Superinfection of other hepatitis viruses on top of chronic hepatitis B: The more, the worse

Abstract

Hepatitis B virus (HBV) is one of the most important causes of end-stage liver disease, including cirrhosis and hepatocellular carcinoma worldwide.¹ Taiwan is known to be hyperendemic for HBV infection. Although the implementation of nationwide universal hepatitis B vaccination program since 1984 significantly decreased the prevalence of chronic HBV infection from 10.9% to 0.5% in children,² the prevalence of seropositivity of hepatitis B surface antigen (HBsAg) in adults was still up to 13.7% in 2002.³ In addition to HBV, Taiwan is also threatened by other hepatitis viruses, including hepatitis A, C, D, and E viruses. Thus, patients with chronic HBV infection coinfected or superinfected with other hepatitis viruses are not uncommon. Among these viral hepatitis, hepatitis C virus (HCV) coinfection in HBV carriers is most common in Asia. Previous studies revealed that patients with HBV and HCV coinfection have a greater risk of developing cirrhosis and hepatocellular carcinoma, leading to a poorer outcome than those with HBV or HCV monoinfection.⁴ However, little is known about the clinical manifestations and long-term outcomes of HBV carriers with hepatitis A virus (HAV) and hepatitis D virus (HDV) coinfection or superinfection.

In this issue of the Advances in Digestive Medicine, Wu et al investigated whether prior exposure of HAV or HDV was associated with adverse long-term outcomes in patients with chronic HBV infection.⁵ Compared with HBV carriers without exposure to HAV or HDV, the risk of advanced liver disease increased by more than 10 times in patients with seropositivity of anti-HAV or anti-HDV. Their findings confirmed that the superinfection of other hepatitis virus in patients with chronic HBV infection will aggravate the underlying liver disease. However, several issues were worthy of discussion.

First, HAV is one of the most common etiologies of acute hepatitis worldwide.⁶ Because of poor sanitation and inadequate hygiene, the prevalence of HAV infection was high and most individuals infected with HAV in childhood before 1990 in Taiwan. The annual incidence of HAV infection dramatically decreased after improving sanitation conditions and providing HAV vaccination for high-risk children since 1995.⁷ Since then, the seroprevalence of anti-HAV continued to decline in Taiwan. The age-stratified seroprevalence of anti-HAV was lower than 5% in the younger population.⁸ In the current study of Wu et al, the anti-HAV seropositive rates were quite low in inactive carriers younger than 60 years old. The most worrisome thing is that the risk of a sudden outbreak of HAV infection in patients with chronic HBV infection may increase in the future. To avoid severe clinical course of HAV superinfection, HAV vaccination is recommended for patients with chronic HBV infection and seronegativity of anti-HAV.⁹

Second, HDV is a defective RNA virus, and HDV infection occurs only when HBV exists. The prevalence of anti-HDV was 4.4% in patients with chronic HBV infection.¹⁰ However, the risk of HDV coinfection or superinfection was potentially higher in special populations of HBV carriers, such as injected drug users, individuals with human immunodeficiency virus infection, and commercial sex workers.¹¹ Thus, it is important to accurately estimate the prevalence of anti-HDV in HBV endemic areas. Until now, only a small number of patients with chronic HBV infection were tested anti-HDV by in-house assays. The lack of commercial kits for the detection of anti-HDV leads to an underestimation of the prevalence of anti-HDV. An anti-HDV enzyme-linked immunosorbent assay with high sensitivity and specificity has been approved in Taiwan since 2018.¹² The use of commercially available reagents will increase HDV awareness among physicians as well as increase the identification of HDV infection in patients with chronic HBV infection. Although anti-HDV screening increases after the existing commercial kit, the detection of HDV RNA to confirm active chronic hepatitis D is still an unmet need in general practice. In a long-term follow-up of 2850 patients with chronic hepatitis B receiving nucleos(t)ides analogs treatment, the seropositive rate of anti-HDV and HDV RNA was 2.7% and 0.9%, respectively.¹³ During a follow-up of 3.5 years, spontaneous HDV RNA clearance rate was very low: only 4.3 per 100 person-years. Jang et al further investigated the impact of HDV coinfection on the treatment effect of nucleos(t)ides analogs in patients with chronic hepatitis B. HDV RNA seropositivity was the significant risk factor of persistently abnormal serum level of alanine aminotransferase (odds ratio: 30.00, 95% confidence interval: 3.28-274.05, P = .003) among patients reached undetectable HBV DNA after nucleos(t)ides analogs therapy.¹⁴ Recently, a large cohort study revealed that persistent HDV RNA viremia was a strong risk factor of cirrhosis in patients with HBV and HDV coinfection. During a median follow-up of 8 years, 30% of patients with persistent HDV RNA viremia developed cirrhosis compared with 0% of those with seronegative HDV RNA (P = .002).¹⁵ Although durable, long-term suppression of HBV DNA reduces HBV-related hepatitis activity in the era of antiviral therapy, the persistent HDV RNA viremia will contribute to continuing hepatic inflammation and lead to poor outcomes in patients with HBV and HDV coinfection. Therefore, HDV RNA assay is a desperate need for the detection and monitoring of serum HDV RNA in HBV carriers with or without antiviral therapy.

In summary, the prevalence of anti-HAV antibody is getting lower and lower among younger generation who have not received HAV vaccine. It is important to prevent HAV superinfection by HAV vaccination in patients with chronic HBV infection. On the other hand, there is currently no HDV vaccine to prevent HDV superinfection in patients with chronic HBV infection. The prevalence of chronic HDV infection is not rare in HBV endemic areas. Except interferon was used for treatment of chronic hepatitis D, several drugs such as HBV/HDV entry inhibitor, HBsAg secretion inhibitor, and farnesyl-transferase inhibitor reached promising results in early-phase clinical trials.¹⁶ In combination with the successful prevention of HBV infection by HBV vaccination and significant advances in anti-HDV therapies, elimination of HDV will be achievable in the foreseeable future.

The author declares no conflict of interest.