Hepatitis D Infection in Asia: A Perspective From an Endemic Region

Abbreviations

cDNA

complementary DNA

CHB

chronic hepatitis B

CHD

chronic hepatitis delta

ELISA

enzyme‐linked immunosorbent assay

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HDV

hepatitis delta virus

NA

not applicable

PEG‐INF

pegylated interferon

qHDV

quantified hepatitis delta virus

Q‐MAC

quantitative microarray antibody capture

RT‐PCR

reverse transcription polymerase chain reaction

S/CO

signal/cutoff

Chronic hepatitis delta (CHD) is caused by hepatitis delta virus (HDV), which is the smallest virus infecting mammals. It is estimated that approximately 5% of patients with chronic hepatitis B (CHB) virus are coinfected with HDV; therefore, between 15 and 20 million people live with CHD, with different prevalences depending on the region.¹ Recent epidemiological meta‐analysis studies showed that the global seroprevalence of HDV is approximately 0.8% to 1%, and approximately 10% to 13% of hepatitis B surface antigen (HBsAg)‐positive individuals have HDV coinfection.², ³ This prevalence is probably higher than the estimate. HDV has eight genotypes. HDV genotype 1 has a wide distribution, genotypes 2 and 4 are found predominantly in Asia, genotype 3 is localized to the Amazon Basin, and genotypes 5 to 8 are in Africa. In Turkey, nearly all patients with HDV are infected with genotype 1, which has been associated with more severe disease.

HDV requires HBsAg to complete its life cycle. Moreover, hepatitis B virus (HBV)‐infected individuals are at risk for having HDV coinfection or superinfection. Coinfection with HDV is commonly associated with a more rapid progression to cirrhosis, a higher incidence of hepatocellular carcinoma, and increased liver‐related morbidity and mortality compared with CHB alone.

The geographic distribution of HDV infection varies and is heterogeneous. HDV infection remains endemic in many developing countries. High‐prevalence areas include central and West Africa, the Mediterranean Basin, the Middle East, Eastern Europe, Northern and Southeast Asia, and the Amazon Basin of South America.², ⁴ The seroprevalence of HDV infection in central Asia was 8.3% in the general population and 51.3% in HBsAg‐positive patients; this prevalence is higher than that of South and East Asia (0.36%‐0.69% and 17.5%‐10.1%, respectively).³, ⁴ Table 1 shows the prevalence of HDV among HBV carriers and the general population in Asia and the Middle East.², ³, ⁴, ⁵, ⁶, ⁷ The prevalence was the highest in Mongolia, with 8% in the general populations and 83.3% in HBsAg‐positive patients. In fact, the prevalence of hepatocellular carcinoma in Mongolia is the highest in the world. In Uzbekistan, approximately 80% of patients with HBV‐related cirrhosis were coinfected with HDV, and HDV is the major cause of liver‐related morbidity and mortality. Although HDV prevalence is also high in Taiwan, it was very low in nearby Japan and Korea despite a similar high endemicity of HBV, suggesting that HDV may differ in the capacity to superinfect different populations of HBsAg carriers. However, declines of HDV occurred in the 1990s in Taiwan, from 23.7% to 4.2%.⁵ Previous studies reported that HDV infection is highly endemic in the eastern Mediterranean region and the Middle East; the overall prevalence of anti‐HDV is approximately 15%.⁸ Several factors, such as the prevalence of HBV infection and genetic and environmental factors, are associated with the seroprevalence of HDV. Migration of populations from endemic countries is also associated with high prevalence of HDV, especially in eastern Europe. According to the results of an epidemiological study in 2009, HBsAg positivity in the Turkish population was 4%.⁷ It is estimated that approximately 2 million adults were infected with HBV, and anti‐delta antibody positivity was detected in 2.8% of HBsAg‐positive patients.⁷ The prevalence of HDV was higher in southeastern and eastern Turkey.

TABLE 1.

Summary of Regional Prevalence Estimates of HDV in HBV Carriers and General Populations in Asia and the Middle East², ³, ⁴, ⁵, ⁶, ⁷

Region (Asia and the Middle East)	Prevalence in General Population (%)	Prevalence in HBV Carriers (%)
China	0.45	0.9‐5.6
Mongolia	8.03	61‐83.3
Pakistan	2.43	17‐34.1
Taiwan	NA	4
Korea	NA	0.32
Japan	0.73	6.31
Iran	0.1	3.9‐6.4
Saudi Arabia	0.39	3.3‐7.9
Turkey	0.03	2.8‐14.4
Vietnam	0.24	8.54
Yemen	0.14	0.52

HDV shares some epidemiological patterns with HBV. The risk for HDV infection is high in injection drug users, hemodialysis patients, individuals with multiple sexual partners or high‐risk sexual behavior, patients with human immunodeficiency virus or hepatitis C virus infection, and people from endemic areas.², ⁴ In 1980, the anti‐HDV rates in HBsAg‐positive patients were approximately 17% in southern Europe and more than 90% in Southeast Asia.⁵ Despite the reduction of HBV in injection drug users, HDV infection is still endemic in injection drug users in Asia, even in developed countries.

