Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen.
Journal
AIDS (London, England)
ISSN: 1473-5571
Titre abrégé: AIDS
Pays: England
ID NLM: 8710219
Informations de publication
Date de publication:
15 07 2021
15 07 2021
Historique:
pubmed:
12
5
2021
medline:
7
8
2021
entrez:
11
5
2021
Statut:
ppublish
Résumé
Recycling tenofovir and lamivudine/emtricitabine (XTC) with dolutegravir would provide a more tolerable, affordable, and scalable second-line regimen than dolutegravir with an optimized nucleoside reverse transcriptase inhibitor (NRTI) backbone. We evaluated efficacy of tenofovir/lamivudine/dolutegravir (TLD) in patients failing first-line tenofovir/XTC/efavirenz or nevirapine. Single arm, prospective, interventional study. Two primary care clinics in Khayelitsha, South Africa. Sixty adult patients with two viral loads greater than 1000 copies/ml. Participants were switched to TLD with additional dolutegravir (50 mg) for 2 weeks to overcome efavirenz induction. Proportion achieving viral load less than 50 copies/ml at week 24 using the FDA snapshot algorithm. Baseline median CD4+ cell count was 248 cells/μl, viral load 10 580 copies/ml and 48 of 54 (89%) had resistance (Stanford score ≥15) to one or both of tenofovir and XTC. No participants were lost to follow-up. At week 24, 51 of 60 [85%, 95% confidence interval (CI) 73-93%] were virologically suppressed, six had viral load 50-100 copies/ml, one had viral load 100-1000 copies/ml, one no viral load in window, and one switched because of tenofovir-related adverse event. No integrase mutations were detected in the one participant meeting criteria for resistance testing. Virological suppression was achieved by 29 of 35 (83%, 95% CI 66-93%) with resistance to tenofovir and XTC, 11 of 13 (85%, 95% CI 55-98%) with resistance to XTC, and six of six (100%, 95% CI 54-100%) with resistance to neither. A high proportion of adults switching to second-line TLD achieved virologic suppression despite substantial baseline NRTI resistance and most not suppressed had low-level viraemia (≤100 copies/ml). This suggests recycling tenofovir and XTC with dolutegravir could provide an effective second-line option.
Identifiants
pubmed: 33973876
doi: 10.1097/QAD.0000000000002936
pii: 00002030-202107150-00010
pmc: PMC7612028
mid: EMS124473
doi:
Substances chimiques
Anti-HIV Agents
0
Heterocyclic Compounds, 3-Ring
0
Oxazines
0
Piperazines
0
Pyridones
0
Lamivudine
2T8Q726O95
Tenofovir
99YXE507IL
dolutegravir
DKO1W9H7M1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1423-1432Subventions
Organisme : Wellcome Trust
ID : 203135
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : UM1 AI068634
Pays : United States
Organisme : Wellcome Trust
ID : 214321
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : UM1 AI106701
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068636
Pays : United States
Organisme : Wellcome Trust
ID : 212265/Z/18/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203135/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 214321/Z/18/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
Références
Aboud M, Kaplan R, Lombaard J, Zhang F, Hidalgo JA, Mamedova E, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, noninferiority, phase 3b trial . Lancet Infect Dis 2019; 19:253–264.
The World Health Organization. Update of recommendations on first- and second-line antiretroviral regimens . Geneva: The World Health Organization; 2019.
The TenoRes Study Group. Global epidemiology of drug resistance after failure of WHO recommended fi rst-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study . Lancet Infect Dis 2016; 16:565–575.
Hunt G, Steegen K, Hans L, Cassim N, MacLeod W, Carmona S. High levels of HIV drug resistance in adult patients with unsuppressed viral load, measured through routine viral load programme monitoring in South Africa. 14th INTEREST Conference . Virtual; 2020.
Wijting I, Rokx C, Boucher C, van Kampen J, Pas S, de Vries-Sluijs T, et al. Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised noninferiority trial . Lancet HIV 2017; 4:e547–e554.
