INTRODUCTION — Hepatitis D is caused by a defective virus: the hepatitis D virus (HDV). HDV is often referred to as hepatitis delta virus or delta agent. However, the term HDV is preferred.
HDV infection is closely associated with hepatitis B virus (HBV) infection. Although HDV can replicate autonomously [1], the simultaneous presence of HBV is required for complete virion assembly and secretion. As a result, individuals with hepatitis D are always dually infected with HDV and HBV. Due to interference mechanisms that are not well understood, HBV replication is suppressed in most HDV-infected individuals.
This topic review will provide general information concerning the HDV structure and replication strategy, the nature of its strict association with HBV, and the epidemiology, pathogenesis, and clinical features of HDV infection. Issues related to diagnosis, treatment, prevention, and liver transplantation are discussed separately. (See "Diagnosis of hepatitis D virus infection" and "Treatment and prevention of hepatitis D virus infection" and "Liver transplantation in adults: Prevention and management of hepatitis D virus recurrence after liver transplantation".)
VIRION STRUCTURE — The HD virion comprises an RNA genome, a single HDV encoded antigen, and a lipoprotein envelope provided by HBV (figure 1).
HDV genome — The HDV genome is a small RNA molecule (1676 to 1683 nucleotides in size) bearing some structural analogies with plant viroids and virusoids [1]. HDV RNA is a single-stranded circle, with a high degree of self-complementarity and G+C content causing the circle to collapse as a rod-like structure [1]. Significant sequence heterogeneity (as high as 40 percent) exists among the different HDV isolates that have been sequenced, and a classification into eight HDV genotypes has been proposed [2].
Hepatitis D antigen — The only antigen associated with HDV, the hepatitis D antigen (HDAg), is a structural component of the virion. It consists of a protein encoded by an open reading frame present on the RNA strand complementary to the RNA genome (antigenomic strand) [1]. Approximately 70 molecules of HDAg are complexed with each molecule of HDV RNA to form the viral ribonucleoprotein.
Two forms of HDAg are co-expressed in infected individuals. Each HDAg has a different function as described below. (See 'HDV life cycle' below.)
The two HDAg molecules differ by 19 amino acids at the C-terminus; the molecular weights are approximately 24 and 27 kilodaltons (kd). Their synthesis arises via an RNA editing process during HDV replication [3]. (See 'HDV life cycle' below.)
●The stop codon UAG of the messenger RNA directing the synthesis of the HDAg causes the translation of HDAg to terminate, thereby giving rise to the small HDAg. During HDV RNA replication, this stop codon is deaminated on the antigenomic HDV RNA by a cellular enzyme (the adenosine deaminase acting on RNA 1, ADAR1) to UIC (in which "I" stands for inosine).
●During the next replication cycle, the "I" on the antigenomic RNA is read as a "G," leading to the replacement of the "A" with a "C" in the genomic HDV RNA. During the transcription of the messenger RNA directing the synthesis of the HDAg, the "C" will lead to the replacement of the UAG stop codon with a UGG codon, which directs the incorporation of tryptophan into the nascent HDAg. Translation of HDAg then proceeds until a new stop codon is reached, 19 amino acids downstream, thereby giving rise to the large HDAg.
Lipoprotein envelope of HDV — The lipoprotein envelope of HDV is provided by the HBV and consists of the same proteins (large, middle and small S) that are found in the HB virion; their relative proportion depends upon the level of HBV replication [4].
HDV LIFE CYCLE — HDV replicates at very high levels in hepatocytes [5]. The sodium taurocholate cotransporting polypeptide (NTCP), which is the receptor for hepatitis B virus, has also been identified as the receptor for HDV [6,7]. (See "Characteristics of the hepatitis B virus and pathogenesis of infection", section on 'Replication cycle'.)
