Hepatitis D

Available data suggest that approximately 15 to 20 million of the 257 million HBV carriers worldwide may be infected with HDV.^(1,2)

The prevalence of HDV infection among HBV carriers in Asia is quite variable. Although low in Japan,⁽³⁾ 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.⁽⁴⁾

There are three known genotypes of HDV. Genotype I has a worldwide distribution; genotype 2 exists in Taiwan, Japan, and northern Asia; and genotype 3 is found in South America.⁽⁵⁾

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⁽⁶⁾ and the expression of specific HDAg species.⁽⁷⁾
• Host-associated factors, such as the immune response
• Helper virus-associated factors, such as the HBV genotype and the level of HBV replication.⁽⁸⁾

HDV Infection:

Due to its dependence upon HBV, HDV infection always occurs in association with HBV infection.

Coinfection: Coinfection of HBV and HDV in an individual susceptible to HBV infection (i.e. 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.⁽⁹⁾

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.⁽¹⁰⁾

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.⁽¹¹⁾ However, HBV replication is usually suppressed by HDV.

HDV is transmitted parenterally; it can replicate independently within the hepatocyte, but it requires hepatitis B surface antigen (HBsAg) for propagation.

Risk factors include:

• Intravenous drug use and multiple blood transfusions.
• Sexual transmission is less efficient than with hepatitis B virus (HBV).
• Perinatal transmission is rare.

Genotype 1: In the Western world, where the predominant genotype is genotype 1,⁽¹⁴⁾ acute hepatitis D has an increased risk of acute liver failure when compared with acute hepatitis B.⁽⁹⁾ Once chronic HDV infection is established, it usually exacerbates the preexisting liver disease due to HBV.⁽¹¹⁾ Progression towards cirrhosis may be rapid.^(15,16)

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.^(13,17)

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,⁽¹⁸⁾ the Sierra Nevada de Santa Marta in Colombia,⁽¹⁹⁾ and some remote areas of the Brazilian⁽²⁰⁾ and Peruvian⁽⁶⁾ 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.⁽⁶⁾

Other genotypes: At least five additional HDV genotypes have been described.^(21,22) 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.

Hepatitis D virus (HDV) infection is clinically indistinguishable from other forms of viral hepatitis. As many as 90% of patients are asymptomatic.

The incubation period is 21-45 days but may be shorter in cases of superinfection.

Signs/symptoms include the following:

• Jaundice
• Dark urine
• Abdominal pain
• Nausea with vomiting
• Confusion, bruising, and bleeding (rare)
• Pruritus

Signs/symptoms upon presentation include the following:

• Scleral icterus
• Fever
• Abdominal pain, usually right upper quadrant
• Tea-colored urine
• Encephalopathy (rare)
• Petechia with bruising (rare)

Although screening for hepatitis delta virus (HDV) may be beneficial in patients with hepatitis B virus (HBV), there are currently no consensus statements (for example, from the CDC or the American Association for the Study of Liver Diseases [AASLD]) that recommend general screening.

The HD virion is composed of an outer lipoprotein envelope made of the surface antigen of the HBV (HBsAg) and an inner ribonucleoprotein structure in which the HDV genome resides. The HDV genome consists of a single stranded RNA which is folded as a rod-like structure through internal base-pairing. It is complexed with the only HDV-encoded antigen, the HDAg.⁽²³⁾

HDAg can elicit a specific immune response in the infected host, consisting of antibodies of the IgM and IgG class (anti-HDV). In HDV infected individuals, the timing of appearance and level of HDV RNA, HDAg, and anti-HDV in serum allow the three HDV-related clinical entities to be discriminated:

• Acute HBV/HDV coinfection
• Acute HDV superinfection of a chronic HBV carrier
• Chronic HDV infection

Due to the dependence of HDV on HBV, the presence of HBsAg is necessary for the diagnosis of HDV infection. The additional presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) is necessary for the diagnosis of acute HBV/HDV coinfection (below table).

Detection of serum HDAg

Serum HDAg can be detected by microplate-based, enzyme-linked (EIA) or radioimmunoassays (RIA). At present, these assays are not available for clinical diagnosis in the majority of countries.

• In acute HDV infection, serum HDAg appears early but is very short-lived and may escape detection if repeated testing is not performed.^(24-27) HDAg lasts longer when the immune response is slow and weak as in immunodeficient individuals.⁽²⁸⁾

Schematic representation of the typical serologic response to acute HBV/HDV infection. Patients should be positive for HBsAg and have high titer IgM anti-HBc; serum HDAg and/or HDV RNA are usually positive at presentation. (courtesy Uptodate)

• In chronic HDV infection, anti-HDV is present in high titers. Thus, HDAg cannot be detected by microwell assays since it is complexed with anti-HDV. Serum HDAg is best detected in this setting by immunoblot assay,⁽²⁹⁾ since polyacrylamide gel electrophoresis under denaturing conditions allows separation of HDAg from anti-HDV. Immunoblot assay is very sensitive⁽³⁰⁾ but technically difficult, time- and labor-consuming, and cannot be used for routine detection of HDAg.

