ABSTRACT

Hepatitis delta virus (HDV) infection is an important health and economic problem worldwide. There are approximately 15 million patients with HDV worldwide and effects of 5-10% of all hepatitis B virus (HBV) infections globally. Chronic HDV infection results in 3 times more hepatocellular carcinoma (HCC) and 2 times more hepatic decompensation in cirrhosis patients compared with chronic HBV infection. HDV is associated with a higher economic burden than both HBV and hepatitis C virus (HCV) infection alone. Unlike HBV, HDV infection progresses to liver cirrhosis in 5 years, to HCC in 10 years. Risk factors for HDV infection are hepatitis B surface antigen (HBsAg) positivity, intravenous drug use, multi-partner sexual behaviors, anti-human immunodeficiency virus positivity, anti-HCV positivity, men who have sex with men, healthcare workers, immigrant people moving from high HBV infection endemic areas, prisoners, hemophiliacs, poor hygienic conditions, and low economic income. From West to East, HDV prevalence increased in both patients with chronic active hepatitis (CAH) and cirrhosis. However, the prevalence of HDV infection decreased both CAH and cirrhosis after 1995 in Turkey. Amazon basin, Indian population living in Venezuela, and the Santa Marta region of Colombia are areas of the highest HDV prevalence. Due to immigration from high HBV infection endemic areas to industrialized countries, Delta infection continues stably 5-10 % in HBsAg carriers. Each HBsAg-positive patient should be checked for anti-delta antibody to prevent rapid progress of parenchymal liver diseases.

Keywords:

HDV, anti-HDV, cirrhosis, hepatitis, liver

Introduction

Hepatitis delta virus (HDV) infection is an important health and economic problem all over the world, particularly in endemic areas such as the Mediterranean, Southern and Eastern Europe, the Middle East regions and Turkey. It was reported in the United States of America (USA) that the annual cost of HDV infection was 23,605$, which was 1.32 times higher and significantly more expensive than the annual cost of hepatitis B virus (HBV) infection (1).

HDV: HDV is a small, 36 nm in diameter, defective, negative single-stranded RNA virus requiring hepatitis B surface antigen (HBsAg), which allows HDV to enter hepatocytes. The virus was discovered by Rizzetto (2) in 1977. HDV is wrapped in HBsAg. HBV outer surface antigens such as large (Pre S1), medium (Pre S2), and small antigens are peripherally located surface proteins. Small and large delta antigens and single-stranded HDV-RNA take part in the central portion. Small HD Ag is essential for initiating viral replication, while large HD Ag is necessary for the assembly of new viral particles. Unlike the other RNA viruses, HDV uses host HDV polymerases for viral replication.

Epidemiology of HDV

HDV genotypes: Up to now, eight genotypes of HDV have been reported. Genotype 1 is common in Turkey as well as in North America, Europe, North Africa, Mediterranean countries and the Middle East. Sequence analysis has shown 82-95% similarity in patients with genotype 1. However, high genetic diversity was observed among the isolates, with a mean full-length dissimilarity score of 13.05% (3,4,5). Genotype 3 causes fulminant hepatitis and epidemics in East and South American countries (6).

HDV infection: There are approximately 15 million patients with HDV worldwide. It consists of 5-10.6 % of all HBV infections globally (7,8). People of the Amazon basin and Indian population living in Venezuela and the Santa Marta region of Colombia have long been known to have the highest HDV prevalence in the world (9). Reservoirs and transmission patterns of HDV infection are by nature in accordance with HBV infection. Delta prevalence was initially less than 5% in adults under 30 years of age and when the patients were over 40, the prevalence was around 20-33% in 1993 (9). Değertekin et al. (10) reported in a meta-analysis that HDV prevalence was found to be 84.9% in inactive HBsAg carriers, 20% in patients with chronic active hepatitis (CAH) due to HBV, 32.5% in patients with liver cirrhosis (LC). However, these prevalence rates have decreased from 20% to 11% in CAH, from 32% to 24% in LC patients in the last two decades (10).

