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Tenofovir resistance in early and long-term treated patients on first-line antiretroviral therapy in eight low- and middle-income countries.

OBJECTIVE
We aimed to assess the frequency of tenofovir (TDF) resistance in people failing tenofovir /lamivudine or emtricitabine (XTC)/ non-nucleotide reverse-transcriptase inhibitor (NNRTI)-based first-line ART using data from fifteen nationally representative surveys of HIV drug resistance (HIVDR) conducted between 2014-2018 in Cameroon, Guatemala, Honduras, Nicaragua, Senegal, Uganda, Vietnam and Zambia.


METHODS
Prevalence of NRTI resistance among participants with virological non-suppression (viral load ≥1000 copies/ml) who had received TDF-based ART for 12-24 months (early ART group) and ≥ 40 months (long-term ART group) was assessed using Sanger sequencing and resistance was interpreted using the Stanford HIVdb algorithm. For each group, we estimated a pooled prevalence using random effect meta-analysis.


RESULTS
Of 4 677 participants enrolled in the surveys, 640 (13.7%) had virological non-suppression, 431 (67.3%) were successfully genotyped and were included in the analysis; of those, 60.3% (260) were participants in the early ART group. Overall, 39.1%, 57.9%, 38.5%, and 3.6% patients in the early ART group and 42.9%, 69.3%, 42.9%, and 10.0% patients on long-term ART had resistance to TDF, XTC, TDF+XTC, and TDF+XTC+zidovudine, respectively. Overall, tenofovir resistance was mainly due to K65R or K70E/G/N/A/S/T /Y115F mutations (79%) but also due to thymidine analogue mutations (21%) which arise from exposure to thymidine analogues but causing cross-resistance to TDF.


CONCLUSIONS
Dual resistance to TDF+XTC occurred in more than 40% of the people with viral non-suppression receiving tenofovir-based first-line ART, supporting WHO recommendation to optimize the nucleoside backbone in second-line treatment and cautioning against single drug substitutions in people with unsuppressed VL.