Hepatology highlights
Authors: Jean‐François Dufour
Journal: Hepatology (2015)

The goal of chronic hepatitis C (CHC) therapy is to reduce mortality and morbidity, which is understood to be achievable if the virus is successfully cleared. Now that CHC can be cured, it is time to look beyond sustained viral response (SVR), which acts as a surrogate marker. Innes et al. investigated hard endpoints in a Scottish cohort of more than 3,300 patients treated for CHC. As expected, SVR was associated with reduced risk of liver-related mortality and the benefit was greater in patients with more advanced stage of CHC. Much more intriguing, was the reduction in non-liver-related mortality, reduction in cardiovascular disease, and reduction in violence-related injury with successful treatment. These results clearly suggest extrahepatic benefits of eradicating hepatitis C virus (HCV), some somatic, some behavioral. (Hepatology 2015;62:355-364) The life cycle of HCV has been studied in great detail. Less is known about the life cycle of hepatitis A virus (HAV) from a therapeutic perspective, even if identified many years earlier. There are good reasons for this: In contrast to HCV, there is a vaccine against HAV and hepatitis A never becomes chronic. Nevertheless, Esser-Nobis et al. compared HAV and HCV in a cell line that supports their replication with comparable efficiency. Both viruses were sensitive to interferon. Both replicons were even able to replicate in the same cell, suggesting limited competition. Indeed, HAV replication was independent of microRNA-122 and phosphatidylinositol 4-kinase III. In terms of treatment, HAV replication was sensitive to NIM811, a nonimmunosuppressive cyclosporine analog, and to silibinin. The knowhow developed over the years to study HCV will certainly benefit other hepatitis viruses. (Hepatology 2015;62:397-408) Cancer patients receiving chemotherapy should be protected against acute exacerbation of chronic hepatitis B infection with adequate prophylaxis. The rate of adequate prophylaxis should be 100% and the rate of exacerbation 0%. Reaching such extremes is only possible with electronic controls, steps that are possible currently in the computerized environment of hospitals. Hsu et al. put in place an electronic reminder to test for hepatitis B virus (HBV) and even electronic control of the chemotherapy that is dependent on prophylaxis against HBV. The results speak for themselves: the screening rates jumped from 40% to 99%, prophylaxis rate from 39% to 96%, and severe acute exacerbation from 1.2% to 0%. This study was conducted in an HBV endemic area. Such measures might be even more important in areas with lower prevalence, where physicians are less aware of this issue. (Hepatology 2015;62:387-396) The introduction of passive and active immunization at birth has changed the rate of vertical transmission of HBV, but there remains a residual risk of transmission for infants born to high-viremic mothers. This residual risk can be prevented by administrating anti-HBV treatment during the last weeks of pregnancy. Chen et al. performed a prospective, multicenter, open-label, nonrandomized trial enrolling pregnant women with a viremia level above 7.5 log10 IU/mL. Fifty-six women received no medication, and 56 received tenofovir starting at 30 weeks and continuing treatment up to 1 month postpartum. Infant hepatitis B surface antigen positivity was reduced from 10.7% to 1.5% without congenital anomaly, premature birth, or abnormal growth. Interestingly, this work also confirmed that amniocentesis is associated with an increased risk of mother-to-infant HBV transmission. (Hepatology 2015;62:375-386) Patients with hepatocellular carcinoma (HCC) who demonstrate progression under sorafenib treatment have only three options: (1) continue the treatment hoping that this is only partial resistance; (2) stop the treatment; or (3) receive second-line therapy within a protocol. None of these approaches is based on understanding the mechanisms leading to sorafenib resistance. Lo et al. developed sorafenib-resistant HCC cells to address this issue. They observed that CD47 is up-regulated in resistant cells. CD47, also known as integrin-associated protein, has been reported to be expressed in cancer stem cells. Both genetic ablation of CD47 (knockdown) and pharmacological blockade of CD47 (anti-CD47 antibody) sensitized sorafenib-resistant cells to this treatment. Anti-CD47 antibodies are in early clinical development for solid tumors; HCC should be considered in future clinical trials. (Hepatology 2015;62:534-545) It does not take years of clinical training