Course of HDV infection: Chronic HDV infection is seen mostly during the 5^th decade. It is associated with acute simultaneous co-infection of HBV and HDV, which results in mostly resolution of HBV infection but rarely causes severe or fulminant hepatitis; or superinfection, which is accelerated progressive replication of HDV and finally causes CAH, LC, hepatocellular carcinoma (HCC), and death (9). High HDV-RNA levels are commonly associated with high fibrosis scores, high necro-inflammations, high aspartate transaminase (AST) and alanine transaminase (ALT) levels, and lower albumin levels (11). When patients with chronic HBV are infected with HDV, approximately 76% of those patients may have chronic HDV infection within three years. Chronic HDV infection results in three-fold more HCC. In addition, it results in LC in a shorter period, which was observed 10-15% of patients within two years, in 30% of patients within 3 years. Moreover, hepatic decompensation was observed 2 times more compared with chronic HBV infection (1,7,12,13). Overall, HDV infection progresses to LC in 5 years, to HCC in 10 years (14).

Overall HDV prevalence: HDV prevalence of patients with acute, chronic, or fulminant hepatitis are 3-10 times more common compared with HBV seroprevalence (9). In a meta-analysis assessing 182 studies in 61 countries; the overall HDV prevalence was found to be 0.98% in HBsAg positives, where the pooled prevalence was found to be 14.6%. It was 37.6% in patients using intravenous drugs and 17% in patients with high-risk sexual behaviors (15). In a recent and large meta-analysis containing 120,293 patients in 282 studies, HDV prevalence was found to be 0.16 in the general population, 4.5% in HBsAg positive patients, 16.4% in patients who were followed by the outpatient liver clinics, 18% in patients with LC, 20% in patients with HCC (16).

Acute HBV infection and HDV

During acute HBV infection, HDV positivity rates were found to be 8.1% out of 766 patients in Turkey; 4% in Turin, and 91% in Naples out of 687 patients in Italy, and 0% out of 342 patients in Japan (10,17,18). In a meta-analysis in Turkey, the overall HDV positivity rate was 8.8% in 833 patients with acute hepatitis B (10).

Seroprevalence studies

Seropositivity of HBsAg and anti-delta immunoglobulin G (IgG) was checked in 29,960 volunteer persons from east to west parts of Turkey. Seropositivity of HBsAg and anti-delta IgG was found to be 1,805 (6.02%) and 43 (2.39%) out of 1,805 HBsAg positives; respectively (19). Accordingly, seroprevalence of HBsAg, anti-hepatitis C virus (anti-HCV), and anti-HDV was searched in volunteers; 19,250 persons during the years 2004-2006 in Urfa; and in 2012 individuals between 2007 and 2009 in Bolu. HDV seroprevalence was found 2.5% in Urfa but 0% in Bolu (20).

Chronic HBV-related liver disease and HDV

1. Data from Turkey

Viral hepatitis is one of the significant public health concerns in Turkey (21). Chronic HDV infection is endemically seen in countries where HBsAg positivity is common. It was reported that the positivity of HBsAg is 4% in a pivotal study in Turkey (22). In several studies, HDV rates were found between 1.76-6.8% of patients with HBsAg positive status in İzmir and this rate decreased from 5.2% in 2018 to 3.4% in 2019 (10). Similarly, HDV rates varied between 1.8% and 4.1% in İstanbul during the years between 2012 and 2019 (22,23,24,25,26,27,28,29,30) (Table 1). In East and Southeast provinces of Turkey, which have lower economic status, HDV prevalence rates in HBsAg positives were found to be 4-18.7% between 2002 and 2017 (31,32,33,34,35,36,37,38,39,40) (Table 2). In the central part of Anatolia, the HDV prevalence rate was reported as 23.9 % in 1986 (41). However, this rate became stable between 1.9% and 4.2% during the years 2000 and 2013 in Ankara and Konya (42,43,44,45) (Table 3).

