Global Alert and Response (GAR)

Hepatitis D

The disease

- Diagnosis
- Host immune response
- Prevalence
- Pathogenesis
- Transmission
- Risk groups

An HDV infection absolutely requires an associated HBV infection. The outcome of disease largely depends on whether the two viruses infect simultaneously (coinfection), or whether the newly HDV-infected person is a chronically infected HBV carrier (superinfection).

Coinfection of HBV and HDV (simultaneous infection with the two viruses) results in both acute type B and acute type D hepatitis. The incubation period depends on the HBV titre of the infecting inoculum. Depending on the relative titres of HBV and HDV, a single bout or two bouts of hepatitis may be seen. Coinfections of HBV and HDV are usually acute, self-limited infections. The chronic form of hepatitis D is seen in less than 5% of HBV - HDV coinfected patient.10, 21

Acute hepatitis D occurs after an incubation period of 3 - 7 weeks, and a preicteric phase begins with symptoms of fatigue, lethargy, anorexia and nausea, lasting usually 3 to 7 days. During this phase, ALT and AST activities become abnormal. The appearance of jaundice is typical at the onset of the icteric phase. Fatigue and nausea persist, clay-colored stools and dark urine appear, and serum bilirubin levels become abnormal. In patients with acute, self-limiting infection, convalescence begins with the disappearance of clinical symptoms. Fatigue may persist for longer periods of time.14, 21

Superinfection of HBV and HDV (HDV infection of a chronically infected HBV carrier) causes a generally severe acute hepatitis with short incubation time that leads to chronic type D hepatitis in up to 80% of cases. Superinfection is associated with fulminant acute hepatitis and severe chronic active hepatitis, often progressive to cirrhosis.14, 21

During the acute phase of HDV infection, synthesis of both HBsAg and HBV DNA are inhibited until the HDV infection is cleared.14

Fulminant viral hepatitis is rare, but still about 10 times more common in hepatitis D than in other types of viral hepatitis. It is characterized by hepatic encephalopathy showing changes in personality, disturbances in sleep, confusion and difficulty concentrating, abnormal behavior, somnolence and coma. The mortality rate of fulminant hepatitis D reaches 80%. Liver transplantation is indicated.14, 21

Chronic viral hepatitis D is usually initiated by a clinically apparent acute infection. Symptoms are less severe than in acute hepatitis, and while serum ALT and AST levels are elevated, bilirubin and albumin levels and prothrombin time may be normal. In chronic hepatitis D, the HBV markers are usually suppressed.13, 14, 21

Progression to cirrhosis usually takes 5 - 10 yrs, but it can appear 2 years after onset of infection. About 60 to 70% of patients with chronic hepatitis D develop cirrhosis. A high proportion of these patients die of hepatic failure.21

Hepatocellular carcinoma (HCC) occurs in chronically infected HDV patients with advanced liver disease with the same frequency as in patients with ordinary hepatitis B. HCC may actually be more a secondary effect of the associated cirrhosis than a direct carcinogenic effect of the virus.

Taken together, three phases of chronic hepatitis D have been proposed: a) an early active phase with active HDV replication and suppression of HBV, b) a second moderately active one with decreasing HDV and reactivating HBV, c) a third late one with development of cirrhosis and hepatocellular carcinoma caused by replication of either virus or with remission resulting from marked reduction of both viruses.10

The mortality rate for HDV infections lies between 2% and 20%, values that are ten times higher than for hepatitis B.21

Click here for: Scheme of infection and clinical features

Hepatitis D should be considered in any individual who is HBsAg positive or has evidence of recent HBV infection.21

The diagnosis of acute hepatitis D is made after evaluation of serologic tests for the virus. Total anti-HDV are detected by commercially available radioimmunoassay (RIA) or enzyme immunoassay (EIA) kits.10, 21

The method of choice for the diagnosis of ongoing HDV infection should be RT-PCR, which can detect 10 to 100 copies of the HDV genome in infected serum.10, 11, 18, 21
- acute HBV-HDV coinfection:

