Tenofovir diphosphate levels in dried blood spots are associated with virologic failure and resistance to first‐line therapy in South Africa: a case–control cohort study

Abstract

Introduction:Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), a measure of cumulative antiretroviral therapy (ART) adherence, is associated with viral suppression and predicts future viremia in persons with HIV (PWH). However, its utility to identify those at risk for virologic failure (VF) and drug resistance is unknown. To address this, we aimed to establish the association between this adherence biomarker and VF with drug resistance in a cohort of PWH initiating first-line ART in KwaZulu-Natal, South Africa. Methods: PWH initiating TFV disoproxil fumarate (TDF)-based ART within a parent prospective cohort were evaluated. Using a nested design, DBS for TFV-DP were collected from cases who developed VF (HIV-1 RNA ≥1000 copies/ml) after ≥5 months on ART versus controls, matched 1:2 by site, age, gender, race and ART duration. Cases were categorized as having VF with or without resistance using genotyping. One-way analysis of variance (ANOVA) was used to compare TFV-DP for controls, cases with VF and resistance, and cases with VF without resistance. Data are presented as mean (standard deviation, SD) or geometric mean [95% confidence interval, 95% CI]. Results and discussion: One thousand participants were enrolled in the parent study between 2014 and 2016, of which 288 (29%) had DBS available. Of these, 94 (33%) were cases and 194 (67%) were controls; 59% were women. Mean age of our population was 33 (SD 8) years. Genotyping was available in 50 (53%) of the 94 cases. Geometric mean TFV-DP in DBS from controls was 708 [95% CI; 647-773] fmol/punch, which was higher compared to participants having VF with resistance (n = 36), 386 [95% CI; 241-617] fmol/punch and VF without resistance (n = 14), 61 [95% CI; 22-164] fmol/punch; p<0.001. Genotype could not be obtained in 44 (47%) cases. Conclusions: TFV-DP in DBS showed a stepwise association with VF and drug resistance in South African PWH. Participants having VF with resistance had mid-range concentrations of TFV-DP, which were higher than those for PWH without resistance. Future research on the clinical utility of TFV-DP concentrations in DBS to predict and prevent the development of VF and drug resistance is needed.

Tenofovir diphosphate in dried blood spots predicts future viremia in persons with HIV taking antiretroviral therapy in South Africa

“…In this study, we established the range for TFV-DP concentrations in DBS among a South African population on TDF-based ART associated with sustained viral suppression, and identified a threshold concentration strongly predictive of future viral breakthrough. Although the median TFV-DP concentration in DBS (1041 fmol/ punch) was higher than has been found in other South African studies [9,11,16,22], it was still lower in this population than in US PWH (median 1874 fmol/punch) [8]. This difference could be because of biologic differences in study populations, timing of sampling in relation to ART start, use of generic TDF, use of and/or unboosted ART regimens.…”

Cumulative tenofovir diphosphate exposure in persons with HIV taking single‐ vs. multiple‐tablet regimens

“…Our results are consistent with multiple previous studies that have observed higher ART adherence in PWH taking STR versus MTR 15–17,19–21 and extend these findings using an objective biomarker of cumulative adherence and exposure that has been associated with clinically relevant outcomes 26,28,39,40 . In particular, we investigated whether the higher adherence observed in STR is consistent based on the type of anchor drug used and observed that it did not differ between u/STR and u/MTR in our study population.…”

Point-of-care urine tenofovir testing to predict HIV drug resistance among individuals with virologic failure

“…In addition, a study evaluating detectable plasma protease inhibitor levels, measured by LC-MS/MS, revealed high sensitivity and high NPV for detectable ART levels to predict resistance in a sample with a lower prevalence of HIVDR (27%) [18]. Another study found that intermediate levels of tenofovir-diphosphate (TFV-DP) in dried blood spots, a longer-term measure of adherence, were associated with HIVDR in participants with viremia, as compared to lower levels of TFV-DP for those without HIVDR [19]. These findings are consistent with ours, which suggest that an objective metric of adherence has high PPV for HIVDR in settings with high HIVDR prevalence.…”