Correction: Direct antiviral agents for hepatitis C and drug interaction risk: A retrospective cohort study with real and simulated data on medication interaction, prevalence of comorbidities and comedications.

[This corrects the article DOI: 10.1371/journal.pone.0245767.].

Direct antiviral agents for hepatitis C and drug interaction risk: A retrospective cohort study with real and simulated data on medication interaction, prevalence of comorbidities and comedications.

INTRODUCTION AND AIM: Comorbidities and comedication are common in patients with hepatitis C, which could result in a risk of drug-drug interaction. The objective of this study was to evaluate the prevalence of comorbidities, comedication and drug-drug interactions involving direct-acting antivirals in this population. METHODS: Comorbidities and comedications were evaluated in a retrospective cohort of hepatitis C patients. Drug-drug interactions were estimated in real life and with simulated data on comedications following drug regimens: telaprevir; elbasvir/grazoprevir, ombitasvir/paritaprevir/r/ritonavir (2D regimen), and sofosbuvir/simeprevir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir; 2D/dasabuvir (3D regimen); glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir. The interactions were evaluated according to the University of Liverpool database. Statistical analysis was performed by SPSS® 18.0. RESULTS: Data from 1433 patients with hepatitis C were evaluated. The mean patient age was 51.7 years (SD ± 10.7), and 50.6% were female. Direct-acting antivirals were prescribed for 345 (24.1%) patients, and a sustained virological response occurred in 264 (76.5%). The main comorbidities were systemic arterial hypertension [436 (30.4%)], diabetes mellitus [352 (24.6%)] and depression [130 (9.1%)]. The mean number of comorbidities was 1.52 (median [IQR] of 1.00 [1.00-2.00]). The mean number of comedications was 3.16 (median [IQR] of 3.00 [1.00-5.00]). A total of 12916 drug-drug interactions were found, of which 1.859 (14.4%) were high risk, with a mean of 1.29 ± 3.13 per patient. The 3D regimen, as well as glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir, presented the highest drug-drug interaction indexes. CONCLUSION: Comorbidities and comedications are common in patients with hepatitis C, as are drug-drug interactions. Even when second generation drugs are used, the occurrence of drug-drug interactions still presents a significant risk.

Gut Dysbiosis and Increased Intestinal Permeability Drive microRNAs, NLRP-3 Inflammasome and Liver Fibrosis in a Nutritional Model of Non-Alcoholic Steatohepatitis in Adult Male Sprague Dawley Rats.

BACKGROUND/AIM: The interactions between the gut and liver have been described in the progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to develop an experimental nutritional model of NASH simulating metabolic changes occurring in humans. MATERIALS AND METHODS: Adult male Sprague Dawley rats were randomized into two groups: controls (standard diet) and intervention (high-fat and choline-deficient diet) for 16 weeks, each experimental group with 10 animals. Biochemical analysis, hepatic lipid content, microRNAs, inflammatory, gut permeability markers and gut microbiota were measured. RESULTS: Animals in the intervention group showed significantly higher delta Lee index (p=0.017), abdominal circumference (p<0.001), abdominal adipose tissue (p<0.001) and fresh liver weight (p<0.001), as well as higher serum levels of alanine aminotransferase (p=0.010), glucose (p=0.013), total cholesterol (p=0.033), LDL cholesterol (p=0.011), and triglycerides (p=0.011), and lower HDL cholesterol (p=0.006) compared to the control group. Higher TLR4 (p=0.041), TLR9 (p=0.033), MyD88 (p=0.001), Casp1 (p<0.001), NLPR3 (p=0.019), liver inflammation index interleukin (IL)-1ß/IL10 (p<0.001), IL6/IL10 (p=0.002) and TNFα/IL10 (p=0.001) were observed in the intervention group, and also lower permeability markers Ocln (p=0.003) and F11r (p=0.041). Gene expression of miR-122 increased (p=0.041) and miR-145 (p=0.010) decreased in the intervention group. Liver steatosis, inflammation and fibrosis, along with collagen fiber deposition increment (p<0.001), were seen in the intervention group. Regarding gut microbiota, Bray-Curtis dissimilarity index and number of operational taxonomic units were significantly different (p<0.001) between the groups. Composition of the gut microbiota showed a significant correlation with histopathological score of NAFLD (r=0.694) and index IL-1ß/IL-10 (r=0.522). CONCLUSION: This experimental model mimicking human NASH demonstrated gut and liver interaction, with gut microbiota and intestinal permeability changes occurring in parallel with systemic and liver inflammation, miRNAs regulation and liver tissue damage.