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Randomized Controlled Trial
. 2020 Mar 1;83(3):310-318.
doi: 10.1097/QAI.0000000000002275.

Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials

Pedro Cahn  1 , Juan Sierra Madero  2 , José R Arribas  3 , Andrea Antinori  4 , Roberto Ortiz  5 , Amanda E Clarke  6   7 , Chien-Ching Hung  8 , Jürgen K Rockstroh  9 , Pierre-Marie Girard  10 , Jörg Sievers  11 , Choy Y Man  12 , Rimgaile Urbaityte  13 , Daisy J Brandon  13 , Mark Underwood  12 , Allan R Tenorio  12 , Keith A Pappa  12 , Brian Wynne  12 , Martin Gartland  12 , Michael Aboud  11 , Jean van Wyk  11 , Kimberly Y Smith  12
Affiliations
Randomized Controlled Trial

Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials

Pedro Cahn et al. J Acquir Immune Defic Syndr. .

Erratum in

Abstract

Background: The 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses.

Setting: One hundred eighty-seven centers in 21 countries.

Methods: GEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine.

Results: At week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ≥50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine.

Conclusions: Consistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

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Conflict of interest statement

P.C. has served on advisory boards for GlaxoSmithKline (GSK), ViiV Healthcare, and Merck; served as an investigator for Abbott, Gilead, ViiV Healthcare, GSK, Merck, and Richmond; and has received honoraria for his speaking or chairing engagements from Abbott, GSK, Gilead, Merck, and ViiV Healthcare. J.S.M. has received lecture fees, sponsorship, and honoraria from Gilead, Stendhal, AbbVie, ViiV Healthcare, Janssen, and Merck Sharp & Dohme (MSD; all before 2019). J.R.A. has received advisory fees, speaker fees, and grant support from ViiV Healthcare, Janssen, Gilead, MSD, Alexa, and Teva. A.A. has served as a paid consultant to Gilead, Janssen, Merck, and ViiV Healthcare and received research funding from Gilead, Janssen, and ViiV Healthcare. A.E.C. has received advisory fees from GSK, ViiV Healthcare, and Gilead; conference sponsorship from Gilead and Janssen; and speaker travel fees from GSK. C.-C.H. has received honoraria for speaking at educational events or consulting from AbbVie, Bristol-Myers Squibb (BMS), Gilead, Janssen, and ViiV Healthcare and has received research funding from BMS, Janssen, Gilead, Merck, and ViiV Healthcare. J.K.R. has received grant/research support from Gilead; served as a consultant/advisor to Abbott, AbbVie, Bionor, Gilead, Hexal, Janssen, Merck, and ViiV Healthcare; and was a speaker at educational events for AbbVie, Gilead, Janssen, and Merck. P.-M.G. has received grants from BMS and Janssen and has received honoraria and consulting fees from Gilead, ViiV Healthcare, and AbbVie. J.S., C.Y.M., M.U., A.R.T., K.A.P., B.W., M.G., M.A., J.v.W., and K.Y.S. are employees of ViiV Healthcare and own stock in GSK. R.U. and D.B. are employees of GSK and own stock in GSK. The remaining author has no conflicts of interest to disclose.

Figures

FIGURE 1.
FIGURE 1.
Snapshot analysis of the proportion of participants with plasma HIV-1 RNA <50 copies/mL (A) by visit and (B) at weeks 48 and 96 in the pooled ITT-E population. C, Adjusted treatment differences at week 96 of the Snapshot analysis in the ITT-E populations of the individual trials and the pooled analysis. aOther reasons for discontinuing study included (2DR, n [%] vs 3DR, n [%]) protocol deviation (10 [1.4%] vs 8 [1.1%]), lost to follow-up (18 [2.5%] vs 10 [1.4%]), physician decision (10 [1.4%] vs 4 [0.6%]), withdrew consent (18 [2.5%] vs 15 [2.1%]), and protocol-defined CVW (0 [0%] vs 1 [0.1%]). 2DR, 2-drug regimen (dolutegravir + lamivudine); 3DR, 3-drug regimen (dolutegravir + tenofovir disoproxil fumarate/emtricitabine).
FIGURE 2.
FIGURE 2.
Snapshot and TRDF analyses of the proportion of participants with HIV-1 RNA <50 copies/mL or without TRDF at week 96 by baseline viral load and CD4+ cell count in the pooled ITT-E population from GEMINI-1 and GEMINI-2. 2DR, 2-drug regimen (dolutegravir + lamivudine); 3DR, 3-drug regimen (dolutegravir + tenofovir disoproxil fumarate/emtricitabine). aTRDF was a preplanned analysis at week 96. Percentages estimated from the TRDF Kaplan–Meier analysis.
FIGURE 3.
FIGURE 3.
Profiles of renal and bone biomarkers. Adjusted mean change from baseline in (A) serum or plasma renal biomarkers and (B) ratios of urine renal biomarkers at week 96. C, Adjusted mean change from baseline in bone turnover biomarkers at week 96. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; 2DR, 2-drug regimen (dolutegravir + lamivudine); 3DR, 3-drug regimen (dolutegravir + tenofovir disoproxil fumarate/emtricitabine); GFR, glomerular filtration rate. aThe 96-week analysis used mixed-effect model repeat measurement. Mean change from baseline adjusted for study, treatment, visit, baseline viral load, baseline CD4+ cell count, age, sex, race, baseline biomarker value, treatment-by-visit interaction, and baseline biomarker value-by-visit interaction. For renal biomarkers, mean change from baseline was also adjusted for presence of diabetes and presence of hypertension. For bone biomarkers, mean change was also adjusted for BMI, smoking status, and current vitamin D use. No assumptions were made about the correlations between participant readings of biomarkers (the correlation matrix for within-participant errors was unstructured). bEstimated from geometric means ratio for baseline and week 96. *P < 0.001. **P < 0.005.
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