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

Pedro Cahn; Juan Sierra Madero; José Ramón Arribas; Andrea Antinori; Roberto Ortiz; Amanda Clarke; Chien-Ching Hung; Jürgen Rockstroh; Pierre-Marie Girard; Jörg Sievers; Choy Man; Alexander Currie; Mark Underwood; Allan Tenorio; Keith Pappa; Brian Wynne; Anna Fettiplace; Martin Gartland; Michael Aboud; Kimberly Smith; Lidia Cassetti; Daniel David; Laura Figueras; Marcelo Losso; Gustavo Lopardo; Sergio Lupo; Norma Porteiro; Marisa Sánchez; 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 Granados Reyes; Alma Perez Rios; Mario Santoscoy Gomez; Jan den Hollander; Bart Rijnders; José Hidalgo; Luis Hercilla Vasquez; Luis Illescas; Anita Olczak; Kamal Mansinho; Patricia Paula Correia Pacheco; Eugénio Teófilo; Jose Saraiva da Cunha; Rui Sarmento E Castro; Rosário Serrão; 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 Casado Osorio; Manuel Castaño Carracedo; Ignacio de los Santos Gil; Vicente Estrada Perez; Vicenç Falco Ferrer; Luis Force; Maria Jose Galinda Puerto; Miguel Garcia Deltoro; Josep Gatell; Miguel Goenaga Sanchez; Ana González Cordón; Hernando Knobel; Juan Carlos Lopez Bernaldo de Quiros; Juan Losa Garcia; Mar Masia; Marta Montero-Alsonso; Antonio Ocampo Hermida; Juan Pasquau Liaño; 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

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

Journal Articles The Lancet Year : 2019

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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Pedro Cahn

Function : Author

Universitad de Buenos Aires = University of Buenos Aires [Argentina]

Juan Sierra Madero

Function : Author

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico]

José Ramón Arribas

Function : Author

Hospital Universitario La Paz

Andrea Antinori

Function : Author

Istituto Nazionale di Malattie Infettive "Lazzaro Spallanzani"

Roberto Ortiz

Function : Author

Bliss Healthcare Services

Amanda Clarke

Function : Author

Royal Sussex County Hospital

Chien-Ching Hung

Function : Author

National Taiwan University Hospital [Taipei]

Jürgen Rockstroh

Function : Author

University Hospital Bonn

Pierre-Marie Girard

Function : Author

CHU Saint-Antoine [AP-HP]

Jörg Sievers

Function : Author

ViiV Healthcare [Brentford, UK]

Choy Man

Function : Author

Research Triangle Park

Alexander Currie

Function : Author

Glaxo Smith Kline [Harlow]

Mark Underwood

Function : Author

Research Triangle Park

Allan Tenorio

Function : Author

Research Triangle Park

Keith Pappa

Function : Author

Research Triangle Park

Brian Wynne

Function : Author

Research Triangle Park

Anna Fettiplace

Function : Author

Glaxo Smith Kline [Harlow]

Martin Gartland

Function : Author

Research Triangle Park

Michael Aboud

Function : Author

ViiV Healthcare [Brentford, UK]

