Based on the less than expected changes in sCD and

Based on the less than expected changes in sCD14 and Lp-PLA2 in both arms, in spite of virologic control, we wanted to investigate changes in lipid levels as a potential contributor to immune activation in this study. At weeks 24 and 48, there were small, statistically significant differences in increases in total cholesterol, LDL cholesterol, and HDL cholesterol for participants receiving TAF compared with those receiving TDF, but no difference in the TC:HDL ratio, which is associated with cardiovascular risk (Deeks et al., 2013; Wilson et al., 1998; D\'Agostino et al., 2008; Goff et al., 2014). These findings are consistent with what has been seen in other TAF vs TDF studies (Sax et al., 2015; Mills et al., 2015; Wohl et al., 2016) and are thought to be due to greater plasma TFV concentrations with TDF (Wohl et al., 2016; Tungsiripat et al., 2010; Santos et al., 2015; Mulligan et al., 2013; Behrens et al., 2012; Patel et al., 2014). Traditional lipid panels may underestimate cardiovascular risk in HIV-infected individuals, (Munger et al., 2015) and there is growing appreciation that pro-inflammatory gpr120 agonist may contribute to immune activation in persons infected with HIV, including oxidized LDL, as levels of oxidized LDL have been associated with levels of sCD14 in this population (Zidar et al., 2015; Hileman et al., 2016; Nou et al., 2016). The basic lipid assessment performed in this substudy may not be sufficient to entirely capture changes in pro-inflammatory lipid subspecies and their contribution to persistent immune activation. In addition to the lack of change in the TC: HDL ratio, it is also reassuring, however, that there were no differences between the TAF arm and the TDF arm in Lp-PLA2 or hsCRP, indicating that the modest increases in lipid levels in the TAF arm are likely not associated with increased cardiovascular risk. Limitations of the present analysis include that it was a post-hoc substudy and may not have been appropriately powered to be able to see differences between arms, and that we did not adjust for multiple comparisons conducted. Another potential limitation of this study is the lack of single copy assay measurement of viral replication or measurement of HIV-1 replication in the tissues. Based on the higher intracellular concentrations of TFV associated with TAF, a more sensitive assay may have identified a differential decline in viral replication between the two arms; however, as both TAF and TDF were given with the highly effective boosted integrase regimens, it may not be possible to have seen this effect, even with a more sensitive assay. Indeed, when using an HIV-1 RNA lower limit of detection of <20 copies/mL at Week 48, no differences in the rate of viral suppression was seen between the two treatment arms (Sax et al., 2015). Also, as there are likely several contributors of immune activation and inflammation in ART-treated HIV infection, the plasma based assays we used to measure changes in immune activation indices may not be sensitive enough to detect subtle changes associated with modulation of any of these potential drivers of activation, including viral replication on single cell level. We report that after initiation of ART, regimens containing either TAF or TDF have equivalent reductions in markers of immune activation and inflammation in persons living with HIV. This is a key finding, as HIV-infected individuals are living longer, experiencing a greater cumulative exposure to ART, and are at a greater risk for treatment-associated toxicities. Treatment with a TAF-based therapy, compared to one containing TDF, has been associated with smaller declines in bone mineral density and decreased renal toxicity (Sax et al., 2015).
Conclusions
Funding Sources
Conflicts of Interests
Author Contributors
Acknowledgements
Introduction Staphylococcus aureus (S. aureus) causes a number of opportunistic infections that range from relatively benign skin infections to life-threatening diseases including endocarditis, pneumonia and sepsis (Kristinsson, 1989; Lowy, 1998). Clumping factor A (ClfA) is a fibrinogen (Fg) binding microbial surface component recognizing adhesive matrix molecules (MSCRAMM), and an important virulence factor of S. aureus. ClfA plays a role in the molecular pathogenesis of several types of experimental infections such as septic arthritis, infective endocarditis, kidney abscesses and sepsis/septicemia (Flick et al., 2013; Josefsson et al., 2001; McAdow et al., 2011; Sullam et al., 1996). Furthermore ClfA is important for S. aureus colonization of biomaterials, which presumably becomes coated with plasma proteins such as Fg once implanted (Vaudaux et al., 1995). ClfA binds to the carboxy terminal of the γ-chain of Fg (McDevitt et al., 1995; McDevitt et al., 1997), a region that is important for platelet aggregation and coagulation (Heemskerk et al., 2002; Jackson, 2007; Kamath et al., 2001) and recombinant ClfA has been reported to inhibit the interaction of Fg with the platelet integrin αIIbβ3 (Liu et al., 2007; Liu et al., 2005). However, the virulence potential of ClfA in a mouse model of septicemia does not appear to correlate with altered platelet aggregation or Fg coagulation but rather seems to be a function of impaired bacterial clearance (Flick et al., 2013). In fact ClfA can protect S. aureus against phagocytosis by macrophages (Palmqvist et al., 2004) and it appears that Fg binding to the MSCRAMM is required for the ClfA mediated inhibition of phagocytosis (Higgins et al., 2006). In addition, ClfA has been reported to bind complement factor I. This interaction may also play a role in ClfA dependent resistance to bacterial clearance (Hair et al., 2010; Hair et al., 2008).