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

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From: The Lancet(Vol. 393, Issue 10167)
Publisher: Elsevier B.V.
Document Type: Article
Length: 1,218 words

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Summary 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 ([greater than or equal to]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. Author Affiliation: (a) Department of Infectious Diseases, Buenos Aires University, Buenos Aires, Argentina (b) Fundacion Huesped, Buenos Aires, Argentina (c) Infectious Diseases, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico (d) Hospital Universitario La Paz, Instituto de Investigacion Hospital La Paz, Madrid, Spain (e) UOC Immunodeficienze virali, Instituto Nazionale per le Malattie Infettive Lazzaro Spallanzani-IRCCS, Rome, Italy (f) Bliss Healthcare Services, Orlando, FL, USA (g) Sexual Health and Clinical Trials, Royal Sussex County Hospital, Brighton, UK (h) Division of Infectious Diseases, National Taiwan University Hospital, Taipei, Taiwan (i) Department of Medicine, University Hospital Bonn, Bonn, Germany (j) Service des Maladies Infectieuses et Tropicales, Hopital Saint Antoine, Paris, France (k) Clinical Development, ViiV Healthcare, Brentford, UK (l) Global Medical Affairs, ViiV Healthcare, Brentford, UK (m) Clinical Development, ViiV Healthcare, Research Triangle Park, NC, USA (n) Clinical Virology, ViiV Healthcare, Research Triangle Park, NC, USA (o) Medicine Development, ViiV Healthcare, Research Triangle Park, NC, USA (p) Global Research and Medical Strategy, ViiV Healthcare, Research Triangle Park, NC, USA (q) Statistics, GlaxoSmithKline, Stockley Park, UK (r) Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Stockley Park, UK * Correspondence to: Dr Jorg Sievers, Clinical Development, ViiV Healthcare, Brentford TW8 9GS, UK Byline: Prof Pedro Cahn, MD (a,b), Prof Juan Sierra Madero, MD (c), Jose Ramon Arribas, MD (d), Andrea Antinori, MD (e), Roberto Ortiz, MD (f), Amanda E Clarke, BM (g), Prof Chien-Ching Hung, MD (h), Prof Jurgen K Rockstroh, MD (i), Prof Pierre-Marie Girard, MD (j), Jorg Sievers, DPhil [jorg.x.sievers@viivhealthcare.com] (k,*), Choy Man, BSc (m), Alexander Currie, MSc (q), Mark Underwood, PhD (n), Allan R Tenorio, MD (m), Keith Pappa, PharmD (m), Brian Wynne, MD (m), Anna Fettiplace, PhD (r), Martin Gartland, PhD (o), Michael Aboud, MD (l), Kimberly Smith, MD (p), Lidia Cassetti, Daniel David, Laura Figueras, Marcelo Losso, Gustavo Lopardo, Sergio Lupo, Norma Porteiro, Marisa Sanchez, Mark Bloch, David Cooper, Robert Finlayson, Anthony Kelleher, Kenneth Koh, David Lewis, James McMahon, Richard Moore, Norman Roth, Matthew Shields, Stephane De Wit, Eric Florence, Jean-Christophe Goffard, Remy Demeester, Patrick Lacor, Bernard Vandercam, Linos Vandekerckhove, Jonathan Angel, Jean-Guy Baril, Brian Conway, Alexandra De Pokomandy, Jason Szabo, Sharon Walmsley, Olivier Bouchaud, Christian Chidiac, Pierre Delobel, Cecile Goujard, Christine Katlama, Jean-Michel Molina, Gilles Pialoux, Patrick Philibert, Johannes Bogner, Stefan Esser, Ivanka Krznaric, Clara Lehmann, Christoph Spinner, Hans-Jurgen 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 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, Jose A Hidalgo, Luis Hercilla Vasquez, Luis Illescas, Anita Olczak, Kamal Mansinho, Patricia Paula Correia Pacheco, Eugenio Teofilo, Jose Saraiva da Cunha, Rui Sarmento e Castro, Rosario Serrao, Manuela Arbune, Cristian Jianu, Anca Oprea, Liliana Preotescu, Liviu-Jany Prisacariu, Elena Belonosova, Olga Borodkina, Oxana Chernova, Natalia Gankina, Svetlana Kizhlo, Valeriy Kulagin, Nadezhda Kurina, Firaya Nagimova, Vadim Pokrovsky, Elena Ryamova, Evgeny Voronin, Alexey Yakovlev, Richard Kaplan, Sun Hee Lee, Shin-Woo Kim, Sang-Il Kim, Woo Joo Kim, Antonio Antela Lopez, Jose L Casado Osorio, Manuel A Castano Carracedo, Ignacio De Los Santos Gil, Vicente Estrada Perez, Vicenc Falco Ferrer, Luis Force, Maria Jose Galinda Puerto, Miguel Garcia Deltoro, Josep M Gatell, Miguel A Goenaga Sanchez, Ana Gonzalez Cordon, Hernando Knobel, Juan Carlos Lopez Bernaldo de Quiros, Juan E Losa Garcia, Mar Masia, Marta Montero-Alsonso, Antonio Ocampo Hermida, Juan Pasquau Liano, Joaquin Portilla Sogorb, Federico Pulido Ortega, Antonio Rivera Roman, Jose Ramon Santos Fernandez, Rafael Torres Perea, Jesus Troya Garcia, 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 Arduino, Paul Benson, Mezgebe Berhe, Fritz Bredeek, Cynthia Brinson, Thomas Campbell, Gordon Crofoot, Douglas Cunningham, Edwin DeJesus, Robin Dretler, Joseph Eron, Kenneth Fife, Carl Fichtenbaum, Jason Flamm, Deborah Goldstein, Samir Gupta, Debbie Hagins, Margaret Hoffman-Terry, Dushyantha Jayaweera, Clifford Kinder, Daniel Klein, Cheryl McDonald, Anthony Mills, Ronald Nahass, Olayemi Osiyemi, Edgar Overton, David Parks, David Prelutsky, Moti Ramgopal, Shannon Schrader, Beverly Sha, Gary Simon, James Sims, Daniel Skiest, Jihad Slim, Karen Tashima, Blair Thedinger, Brian Gazzard, Julie Fox, Margaret Johnson, Stephen Kegg, Saye Khoo, Charles Mazhude, Chloe Orkin, Gabriel Schembri, Andrew Ustianowski

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Gale Document Number: GALE|A569180937