The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log₁₀ IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome. The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.)

Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease. The incidence of HCV-related cirrhosis and its complications is expected to increase in upcoming years.^1,2 Davis et al² estimated that currently 25% of the approximately 3.5 million US patients with chronic HCV infection have cirrhosis and that the proportion of patients with cirrhosis is likely to increase up to 45% by 2030.

Objective: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus. Methods: In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma. Results: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii , Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase. Conclusion: Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease globally and is currently estimated to affect 38% of the global population. Only a minority of patients with NAFLD will progress to cirrhosis or hepatocellular carcinoma, but from this vast population the total number of patients who are at risk of such severe outcomes is increasing. Worryingly, individuals are increasingly being affected by NAFLD at an earlier age, meaning there is more time for them to develop severe complications. With considerable changes in dietary composition and urbanisation, alongside the growth in obesity and type 2 diabetes in the global population, in particular in developing countries, the global proportion of persons affected by NAFLD is projected to increase further. Yet, there are large geographical discrepancies in the prevalence rates of NAFLD and its inflammatory component non-alcoholic steatohepatitis (NASH). Such differences are partly related to differing socio-economic milieus, but also to genetic predisposition. In this narrative review, we discuss recent changes in the epidemiology of NAFLD and NASH from regional and global perspectives, as well as in special populations. We also discuss the potential consequences of these changes on hepatic and extrahepatic events.