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  • Tenofovir alafenamide TAF National Center

    2018-10-23

    Tenofovir alafenamide (TAF) (National Center for Biotechnology Information, n.d.-b, CID=9,574,768) is a prodrug of TFV that is more stable in plasma, allowing for a ten-fold reduction in dose and resulting in a 91% reduction in azd2171 TFV while achieving a four-fold increase in intracellular levels of TFV-DP (Sax et al., 2015). A single tablet co-formulation of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) demonstrated high efficacy and improved renal and bone safety across multiple populations in Phase 3 trials: treatment-naïve adults and adolescents, and in adults switching from TDF-based regimens with or without chronic kidney disease (Sax et al., 2015; Mills et al., 2011; Pozniak et al., 2016; Gaur et al., 2014). It is approved by the U.S. Food and Drug Administration, 2014 and European Medicines Agency for treatment of naïve and stably suppressed patients age 12 and older and is a recommended initial regimen in U.S. Department of Health and Human Services guidelines (U.S. Department of Health and Human Services, 2015). Here, in this randomized, selected substudy of a treatment naïve adult trial (GS-US-292-0104 [Sax et al., 2015]), we compare the effects of E/C/F/TAF versus E/C/F/TDF, referred to as the TAF and TDF groups, respectively, on biomarkers of systemic (IL-6, hsCRP, sTNFR-I) and vascular (lipoprotein-associated phospholipase A2 [Lp-PLA2]) inflammation, coagulation (D-dimer), and soluble markers of myeloid cell activation (sCD14 and sCD163) from baseline through 48weeks of treatment. In this exploratory analysis, we hypothesized that changes in markers of immune activation would be similar between the groups, as participants in both arms were treated with a potent, integrase-based regimen, and because there were no differences in plasma virologic suppression between the TAF and TDF arms in the parent study. Several potential contributors to chronic immune activation in ART-treated HIV infection have been identified, however, including: microbial translocation and dysbiosis, co-infections, elevations in pro-inflammatory lipid levels, and low level HIV-1 replication in tissue sites that may not be captured by measurement of HIV-1 levels in plasma (Lederman et al., 2013). The differential effects of TDF and TAF on these other drivers of immune activation are also currently not known. As new ART compounds are identified, their effects on indices of immune activation and inflammation that have been linked to morbidity and mortality (Funderburg, 2014; Lederman et al., 2013) will need to be assessed.
    Materials and Methods
    Results Of the 200 participants selected for this substudy, 194 had evaluable samples (TAF: n=98; TDF: n=96). Baseline demographic and clinical information is provided in Table 1. Median baseline age, CD4+ cell count, and viral load for the subpopulation were similar to those for the parent study. A total of 19% (37 of 194 participants) were women, 44% (85 of 194) were non-white, and 28% (55 of 194) were smokers; the median age was 33years. The only significant differences between groups were in body mass index (median, TAF: 24kg per m2, TDF: 25kg per m2; p=0.043) and percentage of smokers (TAF: 35% [34 of 98], TDF: 22% [21 of 96]; p=0.043). Participants had a median CD4+ cell count of 405 cells per μL and a median level of viremia of 4.7 log10 copies per mL; 25% had viral load >100,000 copies per mL. Mean increases in CD4 cell counts were similar between groups at week 48 (TAF: 240 cells per μL, TDF: 238 cells per μL; p=0.98). Consistent with the parent study, we found similar declines in viremia between arms. A greater proportion of those receiving the TAF-containing regimen had undetectable viremia (<50 copies per mL of HIV-1 RNA, Missing=Failure Analysis) at week 2 compared with those receiving TDF (34% [33 of 98] versus 23% [22 of 96]; p=0.046), but this difference was not maintained through 48weeks. From week 16 through week 48, >95% of participants in both arms had undetectable levels of HIV-1. There were increases from baseline at week 48 in total cholesterol (TC) (TAF: 20mg per dL; TDF: 12mg per dL; p=0.004), low density lipoprotein (LDL) (TAF: 12mg per dL; TDF: 3mg per dL; p=0.006), high density lipoprotein (HDL) (TAF: 5mg per dL; TDF: 3mg per dL; p=0.045), TC:HDL ratio (TAF: 0.1, TDF: 0.2; p=0.97), and triglycerides (TAF: 16mg per dL, TDF: 10mg per dL; p=0.90) (Fig. 1).