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
(1)
,
Juan Sierra Madero
(2)
,
José Ramón Arribas
(3)
,
Andrea Antinori
(4)
,
Roberto Ortiz
(5)
,
Amanda Clarke
(6)
,
Chien-Ching Hung
(7)
,
Jürgen Rockstroh
(8)
,
Pierre-Marie Girard
(9)
,
Jörg Sievers
(10)
,
Choy Man
(11)
,
Alexander Currie
(12)
,
Mark Underwood
(11)
,
Allan Tenorio
(11)
,
Keith Pappa
(11)
,
Brian Wynne
(11)
,
Anna Fettiplace
(12)
,
Martin Gartland
(11)
,
Michael Aboud
(10)
,
Kimberly Smith
(11)
,
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
(13)
,
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
1
Universitad de Buenos Aires = University of Buenos Aires [Argentina]
2 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico]
3 Hospital Universitario La Paz-Carlos III [Madrid]
4 INMI - Istituto Nazionale di Malattie Infettive "Lazzaro Spallanzani"
5 Bliss Healthcare Services
6 Royal Sussex County Hospital
7 NTUH - National Taiwan University Hospital [Taipei]
8 University Hospital Bonn
9 CHU Saint-Antoine [AP-HP]
10 ViiV Healthcare [Brentford, UK]
11 Research Triangle Park
12 Glaxo Smith Kline [Harlow]
13 THERAVIR - Stratégies thérapeutiques contre l'infection VIH et les maladies virales associées [iPLesp]
2 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico]
3 Hospital Universitario La Paz-Carlos III [Madrid]
4 INMI - Istituto Nazionale di Malattie Infettive "Lazzaro Spallanzani"
5 Bliss Healthcare Services
6 Royal Sussex County Hospital
7 NTUH - National Taiwan University Hospital [Taipei]
8 University Hospital Bonn
9 CHU Saint-Antoine [AP-HP]
10 ViiV Healthcare [Brentford, UK]
11 Research Triangle Park
12 Glaxo Smith Kline [Harlow]
13 THERAVIR - Stratégies thérapeutiques contre l'infection VIH et les maladies virales associées [iPLesp]
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
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.