title: High prevalence of the K65R mutation in HIV-1 subtype C infected patients failing tenofovir-based first-line regimens in South Africa.
abstract: BACKGROUND
  Tenofovir (TDF) has replaced stavudine (d4T) as the preferred nucleoside reverse transcriptase inhibitor (NRTI) in first-line regimens in South Africa, but limited information is available on the resistance patterns that develop after the introduction of TDF. This study investigated the antiretroviral drug resistance patterns in South African HIV-1 subtype C-infected patients failing stavudine- (d4T) and tenofovir- (TDF) based first-line regimens and assess the suitability of TDF as the preferred first-line nucleotide reverse transcriptase inhibitor (NRTI).
  
  
  METHODS
  Resistance patterns of HIV-1 from 160 adult patients virologically failing TDF- (n = 80) and d4T- (n = 80) based first-line regimens were retrospectively analyzed. The pol gene was sequenced using an in-house protocol and mutations were analysed using the IAS-USA 2014 Drug Resistance Mutation list.
  
  
  RESULTS
  Compared to d4T-exposed patients (n = 7), patients failing on a TDF-containing regimen (n = 43) were almost 5 times more likely to present with a K65R mutation (aRR 4.86 95% CI 2.29 - 10.34). Y115F was absent in the d4T group, and detected in 13.8% (n = 11) of TDF-exposed patients, p = 0.0007. Virus from 9 of the 11 patients (82.0%) who developed the Y115F mutation also developed K65R. Intermediate or high-level resistance to most NRTIs was common in the TDF-treatment group, but these patients twice more likely to remain susceptible to AZT as compared to those exposed to d4T (aRR 2.09 95% CI 1.13 - 3.90).
  
  
  CONCLUSIONS
  The frequency of the TDF induced K65R mutation was higher in our setting compared to non-subtype C dominated countries. However, despite the higher frequency of cross-resistance to NRTIs, most patients remained susceptible to AZT, which is reflected in the South African treatment guidelines that recommend AZT as an essential component of second-line regimens.
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Lindiwe
authors: L
authors: Skhosana
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Kim
authors: K
authors: Steegen
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Michelle
authors: M
authors: Bronze
authors: National Health Laboratory Services, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa.
authors: Azwidowi
authors: A
authors: Lukhwareni
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Esrom
authors: E
authors: Letsoalo
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Maria A
authors: MA
authors: Papathanasopoulos
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa.
authors: Sergio C
authors: SC
authors: Carmona
authors: Department of Haematology and Molecular Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa.
authors: Wendy S
authors: WS
authors: Stevens
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D015995:Prevalence; D013019:South Africa / Q000453:epidemiology; D000068698:Tenofovir; D019562:Viral Load; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine