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.

Conclusions: In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.

Fig 1

A: Flow diagram of enfuvirtide crossover. From a total of 12 healthy volunteers; 50% were randomized to placebo/enfuviride sequence. B: Flow diagram of raltegravir crossover. From a total of 14 healthy volunteers; 50% were randomized to placebo/raltegravir sequence. Blood samples (upper arrows) were obtained before (PRE) and after (POST) both phases. Each phase was 1 week long, separated from each other by a washout period of four weeks. Volunteers started with phase 1 trial (placebo/treatment) followed by a washout period and posterior phase 2 (treatment/placebo, according to the first made intervention).

Fig 2. Percentage of change between final and baseline measurements for enfuvirtide (T20) and placebo interventions.

Significance was assessed through a Wilcoxon test. Variation is represented with error bars through the SEM value. No significant change was detected after T20 treatment.

Fig 3. Percentage of change between final and baseline measurements for raltegravir (RAL) and placebo interventions.

Significance was assessed through a Wilcoxon test. Variation is represented with error bars through the SEM value. No significant change was detected after T20 treatment.