Kimberly Smith

Function : Author

Research Triangle Park

Lidia Cassetti

Function : Author

Daniel David

Function : Author

Laura Figueras

Function : Author

Marcelo Losso

Function : Author

Gustavo Lopardo

Function : Author

Sergio Lupo

Function : Author

Norma Porteiro

Function : Author

Marisa Sánchez

Function : Author

Mark Bloch

Function : Author

David Cooper

Function : Author

Robert Finlayson

Function : Author

Anthony Kelleher

Function : Author

Kenneth Koh

Function : Author

David Lewis

Function : Author

James Mcmahon

Function : Author

Richard Moore

Function : Author

Norman Roth

Function : Author

Matthew Shields

Function : Author

Stephane de Wit

Function : Author

Eric Florence

Function : Author

Jean-Christophe Goffard

Function : Author

Remy Demeester

Function : Author

Patrick Lacor

Function : Author

Bernard Vandercam

Function : Author

Linos Vandekerckhove

Function : Author

Jonathan Angel

Function : Author

Jean-Guy Baril

Function : Author

Brian Conway

Function : Author

Alexandra de Pokomandy

Function : Author

Jason Szabo

Function : Author

Sharon Walmsley

Function : Author

Olivier Bouchaud

Function : Author

Christian Chidiac

Function : Author
PersonId : 1062515

Pierre Delobel

Function : Author

Cecile Goujard

Function : Author

Christine Katlama

Function : Author

Stratégies thérapeutiques contre l'infection VIH et les maladies virales associées [iPLesp]

