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.

Ruth L Goodall,On Behalf Of The Dart Virology Group ,Paula Munderi,Pontiano Kaleebu,Lincoln Mugarura,David T Dunn,Cissy Kityo,Ravindra K Gupta,Deenan Pillay,Charles Gilks,Peter Nkurunziza,Theresa Pattery

doi:10.1093/jac/dkw583

Ruth L Goodall, On Behalf Of The Dart Virology Group + Show 10 more

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https://doi.org/10.1093/jac/dkw583

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Background: 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. Patients and methods: 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). Results: 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). Conclusions: 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.

Highlights

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

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Introduction

Virological failure occurs in 15%–35% of patients treated with thymidine analogue-containing first-line cART within the first year, with the majority harbouring resistance to NNRTI and lamivudine in areas without access to viral load monitoring.[4,5] As tenofovir becomes available, increasing numbers of individuals are substituting thymidine analogues for tenofovir without documented viral suppression at switch, carrying risk for acquisition of drug resistance.[4,5]. There is evidence pointing to prior undisclosed thymidine analogue-containing ART in patients presenting for first-line tenofovir-based ART in sub-Saharan Africa.[6,7] Unsurprisingly, thymidine analogue mutations (TAMs) have been reported in patients following viral failure of tenofovir-containing first-line regimens,[8] contributing to multidrug resistance in these individuals.[9] As limitation of emergence and transmission of MDR. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as firstline ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting

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