Detection of serum HDV RNA

HDV RNA can be detected in serum by reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays.

RT-PCR assays have a detection limit of less than 10 genomes per mL.^(31-35) However, the extensive sequence heterogeneity of different HDV isolates makes it difficult to choose suitable primers for the amplification of HDV RNA since only a few conserved regions exist in the HDV genome. Furthermore, the secondary and tertiary structure of the HDV RNA may hamper efficient amplification even of highly conserved regions.⁽³⁴⁾

An interesting application of the RT-PCR assay for serum HDV RNA is the analysis of the different HDV genotypes. Genotyping can be performed by direct sequencing or restriction fragment length polymorphism of the amplicon.^(6,36-38) Since the clinical relevance of HDV genotyping is uncertain, its widespread use is at present not recommended.

Detection of anti-HDV antibody:

Total (IgM and IgG) anti-HDV antibodies can be detected by EIAs or RIAs.

• Total anti-HDV antibody appears usually after four weeks of acute infection in acute hepatitis D. As a result, its clinical value is limited unless repeated testing is performed.^(24,27) Nevertheless, a well-documented anti-HDV seroconversion may be the only way to diagnose acute HDV infection in the absence of other markers of HDV infection.
• High-titer anti-HDV of the IgG class is present in chronic HDV infection. It correlates well with ongoing HDV replication and may help in differentiating current from past HDV infection.⁽³⁹⁾
• IgM anti-HDV is transient and delayed if the course of acute hepatitis D is self-limited, but it may be the only serum marker of acute HDV infection.⁽²⁴⁾ In patients who progress to chronic HDV infection, which is usually the case in those with HDV superinfection, IgM anti-HDV is brisk and long-lasting. It should be remembered, however, that differentiating between HBV/HDV coinfection and HDV superinfection in an HBV carrier relies mainly on the detection of high-titer IgM anti-HBc in patients with coinfection.

IgM anti-HDV is present in high titers during chronic HDV infection, and the titers correlate with the level of HDV replication and severity of liver disease.⁽⁴⁰⁾ IgM anti-HDV gradually disappears from serum in patients who have persistent remission after interferon therapy and following liver transplantation.⁽⁴¹⁾

Tissue markers of HDV infection:

Both HDAg and HDV RNA can be detected in liver tissues routinely processed for histopathologic evaluation.

• HDAg can be detected by direct immunofluorescence or immunohistochemical staining. The detection of intrahepatic HDAg has been proposed as the “gold” standard for the diagnosis of current HDV infection.⁽⁴²⁾ However, as many as 50 percent of liver biopsy specimens from patients who have been infected for 10 or more years may be negative for HDAg, suggesting that the levels of HDV replication may decrease with time.^(17,43) In patients who are negative for HDAg, the diagnosis of current HDV infection has to rely on the detection of HDV RNA and high-titer anti-HDV antibodies in the serum.
• HDV RNA can be detected by in-situ hybridization. However, the techniques involved are too time-consuming, tedious, and difficult for clinical use.⁽⁴⁴⁾

Imaging studies

Right upper quadrant ultrasonography helps in the evaluation for biliary obstruction and hepatocellular carcinoma.

Perform cholescintigraphy (hydroxy iminodiacetic acid) to exclude acute cholecystitis, if clinically indicated.

Perform computed tomography (CT) scanning or magnetic resonance imaging (MRI) if hepatocellular carcinoma is suggested. (An alpha-fetoprotein (AFP) level greater than 250 ng/mL is highly suggestive of hepatocellular carcinoma (HCC).)

For patients with chronic hepatitis D virus (HDV) infection, treatment for those with elevated HDV RNA levels and active liver disease (as evidenced by elevated serum aminotransferase [ALT] levels and/or chronic hepatitis on liver biopsy) is suggested. Patients should be treated early, particularly if there is advanced fibrosis. Asymptomatic HDV carriers with persistently normal ALT levels do not require therapy but should be monitored for signs of active disease (e.g. every six months).

Eradication of HBV infection with development of hepatitis B surface antibody (anti-HBs) will protect the individual from reinfection with HBV as well as HDV. Patients who have cleared HDV but who remain hepatitis B surface antigen (HBsAg) positive are still at risk of reinfection with HDV.

Treatment for infection with hepatitis D virus (HDV) consists primarily of supportive measures. Observe synthetic liver function markers and mental status closely. Deterioration of either should prompt early consultation with hospital personnel capable of performing liver transplantation.

Liver transplantation is indicated in patients with fulminant liver failure. Patients with evidence of decompensated liver disease or fulminant liver failure should be immediately transferred to a center capable of performing a liver transplantation.

No vaccine is available for HDV, but the hepatitis B virus (HBV) vaccination is effective against HDV.

For those who require therapy, pegylated interferon alfa (IFNa) is generally the treatment of choice and should be administered for one year.⁽⁴⁵⁾ Either pegylated IFN alfa-2a (180 mcg weekly) or pegylated IFN alfa-2b (1.5 mcg/kg weekly) can be used. However, the optimal treatment for HDV is uncertain, and patients can be referred to specialized centers that offer experimental therapies.

