is used in practice. Read together, the evidence supports dolutegravir-based first-line therapy as virologically durable and resistance-resilient in treatment-naive adults, while leaving the mechanism and long-term clinical significance of dolutegravir-associated weight gain, and the operating characteristics of its resistance barrier under routine programmatic monitoring, as open areas for continued research.