Revolution in hepatitis C antiviral therapy.

INTRODUCTION: Management of hepatitis C virus (HCV) is rapidly changing as a result of new direct-acting antivirals (DAA). SOURCES OF DATA: Several peer-reviewed papers featuring new DAAs are now available. Additionally, as new data are emerging so quickly, we also reviewed recent presentations at international congresses, published in abstract form. AREAS OF AGREEMENT: New DAAs are efficacious and superior to prior treatment regimens, with minimal side effects. Shorter interferon-free regimens will soon be the mainstay of HCV treatment. AREAS OF CONTROVERSY: Access to new DAAs is variable across global regions. One approach to treating HCV may be to assess early viral kinetics of treatment to identify who may be cured with standard peg-interferon/ribavirin therapy as opposed to using a DAA in all patients. GROWING POINTS: Newer studies with combination of DAAs are being conducted. The ideal interferon-free regimen has yet to be determined. AREAS TIMELY FOR DEVELOPING RESEARCH: HCV genotype 3 is the new difficult-to-treat genotype. More efficacious regimens for treating HCV genotype 3 are needed. Subgroups of patients who only require even shorter regimens of 6-8 weeks need to be identified. There is still very little data on interferon-free regimens in patients with decompensated cirrhosis and certain other subgroups.

Molecular epidemiology and clinical characteristics of hepatitis D virus infection in Canada.

Background & Aims: HDV affects 4.5-13% of chronic hepatitis B (CHB) patients globally, yet the prevalence of HDV infection in Canada is unknown. To investigate the prevalence, genotype, demographics, and clinical characteristics of HDV in Canada, we conducted a retrospective analysis of (1) HDV antibody and RNA positivity among referred specimens, and (2) a cross-sectional subset study of 135 HDV seropositive +/-RNA (HDV+) patients compared with 5,132 HBV mono-infected patients in the Canadian HBV Network. Methods: Anti-HDV IgG-positive specimens collected between 2012 and 2019 were RNA tested and the genotype determined. Patients enrolled in the Canadian HBV Network were >18 years of age and HBsAg-positive. Clinical data collected included risk factors, demographics, comorbidities, treatment, fibrosis assessment, and hepatic complications. Results: Of the referred patients, 338/7,080 (4.8%, 95% CI 4.3-5.3) were HDV seropositive, with 219/338 RNA-positive (64.8%, 95% CI 59.6-69.7). The HDV+ cohort were more likely to be born in Canada, to be White or Black/African/Caribbean than Asian, and reporting high-risk behaviours, compared with HBV mono-infected patients. Cirrhosis, complications of end-stage liver disease, and liver transplantation were significantly more frequent in the HDV+ cohort. HDV viraemia was significantly associated with elevated liver transaminases and cirrhosis. Five HDV genotypes were observed among referred patients but no association between genotype and clinical outcome was detected within the HDV+ cohort. Conclusions: Nearly 5% of the Canadian HBV referral population is HDV seropositive. HDV infection is highly associated with risk behaviours and both domestic and foreign-born patients with CHB. HDV was significantly associated with progressive liver disease highlighting the need for increased screening and surveillance of HDV in Canada. Lay summary: Evidence of HDV infection was observed in approximately 5% of Canadians who were infected with HBV referred to medical specialists. HDV-positive patients were more likely to be male, born in Canada, or White or Black/African/Caribbean compared to Asian, and to have reported high-risk activities such as injection or intranasal drug use or high-risk sexual contact compared with patients infected with only HBV. Patients infected with HDV were also more likely to suffer severe liver disease, including liver cancer, compared with HBV mono-infected patients.

Real-world tertiary referral centre experience stopping nucleos(t)ide analogue therapy in patients with chronic hepatitis B.

BACKGROUND: Identifying strategies for stopping nucleos(t)ide analogues (NUC) in patients with chronic hepatitis B (CHB) is a major goal in CHB management. Our study describes our tertiary-centre experience stopping nucleos(t)ide analogues (NUC) in CHB. METHODS: We conducted a retrospective cohort study of all individuals with CHB seen at the Calgary Liver Unit between January 2009 and May 2020 who stopped NUC. We collected baseline demographics and HBV lab parameters before and after stopping NUC with results stratified by off-treatment durability. Clinical flare was defined as alanine aminotransferase (ALT) over twice the upper limit of normal and virological flare as HBV DNA >2000 IU/mL. RESULTS: Forty-seven (3.5%) of the 1337 individuals with CHB stopped NUC therapy. During follow-up, six patients (12.8%) restarted NUCs because of a flare. All flares occurred within six months of discontinuation. Median time to restart treatment was 90 days (Q1 65, Q3 133). Upon restarting, all showed suppression of HBV DNA and ALT normalization. Factors associated with restarting NUC therapy included hepatitis B e antigen (HBeAg) positive status at first appointment and longer NUC consolidation therapy. Age, sex, ethnicity, liver stiffness measurement, choice of NUC, and quantitative hepatitis B surface antigen (qHBsAg) level at stopping were not associated with sustained response off-treatment. Six patients had functional cure with HBsAg loss. CONCLUSIONS: Stopping long-term NUC is feasible in HBeAg negative CHB. Hepatic flares can occur despite low levels of qHBsAg. Finite NUC therapy can be considered in eligible patients who are adherent to close monitoring and follow-up, particularly in the first six months after stopping NUC therapy.

Assessment of Canadian policies regarding liver transplant candidacy of people who use alcohol, tobacco, cannabis, and opiates.

Background: When last assessed in 2013, all Canadian liver transplant programs required 6 months of abstinence from alcohol. New studies have questioned the validity of this policy. Moreover, with recreational cannabis now legal in Canada, more transplant candidates may use cannabis. Given these changes, our objective was to obtain an understanding of current Canadian practices regarding liver transplantation and candidates with addiction or alcohol, tobacco, cannabis, or opiate use. Methods: Electronic surveys were distributed to the medical directors of all seven adult liver transplant programs in Canada. Questions were based on either a Likert-scale ranking or free response. The complete data set was aggregated to provide a national perspective on this topic and ensure each individual program remained anonymous. Results: All seven programs responded to the survey. Of these programs, 43% always require 6-month abstinence from alcohol, 29% usually require it, and 14% sometimes require it. Formal alcohol rehabilitation is mandatory in two programs. The majority (57%) of programs never or rarely consider transplant for patients with acute alcoholic hepatitis; 29% require smoking cessation before consideration for transplant; and 71% felt that cannabis use is rarely or never a contraindication to liver transplantation. Conclusions: Significantly more Canadian programs now perform liver transplant for patients who have less than 6 months abstinence from alcohol, and alcoholic hepatitis is no longer an absolute contraindication in Canada. Policies on smoking and opiates are quite variable. Further study and discussion are critical for development of national policies to obtain equitable access to liver transplant for all.

Practical management of esophageal varices in the context of SARS-CoV-2 (COVID-19): the Alberta protocol.

The challenges of managing varices during the COVID-19 pandemic are reviewed, and a treatment algorithm is presented to best manage patients with advanced liver disease during periods of limited access to endoscopy.

Real-world clinical and virological outcomes in a retrospective multiethnic cohort study of 341 untreated and tenofovir disoproxil fumarate-treated chronic hepatitis B pregnant patients in North America.