The steps in HDV replication cycle can be summarized as follows:
●Once inside the hepatocyte, HDV RNA is found within the nucleus, where it is transcribed into its complementary RNA (antigenomic HDV RNA). Two forms of antigenomic HDV RNA exist: a 0.8 kilobase (kb) RNA, which is the messenger RNA being translated into the HDAg [8], and the full-length 1.7 kb RNA, which is the template directing the transcription back into the HDV genome [1]. The host RNA polymerase II appears to be involved in the transcription of the 0.8 kb mRNA in a process that is regulated by direct binding with the HDAg itself [9,10]. In addition, the transcription of the full-length genomic and antigenomic RNAs occurs by the cellular RNA polymerase II [11].
●HDV RNA replication is activated by the small HDAg through direct binding of the HDAg to the HDV RNA.
●The large HDAg suppresses HDV replication. In addition, it directs packaging of the HD virion through an interaction between the extra 19 amino acids at the C-terminal end and the small S protein (surface antigen of the hepatitis B virus [HBsAg]) of the helper HBV [3].
●Completion of the HD virion assembly and release is dependent on the simultaneous presence of HBV which provides the envelope.
HDV INFECTION — Due to its dependence upon HBV, HDV infection always occurs in association with HBV infection. The clinical and laboratory findings vary with the type of infection (table 1). (See "Diagnosis of hepatitis D virus infection".)
Coinfection — Coinfection of HBV and HDV in an individual susceptible to HBV infection (ie, anti-HBs-negative) results in acute hepatitis B + D. This entity is clinically indistinguishable from classical acute hepatitis B and is usually transient and self-limited. However, a high incidence of liver failure has been reported among injection drug users [12].
The rate of progression to chronic infection is not different from that observed after classical acute hepatitis B, since persistence of HDV infection is dependent upon persistence of HBV infection [13].
Superinfection — HDV superinfection of a chronic HBsAg carrier may present as a severe acute hepatitis in a previously unrecognized HBV carrier, or as an exacerbation of preexisting chronic hepatitis B. Progression to chronic HDV infection occurs in almost all patients [14]. However, HBV replication is usually suppressed by HDV.
Pathogenesis of HDV-induced hepatitis — The detailed mechanisms by which HDV induces liver damage are unknown. However, the pathogenesis of hepatitis D-related liver disease appears to depend on the interplay of three major factors:
●HDV-associated factors, such as genotype [15] and the expression of specific HDAg species [16]
●Host-associated factors, such as the immune response
●Helper virus-associated factors, such as the HBV genotype and the level of HBV replication [17]
HDV is believed to cause directly cytopathic damage during acute infection, whereas immune-mediated damage predominates during chronic infection [1].
NATURAL HISTORY OF CHRONIC HEPATITIS D — The clinical sequelae of HDV infection encompass a spectrum of manifestations from acute liver failure to the asymptomatic carrier state. The severity of the clinical course is influenced by several factors (eg, persistent HDV replication, HDV genotype).
As an example, a study of 299 patients followed for up to 28 years found that persistent HDV replication was associated with annual rates of development of cirrhosis and HCC of 4 and 2.8 percent, respectively [18]. The only predictor of liver-related mortality was persistent HDV replication.
Other studies have suggested that clinical outcomes may be related to the different HDV genotypes [15,19,20]. HDV genotypes and, more interestingly, specific clinical features of hepatitis D, seem to cluster in distinct geographical areas. However, superinfection, or mixed infection with different genotypes can occur, particularly in patients who are at high risk for multiple exposures. In such patients, a single genotype usually predominates, with the minor genotype representing only approximately 10 percent of the total viral population [21].
Genotype 1 — In the Western world, where the predominant genotype is genotype 1 [20], acute hepatitis D has an increased risk of acute liver failure when compared with acute hepatitis B [12]. Once chronic HDV infection is established, it usually exacerbates the preexisting liver disease due to HBV [14]. Progression towards cirrhosis may be rapid [22,23]. HDV-associated chronic liver disease may also run an indolent course [24] and asymptomatic HDV carriers have been found in some geographical areas [25].
Patients who are currently referred for HDV infection appear to represent cohorts infected years ago in whom the HDV-related disease rapidly developed to cirrhosis, but whose subsequent disease progression has been slow. This was illustrated in a report from Italy in which the estimated 5- and 10-year probability of survival free of liver transplantation in patients who had already developed clinically overt cirrhosis was 49 and 40 percent, respectively [26]. A more ominous course toward liver decompensation has been documented in patients with active HBV and HDV replication [17].
Whether superimposed HDV infection accelerates the development of hepatocellular carcinoma in patients with HBsAg-positive cirrhosis is controversial. However, a retrospective study involving 200 patients with compensated HBV-related cirrhosis, of whom 20 percent were anti-HDV positive, found that HDV infection increased the risk of HCC threefold and mortality twofold [27]. After adjustment for clinical and serological differences at baseline, the estimated five-year risk for developing HCC was 13, 4, and 2 percent for anti-HDV-positive/HBeAg-negative, anti-HDV-negative/HBeAg-negative, and anti-HDV-negative/HBeAg-positive patients, respectively. The corresponding figures for hepatic decompensation were 18, 8, and 14 percent, respectively.
Genotype 2 — In the Far East, where the predominant genotype is genotype 2, there is a reduced risk of acute liver failure and rapidly progressive liver disease [19,28].
Genotype 3 — Severe outbreaks of acute hepatitis D with a high incidence of acute liver failure have been reported among the Yukpa Indians of Venezuela [29], the Sierra Nevada de Santa Marta in Colombia [30], and some remote areas of the Brazilian [31] and Peruvian [15] Amazon basin. Viral factors have been postulated to be related to the fulminant course in these outbreaks, as HDV isolates from Colombia and Peru belong to a distinct viral genotype denoted genotype 3 [15].
Other genotypes — At least five additional HDV genotypes have been described [2,32]. Sequences previously assigned to genotype 2b are now classified as genotype 4, and African sequences seem to cluster into four additional genotypes, named from 5 to 8. These new genotypes are less well characterized as to their disease features compared with genotypes 1 to 3.
EPIDEMIOLOGY OF HDV INFECTION — Hepatitis D virus (HDV) is endemic in certain geographic areas; however, in others, HDV is predominantly confined to high-risk groups (eg, injection drug users, individuals who have received multiple transfusions in the past, and persons who emigrated from countries with a high prevalence of HDV infection).
Data on HDV epidemiology have mostly been gathered in chronic hepatitis B virus (HBV) carriers superinfected with HDV, in whom HDV infection has progressed to chronicity. HDV antibody (anti-HDV) is present in high titers in these patients, and the prevalence of chronic HDV infection can be reliably determined.
However, the incidence of acute hepatitis D may be underestimated [33]. Although the commercial availability of assays for the detection of anti-HDV has improved our understanding of the epidemiology of HDV infection, these assays have limitations. As an example, in acute hepatitis D, anti-HDV appears very late and may be missed if repeated testing is not performed. This is especially true in immunocompromised individuals (eg, patients with HIV) in whom a strong antibody response to HDV may be delayed or absent. Furthermore, after resolution of acute hepatitis D, anti-HDV may disappear with time. Thus, in some patients, recognition of past HDV infection may be impossible. More detailed discussion of diagnostic testing is presented elsewhere. (See "Diagnosis of hepatitis D virus infection".)
Prevalence of disease — The prevalence of HDV in patients with chronic HBV infection varies across studies. Most historical data suggest that approximately 15 to 20 million of the 257 million HBV carriers worldwide may be infected with HDV [34,35], and in a more recent report, the global HDV burden was estimated at around 12 million people [36]. However, in other reports, the prevalence was higher. As an example, in one systematic review and meta-analysis, the HDV pooled prevalence in the global HBsAg-positive population (excluding drug users and persons with high-risk sexual behavior) was estimated at around 10.6 percent, approximately twice that of previous estimates [37]. The prevalence of HDV among HBV carriers was even higher (13 percent) in another study, corresponding to 48 to 60 million infections globally [38]; in this report, the HDV prevalence was estimated at 25.8 and 19.8 percent in HBV patients with cirrhosis or hepatocellular carcinoma, respectively. These variations may be due to lack of high-quality data, which is in due in part to under-testing of HDV in persons with chronic HBV infection, as well as lack of population-based studies.
