title: From antiretroviral therapy access to provision of third line regimens: evidence of HIV Drug resistance mutations to first and second line regimens among Ugandan adults.
abstract: BACKGROUND
  HIV care programs in resource-limited settings have hitherto concentrated on antiretroviral therapy (ART) access, but HIV drug resistance is emerging. In a cross-sectional study of HIV-positive adults on ART for ≥6 months enrolled into a prospective cohort in Uganda, plasma HIV RNA was measured and genotyped if ≥1000 copies/ml. Identified Drug resistance mutations (DRMs) were interpreted using the Stanford database, 2009 WHO list of DRMs and the IAS 2014 update on DRMs, and examined and tabulated by ART drug classes.
  
  
  RESULTS
  Between July 2013 and August 2014, 953 individuals were enrolled, 119 (12.5%) had HIV-RNA ≥1000 copies/ml and 110 were successfully genotyped; 74 (67.3%) were on first-line and 36 (32.7%) on second-line ART regimens. The predominant HIV-1 subtypes were D (34.5%), A (33.6%) and Recombinant forms (21.8%). The commonest clinically significant major resistance mutations associated with the highest levels of reduced susceptibility or virological response to the relevant Nucleoside Reverse Transcriptase Inhibitor (NRTI) were; the Non-thymidine analogue mutations (Non-TAMS) M184V-20.7% and K65R-8.0%; and the TAMs M41L and K70R (both 8.0%). The major Non-NRTI (NNRTI) mutations were K103N-19.0%, G190A-7.0% and Y181C-6.0%. A relatively nonpolymorphic accessory mutation A98G-12.0% was also common. Seven of the 36 patients on second line ART had major Protease Inhibitor (PI) associated DRMS including; V82A-7.0%, I54V, M46I and L33I (all 5.0%). Also common were the accessory PI mutations L10I-27%, L10V-12.0% and L10F-5.0% that either reduce PI susceptibility or increase the replication of viruses containing PI-resistance mutations. Of the 7 patients with major PI DRMs, five had high level resistance to ritonavir boosted Lopinavir and Atazanavir, with Darunavir as the only susceptible PI tested.
  
  
  CONCLUSIONS
  In resource-limited settings, HIV care programs that have previously concentrated on ART access, should now consider availing access to routine HIV viral load monitoring, targeted HIV drug resistance testing and availability of third-line ART regimens.
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Ivan
authors.initials: I
authors.lastname: Namakoola
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.|MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kasamba
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda. billy.mayanja@mrcuganda.org.
authors.forename: Billy N
authors.initials: BN
authors.lastname: Mayanja
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kazooba
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lutaakome
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Fred
authors.initials: F
authors.lastname: Lyagoba
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Kapaata
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.|Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Pontiano
authors.initials: P
authors.lastname: Kaleebu
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Paula
authors.initials: P
authors.lastname: Munderi
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D000069454:Darunavir / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D014454:Uganda; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D000069454:Darunavir
keywords: Antiretroviral therapy; Drug resistance; Mutations; Third-line regimen