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Dolutegravir plus two different prodrugs of Tenofovir to treat HIV

Dolutegravir plus two different prodrugs of Tenofovir to treat HIV
Dolutegravir plus two different prodrugs of Tenofovir to treat HIV
Background Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. Methods We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data. Results A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. Conclusions Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262. opens in new tab.)
0028-4793
803-815
Venter, Willem D.F.
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Moorhouse, Michelle
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Sokhela, Simiso
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Fairlie, Lee
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Mashabane, Nkuli
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Masenya, Masebole
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Serenata, Celicia
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Akpomiemie, Godspower
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Qavi, Ambar
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Chandiwana, Nomathemba
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Norris, Shane
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Chersich, Matthew
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Clayden, Polly
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Abrams, Elaine
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Arulappan, Natasha
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Vos, Alinda
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Mccann, Kaitlyn
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Simmons, Bryony
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Hill, Andrew
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Venter, Willem D.F.
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Moorhouse, Michelle
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Sokhela, Simiso
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Fairlie, Lee
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Mashabane, Nkuli
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Masenya, Masebole
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Serenata, Celicia
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Akpomiemie, Godspower
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Qavi, Ambar
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Chandiwana, Nomathemba
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Norris, Shane
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Chersich, Matthew
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Clayden, Polly
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Abrams, Elaine
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Arulappan, Natasha
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Vos, Alinda
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Mccann, Kaitlyn
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Simmons, Bryony
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Hill, Andrew
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Venter, Willem D.F., Moorhouse, Michelle, Sokhela, Simiso, Fairlie, Lee, Mashabane, Nkuli, Masenya, Masebole, Serenata, Celicia, Akpomiemie, Godspower, Qavi, Ambar, Chandiwana, Nomathemba, Norris, Shane, Chersich, Matthew, Clayden, Polly, Abrams, Elaine, Arulappan, Natasha, Vos, Alinda, Mccann, Kaitlyn, Simmons, Bryony and Hill, Andrew (2019) Dolutegravir plus two different prodrugs of Tenofovir to treat HIV. New England Journal of Medicine, 381 (9), 803-815. (doi:10.1056/NEJMoa1902824).

Record type: Article

Abstract

Background Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. Methods We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data. Results A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. Conclusions Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262. opens in new tab.)

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More information

Submitted date: 30 June 2019
Accepted/In Press date: 1 July 2019
e-pub ahead of print date: 24 July 2019
Published date: 29 August 2019

Identifiers

Local EPrints ID: 437073
URI: http://eprints.soton.ac.uk/id/eprint/437073
ISSN: 0028-4793
PURE UUID: 0936a4c9-f62c-4e8a-a751-5a91fd395f7f
ORCID for Shane Norris: ORCID iD orcid.org/0000-0001-7124-3788

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Date deposited: 16 Jan 2020 17:33
Last modified: 17 Mar 2024 03:57

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Contributors

Author: Willem D.F. Venter
Author: Michelle Moorhouse
Author: Simiso Sokhela
Author: Lee Fairlie
Author: Nkuli Mashabane
Author: Masebole Masenya
Author: Celicia Serenata
Author: Godspower Akpomiemie
Author: Ambar Qavi
Author: Nomathemba Chandiwana
Author: Shane Norris ORCID iD
Author: Matthew Chersich
Author: Polly Clayden
Author: Elaine Abrams
Author: Natasha Arulappan
Author: Alinda Vos
Author: Kaitlyn Mccann
Author: Bryony Simmons
Author: Andrew Hill

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