Hocqueloux L, Allavena C, Prazuck T, Bernard L, Sunder S, Esnault J-L, et al. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for HIV-1-infected virologically suppressed patients: Results from the randomized noninferiority MONCAY trial. AIDS2018 . Amsterdam; 2018.
Stanford University. NRTI Resistance Notes [Internet]. HIV Drug Resistance Database. 2016. Available at: https://hivdb.stanford.edu/dr-summary/resistance-notes/NTRV . [Accessed 25 September 2020]
Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, et al. Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV . N Engl J Med 2006; 354:251–260.
Hakim JG, Thompson J, Kityo C, Hoppe A, Kambugu A, van Oosterhout JJ, et al. Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team. Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial . Lancet Infect Dis 2018; 18:47–57.
La Rosa AM, Harrison LJ, Taiwo B, Wallis CL, Zheng L, Kim P, et al. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, noninferiority study . Lancet HIV 2016; 3:E247–E258.
Boyd M, Kumarasamy N, Moore C, Nwizu C, Losso M, et al. SECOND-LINE Study Group. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen . Lancet 2013; 381:2091–2099.
Pierre S, GHESKIO Centers. Sub-optimal outcomes with switching to zidovudine vs. recycling tenofovir in second-line treatment in Haiti. AIDS 2020 . Virtual; 2020.
Ross L, Parkin N, Lanier R. The number of HIV major NRTI mutations correlates directly with other antiretroviral-associated mutations and indirectly with replicative capacity and reduced drug susceptibility . AIDS Res Hum Retroviruses 2008; 24:617–620.
Song I, Borland J, Chen S, Guta P, Lou Y, Wilfret D, et al. Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir . Eur J Clin Pharmacol 2014; 70:1173–1179.
Van Zyl GU, Liu TF, Claassen M, Engelbrecht S, de Oliveira T, Preiser W, et al. Trends in genotypic HIV-1 antiretroviral resistance between 2006 and 2012 in South African patients receiving first- and second-line antiretroviral treatment regimens . PLoS One 2013; 8:e67188.
Morin CM, Belleville G, Bélanger L, Ivers H. The insomnia severity index: Psychometric indicators to detect insomnia cases and evaluate treatment response . Sleep 2011; 34:601–608.
Alexander MJ, Haugland G, Lin SP, Bertollo DN, McCorry FA. Mental health screening in addiction, corrections and social service settings: validating the MMS . Int J Ment Health Addict 2008; 6:105–119.
Castillo-Mancilla JR, Zheng JH, Rower JE, Meditz A, Gardner EM, Predhomme J, et al. Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure . AIDS Res Hum Retroviruses 2013; 29:384–390.
Phillips TK, Sinxadi P, Abrams E, Zerbe A, Orrell C, Hu N-C, et al. A comparison of plasma efavirenz and tenofovir, dried blood spot tenofovir-diphosphate, and self-reported adherence to predict virologic suppression among South African women . J Acquir Immune Defic Syndr 2019; 81:311–318.
U.S. Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment Guidance for Industry Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment Guidance for Industry. 2015.
Stanford University. DRM penalty scores and resistance interpretation [Internet]. HIV Drug Resistance Database. 2020 [cited 4 September 2020]. Available at: https://hivdb.stanford.edu/page/release-notes . [Accessed 4 September 2020]
DAIDS. Division of Aids Table for Grading the Severity of Adult and Pediatric Adverse Events Division of Aids Table for Grading the Severity of Adult and Pediatric Adverse Events. National Institute of Allergy and Infectious Diseases. 2017.
Anderson PL, Liu AY, Castillo-Mancilla JR, Gardner EM, Seifert SM, Mchugh C, et al. Intracellular tenofovir-diphosphate and emtricitabine-triphosphate in dried blood spots following directly observed therapy . Antimicrob Agents Chemother 2018; 62:1–13.
De Miguel R, Rial-Crestelo D, Dominguez-Dominguez L, Montejano R, Esteban-Cantos A, Aranguren-Rivas P, et al. Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a nonrandomized, pilot clinical trial (ART-PRO) . EBioMedicine 2020; 55:102779.
