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
2018; Elsevier BV; Volume: 393; Issue: 10167 Linguagem: Inglês
10.1016/s0140-6736(18)32462-0
ISSN1474-547X
AutoresPedro Cahn, Juan Sierra Madero, José Ramón Arribas, Andrea Antinori, Roberto Ortiz, Amanda E. Clarke, Chien‐Ching Hung, Jürgen K. Rockstroh, Pierre‐Marie Girard, Jörg Sievers, Choy Man, Alexander Currie, Mark Underwood, Allan R. Tenorio, Keith A. Pappa, Brian Wynne, Anna Fettiplace, Martin Gartland, Michael Aboud, Kimberly Y. Smith, Lidia Isabel Cassetti, Daniel David, Laura Figueras, Marcelo H. Losso, Gustavo Lopardo, Sergio Lupo, Norma Porteiro, Marisa Sánchez, Mark Bloch, D. James Cooper, Robert Finlayson, Anthony D. Kelleher, Kenneth Koh, David John Lewis, James McMahon, Richard Moore, Norman Roth, Matt Shields, Stéphane De Wit, Éric Florence, Jean‐Christophe Goffard, Rémy Demeester, Patrick Lacor, Bernard E. Van Beers, Linos Vandekerckhove, Jonathan B. Angel, Jean‐Guy Baril, Brian Conway, Alexandra de Pokomandy, Jason Szabo, Sharon Walmsley, Olivier Bouchaud, Christian Chidiac, Pierre Delobel, Cécile Goujard, Christine Katlama, Jean‐Michel Molina, Gilles Pialoux, Patrick Philibert, Johannes R. Bogner, Stefan Esser, Ivanka Krznaric, Clara Lehmann, Christoph D. Spinner, Hans‐Jürgen Stellbrink, Christoph Stephan, Albrecht Stoehr, Enrico Barchi, Pietro Caramello, Francesco Castelli, Anna Maria Cattelan, Antonella D'Arminio Monforte, Antonio Di Biagio, Giovanni Di Perri, Andrea Gori, Franco Maggiolo, Barbara Menzaghi, Guglielmo Marco Migliorino, Cristina Mussini, Giovanni Penco, Massimo Puoti, Giuliano Rizzardini, Roberto Gulminetti, Adriano Lazzarin, Tiziano Quirino, Laura Sighinolfi, Pierluigi Viale, Gerardo Amaya Tapia, Jaime Andrade‐Villanueva, Enrique R Granados Reyes, Alma Perez Rios, Mario Santoscoy Gomez, Jan Den Hollander, Bart Rijnders, José A. Hidalgo, Luis Hercilla Vásquez, Luis Ricardo Illescas, Anita Olczak, Kamal Mansinho, Patrícia Pacheco, Eugénio Teófilo, José Saraiva da Cunha, Rui Sarmento e Castro, Rosário Serrão, Manuela Arbune, Cristian Jianu, Anca Oprea, Liliana Preoțescu, Liviu-Jany Prisacariu, Elena Belonosova, Olga Borodkina, Oxana Chernova, Natalia Gankina, Svetlana Kizhlo, Valeriy Viktorovich Kulagin, Nadezhda Kurina, Ф. И. Нагимова, Vadim Pokrovsky, E. P. Ryamova, Evgeny Voronin, A. N. Yakovlev, Richard Kaplan, Sun Hee Lee, Shin‐Woo Kim, Sangil Kim, Woo Joo Kim, Antonio Antela Lopez, José L. Casado, Manuel Angel Castano Carracedo, Ignacio de los Santos, Vicente Estrada Pérez, Vicenç Falcó Ferrer, Luís Force, Maria Jose Galinda Puerto, Miguel García Deltoro, Josep M. Gatell, Miguel A Goenaga Sanchez, Ana González-Cordón, Hernando Knobel, Juan Carlos Lopez Bernaldo de Quirós, Juan E Losa Garcia, Mar Masiá, Marta Montero, Antonio Ocampo Hermida, Juan Pasquau Liaño, Joaquin Portilla Sogorb, Federico Pulido, Antonio Rivera Roman, Jose Ramon Santos Fernandez, Rafael Torres Perea, Jesús Troya, Pompeyo Viciana Fernandez, Alexandra Calmy, Christoph Hauser, Jan Fehr, Shu‐Hsing Cheng, Wen‐Chien Ko, Hsi-Hsun Lin, Po‐Liang Lu, Yu‐Ting Tseng, Ning‐Chi Wang, Wing-Wai Wong, Chia‐Jui Yang, Roberto C. Arduino, Paul Benson, Mezgebe Berhe, Fritz Bredeek, Cynthia Brinson, Thomas L. Campbell, Gordon Crofoot, Douglas Cunningham, Edwin DeJesus, Robin Dretler, Joseph J. Eron, Kenneth H. Fife, Carl J. Fichtenbaum, Jason Flamm, Deborah Goldstein, Samir K. Gupta, Debbie Hagins, Margaret Hoffman-Terry, Dushyantha Jayaweera, Clifford Kinder, Daniel B. Klein, Cheryl McDonald, Anthony Mills, Ronald Nahass, Olayemi Osiyemi, Edgar T. Overton, David Parks, David James Prelutsky, Moti Ramgopal, Shannon Schrader, Beverly E. Sha, Gary L. Simon, James J. Sims, Daniel J. Skiest, Jihad Slim, Karen T. Tashima, Blair Thedinger, Brian Gazzard, Julie Fox, Margaret Johnson, Stephen Kegg, Saye Khoo, C Mazhude, Chloe Orkin, Gabriel Schembri, Andrew Ustianowski,
Tópico(s)HIV-related health complications and treatments
ResumoSummary 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.
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