title: Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study.
abstract: HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART.
  
  
  
  We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs.
  
  
  
  Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL [IQR 21·0-128·0] in patients with TAMS vs 95·0 cells per μL [37·0-177·0] in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0·0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13-1·47; p<0·0001) INTERPRETATION: TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains.
  
  
  
  The Wellcome Trust.
authors.affiliation: Department of Statistics, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gregson
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda; Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: Pontiano
authors.initials: P
authors.lastname: Kaleebu
authors.affiliation: Department of Global Health, Emory University Rollins School of Public Health, Emory University, Atlanta, GA, USA; Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Marconi
authors.affiliation: Division of Infectious Diseases, University of the Free State, and 3 Military Hospital, Bloemfontein, South Africa.
authors.forename: Cloete
authors.initials: C
authors.lastname: van Vuuren
authors.affiliation: Institute of Human Virology Nigeria, Abuja, Nigeria.
authors.forename: Nicaise
authors.initials: N
authors.lastname: Ndembi
authors.affiliation: Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, University of Amsterdam, Netherlands.
authors.forename: Raph L
authors.initials: RL
authors.lastname: Hamers
authors.affiliation: Department of Immunology and Infectious Disease, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Kanki
authors.affiliation: Aurum Institute, Johannesburg South Africa; Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hoffmann
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Lockman
authors.affiliation: Department of Infection, University College London, London, UK; Africa Health Research Institute, KwaZulu Natal, South Africa.
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: Nelson R Mandela School of Medicine, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu Natal, Durban, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
authors.forename: Tulio
authors.initials: T
authors.lastname: de Oliveira
authors.affiliation: Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.affiliation: National Institute for Communicable Diseases, Sandringham, South Africa.
authors.forename: Gillian
authors.initials: G
authors.lastname: Hunt
authors.affiliation: Médecins Sans Frontières (Operational Centre Geneva), Mbabane, Swaziland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kerschberger
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.affiliation: International Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Yang
authors.affiliation: Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Raizes
authors.affiliation: Division of Infectious Diseases, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Rami
authors.initials: R
authors.lastname: Kantor
authors.affiliation: Department of Infection, University College London, London, UK; Africa Health Research Institute, KwaZulu Natal, South Africa. Electronic address: ravindra.gupta@ucl.ac.uk.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara; D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009154:Mutation / Q000235:genetics; D019829:Nevirapine / Q000627:therapeutic use; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000068698:Tenofovir / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D019829:Nevirapine; D000068698:Tenofovir; C098320:efavirenz