Reynes J, Meftah N, Tuaillon E, Charpentier C, Montes B. Dual regimen with dolutegravir and lamivudine maintains virologic suppression even in heavily treatment experienced HIV-infected patients: 96 weeks results from maintenance DOLULAM study. International AIDS Society Conference . Paris; 2017.
Charpentier C, Peytavin G, Lê MP, Joly V, Cabras O, Perrier M, et al. High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort . J Antimicrob Chemother 2018; 73:1665–1671.
Oliveira M, Ibanescu RI, Pham HT, Brenner B, Mesplede T, Wainberg MA. The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir . AIDS 2016; 30:2267–2273.
Bvochora T, Satyanarayana S, Takarinda KC, Bara H, Chonzi P, Komtenza B, et al. Enhanced adherence counselling and viral load suppression in HIV seropositive patients with an initial high viral load in Harare, Zimbabwe: operational issues . PLoS One 2019; 14:e0211326.
Etoori D, Ciglenecki I, Ndlangamandla M, Edwards CG, Jobanputra K, Pasipamire M, et al. Successes and challenges in optimizing the viral load cascade to improve antiretroviral therapy adherence and rationalize second-line switches in Swaziland . J Int AIDS Soc 2018; 21:e25194.
Pepperrell T, Venter WDF, Moorhouse M, McCann K, Bosch B, Tibbatts M, et al. Time to rethink endpoints for new clinical trials of antiretrovirals? Long-term re-suppression of HIV RNA with integrase inhibitors . AIDS 2020; 34:321–324.
Aleman S, Söderbärg K, Visco-Comandini U, Sitbon G, Sönnerborg A. Drug resistance at low viraemia in HIV-1-infected patients with antiretroviral combination therapy . AIDS 2002; 16:1039–1044.
Vandenhende M-A, Ingle S, May M, Chene G, Zangerle R, Van Sighem A, et al. Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients . AIDS 2015; 29:373–383.
Generaux G, Song I, Bowers G, Piscitelli S. A mechanistic SimCYP simulation evaluating dolutegravir and efavirenz pharmacokinetics following a switch from once-daily efavirenz to once-daily dolutegravir. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy . Washington, DC; 2014.
DeWet J, DeJesus E, Sloan L, Koteff J, Brennan C, Adkison K, et al. Pharmacokinetics of dolutegravir after switching to abacavir/dolutegravir/lamivudine from an efavirenz-based regimen: a pk sub-study from STRIIVING. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy . Washington; 2016.
Cahn P, Sierra-Madero J, Arrivas J, Antinori A, Ortiz R, Clarke A, et al. 13120: Noninferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in antiretroviral treatment-naïve adults with HIV-1 infection - 48-week results from the GEMINI studies. AIDS . Amsterdam; 2018.
Charpentier C, Descamps D. Resistance to HIV integrase inhibitors: about R263K and E157Q mutations . Viruses 2018; 10:1–8.
Temfack E, Jahn A, Kalua T, Bitilinyu-Bangoh J, Nyirenda R, Marcelin A-G, et al. Prospective enhanced monitoring of dolutegravir-based first line in Malawi. CROI. Boston; 2020.
Chimukangara B, Lessells RJ, Rhee SY, Giandhari J, Kharsany ABM, Naidoo K, et al. Trends in pretreatment HIV-1 drug resistance in antiretroviral therapy-naive adults in South Africa, 2000-2016: a pooled sequence analysis . EClinicalMedicine 2019; 9:26–34.
Kirby Institute. Protocol for Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D 2 EFT) NCT03017872 [Internet]. ClinicalTrials.gov. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT03017872 . [Accessed 3 September 2020]
Makerere University. Nucleosides And Darunavir/Dolutegravir In Africa (NADIA) NCT03988452 [Internet]. ClinicalTrials.gov. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT03988452 . [Accessed 3 September 2020]
Phillips AN, Venter F, Havlir D, Pozniak A, Kuritzkes D, Wensing A, et al. Risks and benefits of dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study . Lancet HIV 2019; 6:e116–e127.