Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers

Abstract

Context Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL). Methods Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/ 400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point. Results Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject.

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging

“…Furthermore, given the overwhelming use of combined therapy, it is difficult to critically assess the differential roles of ART regimens. This review highlights various mechanisms by which both HIV-encoded proteins and ART treatments damage critical mitochondrial functions; however, a multitude of other mechanisms have been studied but are not mentioned here for brevity [ 14 , 68 , 69 , 85 , 107 ].…”

“…Understanding the unique processes by which HIV-infection in combination with ART leads to mitochondrial dysfunction may allow for the development of improved therapeutics and quality of life for PLHIV. Considering the prevalence of the inclusion of NRTIs, NNRTIs, PIs, and INSTIs, as well as the evidence supporting increased adverse effects of these drugs compared to fusion inhibitors and coreceptor agonists, for the purposes of this review we hereafter focus on mitochondrial toxicity associated with NRTIs, NNRTIs, PIs, and INSTIs [ 107 , 108 ]. These results, along with mitochondrial deregulation by all ART classes, are summarized in Table 1 .…”

3TC-DTG Dual Therapy and Its Implications in Hepatic Steatosis in People Living With HIV

“…In our cohort, patients on a 2-drug regimen with 3TC-DTG show a lower rate of hepatic steatosis compared with those on other ARV regimens. The good tolerability of this strategy has already been described, with various real-life studies highlighting the favorable effects on total cholesterol and tryglicerides even in the short-term [22][23][24], The class of Integrase Inhibitors has shown since its introduction an overall better tolerability compared with boosted-Pis and NNRTIs [25,26] and this reflects also on mitochondrial toxicity and fasten lipids profile [27]. Most recent guidelines [28] have become aware of the importance of ARV regimens in preventing NAFLD and suggest the use of lipid-neutral ARV regimens in patients at risk of developing NAFLD.…”

Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients

“…Likewise, we are aware that assessing specific PBMC composition would be of interest to assess potential interference of cell populations in observed findings, as well as preventing platelet contamination (Tin et al, 2016;Sun et al, 2018). However, we should take into consideration that PBMCs have been demonstrated to be a reliable and non-invasive model to perform mitochondrial studies and that is the present gold standard for mitochondrial toxicity evaluation (Garrabou et al, 2009;Moren et al, 2015;Barroso et al, 2019). Additionally, the potential follow-up of patients for an extended period of time over PEP administration and additional measures for evaluation of mitochondrial toxicity or specific cell toxicity profiling may be of interest for further approaches.…”

“…For mtDNA quantification, a fragment of the mitochondrial conserved gene mt12SrRNA and the nuclear constitutive gene nRNAseP were amplified simultaneously and in duplicate by multiplex quantitative Real-Time PCR. We used Applied Biosystems technology (CA, USA) in a 96-well plate and results were expressed in relative units as the ratio between mtDNA to nuclear DNA (mt12SrRNA/nRNaseP), as previously validated (Côté et al, 2011) and reported by our group (Moren et al, 2015;Catalán-García et al, 2016;Barroso et al, 2019) and other groups FIGURE 1 | Non significant differences in mtDNA content were observed within each therapeutic group intervention (before and after each treatment), but significant differences were found between the different PEP regimens (PI plus AZT + 3TC vs. PI plus TDF + FTC). Results were expressed as the ratio of mitochondrial 12SrRNA gene with respect to the constitutive nuclear RNAseP gene.…”