BACKGROUND: There are limited long-term data on outcomes of chronic hepatitis B (CHB) in untreated and tenofovir disoproxil fumarate (TDF)-treated women during pregnancy. AIMS: To assess clinical outcomes in a multiethnic cohort of patients during pregnancy and post-partum in a low HBV endemic region. METHODS: Retrospective real-world study of women with CHB (treated or untreated with TDF) from 2011 to 2019; data including ALT, HBV DNA, HBeAg and liver stiffness measurement were collected during pregnancy and post-partum. RESULTS: In 341 women (446 pregnancies) followed for a median of 33 months (IQR: 26.7-39.5) post-partum, 19% (65/341) received TDF (11 initiated pre-pregnancy, 53 for mother-to-child transmission (MTCT) prevention). During follow-up, 72/341 had subsequent pregnancy, including 18/53 on TDF for MTCT risk, of whom 7/18 were re-treated. In all TDF-treated women, HBV DNA declined but rebounded after TDF withdrawal (median baseline, near birth and early follow-up levels were 7.2, 3.0 and 5.5 log IU/mL respectively [P < 0.01]). In HBeAg+ patients (65/341) ALT flares were more common (P = 0.03), especially for those who stopped TDF post-partum, requiring re-treatment in 21% (11/53). In comparison, 54% (116/215) of untreated women had a post-partum ALT flare; one with fulminant hepatitis underwent transplant 13 months post-partum. HBsAg clearance occurred in 2.6% (9/341, 3/9 HBeAg+, 2/9 TDF treated) at median 30 months (IQR: 23-40) and 37% (24/65) of HBeAg+ patients had HBeAg loss at median 17 months (IQR: 12-26) post-partum. CONCLUSIONS: Post-partum ALT flares were common, especially after TDF withdrawal. Overall, 37% achieved HBeAg clearance and 2.9% had HBsAg loss during long-term follow-up.

Transient Elastography in the Evaluation of Cystic Fibrosis-Associated Liver Disease: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Complications of cystic fibrosis-associated liver disease (CFLD) are a leading nonpulmonary cause of death. Transient elastography (TE) has recently been investigated to detect CFLD. This study reviews the current literature for TE in the detection CFLD. A meta-analysis was performed to determine the ideal liver stiffness measurement (LSM) cutoff. METHODS: PubMed, Medline, EMBASE and Web of Science were searched from inception until April 2016 for publications involving the detection of CFLD with TE. Data were extracted using a fixed protocol (a priori design) including study design, population characteristics, probe size and AST Platelet Ratio Index (APRI). RESULTS: Diagnostic properties were summarized from six studies of 605 patients. Cutoff for LSM was determined using pooled data submitted by authors. The cutoff for LSM and APRI were ≥5.95 kPa and ≥0.329 respectively, yielding a sensitivity, specificity and area under receiver operator characteristic of 55%, 87%, 0.76, 52%, 93% and 0.84 for LSM and APRI, respectively. When LSM ≥5.95 kPa and APRI ≥0.329, the sensitivity, specificity, positive predictive value and negative predictive value were 43%, 99%, 92% and 87% with a diagnostic odds ratio of 74.9. A bivariate metaregression model showed that pediatric specific cutoffs for liver stiffness and APRI may not be necessary. CONCLUSION: Individually, LSM and APRI have poor sensitivity but good specificity for detecting CFLD. They are most useful when combined. We propose that patients with LSM ≥5.95 kPa and APRI ≥0.329 be investigated thoroughly for the presence of cystic fibrosis-associated liver disease.

Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.

BACKGROUND: Liver disease is the third leading cause of mortality in patients with cystic fibrosis (CF). However, detection of CF-associated liver disease (CFLD) is challenging. OBJECTIVE: To evaluate the diagnostic performance of noninvasive methods for the detection of CFLD with a focus on transient elastography (TE). METHODS: Patients at the Adult CF Clinic of Calgary and Southern Alberta (n=127) underwent liver stiffness measurement (LSM) by TE using the FibroScan (FS, Ecosens, France) M probe; aspartate aminotransferase to platelet ratio index (APRI) and FibroTest (FT) scores were also calculated. The diagnostic performance of these tools for the detection of CFLD (defined as two or more the following criteria: abnormal liver biochemistry, hepatomegaly or sonographic abnormalities other than steatosis) were compared using the area under ROC curves. RESULTS: Forty-seven percent of the cohort was male. The median age was 27 years (interquartile range [IQR] 22 to 37 years) and body mass index 21 kg/m(2) (IQR 19 kg/m(2) to 23 kg/m(2)); 25% of patients were on ursodeoxycholic acid and 12% had undergone lung transplantation. The prevalence of CFLD was 14% (n=18). FS was successful in all patients; one (0.8%) patient had poorly reliable results (IQR/M >30% and LSM ≥7.1 kPa). Compared with patients without CFLD (n=109), individuals with CFLD had higher median LSM according to FS (3.9 kPa [IQR 3.4 to 4.9 kPa] versus 6.4 kPa [IQR 4.4 to 8.0 kPa]), APRI (0.24 [IQR 0.17 to 0.31] versus 0.50 [IQR 0.22 to 1.18]) and FT scores (0.08 [IQR 0.05 to 1.5] versus 0.18 [IQR 0.11 to 0.35]; all P<0.05). Area under ROC curve for FS, APRI and FT for the detection of CFLD were 0.78 (95% CI 0.65 to 0.92), 0.72 (95% CI 0.56 to 0.87) and 0.76 (95% CI 0.62 to 0.90) (P not significant). At a threshold of >5.2 kPa, the sensitivity, specificity, positive and negative predictive values of LSM according to FS for detecting CFLD were 67%, 83%, 40% and 94%, respectively. CONCLUSIONS: FS, APRI and FT were useful noninvasive methods for detecting CFLD in adults.

