Hepatitis E Virus Superinfection and Clinical Progression in Hepatitis B Patients

Abstract

Hepatitis E virus (HEV) infection may cause acute hepatitis and lead to hepatic failure in developing and developed countries. We studied HEV seroprevalences in patients with hepatitis B virus (HBV) infection to understand the consequences of HEV superinfection in a Vietnamese population. This cross-sectional study was conducted from 2012 to 2013 and included 1318 Vietnamese patients with HBV-related liver diseases and 340 healthy controls. The case group included patients with acute (n = 26) and chronic hepatitis B (n = 744), liver cirrhosis (n = 160), hepatocellular carcinoma (n = 166) and patients with both liver cirrhosis and hepatocellular carcinoma (n = 222). Anti-HEV IgG and IgM antibodies were assessed in patients and controls by ELISA. HEV-RNA was identified by PCR assays and sequencing. Seroprevalences of anti-HEV IgG among hepatitis B patients and controls were 45% and 31%, respectively (adjusted P = 0.034). Anti-HEV IgM seroprevalences were 11.6% and 4.7% in patients and controls, respectively (adjusted P = 0.005). Seroprevalences were higher among the elder individuals. When stratifying for patient groups, those with liver cirrhosis had the highest anti-HEV IgG (52%) and anti-HEV IgM (19%) seroprevalences. Hepatitis B patients with current HEV infection had abnormal liver function tests compared to patients with past or without HEV infection. One HEV isolate was retrieved from a patient with both liver cirrhosis and hepatocellular carcinoma and identified as HEV genotype 3. This study indicates high prevalences of HEV infection in Vietnamese HBV patients and among healthy individuals and shows that HEV superinfection may influence the outcome and progression of HBV-related liver disease.

Keywords: AFP, alpha-feto protein; AHB, acute hepatitis B; ALT, alanine amino transferase; AST, aspartate amino transferase; CHB, chronic hepatitis B; HBV infection; HBV, hepatitis B virus; HBV-related liver diseases; HCC, hepatocellular carcinoma; HEV seroprevalence; HEV superinfection; HEV, hepatitis E virus; Hepatitis E virus; IgG, immunoglobulin G; IgM, immunoglobulin M; LC, liver cirrhosis; ORF, open reading frame; PLT, platelets; RBC, red blood cells; WBC, white blood cells.

Fig. 1

Seroprevalence of HEV infection in patients with HBV infection and in healthy population. (A): Anti-HEV IgG and anti-HEV IgM in healthy controls (HC) and in HBV patients including acute hepatitis B (AHB), chronic hepatitis B (CHB), patients with only liver cirrhosis (LC), patients with only hepatocellular carcinoma (HCC) and patients with both LC and HCC; (B): Anti-HEV IgM positivity in individuals positive for anti-HEV IgG; (C): Anti-HEV IgG seroprevalence increasing with age; (D): Anti-HEV IgM prevalence in different age groups. P values were calculated by Chi square or Fisher's exact tests for comparisons of the seroprevalence among different groups.

Fig. 2

Clinical outcomes of HEV superinfection in HBV patients. Based on the positivity of anti-HEV IgG and anti-HEV IgM, HBV patients were categorized into three different groups as “no HEV infection”, “past HEV infection” and “current HEV infection”. Different clinical and biochemical parameters including AST (A), ALT (B), albumin (C), total bilirubin (D), direct bilirubin (E), prothrombin (F), platelets (G) and HBV-DNA viral loads (H) were compared. Box-plots illustrate medians with 25 and 75 percentiles and P values were calculated by using Kruskal–Wallis test. The number in parenthesis indicates number of samples analyzed and those numbers in the respective groups vary for the clinical parameters because some patients were not tested for all the clinical parameters.

Fig. 3

Clinical outcomes of HEV superinfection in patients with chronic HBV. HBV patients were categorized into three different groups as “no HEV infection”, “past HEV infection” and “current HEV infection” based on the positivity of anti-HEV IgG and anti-HEV IgM. The levels of aspartate aminotransferase (AST) (A) and prothrombin (B) were compared. Box-plots illustrated medians with 25 and 75 percentiles and P values were calculated by using Kruskal–Wallis test. The number in parenthesis indicates number of analyzed subject samples.