Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial

Jean-Michel Molina; Kathleen Squires; Paul Sax; Pedro Cahn; Johan Lombaard; Edwin Dejesus; Ming-Tain Lai; Anthony Rodgers; Lisa Lupinacci; Sushma Kumar; Peter Sklar; George Hanna; Carey Hwang; Elizabeth Anne Martin; Debbie Hagins; Olayemi Osiyemi; David James Prelutsky; Moti Ramgopal; Anthony John Scarsella; Robin Dretler; Christopher Bettacchi; James Sims; Patrick Clay; Nicholaos Bellos; Melanie Thompson; Jose Montero; Cheryl Mcdonald; Catherine Creticos; David Shamblaw; Miguel Mogyoros; Antonio Terrelonge; Martin Valdes; Karen Tashima; William Robbins; Franco Antonio Felizarta; Richard Elion; Jihad Slim; Sandra Win; Sujata Lalla-Reddy; Peter Jerome Ruane; Anthony Mills; Jerry Cade; Craig Dietz; David Scott Rubin; Cynthia Mayer; Juan Carlos Rondon; Paul Cook; Eric Daar; Princy Kumar; Susan Swindells; Jose Guillermo Castro; Ivan Melendez-Rivera; Javier Morales-Ramirez; Lizette Santiago; Jorge Santana-Bagur; 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 Campos; 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; 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; Marleen de Jager; Joaquin Portilla Segorb; Josep Mallolas; Maria Jesus Perez Elias; Josep Gatell; Jose Ramon Arribas Lopez; Eugenia Negredo Puigmal; Daniel Podzamczer Palter; Federico Pulido Ortega; Jesus Troya Garcia; Ignacio de los Santos Gil; Juan Berenguer Berenguer; Ian Williams; Margaret Johnson; Gabriel Schembri; Amanda Clarke; Mark Gompels; Julie Meriel Fox; Steven John Taylor; David Harold Dockrell; Stephen Kegg

doi:10.1016/S2352-3018(19)30336-4

Journal Articles The Lancet HIV Year : 2020

Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial

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Jean-Michel Molina

Function : Author

Université Paris Diderot - Paris 7

Hopital Saint-Louis [AP-HP]

Kathleen Squires

Function : Author

Merck Sharp and Dohme

Sidney Kimmel Medical College [Philadelphia]

Paul Sax

Function : Author

Brigham and Women's Hospital [Boston]

Pedro Cahn

Function : Author

Fundación Huésped [Buenos Aires]

