Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study

Abstract

SummaryBackgroundHIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART.MethodsWe retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs.FindingsOf 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL [IQR 21·0–128·0] in patients with TAMS vs 95·0 cells per μL [37·0–177·0] in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0·0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13–1·47; p<0·0001)InterpretationTAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains.

Lack of effectiveness of adherence counselling in reversing virological failure among patients on long‐term antiretroviral therapy in rural Uganda

“…We also noted a very high prevalence of TAMs, with 65% of those with virological failure having at least one TAM and 50% having two or more TAMs; similar prevalences have been reported in other studies for patients receiving regimens containing stavudine, zidovudine, lamivudine, efavirenz and nevirapine [22][23][24]. However, a lower prevalence of TAMs of between 5 and 25% has been reported in a retrospective multicentre cohort study in sub-Saharan Africa among patients using tenofovir [25]. As many second-line regimens in sub-Saharan Africa will by necessity include didanosine and abacavir, which can have reduced effectiveness in the presence of increasing numbers of TAMs [26], these are probably the most concerning mutation patterns we found.…”

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

“…There is also 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, therefore, 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 HIV is a priority, understanding the accumulation and phenotypic impact of TAMs remains important.…”

Expansion of Viral Load Testing and the Potential Impact on Human Immunodeficiency Virus Drug Resistance

“…Other factors contributing to the selection and transmission of HIVDR include treatment interruptions secondary to poor adherence, interruption of ARV commodities supply, drug–drug interactions, and delayed switching to second-line ART in the setting of VF [19]. Viral load suppression (VLS) confirmation may prevent DRM development and trigger enhanced adherence counseling and subsequent switch to a second-line protease inhibitor–based regimen [20, 21]. …”