title: HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.
abstract: To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs.
  
  
  
  Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure.
  
  
  
  The median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02].
  
  
  
  Non-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens.
authors.affiliation: *Joint Clinical Research Centre (JCRC), Kampala, Uganda; †MRC Clinical Trials Unit at University College London, London, United Kingdom; ‡University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; §Infectious Diseases Institute, Kampala, Uganda; ‖Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi; ¶Dignitas International, Zomba, Malawi; #Department of Medicine, Moi University School of Medicine, Eldoret, Kenya; **World Health Organisation, Geneva, Switzerland; and ‡‡Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thompson
authors.forename: Immaculate
authors.initials: I
authors.lastname: Nankya
authors.forename: Anne
authors.initials: A
authors.lastname: Hoppe
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Ndashimye
authors.forename: Colin
authors.initials: C
authors.lastname: Warambwa
authors.forename: Ivan
authors.initials: I
authors.lastname: Mambule
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.forename: Kara
authors.initials: K
authors.lastname: Wools-Kaloustian
authors.forename: Silvia
authors.initials: S
authors.lastname: Bertagnolio
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Easterbrook
authors.forename: Peter
authors.initials: P
authors.lastname: Mugyenyi
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Paton
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase