Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper.

The COVID-19 pandemic has presented a serious challenge to the hepatology community, particularly healthcare professionals and patients. While the rapid development of safe and effective vaccines and treatments has improved the clinical landscape, the emergence of the omicron variant has presented new challenges. Thus, it is timely that the European Association for the Study of the Liver provides a summary of the latest data on the impact of COVID-19 on the liver and issues guidance on the care of patients with chronic liver disease, hepatobiliary cancer, and previous liver transplantation, as the world continues to deal with the consequences of the COVID-19 pandemic.

EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.

According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.

Evidence for Hepatitis A virus endemic circulation in Israel despite universal toddlers' vaccination since 1999 and low clinical incidence in all age groups.

Background: Universal toddlers vaccination (UTV) introduced in 1999, reduced hepatitis A incidence in Israel from 50.4 to <1.0/100,000. The current Hepatitis A virus (HAV) molecular epidemiology in Israel was studied 13-14y post UTV introduction.. Methods: An outbreak in Tel-Aviv with 75 cases in 2012-2013 was investigated. Real-time RT-PCR and sequencing of the VP1-2A region (1100bp) was done on: a. serum samples from patients with acute Hepatitis A (12/ 75 in Tel-Aviv and 31 patients hospitalized in 3 other major cities in 2011-2013); b. in sewage samples (27 from metropolitan Tel-Aviv, 14 from the other 3 cities and 6 from Gaza). Results: The outbreak began among intravenous drug users then spread to the general population. Patients' mean age was 33.2y, 4/75(5.3%) had been vaccinated and 58/75(77.3%) were hospitalized. No common environmental source was found. HAV was detected in sewage samples: 16/27(59.2%) from Tel-Aviv; 4/14(28.6%) collected throughout Israel and 6/6 (100%) from Gaza. Genotype IB predominated (52/53 sequenced samples) and identical strains were demonstrated in the Israeli and Palestinian populations by phylogenetic analysis. Conclusions: Despite the UTV success, HAV circulation in the Israeli population continues, apparently due to its close contacts with the endemic Palestinian population. Reassessment of vaccination policy is recommended.

Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention.

Although epidemic jaundice was well known to physicians of antiquity, it is only in recent years that medical science has begun to unravel the origins of hepatitis A virus (HAV) and the unique pathobiology underlying acute hepatitis A in humans. Improvements in sanitation and the successful development of highly efficacious vaccines have markedly reduced the worldwide prevalence and incidence of this enterically-transmitted infection over the past quarter century, yet the virus persists in vulnerable populations and remains a common cause of food-borne disease outbreaks in economically-advantaged societies. Reductions in the prevalence of HAV have led to increases in the median age at which infection occurs, often resulting in more severe disease in affected persons and paradoxical increases in disease burden in some developing nations. Here, we summarize recent advances in the molecular virology of HAV, an atypical member of the Picornaviridae family, survey what is known of the pathogenesis of hepatitis A in humans and the host-pathogen interactions that typify the infection, and review medical and public health aspects of immunisation and disease prevention.

Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S vaccine.

Efficacy and safety of recombinant yeast-derived hepatitis B vaccines for prevention of hepatitis B have been demonstrated unequivocally worldwide as reflected in reduction in HBsAg carrier rates and hepatocellular carcinoma. A new generation of recombinant HBV vaccines expressed in mammalian cells containing Pre-S/S epitopes has been developed in several countries. Such vaccines are useful in special risk groups, i.e., in non-responders to conventional HBV vaccines including older adults, obese people, health care workers, patients with renal failure and on dialysis, transplant patients, patients with HIV as well as travelers on short notice to HBV endemic regions. The future of such vaccines depends on their enhanced immunogenicity and cost profile. Sci-B-Vac™ is a mammalian cell-derived recombinant Pre-S1/Pre-S2/S hepatitis B vaccine which has been shown to be highly immunogenic, inducing faster and higher seroprotection rates against HBV with higher anti-HBs levels at lower HBsAg doses as compared to conventional yeast-derived vaccines. Recently, it has been suggested that such Pre-S/S vaccines against HBV might be efficacious not only for prevention but also for intervention in persistent HBV infection. Data obtained in a recent clinical trial conducted in Vietnam in patients with chronic hepatitis B suggest that repeated monthly i.m. injections of the Sci-B-Vac™ co-administered with daily oral lamivudine treatment can suppress HBV replication and lead to anti-HBs seroconversion in ~50 % of treated patients. Optimization of protocols and efficacy of such an intervention, intended to bypass T cell exhaustion and immune tolerance to HBV remains to be explored.

