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

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.

Use of non-specific intravenous human immunoglobulins in Spanish hospitals; need for a hospital protocol.

UNLABELLED: Intravenous immunoglobulin (IVIG) use in non-approved indications, the increase in consumption and its high cost recommend rationalisation in its utilisation. AIMS: To assess the use of IVIG in Spanish hospitals. METHODS: An observational, prospective and multicentre drug utilisation study was conducted in 13 tertiary Spanish hospitals. Data were collected for 3 months in patients receiving any IVIG. Patient demographics, indication for IVIG use, dosage regimen and cost of treatment were collected. RESULTS: Five hundred and fifty-four patients (mean age of 52 years) were included in the study. A total of 1,287 prescriptions were administered, and the average number of prescriptions per patient was 2.3. The mean daily dose was 24 g (range 0.6-90 g). Overall, IVIG was prescribed for authorised indications in 335 patients (60%) with 953 prescriptions (74%), for non-authorised indications with scientific evidentiary support in 86 patients (16%) with 137 prescriptions (11%), and non-authorised and non-accepted indications in 133 patients (24%) with 197 prescriptions (15%). The most frequent authorised indications were primary and secondary immunodeficiencies, and the most frequent non-authorised and non-accepted indications were multiple sclerosis and bullous dermatosis. The mean cost of IVIG per patient for authorised indications was 2,636.2 , non-authorised indications with scientific support 5,262.1 and non-accepted indications 3,555.8 . CONCLUSIONS: IVIG is prescribed for a significant number of non-authorised and non-accepted indications with a notable cost. There is an important variability in IVIG prescriptions between hospitals, indicating room for improvement in IVIG use and the need for a consensus of protocol use.

Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C.

BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study. HCV-RNA levels decreased by > or =1 log(10) copies/mL in 4 of 8 patients treated with BILN-2061. One patient showed a weak response of <1 log(10) copies/mL. Three of 8 treated patients showed no response. There was no correlation between baseline viral concentration or genotype and response. BILN-2061 exhibited good systemic exposure after oral administration and was well tolerated. In conclusion, the antiviral efficacy of the HCV serine protease inhibitor BILN-2061 is less pronounced and more variable in patients with HCV genotype 2 or 3 infection compared with previous results in patients with HCV genotype 1. A lower affinity of BILN-2061 for the NS3 protease of genotypes 2 and 3 HCV is most likely a major contributor to these findings.