In the past, liver cirrhosis was considered an irreversible phenomenon. However, many experimental data have provided evidence of the reversibility of liver fibrosis. Moreover, multiple clinical studies have also shown regression of fibrosis and reversal of cirrhosis on repeated biopsy samples. As various etiologies are associated with liver fibrosis via integrated signaling pathways, a comprehensive understanding of the pathobiology of hepatic fibrogenesis is critical for improving clinical outcomes. Hepatic stellate cells play a central role in hepatic fibrogenesis upon their activation from a quiescent state. Collagen and other extracellular material components from activated hepatic stellate cells are deposited on, and damage, the liver parenchyma and vascular structures. Hence, inactivation of hepatic stellate cells can lead to enhancement of fibrolytic activity and could be a potential target of antifibrotic therapy. In this regard, continued efforts have been made to develop better treatments for underlying liver diseases and antifibrotic agents in multiple clinical and therapeutic trials; the best results may be expected with the integration of such evidence. In this article, we present the underlying mechanisms of fibrosis, current experimental and clinical evidence of the reversibility of liver fibrosis/cirrhosis, and new agents with therapeutic potential for liver fibrosis.

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78–1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555

The most widely used method for diagnosing sarcopenia is the skeletal muscle index (SMI). Several studies have suggested that psoas muscle thickness per height (PMTH) is also effective for detecting sarcopenia and predicting prognosis in patients with cirrhosis. The aim of this study was to evaluate the optimal cutoff values of PMTH for detecting sarcopenia in cirrhotic patients. All cirrhotic patients who underwent abdominal computed tomography (CT) scan including L3 and umbilical levels for measuring SMI and transverse psoas muscle thickness, respectively, were included. Two definitions of sarcopenia were used: (1) sex-specific cutoffs of SMI (≤52.4 cm2 /m2 in men and ≤38.5 cm2 /m2 in women) for SMI-sarcopenia and (2) cutoff of PMTH (<16.8 mm/m) for PMTH-sarcopenia. Six hundred fifty-three patients were included. The average age was 53.6 ± 10.2 years, and 499 patients (76.4%) were men. PMTH correlated well with SMI in both men and women (P<0.001). Two hundred forty-one (36.9%) patients met the criteria for SMI-sarcopenia. The best PMTH cutoff values for predicting SMI-sarcopenia were 17.3 mm/m in men and 10.4 mm/m in women, and these were defined as sex-specific cutoffs of PMTH (SsPMTH). The previously published cutoff of PMTH was defined as sex-nonspecific cutoff of PMTH (SnPMTH). Two hundred thirty (35.2%) patients were diagnosed with SsPMTH-sarcopenia, and 280 (44.4%) patients were diagnosed with SnPMTH-sarcopenia. On a multivariate Cox regression analysis, SsPMTH-sarcopenia (hazard ratio [HR], 1.944; 95% confidence interval [CI], 1.144-3.304; P=0.014) was significantly associated with mortality, while SnPMTH-sarcopenia was not (HR, 1.446; 95% CI, 0.861-2.431; P=0.164). PMTH was well correlated with SMI in cirrhotic patients. SsPMTH-sarcopenia was an independent predictor of mortality in these patients and more accurately predicted mortality compared to SnPMTH-sarcopenia.

Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.

Chae HB, et al. Korean J Hepatol. 2009 Dec;15(Suppl 6):S13-S24. http://dx.doi.org/10.3350/kjhep.2009.15.S6.S13

Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (<LLOQ) in a subset of patients. The B-Together study investigated if sequential bepirovirsen and pegylated interferon-α-2a (Peg-IFN) therapy can reduce relapse rates and improve response rates. In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA <LLOQ for 24 weeks after planned end of Peg-IFN treatment, in the absence of newly initiated antiviral therapy. The intent-to-treat population included 108 participants (Arm 1, n = 55; Arm 2, n = 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms. Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse. This phase IIb study investigated whether sequential therapy with bepirovirsen followed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens. NCT04676724.