Hepatotoxicity of herbal and dietary supplements: an update.

Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.

Telaprevir for retreatment of HCV infection.

BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

Telaprevir for previously untreated chronic hepatitis C virus infection.

BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

Trans-arterial chemo-embolization is safe and effective for elderly advanced hepatocellular carcinoma patients: results from an international database.

OBJECTIVE: Hepatocellular carcinoma (HCC) incidence among elderly patients is increasing. Trans-arterial chemo-embolization (TACE) prolongs survival in selected HCC patients. The safety and efficacy of TACE in elderly patients has not been extensively studied. The objective of this study was to assess the safety and efficacy of TACE in elderly patients (older than 75) with HCC. DESIGN: Combined HCC registries (Spain, Italy, China and Israel) and cohort design analysis of patients who underwent TACE for HCC. RESULTS: Five hundred and forty-eight patients diagnosed and treated between 1988 and 2010 were included in the analysis (China 197, Italy 155, Israel 102 and Spain 94,). There were 120 patients (22%) older than 75 years and 47 patients (8.6%) older than 80. Median (95% CI) survival estimates were 23 (17-28), 21 (17-26) and 19 (15-23) months (P=0.14) among patients aged younger than 65, 65-75 and older than 75 respectively. An age above 75 years at diagnosis was not associated with worse prognosis, hazard ratio of 1.05 (95% CI 0.75-1.5), controlling for disease stage, sex, diagnosis year, HBV status and stratifying per database. No differences in complication rates were found between the age groups. CONCLUSIONS: TACE is safe for patients older than 75 years. Results were similar over different eras and geographical locations. Though selection bias is inherent, the results suggest overall adequate selection of patients, given the similar outcomes among the different age groups.

Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrioR) of Chronically HBV Infected Patients.

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 µg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.

Immunosuppression and HBV reactivation.

Hepatitis B virus (HBV) reactivation following immunosuppression is defined by an abrupt rise in HBV replication followed by laboratory signs of hepatocellular injury in a "silent" hepatitis B surface antigen (HBsAg) carrier. Reactivation can also occur, albeit at a lower rate, in patients with occult HBV infection. The clinical presentation of reactivation is variable ranging from an asymptomatic course to severe hepatitis, liver failure, and death. It is most frequently observed in patients with lymphoma treated with rituximab and corticosteroids as well as in patients undergoing stem cell and bone marrow transplantation. Other risk groups include patients with solid tumors, subjects infected with human immunodeficiency virus, organ transplant recipients, and those with autoimmune diseases (i.e., inflammatory bowel disease, rheumatoid arthritis). In cancer patients, HBV reactivation can lead to interruption of chemotherapy with serious impact on prognosis. In HBsAg-positive patients who are candidates for chemotherapy or treatment with biologic agents, preemptive treatment with an antiviral agent such as lamivudine, and lately with the more potent tenofovir or entecavir, has become a standard of care, effectively preventing HBV reactivation. Patients with occult HBV should be monitored for alanine aminotransferase and HBV DNA during the course of immunosuppression. Prompt administration of a potent antiviral agent upon diagnosis of reactivation may be lifesaving in such patients.

Tracing hepatitis B virus to the 16th century in a Korean mummy.

UNLABELLED: A rare find of a mummified child from the 16th century AD, in Korea, with relatively preserved organs, enabled a search for ancient hepatitis B virus (aHBV) DNA sequences from laparoscopic-derived liver biopsies. Analysis of the complete aHBV genome (3,215 base pairs) revealed a unique HBV genotype C2 (HBV/C2) sequence commonly spread in Southeast Asia, which probably represents an HBV that infected the Joseon Dynasty population in Korea. Comparison of the aHBV sequences with contemporary HBV/C2 DNA sequences revealed distinctive differences along four open reading frames. Genetic diversity between contemporary and recovered aHBV/C2 DNA may be the result of immunologic, environmental, and/or pharmacologic pressures. The calculated time of most recent common ancestor suggests that the Korean HBV sequence origin dates back at least 3,000 years and possibly as long as 100,000 years. This isolate most likely represents the earliest human HBV sequence that colonized Southeast Asia by human migration. CONCLUSION: This study describes the complete sequence of the oldest HBV isolate and the most ancient full viral genome known so far.

