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Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

Authors :
Nicholas I Paton
Joseph Musaazi
Cissy Kityo
Stephen Walimbwa
Anne Hoppe
Apolo Balyegisawa
Jesca Asienzo
Arvind Kaimal
Grace Mirembe
Abbas Lugemwa
Gilbert Ategeka
Margaret Borok
Henry Mugerwa
Abraham Siika
Eva Laker A Odongpiny
Barbara Castelnuovo
Agnes Kiragga
Andrew Kambugu
Daniel Kiiza
John Kisembo
John Nsubuga
Max Okwero
Rhona Muyise
Claire Nasaazi
Dridah L. Nakiboneka
Josephine Namusanje
Theresa Najjuuko
Timothy Masaba
Timothy Serumaga
Adolf Alinaitwe
Allan Arinda
Angela Rweyora
Mary Goretti Kangah
Mariam Kasozi
Phionah Tukumushabe
Rogers Akunda
Shafic Makumbi
Sharif Musumba
Sula Myalo
John Ahuura
Annet Mary Namusisi
Daniel Kibirige
Francis Kiweewa
Habert Mabonga
Joseph Wandege
Josephine Nakakeeto
Sharon Namubiru
Winfred Nansalire
Abraham Mosigisi Siika
Charles Meja Kwobah
Chris Sande Mboya
Martha Mokeira Bisieri Mokaya
Mercy Jelagat Karoney
Priscilla Chepkorir Cheruiyot
Salinah Cherutich
Simon Wachira Njuguna
Viola Cherotich Kirui
Ennie Chidziva
Godfrey Musoro
James Hakim
Joyline Bhiri
Misheck Phiri
Shepherd Mudzingwa
Tadios Manyanga
Anchilla Mary Banegura
Betty Agwang
Brian Isaaya
Constantine Tumwine
Eva Laker A. Odongpiny
Nicholas Paton
Peter Senkungu
Yvonne Kamara
Mathius Amperiize
Elizabeth Allen
Charles Opondo
Perry Mohammed
Willemijn van Rein-van der Horst
Yvon Van Delft
Fafa Addo Boateng
Doreen Namara
Pontiano Kaleebu
Sylvia Ojoo
Tapiwanashe Bwakura
Milly Katana
Francois Venter
Sam Phiri
Sarah Walker
Source :
The Lancet HIV. 9:e381-e393
Publication Year :
2022
Publisher :
Elsevier BV, 2022.

Abstract

WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI -3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3-4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.Janssen.

Details

ISSN :
23523018
Volume :
9
Database :
OpenAIRE
Journal :
The Lancet HIV
Accession number :
edsair.doi.dedup.....9294a359496eae0df6d04748de07b343
Full Text :
https://doi.org/10.1016/s2352-3018(22)00092-3