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

Cahn, P.; Madero, J. S.; Arribas, J. R.; Antinori, A.; Ortiz, R.; Clarke, A. E.; Hung, C. -C.; 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.; Sanchez, 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.; Teofilo, E.; Saraiva da Cunha, J.; Sarmento e Castro, R.; Serrao, 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.; Castano 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.; Gonzalez Cordon, A.; Knobel, H.; Lopez Bernaldo de Quiros, J. C.; Losa Garcia, J. E.; Masia, M.; Montero-Alsonso, M.; Ocampo Hermida, A.; Pasquau Liano, 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.; W. -C., Ko; Lin, H. -H.; P. -L., Lu; 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.

doi:10.1016/S0140-6736(18)32462-0

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.

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

Cahn P.;Madero J. S.;Arribas J. R.;Antinori A.;Ortiz R.;Clarke A. E.;Hung C. -C.;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.;Sanchez 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.;Teofilo E.;Saraiva da Cunha J.;Sarmento e Castro R.;Serrao 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.;Castano 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.;Gonzalez Cordon A.;Knobel H.;Lopez Bernaldo de Quiros J. C.;Losa Garcia J. E.;Masia M.;Montero-Alsonso M.;Ocampo Hermida A.;Pasquau Liano 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.

2019-01-01

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.