Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial - Sorbonne Université
Journal Articles The Lancet HIV Year : 2018

Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial

Jean-Michel Molina (1, 2) , Kathleen Squires (3) , Paul Sax (4) , Pedro Cahn (5) , Johan Lombaard (6) , Edwin Dejesus (7) , Ming-Tain Lai (8) , Xia Xu (8) , Anthony Rodgers (8) , Lisa Lupinacci (8) , Sushma Kumar (8) , Peter Sklar (8) , Bach-Yen Nguyen (8) , George Hanna (8) , Carey Hwang (8) , Marcelo Martins , Pedro Enrique Cahn , Gustavo Lopardo , Norma Porteiro , Mark Theo Bloch , David Alfred Baker , Norman Roth , Richard James Moore , Robert James Finlayson , James Mcmahon , Armin Rieger , Alexander Zoufaly , Sylvia Hartl , Robert Zangerle , Fiona Smaill , Sharon Walmsley , Brian Conway , Anita Rachlis , Graham H.R. Smith , Carlos Perez , Alejandro Afani , Maria Isabel E. Campos Barker , Carolina Eugenia Chahin , Marcelo Wolff Reyes , Jan Gerstoft , Nina Weis , Alex Lund Laursen , Yazdan Yazdanpanah , Laurent Cotte , Francois Raffi , Philippe Morlat , Pierre-Marie Girard , Christine Katlama (9) , Juergen Rockstroh , Keikawus Arasteh , Stefan Esser , Albrecht Stoehr , Hans-Juergen Stellbrink , Matthias Stoll , Dirk Schuermann , Gerd Faetkenheuer , Johannes Bogner , Thomas Lutz , Axel Baumgarten , Hans Jaeger , Andrea Gori , Gabriel Coltan , Felicia Constandis , Simona Manuela Erscoiu , Liviu-Jany Prisacariu , Sorin Rugina , Adrian Streinu-Cercel , Vadim Valentinovich Pokrovsky , Natalia Zakharova , Andrey Anatolyevich Shuldyakov , Elena Pavlovna Ryamova , Valeriy Viktorovich Kulagin , Olga Aleksandrovna Tsybakova , Elena Orlova-Morozova , Firaya Nagimova , Evgeniy Voronin , Tatyana Evgenyevna Shimonova , Oleg Anatolyevich Kozyrev , Catherine Orrell , Johannes Jurgens Lombaard , Margaretha Elizabeth Botes , Joaquin Portilla , Josep Maria Gatell , Maria Jesus Perez , Jose Ramon Arribas , Eugenia Negredo , Daniel Podzamczer , Federico Pulido , Jesus Troya , Ignacio de los Santos , Juan Berenguer , Ian Williams , Margaret Johnson , Gabriel Schembri , Amanda Clarke , Mark Gompels , Julie Meriel Fox , Steven John Taylor , Stephen Kegg , Debbie Hagins , Olayemi Osiyemi , David James Prelutsky , Moti Ramgopal , Robin Dretler , Louis Sloan , Stanley Lewis , Patrick Clay , Nicholaos Bellos , Melanie Thompson , Jose Montero , Cheryl Mcdonald , Catherine Creticos , David Shamblaw , Antonio Terrelonge , Martin Valdes , Karen Tashima , William Robbins , Franco Antonio Felizarta , Richard Elion , Jihad Slim , Jacob Paul Lalezari , Sujata Lalla-Reddy , Peter Jerome Ruane , Anthony Mills , Jerry Cade , Rafael Campo , Craig Dietz , Gary Blick , Cynthia Mayer , Juan Carlos Rondon , Paul Cook , Eric Daar , Princy Kumar , Susan Swindells , Jose Guillermo Castro , Javier Morales-Ramirez , Lizette Santiago , Jorge Santana-Bagur
Johan Lombaard
  • Function : Author
Xia Xu
  • Function : Author
Marcelo Martins
  • Function : Author
Pedro Enrique Cahn
  • Function : Author
Gustavo Lopardo
  • Function : Author
Norma Porteiro
  • Function : Author
Mark Theo Bloch
  • Function : Author
David Alfred Baker
  • Function : Author
Norman Roth
  • Function : Author
Richard James Moore
  • Function : Author
Robert James Finlayson
  • Function : Author
James Mcmahon
  • Function : Author
Armin Rieger
  • Function : Author
Alexander Zoufaly
  • Function : Author
Sylvia Hartl
  • Function : Author
Robert Zangerle
  • Function : Author
Fiona Smaill
  • Function : Author
Sharon Walmsley
  • Function : Author
Brian Conway
  • Function : Author
Anita Rachlis
  • Function : Author
Graham H.R. Smith
  • Function : Author
Carlos Perez
  • Function : Author
Alejandro Afani
  • Function : Author
Maria Isabel E. Campos Barker
  • Function : Author
Carolina Eugenia Chahin
  • Function : Author
Marcelo Wolff Reyes
  • Function : Author
Jan Gerstoft
  • Function : Author
Nina Weis
  • Function : Author
Alex Lund Laursen
  • Function : Author
Yazdan Yazdanpanah
  • Function : Author
Laurent Cotte
  • Function : Author
Francois Raffi
  • Function : Author
Philippe Morlat
  • Function : Author
Pierre-Marie Girard
  • Function : Author
Juergen Rockstroh
  • Function : Author
Keikawus Arasteh
  • Function : Author
Stefan Esser
  • Function : Author
Albrecht Stoehr
  • Function : Author
