title: Reverse transcriptase genotypes in pediatric patients failing initial antiretroviral therapy in Gaborone, Botswana.
abstract: BACKGROUND
  Limited data are available on patterns of resistance mutations in pediatric patients in southern Africa, where HIV-1 subtype C (HIV-1C) predominates.
  
  
  METHODS
  Retrospective chart review of pediatric patients. Nucleoside reverse transcriptase inhibitor (NRTI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations quantified from population-based sequencing genotypic resistance assay results taken at time of first-line antiretroviral therapy (ART) failure (first-line ART = stavudine [d4T] or zidovudine [ZDV] + lamivudine [3TC] + nevirapine [NVP] or efavirenz [EFV]).
  
  
  RESULTS
  Total number of patients with resistance assays analyzed is 45. Nucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were M184V (n = 41; 91.1%); thymidine analogue mutations (TAMs; n = 20; 44.4%); >1 TAM (n = 9; 20%); TAM-2 pathway (n = 10; 22.2%); TAM-1 pathway (n = 7; 15.6%); TAM-1 and TAM-2 pathways (n = 3; 6.7%); K65R (n = 2; 4.4%); Q151M (n = 1; 2.2%); and L74V (n = 0; 0%). Nonnucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were associated with notable resistance to either/both NVP and EFV (n = 40; 88.9%); K103N (n = 15; 33.3%); ≥1 mutations associated with etravirine (ETR) failure (K101E, Y181C, and G190A; n =20; 44.4%); and ≥2 notable NNRTI mutations (n = 12; 26.7%).
  
  
  CONCLUSIONS
  In this cohort, low-genetic barrier mutations were common, as were TAMs, including more than 1 TAM. Mutations compromising nonthymidine analogue backbones were rare, suggesting that it is likely that children who fail first-line NRTI backbones containing d4T or ZDV/3TC would still respond to abacavir (ABC), didanosine (ddI), and, for adolescents, tenofovir (TDF). Our data support the empiric continuation of 3TC in second-line regimens.
authors.affiliation: 1Botswana-Baylor Children's Clinical Centre of Excellence, Gaborone, Botswana.
authors.forename: Michael
authors.initials: M
authors.lastname: Tolle
authors.forename: Leigh
authors.initials: L
authors.lastname: Howard
authors.forename: Brianna
authors.initials: B
authors.lastname: Kirk
authors.forename: Andres
authors.initials: A
authors.lastname: Gomila
authors.forename: Heidi
authors.initials: H
authors.lastname: Schwarzwald
authors.forename: Gabriel
authors.initials: G
authors.lastname: Anabwani
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use; D001902:Botswana; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D004351:Drug Resistance / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D019829:Nevirapine / Q000627:therapeutic use; D009570:Nitriles; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D018119:Stavudine / Q000627:therapeutic use; D013936:Thymidine / Q000031:analogs & derivatives / Q000235:genetics; D017211:Treatment Failure; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D015215:Zidovudine; D019829:Nevirapine; D018119:Stavudine; D012194:RNA-Directed DNA Polymerase; C098320:efavirenz; D013936:Thymidine