  • appearence of HBsAg, HBeAg and HBV DNA in serum during incubation
  • appearence of anti-HBc at onset of clinical disease
  • appearence of IgM anti-HD, HDV RNA, HDAg in serum
  • anti-HDV antibodies develop late in acute phase and usually decline after infection to subdetectable levels
  • if HDAg is detectable early during infection, it disappears as anti-HDV appears
  • all markers of viral replication disappear in early convalescence, and both IgM and IgG anti-HD disappear within months to years after recovery
- HBV-HDV superinfection:
  • usually results in persistent HDV infection
  • HDV viremia appears in serum during preacute phase
  • high titres of IgM and IgG anti-HDV are detectable in acute phase, persisting indefinitely
  • titre of HBsAg declines when HDAg appears in serum
  • progression to chronicity is associated with persisting high levels of IgM anti-HD and IgG anti-HD
  • HDAg and HDV RNA remain detectable in serum and liver
  • viremia is associated with active liver disease

Each of the markers of HDV infection, including IgM and IgG antibodies, disappears within months after recovery. In contrast, in chronic hepatitis D, HDV RNA, HDAg, and IgM and IgG anti-HD antibodies persist.14, 18

Host immune response
Both humoral and cellular immunity are induced in patients infected with HDV.14, 21

These immune responses may provide protection from HDV re-infection, or simply modulate clinical symptoms. However, second cases of hepatitis D have not been reported.14, 21

Anti-HD antibodies do not always persist after acute infection is cleared. The serological evidence of past HDV infection is therefore not easy to demonstrate.14

Click here for: Typical serologic course

Areas of high prevalence include the Mediterranean Basin, the Middle East, Central Asia, West Africa, the Amazon Basin of South America and certain South Pacific islands.13, 14, 21

Severe, often fatal, acute and chronic type D hepatitis occurs among indigenous people of Venezuela, Colombia, Brazil, and Peru, all regions with high chronic HDV infection rates.21

Hepatitis D is less common in Eastern Asia, but is present in Taiwan, China and India.21

Click here for: Worldwide distribution of HDV infection

Infection with both HBV and HDV is associated with more severe liver injury than HBV infection alone.13

Pathologic changes in hepatitis D are limited to the liver, the only organ in which HDV has been shown to replicate. The histologic changes consist of hepatocellular necrosis and inflammation.21

HDV genome replication is not acutely cytopathic, and both humoral and cellular immune mechanisms may be involved in the pathology of hepatitis D. More experimental data are needed to unravel the underlying mechanisms of HDV-induced disease.10, 14, 21, 25

HBV is an essential cofactor in the evolution of hepatocellular damage.7, 10

Transmission is similar to that of HBV:

  • bloodborne and sexual
  • percutaneous (injecting drug use, haemophiliacs)
  • permucosal (sexual)
  • rare perinatal

Superinfections increase the chance of HDV spread, and at the peak of an acute infection, the amount of HDV in the serum can exceed 1012 RNA-containing particles per ml.25

During an HDV superinfection, the titre of HDV reaches a peak between 2 and 5 weeks postinoculation, after which it declines in 1 to 2 weeks.25

The probability of being productively coinfected, with the coinfection resulting in clinical disease, depends on both the relative and absolute amounts of the two inoculated viruses.25

The main route of transmission is infected blood and blood products.

Risk groups
Here is a list of groups of people who are at risk of contracting HDV:21

  • intravenous drug users using HDV-contaminated injection needles
  • promiscuous homosexual and heterosexual groups (although HDV infections are less frequent than HBV or HIV infections)
  • people exposed to unscreened blood or blood products
  • °haemophiliacs
  • °persons with clotting factor disorders

° the risk has decreased in recent years due to better control of blood sources


Scheme of infection and clinical features

Typical serologic course

From: Purcell RH and Gerin JL, Hepatitis Delta virus. In: Fields Virology, 3rd ed. Philadelphia, Lippincott - Raven, 1996:2819-2829,21 with permission (

The serological patterns of type D hepatitis: coinfection and superinfection. Top: Coexistent acute hepatitis B and hepatitis D. Middle: Acute hepatitis D superimposed on a chronic hepatitis B virus infection. Bottom: Acute hepatitis D progressing to chronic hepatitis, superimposed on a chronic hepatitis B virus infection.21


Worldwide distribution of HDV infection

From: Centers for Disease Control and Prevention (CDC), Atlanta, USA:6