Issue Highlights

Abstract

Chronic hepatitis B virus (HBV) infection continues to be a major global health-related threat, affecting 250 million people worldwide. Long-term infection leads to hepatic fibrosis and a substantial increase in the risk of hepatocellular carcinoma (HCC). Chronic therapy with a nucleoside analogue agent (NUC) can suppress inflammation with subsequent reversal of liver fibrosis, and potential decline in the likelihood of HCC. Cessation of NUC therapy is associated with a loss of viral suppression and resultant clinical hepatitis for some patients. Hence there is debate as to whether these agents should be continued indefinitely. Serum levels of hepatitis B surface antigen (HBsAg) have been shown to correlate with disease activity, and low levels of HBsAg may predict an inactive carrier state for patients. In this issue of Clinical Gastroenterology and Hepatology, Hsu et al examined serum HBsAg levels at end-of-therapy (EOT) with Entecavir, and their association with off-therapy relapse. This prospective, multicenter study from Taiwan enrolled 161 consecutive chronic HBV patients who achieved undetectable viral loads after receiving Entecavir for 3 years or longer. Following Entecavir cessation, participants were monitored for clinical relapse (viral DNA >2000 IU/mL plus ALT >2 folds upper normal limit), and virological relapse (solely viral DNA >2000 IU/mL). Clinical relapse occurred with a 2-year cumulative incidence of 49.2% (95% confidence interval [CI], 40.9–58.1) for the entire cohort, and 39.2% (95% CI, 30.3–49.6) in the 124 EOT patients who were hepatitis B e antigen (HBeAg)-negative. Virological relapse occurred with a 2-year cumulative incidence of 81.7% (95% CI, 74.3–88.0) for the entire cohort; and 77.4% (95% CI, 68.6–85.2) in the 124 EOT HBeAg-negative patients. There was a dose-response association between serum level of EOT HBsAg, and the relapse risk among EOT HBeAg-negative patients (Figure 1). In 9 patients (11%) with EOT HBsAg <10 IU/mL, clinical remission was sustained over the entire follow-up period. Overall, the authors concluded that EOT HBsAg levels are associated with a relapse risk in HBeAg-negative patients, and a low titer predicts a durable off-therapy remission. This article is highlighted by an editorial by Stephanos J. Hadziyannis (page 1499). See page 1490. Also examining the predictive capabilities of HBsAg levels in this issue of Clinical Gastroenterology and Hepatology is a study from the Netherlands by Brouwer et al. Chronic hepatitis B virus (HBV) infection is believed to have 5 phases of disease progression. In the inactive carrier (IC) phase, patients have normal alanine aminotransferase (ALT) levels, low or undetectable HBV DNA levels, negative hepatitis B e antigen (HBeAg) titres, and positive hepatitis B surface antigen (HBsAg) titres. This phase has favorable long-term outcomes with a low risk of developing hepatocellular carcinoma (HCC), and a high probability of achieving loss in serum HBsAg titres. Nevertheless, patients can develop viral reactivation from the IC phase. Accurately distinguishing the phases of chronic HBV infection is critical for predicting prognosis, and for guiding management. In this retrospective dynamic regression analysis of 292 HBeAg-negative patients with chronic HBV infection; the authors assessed the performance of repeated HBsAg measurements for the prediction of the IC phase. Patients were determined to be carriers of inactive HBV (level of HBV DNA below 2000 IU/mL and serum levels of ALT that remained normal), or to have HBV activity (level of HBV DNA fluctuating above 2000 IU/mL and/or abnormal levels of ALT) after each year of follow-up. The median time of follow-up was 8 years. After 1 year, 189 patients (65%) had IC HBV, and 103 patients (35%) had HBV activity. The probability that a patient would have IC HBV at any following year differed according to level of HBsAg: the positive predictive value was 97% for patients with initial level of HBsAg below 100 IU/mL, 85% for patients with initial levels 100–1000 IU/mL, and 76% for patients with initial levels above 1000 IU/mL (P < .001). The cumulative probability of remaining in the IC phase during follow-up given HBsAg at inclusion is depicted in Figure 2. The combination of HBsAg level below 100 IU/mL, and HBV DNA level below 2000 IU/mL, identified patients whose virus remained inactive for the entire follow-up period, with 98% specificity and a positive predictive value of 97% for all HBV genotypes. The authors conclude that HBsAg levels below 100 IU/mL identify patients with inactive virus at a high level of specificity; therefore they should be used to define the phases of HBV infection in HBeAg-negative patients. This article is highlighted by an editorial by Stephanos J. Hadziyannis (page 1499). See page 1481. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and thus often coexists with obesity, dyslipidemia, and insulin resistance. Approximately one quarter of the American population is believed to have NAFLD, and estimated prevalence rates are as high as 30%–35% in some Asia-Pacific regions. The risk of hepatic fibrosis in NAFLD is related to the duration and degree of steatohepatitis. Once cirrhosis develops, patients are at increased risk for developing hepatocellular carcinoma (HCC). Weight loss is the first step in the management of NAFLD, as it independently correlates with improved liver histology. Weight reduction can be achieved by both caloric restriction and increased physical activity. There is little evidence, however, demonstrating that exercise improves liver fat content independent of a hypocaloric diet. In this issue of Clinical Gastroenterology and Hepatology, Orci et al evaluate the existing literature to address the effectiveness of physical activity on liver-specific endpoints. The authors searched PubMed/Medline, Embase, and the Cochrane Central registry through October, 2015. They included only randomized trials of exercise-based lifestyle interventions on the following endpoints: intrahepatic lipid content, and serum ALT and AST levels. Effect sizes were reported as standardized mean difference (SMD) and weighted mean difference (WMD). A total of 28 trials were used for analysis. Physical activity, independent of dietary changes, was associated with a significant reduction in intrahepatic lipid content (SMD -0.69; 95% confidence interval [CI], –0.90 to –0.48), and with a reduction in ALT (WMD –3.30 IU/l; 95% CI, –5.57 to –1.04), and AST (WMD –4.85 IU/l; 95% CI, –8.68 to –1.02). Using meta-regression, individuals with increasing body mass index were increasingly likely to benefit from the intervention (β coefficient = −0.10 P = .037) (Figure 3). The authors conclude there is good evidence suggesting that exercise alone improves fat content and markers of hepatocellular injury in patients with NAFLD. See page 1398. Both patients and physicians share concern when starting biologic agents for inflammatory bowel disease (IBD) about risks of infection and malignancy. Bonovas et al conducted a systematic review and meta-analysis of randomized trials to examine the different anti-TNF and anti-integrin agents used in IBD and their risk of causing infections (primary outcome) and malignancies (secondary outcome). The authors searched multiple databases, including PubMed, Embase, Scopus, and ClinicalTrials.gov through March, 2016. Only randomized or head-to-head trials of biologic agents approved for the treatment of adults with IBD were included (ie, adalimumab, certolizumab, golimumab, infliximab, natalizumab, or vedolizumab). A total of 49 randomized placebo-controlled studies comprising 14,590 participants were ultimately used for their analysis. Patients treated with biologics had a mild to moderate increase in risk of any infection (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.10–1.29), but a significant increase in risk of opportunistic infections (OR, 1.90; 95% CI, 1.21–3.01). Opportunistic infections were defined as: Mycobacterium tuberculosis, JC virus infection, Nocardia infection, cytomegalovirus or Epstein-Barr virus infection, oral or esophageal candidiasis, varicella-zoster virus infection, herpes zoster infection, Pneumocystis jirovecii infection, Histoplasma capsulatum infection, Legionella-induced pneumonia, herpes simplex infection, or other unspecified opportunistic infections. However, there was no significant increase in the risk of serious infections (OR, 0.89; 95% CI, 0.71–1.12), defined as infections associated with hospital admission, use of intravenous antibiotics, or death. The authors did not find an increased risk of cancer with use of any of the biologic agents (OR, 0.90; 95% CI, 0.54–1.50), yet data were considered to be insufficient with regards to exposure time and duration of follow-up. None of the indirect comparisons, either among the individual agents or between the anti-TNF and anti-integrin classes, reached significance for any of the outcomes analyzed. Based on their analysis, the authors conclude that biologic agents in IBD increase the risk of opportunistic infections, but not the risk of serious infections. Further longitudinal studies are needed to better assess the long-term risk of malignancy. See page 1385. Exercise-based Interventions for Nonalcoholic Fatty Liver Disease: A Meta-analysis and Meta-regressionClinical Gastroenterology and HepatologyVol. 14Issue 10PreviewThe burden of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. We performed a meta-analysis to determine the effectiveness of exercise-based lifestyle interventions on liver-specific end points in populations with NAFLD and underlying metabolic disorders such as obesity, type 2 diabetes, or metabolic syndrome. Full-Text PDF Repeated Measurements of Hepatitis B Surface Antigen Identify Carriers of Inactive HBV During Long-term Follow-upClinical Gastroenterology and HepatologyVol. 14Issue 10PreviewMeasurements of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA might help to identify carriers of inactive HBV. We assessed the performance of repeated measurements of HBsAg over a median time period of 8 years. Full-Text PDF Association Between Serum Level of Hepatitis B Surface Antigen at End of Entecavir Therapy and Risk of Relapse in E Antigen–Negative PatientsClinical Gastroenterology and HepatologyVol. 14Issue 10PreviewThis study investigated whether serum level of hepatitis B surface antigen (HBsAg) at the end of entecavir treatment was associated with risk of relapse. Full-Text PDF Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysisClinical Gastroenterology and HepatologyVol. 14Issue 10PreviewSafety issues are a major concern for patients considering treatments for inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis to determine whether biologic agents affect the risk of infection or malignancy in adults with IBD. Full-Text PDF