HDV requires HBV to complete its life cycle; therefore, all HBV‐infected individuals should be screened for HDV. Diagnosis of the HDV infection is mainly based on serological and molecular viral load assays. There are many issues in the screening and diagnosis of HDV infection. Detection of HDV antigen is an indicator of acute infection. Serum HDV antigen can be detected by either enzyme‐linked immunosorbent assay (ELISA) or radioimmunoassay but is less sensitive than measuring HDV RNA.⁹ ELISA for anti‐HDV is the first‐line screening test. A positive test result implies previous or ongoing exposure to virus. Although the sensitivity of ELISA tests is high, populations with low prevalence have lower positive predictive values and higher false positivity rates. Anti‐HDV was investigated semiquantitatively by determining the signal/cutoff (S/CO) ratio; in addition to anti‐HDV ELISA results, reporting of the S/CO ratio and determining each laboratory’s optimal cutoff value may be helpful for the accurate diagnosis of HDV infection.¹⁰ Recently, a new serological test (a novel quantitative microarray antibody capture [Q‐MAC] assay) has been developed, with higher sensitivity in antibody measurement and viremia detection compared with current ELISA tests across the different HDV genotypes. The Q‐MAC assay’s sensitivity was 10⁶‐ and 10³‐fold higher than the commercial anti‐HDV immunoglobulin G ELISA kit and western blot analysis.¹¹

If a positive result is detected by serology, an HDV RNA test should be done to confirm the infection. Serum HDV RNA can be detected by both qualitative and quantitative reverse transcription polymerase chain reaction (RT‐PCR) assays. The available commercial HDV RNA viral load tests are more standardized compared with the previous decade. Sensitivity was markedly improved (Fig. 1).¹² Nucleic acid amplification techniques detect HDV RNA are the most sensitive to confirm active disease and determine treatment response.¹³

FIG 1.

HDV RNA sensitivity with different tests. Adapted with permission from Methods in Molecular Medicine.¹² Copyright 2004, Humana Press.

Early diagnosis and treatment should be considered for all patients with HDV infection. The ideal goal of any treatment is not only clearance of HDV but also clearance of HBsAg. HBV vaccination is the most effective way to prevent HBV infection and also HDV coinfection. In Turkey, three doses of HBV vaccinations were added to the childhood vaccination program in 1998. Since 2016, the successful vaccination rate has been 98%.¹⁴ In addition, the Turkish Viral Hepatitis Prevention and Control Program was implemented in October 2018.¹⁴ Moreover, the incidence of acute HBV infection in Turkey in childhood has gradually decreased. Therefore, successful vaccination programs, public health measures, and national viral hepatitis road maps will eventually decrease HDV seroprevalence in Asia and eastern European countries.

Current treatment of CHD is pegylated interferon (PEG‐IFN) for 48 weeks. Previous studies reported that PEG‐IFN treatment was beneficial for HDV infection in terms of serum aminotransferase levels reduction and HDV RNA clearance in some patients, but the response was poorly sustained after discontinuation of PEG‐IFN treatment. Sustained virological response rate with PEG‐IFN treatment varies from 21% to 43%.¹⁵ Some studies have shown no additional benefit in giving treatment for 96 weeks rather than 48 weeks.¹⁶ Unfortunately, there is no therapeutic option for patients who do not improve with PEG‐IFN treatment. Nucleos(t)ide analogues with or without PEG‐IFN treatment are ineffective against HDV.¹⁷ Also, combination therapy with ribavirin does not improve outcomes.¹⁸

Many drugs, such as entry inhibitors, prenylation inhibitors, and HBsAg release inhibitors, are in the pipeline. These compounds are in preclinical and clinical development. Prenylation, the process by which proteins are modified, plays a vital role in the life cycle of HDV, and distribution of prenylation of the large delta antigen prevents its ability to interact with the HBsAg. Lonafarnib inhibits the farnesyl transferase enzyme, which is involved in the prenylation process. Lonafarnib significantly reduced HDV viral load in patients with CDH in a placebo‐controlled phase 2 trial study, and HDV RNA decline significantly correlated with serum drug concentrations.¹⁹

In conclusion, the prevalence of HDV infection remains unknown and is still endemic in Asia, as well as in many developing countries. The prevalence among injection drug users and individuals with high‐risk sexual behaviors is high. HDV infection represents a major health problem associated with increased liver‐related morbidity and mortality. More reliable and sensitive serological diagnostic tests for HDV are necessary. HDV screening should be recommended in all HBV‐infected individuals. Currently, the only evidence‐based effective therapy for CHD is PEG‐INF treatment.