Predictors of mortality among patients undergoing colectomy for ischemic colitis: A population-based United States study.

BACKGROUND: Ischemic colitis is a potentially life-threatening condition that can require colectomy for management. OBJECTIVE: To assess independent predictors of mortality following colectomy for ischemic colitis using a nationally representative sample of hospitals in the United States. METHODS: The Nationwide Inpatient Sample was used to identify all patients with a primary diagnosis of acute vascular insufficiency of the colon (International Classification of Diseases, Ninth Revision codes 557.0 and 557.9) who underwent a colectomy between 1993 and 2008. Incidence and mortality are described; multivariate logistic regression analysis was performed to determine predictors of mortality. RESULTS: The incidence of colectomy for ischemic colitis was 1.43 cases (95% CI 1.40 cases to 1.47 cases) per 100,000. The incidence of colectomy for ischemic colitis increased by 3.1% per year (95% CI 2.3% to 3.9%) from 1993 to 2003, and stabilized thereafter. The postoperative mortality rate was 21.0% (95% CI 20.2% to 21.8%). After 1997, the mortality rate significantly decreased at an estimated annual rate of 4.5% (95% CI -6.3% to -2.7%). Mortality was associated with older age, 65 to 84 years (OR 5.45 [95% CI 2.91 to 10.22]) versus 18 to 34 years; health insurance, Medicaid (OR 1.69 [95% CI 1.29 to 2.21]) and Medicare (OR 1.33 [95% CI 1.12 to 1.58]) versus private health insurance; and comorbidities such as liver disease (OR 3.54 [95% CI 2.79 to 4.50]). Patients who underwent colonoscopy or sigmoidoscopy (OR 0.78 [95% CI 0.65 to 0.93]) had lower mortality. CONCLUSIONS: Colectomy for ischemic colitis was associated with considerable mortality. The explanation for the stable incidence and decreasing mortality rates observed in the latter part of the present study should be explored in future studies.

Entecavir for the treatment of patients with hepatitis B virus-related decompensated cirrhosis.

INTRODUCTION: Chronic hepatitis B (CHB) infection is common and carries a significant risk for the development of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The goal of treatment in patients with CHB-related decompensated cirrhosis is to improve hepatic dysfunction and reduce mortality through the inhibition of viral replication. Several studies have now shown nucleot(s)ide analogs to be safe and effective in decompensated cirrhosis due to CHB. AREAS COVERED: A review of the evidence for the use of entecavir in the treatment of decompensated hepatitis B cirrhosis is discussed. EXPERT OPINION: Entecavir is an effective treatment option for most patients with CHB. In treatment naïve patients, it is a potent antiviral agent with a very low resistance rate, making it an excellent option for the treatment of decompensated hepatitis B cirrhosis. The use of entecavir monotherapy in patients with a known rtM204V lamivudine-resistant mutation should be avoided due to increased risk of developing entecavir resistance and failing treatment.