Hans-Juergen Stellbrink
  • Function : Author
Matthias Stoll
  • Function : Author
Dirk Schuermann
  • Function : Author
Gerd Faetkenheuer
  • Function : Author
Johannes Bogner
  • Function : Author
Thomas Lutz
  • Function : Author
Axel Baumgarten
  • Function : Author
Hans Jaeger
  • Function : Author
Andrea Gori
  • Function : Author
Gabriel Coltan
  • Function : Author
Felicia Constandis
  • Function : Author
Simona Manuela Erscoiu
  • Function : Author
Liviu-Jany Prisacariu
  • Function : Author
Sorin Rugina
  • Function : Author
Adrian Streinu-Cercel
  • Function : Author
Vadim Valentinovich Pokrovsky
  • Function : Author
Natalia Zakharova
  • Function : Author
Andrey Anatolyevich Shuldyakov
  • Function : Author
Elena Pavlovna Ryamova
  • Function : Author
Valeriy Viktorovich Kulagin
  • Function : Author
Olga Aleksandrovna Tsybakova
  • Function : Author
Elena Orlova-Morozova
  • Function : Author
Firaya Nagimova
  • Function : Author
Evgeniy Voronin
  • Function : Author
Tatyana Evgenyevna Shimonova
  • Function : Author
Oleg Anatolyevich Kozyrev
  • Function : Author
Catherine Orrell
  • Function : Author
Johannes Jurgens Lombaard
  • Function : Author
Margaretha Elizabeth Botes
  • Function : Author
Joaquin Portilla
  • Function : Author
Josep Maria Gatell
  • Function : Author
Maria Jesus Perez
  • Function : Author
Jose Ramon Arribas
  • Function : Author
Eugenia Negredo
  • Function : Author
Daniel Podzamczer
  • Function : Author
Federico Pulido
  • Function : Author
Jesus Troya
  • Function : Author
Ignacio de los Santos
  • Function : Author
Juan Berenguer
  • Function : Author
Ian Williams
  • Function : Author
Margaret Johnson
  • Function : Author
Gabriel Schembri
  • Function : Author
Amanda Clarke
  • Function : Author
Mark Gompels
  • Function : Author
Julie Meriel Fox
  • Function : Author
Steven John Taylor
  • Function : Author
Stephen Kegg
  • Function : Author
Debbie Hagins
  • Function : Author
Olayemi Osiyemi
  • Function : Author
David James Prelutsky
  • Function : Author
Moti Ramgopal
  • Function : Author
Robin Dretler
  • Function : Author
Louis Sloan
  • Function : Author
Stanley Lewis
  • Function : Author
Patrick Clay
  • Function : Author
Nicholaos Bellos
  • Function : Author
Melanie Thompson
  • Function : Author
Jose Montero
  • Function : Author
Cheryl Mcdonald
  • Function : Author
Catherine Creticos
  • Function : Author
David Shamblaw
  • Function : Author
Antonio Terrelonge
  • Function : Author
Martin Valdes
  • Function : Author
Karen Tashima
  • Function : Author
William Robbins
  • Function : Author
Franco Antonio Felizarta
  • Function : Author
Richard Elion
  • Function : Author
Jihad Slim
  • Function : Author
Jacob Paul Lalezari
  • Function : Author
Sujata Lalla-Reddy
  • Function : Author
Peter Jerome Ruane
  • Function : Author
Anthony Mills
  • Function : Author
Jerry Cade
  • Function : Author
Rafael Campo
  • Function : Author
Craig Dietz
  • Function : Author
Gary Blick
  • Function : Author
Cynthia Mayer
  • Function : Author
Juan Carlos Rondon
  • Function : Author
Paul Cook
  • Function : Author
Eric Daar
  • Function : Author
Princy Kumar
  • Function : Author
Susan Swindells
  • Function : Author
Jose Guillermo Castro
  • Function : Author
Javier Morales-Ramirez
  • Function : Author
Lizette Santiago
  • Function : Author
Jorge Santana-Bagur
  • Function : Author

Abstract

Background: Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. Methods: In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than -10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. Findings: Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI -1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one (<1%) participant of each group. Interpretation: In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection.
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Dates and versions

hal-03721466 , version 1 (12-07-2022)

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Cite

Jean-Michel Molina, Kathleen Squires, Paul Sax, Pedro Cahn, Johan Lombaard, et al.. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. The Lancet HIV, 2018, 5 (5), pp.e211-e220. ⟨10.1016/S2352-3018(18)30021-3⟩. ⟨hal-03721466⟩
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