Hepatitis E VirusReviewPathogenesis and Treatment of Hepatitis E Virus Infection
Section snippets
The Virus and Its Epidemiology
HEV is a single-stranded, nonenveloped RNA virus and is the only virus within the genus Hepevirus and the family Hepeviridae.1 The HEV genome includes 2 short, noncoding regions that surround 3 open reading frames (ORFs 1–3) (Figure 1A). ORF-1 encodes the nonstructural proteins required for replication and protein processing, including an RNA helicase, an RNA-dependent RNA polymerase, a methyltransferase, and a cysteine protease.11 ORF-1 contains a hypervariable region that does not have a
Diagnosis
Testing for hepatitis E should be part of the diagnostic analysis of all patients with acute or chronic hepatitis that cannot be explained by other causes. Acute HEV infection is diagnosed in immunocompetent individuals based on detection of anti-HEV IgM. Increased titers of anti-HEV IgG can indicate recent HEV infection (Figure 3). However, there are variations in sensitivity, specificity, and agreement of results among assays that detect these antibodies.46, 47 Several assays are based on
Clinical Course of Infection
Most HEV infections have a clinically silent course. In an HEV vaccine trial in China of >110,000 individuals, <5% of individuals who seroconverted (began producing anti-HEV) during the observation time developed symptoms of acute hepatitis.50 HEV infections are rarely associated with clinical symptoms during childhood.51 In symptomatic cases, the incubation period ranges from 2 to 8 weeks, with a mean of 40 days.1 Initial symptoms of acute hepatitis E are typically unspecific and include
Infections in Organ Transplant Recipients
Chronic HEV infection has been described in liver and kidney transplant recipients in Europe since 2008.29, 59, 60, 61 Kamar et al initially reported 14 cases of acute hepatitis E in Southwest France among patients who received kidney or liver transplants.59 Eight developed a chronic course that led to persistent increases in levels of alanine aminotransferase, significant histological activity, and fibrosis after a median follow-up period of >12 months (range, 10–18 months). Additional cases
Patients With HIV Infection
Human immunodeficiency virus (HIV)–infected individuals more frequently have positive results from tests for anti-HEV than individuals without HIV infection,67, 68 but chronic hepatitis E was not described in an HIV-infected patient before 2009.69 This patient had acquired immunodeficiency syndrome with a CD4+ T-cell count <200 and high levels of HIV RNA (>100,000 copies/mL). However, subsequent studies from Spain (93 patients),70 Germany (123 patients),71 and England (138 patients)72 could not
Extrahepatic Manifestations
There is some evidence that HEV infections are associated with extrahepatic manifestations. One case report described muscular weakness and a pyramidal syndrome in a kidney transplant recipient with persistent HEV infection.74 In addition, neurological disorders, including polyradiculopathy, Guillain–Barré syndrome, bilateral brachial neuritis, encephalitis, or proximal myopathy have been reported in patients with acute and chronic HEV infections.75 The mechanisms and clinical relevance of
Treatment
In immunocompetent individuals, acute hepatitis E does not usually require antiviral therapy. Some patients might require treatment of symptoms, but almost all are able to clear the HEV infection spontaneously. A patient infected with HEV genotype 3 who developed severe acute hepatitis E and impaired liver function was treated with ribavirin monotherapy. This patient responded with a rapid decrease in liver transaminases and had improved international normalized ratio and level of bilirubin.77
Vaccination
Recovery from HEV infection results in protective immunity—neutralizing antibodies can be detected in sera of individuals exposed to HEV genotypes 1–4.83 HEV-specific CD4+ and CD8+ T-cell responses are detectable in patients with acute hepatitis E84 and long-term in individuals who have recovered from infection.66 Immunodominant regions within ORFs 2 and 3 induce T-cell responses.84, 85 Immunity against HEV seems to persist for life—seropositive patients who become reinfected do not develop
Future Directions
HEV infection is a major global health burden that causes significant morbidity and mortality worldwide. Pregnant women have increased risks for fulminant hepatic failure upon HEV infection. Hepatitis E also occurs in industrialized countries; zoonotic transmission seems to be a major cause of HEV infections in the United States, Europe, and Japan. Tests for hepatitis E should therefore be included in evaluations of all patients with increased levels of liver transaminases. It is particularly
Supplementary material
Acknowledgments
The authors thank Dr Svenja Hardtke (Hannover Medical School), Sarah Williamson, and Brook Ashley Simpson (Gastroenterology editorial office) for editorial assistance.
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Conflicts of interest The authors disclose no conflicts.