to recognize that patients with cirrhosis who are in poor condition have a poor prognosis. The question is: What represents poor condition and can we measure it? By introducing the concept of frailty, the answer is, “Yes we can!” Tapper et al. performed a retrospective analysis of 734 patients hospitalized for decompensated cirrhosis (average Model for End-Stage Liver Disease score: 18) in their transplant unit. Frailty was assessed by the admitting nurse using standardized metrics (activities of daily living and Braden scale). Both metrics predicted 90-day mortality. These metrics were also associated with length of stay and rehabilitation needs. In their article, the researchers discuss how frailty is linked to sarcopenia, suggesting that nutritional support and physical therapy may reverse it. This underlies crucial aspects that should not be neglected in the management of these patients. (Hepatology 2015;62:584-590) Resection is curative for many patients with HCC. However, hepatic resection in a patient with cirrhosis can lead to major complications. Therefore, patients have to be selected. Based on the analysis of its well-characterized collective, the Barcelona group reported that portal hypertension (PH) and hyperbilirubinemia are key parameters in this selection. Roayaie et al. assembled a large database of more than 8,600 patients with HCCs from 20 centers around the world. The researchers found that the combined presence of hyperbilirubinemia and PH (defined clinically) negatively affects the postresection survival, but not each one taken separately. Moreover, multivariate analysis of the nonideal candidate for resection suggested that it may nevertheless perform better than transarterial chemoembolization. If these findings test the limits, they are not delivering new rules to resect beyond these limits. (Hepatology 2015;62:440-451) The appearance of extrahepatic metastases completely changes the therapeutic approach for patients with HCC. This process can be seen as single cells gaining access to the circulation with distant homing. Fang et al. propose another mechanism. In a series of elegant experiments, they found that the formation of a cobweb-like network of intratumoral vessels, a vascular pattern, which can be assessed by histology, detaches in the circulation clusters of tumor cells encapsulated in endothelial cells. These cargos then circulate until becoming trapped in small vessels some distance away. Mechanistically, the investigators were able to show that this process is independent of endothelial-mesenchymal transformation, but requires angiopoietin 2. This work links a histological finding with a new metastasis mechanism. (Hepatology 2015;62:452-465) The dismal outcome of hepatorenal syndrome can be reversed by administration of terlipressin and albumin; terlipressin to attenuate the splanchnic and peripheral vasodilation, and albumin to expand the plasma volume. This combination is not available everywhere. Alternative therapies are needed. Cavallin et al. randomized 27 patients to this standard of care (terlipressin/albumin) and 22 to midodrine in combination with octreotide (two splanchnic vasoconstrictors) and albumin. An interim analysis led to the termination of the trial: The rate of renal function recovery was significantly higher with terlipressin/albumin, compared with the tested combination (70% vs. 29%). This was an important question, which has been addressed in a well-designed trial that has provided a clear answer. (Hepatology 2015;62:567-574) Patients with cirrhosis may require anticoagulation in the case of acute portal vein thrombosis (PVT). However, there are always physicians involved in the care of these patients to argue against it, claiming an increased risk of upper gastrointestinal bleeding (UGIB). Hepatologists need data to prevail in this discussion. Thanks to Cerini et al., we have differentiated data. These researchers evaluated 52 patients with cirrhosis who had a UGIB matching them with 104 similar patients, who were not receiving an anticoagulation. Multivariate analysis indicated that the 6-week mortality was associated with anticoagulation for chronic vascular disease, but not with anticoagulation for PVT. The 5-day treatment failure was associated with the type of bleeding lesion, but not with anticoagulation. Even if the bleeding may be more severe under anticoagulation, as assessed by hypotension and hemoglobin, these results led the researchers to conclude that comorbidities, but not anticoagulation, are associated with a poor bleeding outcome in patients with cirrhosis. (Hepatology 2015;62:575-583)