Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa.
Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting.



A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics).



At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P  =   0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P  =   0.18).



Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring.
MRC CTU at UCL, London, UK.
Ruth L
RL
Goodall
MRC CTU at UCL, London, UK.
David T
DT
Dunn
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
Peter
P
Nkurunziza
Joint Clinical Research Centre, Kampala, Uganda.
Lincoln
L
Mugarura
Janssen Diagnostics, a division of Janssen Pharmaceuticals NV, Beerse, Belgium.
Theresa
T
Pattery
Joint Clinical Research Centre, Kampala, Uganda.
Paula
P
Munderi
Joint Clinical Research Centre, Kampala, Uganda.
Cissy
C
Kityo
School of Population Health, University of Queensland, Brisbane, Australia.
Charles
C
Gilks
Joint Clinical Research Centre, Kampala, Uganda.
Pontiano
P
Kaleebu
Africa Health Research Institute, KwaZulu Natal, South Africa.|Division of Infection and Immunity, University College London, London, UK.
Deenan
D
Pillay
Africa Health Research Institute, KwaZulu Natal, South Africa.|Division of Infection and Immunity, University College London, London, UK.
Ravindra K
RK
Gupta
D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D015224:Dideoxynucleosides / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D019829:Nevirapine / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000235:genetics; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects / Q000379:methods; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use*; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D019259:Lamivudine; D019829:Nevirapine; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D013936:Thymidine; D015215:Zidovudine; D000099227:Abacavir