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

DRIVE-FORWARD Study Group

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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. Funding: Merck & Co.

Original languageEnglish
Pages (from-to)e211-e220
JournalThe Lancet HIV
Volume5
Issue number5
DOIs
StatePublished - May 2018

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Ritonavir
HIV-1
Reverse Transcriptase Inhibitors
Nucleosides
HIV Infections
RNA
Tenofovir
Pharmaceutical Preparations
Therapeutics
Darunavir
Research Personnel
Virus Diseases
United States Food and Drug Administration
Immunosuppressive Agents
Random Allocation
Drug-Related Side Effects and Adverse Reactions
Nausea
Hepatitis
Headache
Diarrhea

Cite this

@article{809843b032704a84a21b4680f4c34c98,
title = "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",
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. Funding: Merck & Co.",
author = "{DRIVE-FORWARD Study Group} and Molina, {Jean Michel} and Kathleen Squires and Sax, {Paul E.} and Pedro Cahn and Johan Lombaard and Edwin DeJesus and Lai, {Ming Tain} and Xia Xu and Anthony Rodgers and Lisa Lupinacci and Sushma Kumar and Peter Sklar and Nguyen, {Bach Yen} and Hanna, {George J.} and Carey Hwang and Marcelo Martins and Cahn, {Pedro Enrique} and Lopardo, {Gustavo D.} and Norma Porteiro and Bloch, {Mark Theo} and Baker, {David Alfred} and Norman Roth and Moore, {Richard James} and Finlayson, {Robert James} and James McMahon and Armin Rieger and Alexander Zoufaly and Sylvia Hartl and Robert Zangerle and Fiona Smaill and Walmsley, {Sharon L.} and Brian Conway and Anita Rachlis and Smith, {Graham H.R.} and Carlos Perez and Alejandro Afani and {Campos Barker}, {Maria Isabel E.} and Chahin, {Carolina Eugenia} and {Wolff Reyes}, Marcelo and Jan Gerstoft and Nina Weis and Laursen, {Alex Lund} and Molina, {Jean Michel} and Yazdan Yazdanpanah and Laurent Cotte and Francois Raffi and Philippe Morlat and Girard, {Pierre Marie} and Christine Katlama and Rockstroh, {Juergen K.}",
year = "2018",
month = "5",
doi = "10.1016/S2352-3018(18)30021-3",
language = "English",
volume = "5",
pages = "e211--e220",
journal = "The Lancet HIV",
issn = "2352-3018",
publisher = "Elsevier Ltd",
number = "5",

}

TY - JOUR

T1 - Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD)

T2 - 48-week results of a randomised, double-blind, phase 3, non-inferiority trial

AU - DRIVE-FORWARD Study Group

AU - Molina, Jean Michel

AU - Squires, Kathleen

AU - Sax, Paul E.

AU - Cahn, Pedro

AU - Lombaard, Johan

AU - DeJesus, Edwin

AU - Lai, Ming Tain

AU - Xu, Xia

AU - Rodgers, Anthony

AU - Lupinacci, Lisa

AU - Kumar, Sushma

AU - Sklar, Peter

AU - Nguyen, Bach Yen

AU - Hanna, George J.

AU - Hwang, Carey

AU - Martins, Marcelo

AU - Cahn, Pedro Enrique

AU - Lopardo, Gustavo D.

AU - Porteiro, Norma

AU - Bloch, Mark Theo

AU - Baker, David Alfred

AU - Roth, Norman

AU - Moore, Richard James

AU - Finlayson, Robert James

AU - McMahon, James

AU - Rieger, Armin

AU - Zoufaly, Alexander

AU - Hartl, Sylvia

AU - Zangerle, Robert

AU - Smaill, Fiona

AU - Walmsley, Sharon L.

AU - Conway, Brian

AU - Rachlis, Anita

AU - Smith, Graham H.R.

AU - Perez, Carlos

AU - Afani, Alejandro

AU - Campos Barker, Maria Isabel E.

AU - Chahin, Carolina Eugenia

AU - Wolff Reyes, Marcelo

AU - Gerstoft, Jan

AU - Weis, Nina

AU - Laursen, Alex Lund

AU - Molina, Jean Michel

AU - Yazdanpanah, Yazdan

AU - Cotte, Laurent

AU - Raffi, Francois

AU - Morlat, Philippe

AU - Girard, Pierre Marie

AU - Katlama, Christine

AU - Rockstroh, Juergen K.

PY - 2018/5

Y1 - 2018/5

N2 - 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. Funding: Merck & Co.

AB - 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. Funding: Merck & Co.

UR - http://www.scopus.com/inward/record.url?scp=85044326687&partnerID=8YFLogxK

U2 - 10.1016/S2352-3018(18)30021-3

DO - 10.1016/S2352-3018(18)30021-3

M3 - Article

C2 - 29592840

AN - SCOPUS:85044326687

VL - 5

SP - e211-e220

JO - The Lancet HIV

JF - The Lancet HIV

SN - 2352-3018

IS - 5

ER -