In a meta-analysis, 6,734 patients with CAH and 1,503 patients with LC were investigated in terms of HDV prevalence. From Western to Eastern Turkey, HDV prevalence increased in patients with CAH (from 5% to 19.6%) and LC (from 32.1% to 46.3%). However, both CAH (to 12%) and LC decreased to 27% after 1995 in Turkey (46). The reasons for the decrease in delta prevalence are the augmented hygienic measures, such as the use of disposable syringes, the decrease in sexual activity with multi-partners, the increase in awareness of HDV infection, improving education and socio-economic levels, and the vaccination of HBV.

In another study, HDV prevalence was found to be 1.56% of 2,314 patients with HBsAg positive status in Samsun, the Northern part of Anatolia, between 2005 and 2010 (47). In İzmir, located at the western tip of the country, it was found to be 6.8% among HBsAg carriers (48).

In a meta-analysis, anti-HDV positivity rates varied widely between 0.5-16.2% (mean was 4.9%) in 6,613 inactive HBsAg carriers. It decreased from 5.4% to 2.9%, years from 1991 to 2005. In the same paper, it was reported that HDV positivity in 5,961 patients with CAH-B and in 1,421 patients with LC was 20% and 32%, respectively. These rates increased from west to east. However, these ratios decreased in the West, Central, and East Anatolia years between 1980 and 2005. Anti-HDV positivity in patients with HCC was found 23% of 748 patients, but it varied widely from east to the west of Anatolia (10).

In another meta-analysis comprising 30 original studies, 6,734 patients with chronic liver diseases (n=5231) and LC (n=1503) were analyzed in terms of HDV seropositivity. When it was compared to anti-HDV seropositivity between east and west parts of Turkey, it was found that the prevalence of HDV was the lowest (5% and 20%; p<0.0001) in the west and the highest (27% and 46%; p<0.0001) in the southeast part of Turkey for chronic liver diseases and LC. However, when it was compared to HDV prevalence; both west and east, before and after the year of 1995; for chronic liver diseases and LC, it was reported that HDV prevalence decreased in both diseases after the year 1995. In conclusion, chronic delta infection is the most common of Turkey and is responsible for 1/4^th of patients with CAH and 1/2^nd of patients with LC in that area (46).

In a study from Elazığ located in the eastern part of Turkey, including the 2006-2009 period, 282 patients with CAH-B were investigated in terms of anti-delta seropositivity and HDV-RNA, and liver biopsy was performed. Anti-delta was positive in 128 (45.5%) patients. HDV-RNA was detected in 56.9% of patients. There was a close relationship between liver fibrosis stage, ALT levels, and serum albumin levels. HDV-RNA levels were higher in patients with high fibrotic stage and elevated ALT levels but low albumin levels. In patients with chronic HBV, chronic HDV infection and LC were 23.4% and 29.4%, respectively (11).

2. Global Data

In a meta-analysis analyzing 182 articles from 61 countries, it was reported that the global prevalence of HDV was 0.98. HDV prevalence was 14.57% in patients with HBsAg positive status; 37.57% in patients with intravenous drug users; 17.01% in patients with high-risk sexual behavior (15). In another meta-analysis, which included 282 studies from 95 countries, it was reported that the estimated global HDV prevalence among HBsAg-positives was 4.5%. In the general population, it was 0.16%, and in patients with LC and HCC were 18% and 20%, respectively (16).

In a meta-analysis including 332,155 people from 83 countries, it was reported that pooled HDV prevalence was 0.80 in the general population. HDV prevalence in HBsAg carriers was 13% out of 27,1,629 people in 83 countries. It was 26.75% in acute fulminant hepatitis and 25.77% in LC. HDV infection, which is highly prevalent in Central Asia, East and South Europe, Central Latin America, and Central and West Sub-Saharan Africa, was the leading cause of 19.8% of HCC. First in Asia, primarily in China (44.41%) and India (56.55%), then in Africa (22.30%) particularly in Nigeria (38.37%), HDV prevalence were predominant (14).

HDV prevalence was found to be higher than 20% in patients with HBsAg positivity between 1980 and 1990, and it decreased to 5-10% after 1990, most particularly due to HBV vaccination (49).

Buti et al. (50) reported from Spain that HDV prevalence was 1% until 1995. However, it increased to 28% between 1996 and 2008. Recently, HDV prevalence seems stable in West European countries; 8.5% in England, 8.1% in Italy, 11% in Germany (50).

HDV infection rates vary according to endemic areas, such as countries with limited resources in Africa, South America, throughout the Western Pacific (27.7%), Kiribati and Nauru Islands (84%) as high endemic areas; Mediterranean Basin, Italy (25%), Taiwan (24.7%) as intermediate endemic areas; North America, Korea; and cold areas with a low prevalence of HCV, HBV infection (0.85%) (51,52,53,54,55,56,57,58,59,60,61,62) (Table 4). The reason for wide differences the prevalence of HDV infection among all countries is associated with local socio-economic differences, genotype and virulence differences of HDV, and genetic differences of ethnic groups (63).

Immigrants and HDV Infection

In a study reported from USA, the overall estimated prevalence of HBsAg was found to be 0.36% and 3.4% in non-Hispanic Asian population between 2011 and 2016. However, the prevalence of HDV was found 42% in HBsAg carriers. HDV prevalence was 45% in Asian HBsAg-positive adults, while it was found 39% in HBsAg-positive adults of all other races (64). This study indicated that HDV seroprevalence was significantly higher in the United States than previously acknowledged, and it was disproportionately higher among Asians and persons born outside the United States.

HDV prevalence increased from 4.1% to 6.2% (p<0.06) among 1,307 HBsAg carriers in Dusseldorf between 1989 and 2008. Similarly, HDV prevalence increased from 32.1% to 46.2% in the former Soviet Union and from 0 to 17.2% in Africa. Seemingly, the reason for this increase is immigrants from high endemic areas of HBsAg carriers (49).

HDV prevalence in Italy was found to be 6.4% in native Italian and 26.4% in non-native Italian population in 2019 (58). Manesis et al. (62) reported that HDV prevalence was found 4.7% among 4,673 persons in Greece. However, this ratio was 2.8% in Greek people compared to 7.5% non-Greek immigrants (62). Hence, immigration seems to be a great facilitator for HDV spread in the community.

Use of Blood and Blood Products and HDV

Delta prevalence in patients with hemophilia and poly-transfused carriers was found to be significantly higher than in non-poly-transfused HBsAg carriers. In a multicentric study, HDV prevalence was found 50% in Italy, 48% of 273 patients with hemophilia in Maryland (65). HDV prevalence was found 6.98% of 6200 blood donors in Diyarbakır (38). This rate was found 3.8% in America (7).

HIV and HDV Co-infection

There was a close relationship among HDV, human immunodeficiency virus (HIV), and intravenous drug users (66). HDV infection predisposes co-infections such as HDV/HBV/HCV or HBV/HDV/HIV or HBV/HDV/hepatitis E virus (HEV) infections compared to HBV infection alone (25,61,67). HDV/HIV co-infection varies from 5% to 10.6% in the world, from 6% to 14% in North America and Europe, and from 10% to 20% in Asia and Africa (7). Soriano et al. (68) reported that HBsAg was positive in 1,319 (7.9%) out of 16,597 patients with HIV (EuroSIDA study) in European countries. HDV prevalence was found in 422 (14.5%) patients with CAH B and HIV carriers (68). The combination of HBV and HIV infection progresses fast to chronic liver diseases. HCV is also a major cause of chronic liver diseases in patients with HIV (69). The most common cause of HIV, HBV, and HDV co-infection is intravenous drug use due to the similar transmission of those hepatotropic infections (70). Four hundred and eighty-four patients with HIV were assessed for hepatotropic virus in Buenos Aires. The prevalence of hepatitis B core antibody (58.5%), anti-HCV (14.5%), and anti-HEV (6.6%); were found to be higher than the control cases (p=0.001). Delta prevalence was 1.9% in those populations (71).

Sexual Associations

In an U.S. study, the prevalence of anti-delta in patients with men having sex with men varied from city to city. It was 0% in Chicago, 9.4% in San Francisco, 1.3% in Pittsburg, and 15.1% in Los Angeles. In addition, HDV prevalence was found to be 14.3% in 40 homosexual men in France and 21.73% in 154 homosexual men in Italy (72,73).