Hepatitis A virus infection.

Hepatitis A is a vaccine-preventable infection caused by the hepatitis A virus (HAV). Over 150 million new infections of hepatitis A occur annually. HAV causes an acute inflammatory reaction in the liver that usually resolves spontaneously without chronic sequelae. However, up to 20% of patients experience a prolonged or relapsed course and <1% experience acute liver failure. Host factors, such as immunological status, age, pregnancy and underlying hepatic diseases, can affect the severity of disease. Anti-HAV IgG antibodies produced in response to HAV infection persist for life and protect against re-infection; vaccine-induced antibodies against hepatitis A confer long-term protection. The WHO recommends vaccination for individuals at higher risk of infection and/or severe disease in countries with very low and low hepatitis A virus endemicity, and universal childhood vaccination in intermediate endemicity countries. To date, >25 countries worldwide have implemented such programmes, resulting in a reduction in the incidence of HAV infection. Improving hygiene and sanitation, rapid identification of outbreaks and fast and accurate intervention in outbreak control are essential to reducing HAV transmission.

[Israeli guidelines for the treatment of chronic hepatitis C infection--2012 Israeli Association for the Study of the Liver].

The current standard of care for the treatment of hepatitis C virus (HCV) is a combination of pegylated interferon alpha (PeglFN] -2a/2b and ribavirin for 24-48 weeks, according to the viral genotype. This treatment is associated with significant side effects and achieves sustained virologic response (SVR) in only 40%-50% of genotype 1 HCV-infected patients. The recent development of direct-acting antiviral agents (DAAs] targeting critical steps of the virus life-cycle led to a major breakthrough in the management of HCV infection. The DAAs include protease inhibitors and polymerase inhibitors. The recently approved protease inhibitors boceprevir and telaprevir, when given with PeglFN and ribavirin in HCV genotype 1 patients, result in a much higher SVR rate [70%] among treatment-naïve and treatment-experienced patients, compared with Peg-IFN and ribavirin. In specific groups of patients this enables a shorter duration of treatment. The DAA-containing regimens are approved for HCV genotype 1 infection in HCV treatment-naïve and HCV treatment-experienced including cirrhotic patients. The Israeli Ministry of Health has recently approved the use of boceprevir (Victretis) and telaprevir (Incivo) in combination with PeglFN and ribavirin for the current standard of care treatment of HCV genotype 1 patients. The consensus opinion of a panel of national HCV-experts appointed by the Israeli Association for the Study of the Liver is presented in this report. These Israeli consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

Endotipsitis-persistent infection of transjugular intrahepatic portosystemic shunt: pathogenesis, clinical features and management.

Transjugular intrahepatic portosystemic shunt (TIPS) is in widespread use for the decompression of portal pressure. The entity of persistent TIPS infection, also known as 'endotipsitis' is a rare but serious complication of TIPS insertion. The exact definition of 'endotipsitis' is still debated, but involves persistent bacteremia and fever together with either shunt occlusion, or vegetation, or bacteremia in the presence of a patent shunt, when other sources of bacteremia have been ruled out. To date, approximately 40 cases of 'endotipsitis' have been described, with predominance for male and alcoholic hepatitis patients. The clinical course is variable, but fever and chills are a constant feature. Bacteremia, can either occur early (<120 days) or late (>120 days) after stent insertion, with some cases occurring many years after the procedure. Although no predominant bacterial species have been described in 'endotipsitis', staphylococci and other Gram-positive bacteria are more commonly seen in early infection. The diagnosis of 'endotipsitis' is difficult and requires a high index of suspicion. A rigorous imaging work-up to rule out other sources of endovascular infection is usually required including ultrasonography, computed tomography and echocardiography. Because removal of the infected stent is impractical, treatment is empirical and based on a prolonged course of antibiotics. If eligible, some patients may be referred for liver transplantation. The use of prophylactic antibiotics during the initial TIPS procedure is controversial, and despite the lack of evidence, prophylaxis is the common practice. The aim of this review was to describe the definition, clinical course, diagnosis, pathogenesis, microbiology, treatment and outcome of endotipsitis.

The History of Hepatitis A.

Watch an interview with the author.