Jean-Michel Molina

Function : Author

Gilles Pialoux

Function : Author

Patrick Philibert

Function : Author

Johannes Bogner

Function : Author

Stefan Esser

Function : Author

Ivanka Krznaric

Function : Author

Clara Lehmann

Function : Author

Christoph Spinner

Function : Author

Hans-Jurgen Stellbrink

Function : Author

Christoph Stephan

Function : Author

Albrecht Stoehr

Function : Author

Enrico Barchi

Function : Author

Pietro Caramello

Function : Author

Francesco Castelli

Function : Author

Anna Maria Cattelan

Function : Author

Antonella d'Arminio Monforte

Function : Author

Antonio Di Biagio

Function : Author

Giovanni Di Perri

Function : Author

Andrea Gori

Function : Author

Franco Maggiolo

Function : Author

Barbara Menzaghi

Function : Author

Guglielmo Migliorino

Function : Author

Cristina Mussini

Function : Author

Giovanni Penco

Function : Author

Massimo Puoti

Function : Author

Giuliano Rizzardini

Function : Author

Roberto Gulminetti

Function : Author

Adriano Lazzarin

Function : Author

Tiziano Quirino

Function : Author

Laura Sighinolfi

Function : Author

Pierluigi Viale

Function : Author

Gerardo Amaya Tapia

Function : Author

Jaime Andrade Villanueva

Function : Author

Enrique Granados Reyes

Function : Author

Alma Perez Rios

Function : Author

Mario Santoscoy Gomez

Function : Author

Jan den Hollander

Function : Author

Bart Rijnders

Function : Author

José Hidalgo

Function : Author

Luis Hercilla Vasquez

Function : Author

Luis Illescas

Function : Author

Anita Olczak

Function : Author

Kamal Mansinho

Function : Author

Patricia Paula Correia Pacheco

Function : Author

Eugénio Teófilo

Function : Author

Jose Saraiva da Cunha

Function : Author

Rui Sarmento E Castro

Function : Author

Rosário Serrão

Function : Author

Manuela Arbune

Function : Author

Cristian Jianu

Function : Author

Anca Oprea

Function : Author

Liliana Preotescu

Function : Author

Liviu-Jany Prisacariu

Function : Author

Elena Belonosova

Function : Author

Olga Borodkina

Function : Author

Oxana Chernova

Function : Author

Natalia Gankina

Function : Author

Svetlana Kizhlo

Function : Author

Valeriy Kulagin

Function : Author

Nadezhda Kurina

Function : Author

Firaya Nagimova

Function : Author

Vadim Pokrovsky

Function : Author

Elena Ryamova

Function : Author

Evgeny Voronin

Function : Author

Alexey Yakovlev

Function : Author

Richard Kaplan

Function : Author

Sun Hee Lee

Function : Author

Shin-Woo Kim

Function : Author

Sang-Il Kim

Function : Author

Woo Joo Kim

Function : Author

Antonio Antela Lopez

Function : Author

Jose Casado Osorio

Function : Author

Manuel Castaño Carracedo

Function : Author

Ignacio de los Santos Gil

Function : Author

Vicente Estrada Perez

Function : Author

Vicenç Falco Ferrer

Function : Author

Luis Force

Function : Author

Maria Jose Galinda Puerto

Function : Author

Miguel Garcia Deltoro

Function : Author

Josep Gatell

Function : Author

Miguel Goenaga Sanchez

Function : Author

Ana González Cordón

Function : Author

Hernando Knobel

Function : Author

Juan Carlos Lopez Bernaldo de Quiros

Function : Author

Juan Losa Garcia

Function : Author

Mar Masia

Function : Author

Marta Montero-Alsonso

Function : Author

Antonio Ocampo Hermida

Function : Author

Juan Pasquau Liaño

Function : Author

Joaquin Portilla Sogorb

Function : Author

Federico Pulido Ortega

Function : Author

Antonio Rivera Roman

Function : Author

Jose Ramon Santos Fernandez

Function : Author

Rafael Torres Perea

Function : Author

Jesus Troya Garcia

Function : Author

Pompeyo Viciana Fernandez

Function : Author

Alexandra Calmy

Function : Author

Christoph Hauser

Function : Author

Jan Fehr

Function : Author

Shu-Hsing Cheng

Function : Author

Wen-Chien Ko

Function : Author

Hsi-Hsun Lin

Function : Author

Po-Liang Lu

Function : Author

Yu-Ting Tseng

Function : Author

Ning-Chi Wang

Function : Author

Wing-Wai Wong

Function : Author

Chia-Jui Yang

Function : Author

Roberto Arduino

Function : Author

Paul Benson

Function : Author

Mezgebe Berhe

Function : Author

Fritz Bredeek

Function : Author

Cynthia Brinson

Function : Author

Thomas Campbell

Function : Author

Gordon Crofoot

Function : Author

Douglas Cunningham

Function : Author

Edwin Dejesus

Function : Author

Robin Dretler

Function : Author

Joseph Eron

Function : Author

Kenneth Fife

Function : Author

Carl Fichtenbaum

Function : Author

Jason Flamm

Function : Author

Deborah Goldstein

Function : Author

Samir Gupta

Function : Author

Debbie Hagins

Function : Author

Margaret Hoffman-Terry

Function : Author

Dushyantha Jayaweera

Function : Author

Clifford Kinder

Function : Author

Daniel Klein

Function : Author

Cheryl Mcdonald

Function : Author

Anthony Mills

Function : Author

Ronald Nahass

Function : Author

Olayemi Osiyemi

Function : Author

Edgar Overton

Function : Author

David Parks

Function : Author

David Prelutsky

Function : Author

Moti Ramgopal

Function : Author

Shannon Schrader

Function : Author

Beverly Sha

Function : Author

Gary Simon

Function : Author

James Sims

Function : Author

Daniel Skiest

Function : Author

Jihad Slim

Function : Author

Karen Tashima

Function : Author

Blair Thedinger

Function : Author

Brian Gazzard

Function : Author

Julie Fox

Function : Author

Margaret Johnson

Function : Author

Stephen Kegg

Function : Author

Saye Khoo

Function : Author

Charles Mazhude

Function : Author

Chloe Orkin

Function : Author

Gabriel Schembri

Function : Author

Andrew Ustianowski

Function : Author

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.

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Life Sciences [q-bio]

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https://hal.sorbonne-universite.fr/hal-03719533

Submitted on : Monday, July 11, 2022-12:08:29 PM

Last modification on : Thursday, April 25, 2024-3:12:48 AM

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hal-03719533 , version 1 (11-07-2022)

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HAL Id : hal-03719533 , version 1
DOI : 10.1016/S0140-6736(18)32462-0
PUBMED : 30420123

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Pedro Cahn, Juan Sierra Madero, José Ramón Arribas, Andrea Antinori, Roberto Ortiz, et al.. 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. The Lancet, 2019, 393 (10167), pp.143-155. ⟨10.1016/S0140-6736(18)32462-0⟩. ⟨hal-03719533⟩

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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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