Estimating the Global Prevalence, Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection

Abstract

Background: Hepatitis delta virus (HDV) coinfects with hepatitis B virus (HBV) causing the most severe form of viral hepatitis. However, its exact global disease burden remains largely obscure. We aim to establish the global epidemiology, infection mode-stratified disease progression, and clinical outcome of HDV infection.

Methods: We conducted a meta-analysis with a random-effects model and performed data synthesis.

Results: The pooled prevalence of HDV is 0.80% (95% confidence interval [CI], 0.63-1.00) among the general population and 13.02% (95% CI, 11.96-14.11) among HBV carriers, corresponding to 48-60 million infections globally. Among HBV patients with fulminant hepatitis, cirrhosis, or hepatocellular carcinoma, HDV prevalence is 26.75% (95% CI, 19.84-34.29), 25.77% (95% CI, 20.62-31.27), and 19.80% (95% CI, 10.97-30.45), respectively. The odds ratio (OR) of HDV infection among HBV patients with chronic liver disease compared with asymptomatic controls is 4.55 (95% CI, 3.65-5.67). Hepatitis delta virus-coinfected patients are more likely to develop cirrhosis than HBV-monoinfected patients with OR of 3.84 (95% CI, 1.79-8.24). Overall, HDV infection progresses to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years, on average.

Conclusions: Findings suggest that HDV poses a heavy global burden with rapid progression to severe liver diseases, urging effective strategies for screening, prevention, and treatment.

Keywords: cirrhosis; disease progression; epidemiology; hepatitis delta virus; hepatocellular carcinoma.

Figure 1.

Flowchart of study selection.

Figure 2.

Global prevalence of hepatitis D virus (HDV) infection. (A) General population; (B) hepatitis B virus surface antigens-positive carriers. Blank means HDV-pooled prevalence is not applicable due to lacking HDV epidemiological data. First 10 counties for the estimates of HDV burden were listed, respectively.

Figure 3.

The epidemiological profile of hepatitis D virus (HDV) infection. (A) Prevalence of HDV among acute hepatitis B virus (HBV) patients. (B) Prevalence of HDV among chronic HBV patients. (C) Forest plot of HDV prevalence among patients with chronic liver diseases compared with asymptomatic controls. Data are pooled from a random-effects model. ASC, asymptomatic carrier; CH, chronic hepatitis; CI, confidence interval; FH, fulminant hepatitis; HBsAg, HBV surface antigen; HCC, hepatocellular carcinoma.

Figure 4.

Schematic diagram of hepatitis D virus (HDV) infection and disease progression. (A) Hepatitis D virus infection patterns. Coinfection is that HDV and hepatitis B virus (HBV) simultaneously infect an individual or HDV infects the individual at the early stage after HBV infection. The essential diagnostic marker of this pattern is positive HBV surface antigen (HBsAg) and high titer of anti-hepatitis B core (HBc) immunoglobulin (Ig)M antibodies. Superinfection is that HDV infects the individual who has already established HBV infection or is a chronic HBV carrier (HBsAg positive). Anti-HBc IgM antibodies are absent in this pattern. HDV > HBV, HDV replication dominant; HDV ~ HBV, HDV and HBV codominant; HDV < HBV, HBV replication dominant. (B) Clinical progression of HDV infection. Pooled probability was shown with 95% confidence interval unless specifically indicated. Time was shown as mean (range). The total percentage exceed 100% after data synthesis.

Figure 5.

Clinical outcome comparison between hepatitis D virus (HDV)-positive and HDV-negative patients. (A) Radar chart represents the composition of liver diseases among patients. (B) Forest plot of liver disease ratio among HDV-positive patients compared with HDV-negative patients. Data are pooled from a random-effects model. (C) The development of liver diseases among HDV-positive patients compared with HDV-negative patients. (D) The suppressive effect of HDV on hepatitis B virus (HBV) replication. Hepatitis B e antigen (HBeAg) and HBV deoxyribonucleic acid (DNA) are the indicators of HBV replication. ASC, asymptomatic carrier; CI, confidence interval; HCC, hepatocellular carcinoma; OR, odds ratio.