There is no benefit of adding a nucleos(t)ide analogue for the treatment of HDV. However, tenofovir or entecavir should be added if treatment for hepatitis B virus (HBV) is warranted to achieve maximal suppression of both viruses.

Interferon alfa:

The only available drug effective against HDV is interferon alfa (IFNa). Peginterferon appears to be more effective than standard interferon, but data are limited. Unfortunately, only a minority of patients treated with interferon clear HDV infection. A meta-analysis of five trials comparing interferon with observation (including a total of 169 participants) concluded that there was a modest benefit in suppressing viral and liver disease activity in some patients, but such benefits were not sustained in the majority of patients.⁽⁴⁶⁾

The mechanism of action of IFNa in hepatitis D is unclear. IFNa does not have any antiviral activity against HDV when tested in vitro.^(47,48) Thus, the efficacy of IFNa in patients with chronic hepatitis D may depend upon its antiviral effects on the helper virus (i.e. HBV) or its immunomodulatory effects.

Experimental Treatments:

Several drugs have been evaluated as alternatives to interferon (e.g. ribavirin, foscarnet, acyclovir). Many of these agents were used to treat other infections and were thought to have activity against hepatitis D virus (HDV) based upon in vitro studies or small case reports. However, results in subsequent human studies were discouraging.^(49-59)

Newer agents that have novel mechanisms of action show more promise. As examples:

• Specific inhibitors of HDV prenylation: “Prenylation” involves the covalent addition of a farnesyl or geranylgeranyl isoprenoid molecule to a conserved cysteine residue at or near the C-terminus of a protein.⁽⁶⁰⁾ This link promotes membrane interactions with the prenylated protein since the isoprenoid chain is hydrophobic.

Lonafarnib, a farnesyltransferase inhibitor used to treat other diseases (e.g. progeria), was evaluated in a phase 2a study of 14 patients with HDV.⁽⁶¹⁾ Eight patients received 100 mg of lonafarnib twice daily, and six patients received 200 mg of lonafarnib twice daily. Treatment was administered for 28 days, and when compared with placebo, resulted in a greater decline in HDV RNA (average serum HDV RNA decline of 0.73 log and 1.54 log international units/mL for the lower and higher doses, respectively).

• HDV entry inhibitors: These agents act upon the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor shared by HBV and HDV .^(62,63) Example: Myrcludex B

Inhibitors of virion secretion: REP 2139 is a nucleic acid polymer that has been shown to clear HBsAg by blocking the release of subviral particles. This agent was evaluated for the treatment of HDV infection in an uncontrolled phase 2 study.^(64,65)

The primary goal of treatment is suppression of HDV RNA 24 weeks after completing treatment, accompanied by normalization of the ALT level. Although the rate of virologic suppression with IFN is low, a response is more likely to be attained in patients with a shorter duration of infection. Successful treatment is associated with amelioration of necroinflammatory activity and loss of hepatitis D antigen (HDAg) in the liver.

To view, Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, please click on below email.

https://www.aasld.org/sites/default/files/HBVGuidance_Terrault_et_al-2018-Hepatology.pdf

To view, EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection, please click on below link:

http://www.easl.eu/medias/cpg/management-of-hepatitis-B-virus-infection/English-report.pdf

To view, WHO hepatitis D guidance document, please click on below link:

http://www.who.int/news-room/fact-sheets/detail/hepatitis-d

To view, Diagnosis, management and treatment of hepatitis delta virus infection: Turkey 2017 Clinical Practice Guidelines, please click on below link:

http://www.turkjgastroenterol.org/sayilar/304/buyuk/S84-S89.pdf

Follow-up is recommended for at least 6 months to determine if chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) infection develop. Perform a liver biopsy to stage liver disease prior to beginning interferon alfa therapy. Treatment with interferon can be continued after the 1-year period if well tolerated and efficacy is demonstrated. Monitoring HDV RNA and hepatitis B surface antigen (HBsAg) levels may help in guiding therapy.

Early notification of a hepatologist or gastroenterologist is warranted. Diet need not be restricted. If enteral intake is poor, intravenous fluids can be administered. Total parental nutrition is seldom needed.

• For hepatitis B virus (HBV) carriers, every effort should be made to reduce the risk of hepatitis D virus (HDV) transmission.
• For others, the mainstay of prevention of HDV infection is vaccination against HBV. Partial protection of hepatitis B surface antigen (HBsAg) carriers from HDV infection through active immunization may be feasible. However, worldwide implementation of a vaccination policy against HDV would probably prove too costly and impractical due to the need to screen for HBsAg carriers. Vaccination against HBV remains the most cost-effective means to prevent HDV infection, except for individuals who are already infected with HBV.
• Educate patients regarding modification of high-risk behaviors, including intravenous drug use and unsafe sexual practices.
• Promote the use of universal precautions for health care workers.
• Discuss with patients with chronic HDV and HBV infection that they should not donate blood, share toothbrushes or razors, or consume alcohol. Precautions should be observed regarding blood and body fluids.

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