Intravenous Drug Use and HDV Infection

It is assumed that the number of persons who are using intravenous drugs is 10.6 million worldwide in 2016. Half of this population has been living in China, Russia, and U.S (7). In a study from U.S, 1,368 female prostitutes were checked for HBV and HDV viral markers and intravenous drug use. Fifty-six percent of them were HBsAg positives, 74% were intravenous drug users, and 38% were non-intravenous drug users. The HDV prevalence of patients who had HBsAg positive and intravenous drug users was 21%, while it was 6% in patients with non-intravenous drug users (74). Hence, intravenous drug use, even by inhalation, increases the risk of HBV, HCV, HIV, and HDV infections (75). Moreover, in Worcester, Massachusetts 135 patients with acute hepatitis were diagnosed due to intravenous drug use between 1983 and 1985. Eleven patients out of 13 with fulminant acute hepatitis died, and acute delta co-infection was found to be 54% among parenteral drug users (76).

HDV prevalence was checked in 194 intravenous drug users in 1988-1989 period and in 258 patients between 2005 and 2006 in Baltimore. HDV prevalence decreased from 15% to 11% between these two periods (77). Ninety-nine intravenous drug users were checked for anti-delta serology during 1972-1975 period in Washington, D.C., Miami, and New Jersey. Anti-delta was found to be positive in 10.1% of 99 patients and in 42.1% of intravenous drug users (78).

Eighty-eight HBsAg positive patients with intravenous drug users were searched in terms of anti-HDV and anti-HIV in New York city from 1985 to 1986. Anti-delta and anti-HIV were found positive in 67% and 58%, respectively. The presence of anti-delta and intravenous drug use were significantly associated with older age, longer duration of drug abuse, and presence of liver disease. The presence of anti-HIV and intravenous drug use are associated with younger age and increased serum globulin levels (79). Consequently, intravenous drug use is a noteworthy factor to facilitate the transmission of HDV infection.

Prisoners

In Taiwan, 1,137 prisoners were checked for HBsAg, anti-HCV, and anti-delta. Eighty-nine and 2% of these patients were intravenous drug users, and none were anti-HIV positive. HDV prevalence was 3.4% and triple infection (HBV, HDV and HCV) rate was 2.8% (80). In addition, inmates at Boston Municipal House were assessed for HBV and HDV in 1985. HBV markers were detected in 173 (43%) out of 406 inmates, whereas HBV markers were found in 10 (8%) out of 129 staff. Fourteen inmates (8%) had anti-HDV positivity among 173 inmates who had positive HBV markers, but no one had anti-delta (0%) among the staff. Intravenous drug use was found to be the strongest risk factor for the detection of HBV and HDV markers (81).

Mental Disorders and HDV Infection

Four thousand six hundred and seventy-one patients with mental retardation were searched in terms of HBsAg and anti-HDV in Illinois, USA in 1984. HBsAg was found in 238 of 4,671 patients. Seventy-one (29.8%) out of 238 patients had anti HDV (82). Hence, mentally disabled populations may impose significant risks for HDV infection.

Conclusion

Delta infection still causes health and economic problems, particularly in endemic countries. HDV infection is associated with HBV epidemiology and is significantly more common with intravenous drug use, multi-partner sexual behaviors, anti-HIV positivity, anti-HCV positivity, men who have sex with men, healthcare workers, immigrant people moving from high endemic areas, prisoners, hemophiliacs, poor hygienic conditions, and in those living in low economic income countries (14,15,16,51,83,84,85). Hence, delta infection continues stably 5-10% in patients with HBsAg carriers. Every patient with HBsAg positivity should be checked for delta infection to protect against the rapid progression of parenchymal liver diseases.

Ethics

Peer-review: Internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: N.Ö., H.E., Concept: N.Ö., H.E., Design: N.Ö., H.E., Data Collection or Processing: N.Ö., H.E., Analysis or Interpretation: N.Ö., H.E., Literature Search: N.Ö., H.E., Writing: N.Ö., H.E.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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