Johan Lombaard

Function : Author

Josha Research

Edwin Dejesus

Function : Author

Orlando Immunology Center

Ming-Tain Lai

Function : Author

Merck Sharp and Dohme

Anthony Rodgers

Function : Author

Merck Sharp and Dohme

Lisa Lupinacci

Function : Author

Merck Sharp and Dohme

Sushma Kumar

Function : Author

Merck Sharp and Dohme

Peter Sklar

Function : Author

Merck Sharp and Dohme

George Hanna

Function : Author

Merck Sharp and Dohme

Carey Hwang

Function : Author

Merck Sharp and Dohme

Elizabeth Anne Martin

Function : Author

Merck Sharp and Dohme

Debbie Hagins

Function : Author

Olayemi Osiyemi

Function : Author

David James Prelutsky

Function : Author

Moti Ramgopal

Function : Author

Anthony John Scarsella

Function : Author

Robin Dretler

Function : Author

Christopher Bettacchi

Function : Author

James Sims

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

Miguel Mogyoros

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

Sandra Win

Function : Author

Sujata Lalla-Reddy

Function : Author

Peter Jerome Ruane

Function : Author

Anthony Mills

Function : Author

Jerry Cade

Function : Author

Craig Dietz

Function : Author

David Scott Rubin

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

Ivan Melendez-Rivera

Function : Author

Javier Morales-Ramirez

Function : Author

Lizette Santiago

Function : Author

Jorge Santana-Bagur

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 Campos

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

Christine Katlama

Function : Author

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

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

Marleen de Jager

Function : Author

Joaquin Portilla Segorb

Function : Author

Josep Mallolas

Function : Author

Maria Jesus Perez Elias

Function : Author

Josep Gatell

Function : Author

Jose Ramon Arribas Lopez

Function : Author

Eugenia Negredo Puigmal

Function : Author

Daniel Podzamczer Palter

Function : Author

Federico Pulido Ortega

Function : Author

Jesus Troya Garcia

Function : Author

Ignacio de los Santos Gil

Function : Author

Juan Berenguer 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

David Harold Dockrell

Function : Author

Stephen Kegg

Function : Author

Abstract

Background: Doravirine is a novel, non-nucleoside reverse transcriptase inhibitor that has shown non-inferior efficacy to ritonavir-boosted darunavir, with a superior lipid profile, in adults with HIV who were treatment naive at week 48 in the phase 3 DRIVE-FORWARD trial. Here we present the 96-week data for the study. Methods: This randomised, controlled, double-blind, multicentre, non-inferiority, phase 3 study was undertaken at 125 clinical centres in 15 countries. Eligible participants were adults (aged ≥18 years) infected with HIV-1 who were naive to antiretroviral therapy, with a plasma HIV-1 RNA concentration of 1000 copies per mL or higher at screening, and no known resistance to any of the study drugs. Participants were randomly assigned (1:1) using an interactive voice and web response system, stratified by baseline HIV-1 RNA concentration and background nucleoside reverse transcriptase inhibitor therapy, to doravirine (100 mg per day) or ritonavir-boosted darunavir (100 mg ritonavir and 800 mg darunavir per day), both with investigator-selected nucleoside reverse transcriptase inhibitors: emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. Participants and investigators were masked to treatment assignment until week 96. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here we report the key secondary efficacy endpoint of the proportion of participants who achieved this concentration by week 96, assessed in all participants who received at least one dose of any study drug, regardless of whether it was their randomly assigned treatment. We used a US Food and Drug Administration snapshot approach and a margin of 10 percentage points to define the non-inferiority of doravirine to ritonavir-boosted darunavir at 96 weeks. Key safety endpoints were change in fasting serum lipid concentrations, the incidence of adverse events, and time to discontinuation due to an adverse event, assessed in all participants who received at least one dose of any study medication. This study is registered with ClinicalTrials.gov, NCT02275780, and is closed to accrual. Findings: Between Dec 1, 2014, and Oct 20, 2015, 1027 individuals were screened, of whom 769 participants were randomly assigned to doravirine (n=385) or ritonavir-boosted darunavir (n=384), and 383 in both groups were given at least one dose of their allocated treatment. Most participants were male (645 [84%] of 766) and white (560 [73%]), with a mean age of 35·2 years (SD 10·6). 292 participants in the doravirine group and 273 in the darunavir group completed 96 weeks of treatment. At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5-13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one (<1%) of 383 in the ritonavir-boosted darunavir group. Significant differences were seen between treatment groups in mean changes from baseline in LDL cholesterol (-14·6 mg/dL, 95% CI -18·2 to -11·0) and non-HDL cholesterol (-18·4 mg/dL, -22·5 to -14·3). Frequencies of adverse events were similar between groups. No significant treatment difference (log-rank nominal p=0·063) through week 96 was observed in time to discontinuation due to an adverse event. The most common adverse events (week 0-96) were diarrhoea (65 [17%] in the doravirine group vs 91 [24%] in the ritonavir-boosted darunavir group), nausea (45 [12%] vs 52 [14%]), headache (57 [15%] vs 46 [12%]), and upper respiratory tract infection (51 [13%] vs 30 [8%]). Two participants, one in each group, died during treatment; neither death was considered to be related to study medication. Interpretation: These results through 96 weeks support the efficacy and safety results reported previously for doravirine at 48 weeks, supporting the use of doravirine for the long-term treatment of adults with previously untreated HIV-1 infection. Funding: Merck.

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https://hal.sorbonne-universite.fr/hal-03722533

Submitted on : Wednesday, July 13, 2022-2:31:49 PM

Last modification on : Wednesday, December 11, 2024-3:46:21 PM

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hal-03722533 , version 1 (13-07-2022)

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HAL Id : hal-03722533 , version 1
DOI : 10.1016/S2352-3018(19)30336-4
PUBMED : 31740348

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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): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. The Lancet HIV, 2020, 7 (1), pp.e16-e26. ⟨10.1016/S2352-3018(19)30336-4⟩. ⟨hal-03722533⟩

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Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial

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