Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials
Journal
The Lancet
Journal Volume
393
Journal Issue
10167
Pages
143-155
Date Issued
2019
Author(s)
Cahn P.
Madero J.S.
Arribas J.R.
Antinori A.
Ortiz R.
Clarke A.E.
Rockstroh J.K.
Girard P.-M.
Sievers J.
Man C.
Currie A.
Underwood M.
Tenorio A.R.
Pappa K.
Wynne B.
Fettiplace A.
Gartland M.
Aboud M.
Smith K.
Cassetti L.
David D.
Figueras L.
Losso M.
Lopardo G.
Lupo S.
Porteiro N.
Sánchez M.
Bloch M.
Cooper D.
Finlayson R.
Kelleher A.
Koh K.
Lewis D.
McMahon J.
Moore R.
Roth N.
Shields M.
De Wit S.
Florence E.
Goffard J.-C.
Demeester R.
Lacor P.
Vandercam B.
Vandekerckhove L.
Angel J.
Baril J.-G.
Conway B.
De Pokomandy A.
Szabo J.
Walmsley S.
Bouchaud O.
Chidiac C.
Delobel P.
Goujard C.
Katlama C.
Molina J.-M.
Pialoux G.
Philibert P.
Bogner J.
Esser S.
Krznaric I.
Lehmann C.
Spinner C.
Stellbrink H.-J.
Stephan C.
Stoehr A.
Barchi E.
Caramello P.
Castelli F.
Cattelan A.M.
D'Arminio Monforte A.
Di Biagio A.
Di Perri G.
Gori A.
Maggiolo F.
Menzaghi B.
Migliorino G.
Mussini C.
Penco G.
Puoti M.
Rizzardini G.
Gulminetti R.
Lazzarin A.
Quirino T.
Sighinolfi L.
Viale P.
Amaya Tapia G.
Andrade Villanueva J.
Granados Reyes E.R.
Perez Rios A.
Santoscoy Gomez M.
Den Hollander J.
Rijnders B.
Hidalgo J.A.
Hercilla Vasquez L.
Illescas L.
Olczak A.
Mansinho K.
Correia Pacheco P.P.
Teófilo E.
Saraiva da Cunha J.
Sarmento e Castro R.
Serrão R.
Arbune M.
Jianu C.
Oprea A.
Preotescu L.
Prisacariu L.-J.
Belonosova E.
Borodkina O.
Chernova O.
Gankina N.
Kizhlo S.
Kulagin V.
Kurina N.
Nagimova F.
Pokrovsky V.
Ryamova E.
Voronin E.
Yakovlev A.
Kaplan R.
Lee S.H.
Kim S.-W.
Kim S.-I.
Kim W.J.
Antela Lopez A.
Casado Osorio J.L.
Castaño Carracedo M.A.
De Los Santos Gil I.
Estrada Perez V.
Falco Ferrer V.
Force L.
Galinda Puerto M.J.
Garcia Deltoro M.
Gatell J.M.
Goenaga Sanchez M.A.
González Cordón A.
Knobel H.
Lopez Bernaldo de Quiros J.C.
Losa Garcia J.E.
Masia M.
Montero-Alsonso M.
Ocampo Hermida A.
Pasquau Liaño J.
Portilla Sogorb J.
Pulido Ortega F.
Rivera Roman A.
Santos Fernandez J.R.
Torres Perea R.
Troya Garcia J.
Viciana Fernandez P.
Calmy A.
Hauser C.
Fehr J.
Cheng S.-H.
Ko W.-C.
Lin H.-H.
Lu P.-L.
Tseng Y.-T.
Wang N.-C.
Wong W.-W.
Yang C.-J.
Arduino R.
Benson P.
Berhe M.
Bredeek F.
Brinson C.
Campbell T.
Crofoot G.
Cunningham D.
DeJesus E.
Dretler R.
Eron J.
Fife K.
Fichtenbaum C.
Flamm J.
Goldstein D.
Gupta S.
Hagins D.
Hoffman-Terry M.
Jayaweera D.
Kinder C.
Klein D.
McDonald C.
Mills A.
Nahass R.
Osiyemi O.
Overton E.
Parks D.
Prelutsky D.
Ramgopal M.
Schrader S.
Sha B.
Simon G.
Sims J.
Skiest D.
Slim J.
Tashima K.
Thedinger B.
Gazzard B.
Fox J.
Johnson M.
Kegg S.
Khoo S.
Mazhude C.
Orkin C.
Schembri G.
Ustianowski A.
GEMINI Study Team
Abstract
Background: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults.
Methods: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively.
Findings: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication.
Interpretation: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection.
Funding: ViiV Healthcare.
SDGs
Other Subjects
alkaline phosphatase; amino terminal telopeptide; beta 2 microglobulin; cystatin C; dolutegravir; emtricitabine; lamivudine; low density lipoprotein cholesterol; osteocalcin; procollagen C proteinase; retinol binding protein; tenofovir disoproxil; triacylglycerol; virus RNA; anti human immunodeficiency virus agent; antiretrovirus agent; dolutegravir; emtricitabine; fused heterocyclic rings; lamivudine; tenofovir; virus RNA; acute heart infarction; adult; amino acid substitution; arthralgia; Article; backache; bronchitis; Burkitt lymphoma; CD4 lymphocyte count; cholesterol blood level; controlled study; creatinine blood level; creatinine urine level; diarrhea; disease course; disease severity; double blind procedure; drug efficacy; drug safety; drug tolerability; drug withdrawal; estimated glomerular filtration rate; female; headache; human; Human immunodeficiency virus 1 infection; influenza; insomnia; intention to treat analysis; limit of quantitation; major clinical study; male; multicenter study; nausea; pharyngitis; phase 3 clinical trial; priority journal; protein blood level; randomized controlled trial; rhinopharyngitis; suicidal ideation; syphilis; treatment duration; treatment response; treatment withdrawal; triacylglycerol blood level; upper respiratory tract infection; virus load; blood; clinical trial; combination drug therapy; drug effect; Human immunodeficiency virus 1; Human immunodeficiency virus infection; isolation and purification; middle aged; virology; Adult; Anti-HIV Agents; Anti-Retroviral Agents; Double-Blind Method; Drug Therapy, Combination; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; RNA, Viral; Tenofovir; Viral Load
Publisher
Lancet Publishing Group
Type
journal article