Three-Year Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Therapy – Naive Adults With HIV-1 Infection

Pedro Cahn; Juan Sierra Madero; José R. Arribas; Andrea Antinori; Roberto Ortiz; Amanda E. Clarke; Chien-Ching Hung; Jürgen K. Rockstroh; Pierre-Marie Girard; Jörg Sievers; Choy Y. Man; Rimgaile Urbaityte; Daisy J. Brandon; Mark Underwood; Keith A. Pappa; Lloyd Curtis; Kimberly Y. Smith; Martin Gartland; Michael Aboud; Jean van Wyk; Brian Wynne

Disclosures

AIDS. 2022;36(1):39-48. 

In This Article

Abstract and Introduction

Abstract

Objective: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2.

Design: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks).

Methods: Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC.

Results: At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], −1.8% [−5.8, 2.1]), GEMINI-1 (−3.6% [−9.4, 2.1]), and GEMINI-2 (0.0% [−5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63–0.92]). Renal and bone biomarker changes favored DTG + 3TC.

Conclusions: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).

Introduction

As people with HIV (PWH) require lifelong therapy, effective treatments with limited toxicity are needed.[1] Two-drug regimens (2DRs) reduce the number of antiretroviral drugs PWH are exposed to and can potentially decrease treatment-associated toxicity and costs.[1] To ensure comparable efficacy with three-drug regimens (3DRs), the optimal antiretroviral agents in a 2DR should have potent and durable antiviral activity and a high barrier to resistance.[1]

Dolutegravir (DTG) is a potent integrase strand transfer inhibitor (INSTI) with a high barrier to resistance, supporting its inclusion in a 2DR,[2] especially with the well tolerated nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (3TC).[3–5] In the week 48, primary analyses of the phase III GEMINI-1 and GEMINI-2 studies in treatment-naive adults, the 2DR DTG + 3TC was noninferior to the 3DR DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving HIV-1 RNA <50 copies/ml.[6] The subsequent week 96 analysis demonstrated the durable efficacy of DTG + 3TC, as evidenced by its sustained noninferiority vs. DTG + TDF/FTC.[7] Few participants met confirmed virologic withdrawal (CVW) criteria, and no treatment-emergent resistance mutations were detected. As a result, the DTG/3TC single-tablet, fixed-dose combination 2DR was approved by the European Medicines Agency and US Food and Drug Administration (FDA) in 2019.[8,9] Additionally, the US Department of Health and Human Services, European AIDS Clinical Society, and International Antiviral Society–USA 2020 guidelines classify DTG + 3TC as a recommended initial antiretroviral regimen for most PWH, with exceptions for individuals with HIV-1 RNA >500 000 copies/ml, hepatitis B virus (HBV) co-infection, or in whom therapy is started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available.[10–12]

As 2DRs are an emerging and important treatment option for PWH, it is critical to assess their long-term durability and genetic barrier to resistance. Here, we present efficacy and safety data from the prespecified 144-week secondary analyses of the GEMINI studies.

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