Geographic distribution — HDV is not distributed uniformly across the globe, and the geographic distribution of HDV infection does not parallel that of HBV. As an example, there is a high prevalence in Mongolia, Moldova, and some countries in Western and Middle Africa [36], whereas other areas, including many Asian countries, are relatively spared despite the high prevalence of HBV infection.
In addition, the global prevalence of HDV has evolved over time. These changes are most noticeable in Italy, a country which was endemic for HDV infection and where HDV was initially described. Improvements in socioeconomic conditions, increased awareness of the risk of transmitting infectious diseases, and aggressive vaccination campaigns against HBV have all contributed to a dramatic decrease in the incidence of HBV infection and the spread of HDV infection among young Italian adults until 1999 [39].
However, this decline appears to have stopped, and some recrudescence of HDV prevalence has been reported in both the Mediterranean area [40] and in Central Europe [41]. Immigration from endemic countries has been suggested to be the cause for this trend [42,43], but is not the only reason: intravenous drug use, sexual practices, and body modification procedures may also be involved.
Additional details of the epidemiology of HDV in certain regions include:
●The Mediterranean Basin – HDV infection is endemic in the Mediterranean Basin, where intrafamilial spread is thought to have been prominent in the past, but data suggest that the prevalence of HDV infection has declined. In a study from Italy, anti-HDV antibodies were detected in only 69 of 834 HBsAg-positive patients (8.3 percent) in 1997, compared with 23 and 14 percent in studies from 1987 and 1992, respectively [39]. The decrease resulted principally from a reduction in chronic HDV infection in young adults. In addition, vaccination campaigns against HBV have decreased HDV infection as well. However, more recent data suggest the prevalence appears to be increasing in immigrant populations [44,45].
●Asia – The prevalence of HDV infection among HBV carriers in Asia is quite variable. Although low in Japan [33], other countries, especially Mongolia and those in Central Asia, are heavily affected, and the prevalence among HBV carriers can be as high as 60 percent in some areas in Pakistan [46]. HDV infection is not infrequent in Taiwan [47], being predominantly sexually transmitted, but is rare in Hong Kong, where it is largely confined to intravenous drug users [48].
●Western countries – HDV infection is uncommon in Western countries and predominantly confined to high-risk groups: injection drug users, individuals who have received multiple transfusions in the past (eg, hemophiliacs), and persons who emigrated from countries with a high prevalence of HDV infection [49]. Interestingly, transmission of HDV among HBsAg-positive men who have sex with men is rare [50].
It should be noted that much of the data describing the epidemiology of HDV are based upon studies conducted more than 20 years ago, and updated information is not available in many countries.
SUMMARY
●HDV infection is closely associated with hepatitis B virus (HBV) infection. Although HDV can replicate autonomously, the simultaneous presence of HBV is required for complete virion assembly and secretion. (See 'Introduction' above.)
●Due to its dependence upon HBV, HDV infection always occurs in association with HBV infection. The clinical and laboratory findings vary with the type of infection (table 1). (See "Diagnosis of hepatitis D virus infection" and 'HDV infection' above.)
●The clinical sequelae of HDV infection encompass a spectrum of manifestations from acute liver failure to the inactive carrier state. The severity of the clinical course is influenced by several factors. (See 'Natural history of chronic hepatitis D' above.)
●HDV infection is endemic in the Mediterranean Basin. By contrast, HDV infection is uncommon in Western countries, and is predominantly confined to high-risk groups (eg, injection drug users, individuals who have received multiple transfusions in the past, and persons who emigrated from countries with a high prevalence of HDV infection). In Asia, the prevalence of HDV infection among HBV carriers is quite variable. (See 'Epidemiology of HDV infection' above.)
