Hepatitis E Virus: An Overview

Introduction

Hepatitis E virus (HEV) is a significant global health concern. It causes hepatitis E, a disease that affects millions worldwide. In this article, we will explore various aspects of HEV, including its characteristics, classification, transmission, infection, diagnosis, prevention, and treatment.

Characteristics of HEV

HEV is a single-stranded, positive-sense RNA virus. Its genome ranges from 6.6 to 7.2kb and contains three open reading frames (ORFs). ORF1 encodes non-structural proteins involved in RNA replication. ORF2 encodes the capsid protein and a secreted form. ORF3 encodes a small protein related to virus release. The virus particle is icosahedral, with a diameter of 27 – 32nm. It is non-enveloped in feces and bile but has a lipid envelope in blood and cell culture supernatant, making it a quasi-enveloped virus. Currently, there is no robust cell culture system for HEV. Suitable animal models include non-human primates, swine, rabbits, and human liver chimeric mice. Rabbits, due to their small size and zoonotic potential for rabbit HEV, are important in HEV studies.

Classification and Host Range of HEV

HEV belongs to the family Hepeviridae. The most studied genotypes are in species Orthohepevirus A, divided into eight genotypes. Genotypes 1 and 2 are human-exclusive, mainly in developing regions with poor sanitation, causing large outbreaks. Genotypes 3 and 4 are zoonotic, causing sporadic cases in developed regions and China. They have various animal hosts like rabbits, deer, pigs, and wild boars. Rabbit HEV was first isolated in China in 2009, and human infections have been reported. Genotypes 5 and 6 were isolated from wild boars in Japan. Genotype 5 can experimentally infect cynomolgus macaques. Genotypes 7 and 8 were from dromedary and Bactrian camels. Genotype 7 can cause chronic infection in immunosuppressed patients, and genotype 8 can infect cynomolgus macaques. Avian HEV (Orthohepevirus B) causes big liver and spleen disease. Orthohepevirus C has animal hosts like rats, shrews, etc. Rat HEV was thought not to infect humans, but recent cases show it can. Orthohepevirus D (bat HEV) has no zoonotic evidence. Piscihepevirus A is from trout. The host range of HEV is expanding. Seroprevalence has been detected in raccoons, cattle, dogs, cats, sheep, etc. HEV RNA is also found in small mammals. Hepe-like viruses, related to HEV, have been detected in insects and prawns, indicating a broader host range.

Transmission of HEV

HEV is mainly transmitted via the fecal-oral route. Genotypes 1 and 2 spread through contaminated water in developing regions. In developed regions with genotypes 3 and 4, it transmits via contaminated animal products like uncooked meat or liver. Other routes include urine-oral (HEV in urine of infected animals and patients, and monkeys infected by urine inoculation). Blood-borne transmission is a concern. Sporadic cases via transfusion are reported, and some regions test blood donors. Vertical transmission occurs, mainly by genotype 1. Genotypes 3 and 4 can also vertically transmit in animal models. It can cause jaundice at birth, mainly self-limited, but also death. HEV RNA in semen suggests sexual transmission needs study. Donor-derived HEV infection in organ transplantation has been reported, so screening organ donors is recommended.

HEV Infection

HEV infection mainly causes self-limited acute hepatitis with symptoms like anorexia, nausea, jaundice (lasting 3 months, mainly with genotypes 3 and 4, leading to cirrhosis. Cases with genotypes 7 and rat HEV have been reported. HEV infection in pregnant women has a high mortality (20 – 30%) and poor outcomes. It can also cause extrahepatic manifestations like neurological (Guillain-Barré, Parsonage-Turner) and renal (membranoproliferative glomerulonephritis, cryoglobulinemia) disorders, as well as hematological, pancreatic, myocardial, arthritic, and autoimmune thyroid issues.

Diagnosis, Prevention, and Treatment of Hepatitis E

The incubation period is 15 – 60 days. HEV RNA detection in blood, stool, or body fluids is the gold standard. Anti-HEV antibodies (IgG, IgM) are important, but immunosuppressed patients may have low titers. Positive IgM (with/without IgG) + HEV RNA = acute infection. Single IgG = past infection. Reinfection shows IgG + HEV RNA, no IgM. Chronic hepatitis E is >3 months. Prevention includes boiling water, cooking animal products, improving sanitation. HEV 239 vaccine (Hecolin) is licensed in China, protective against genotype 1 and cross-protective against genotype 4. It showed high efficacy in trials. Vaccination of high-risk groups (pregnant women, immunosuppressed) is important. For treatment, acute HEV usually doesn’t need antiviral therapy. Chronic patients or pregnant women need treatment. Commonly used drugs are ribavirin (RBV) and pegylated-interferon-a (PEG-IFN-a). RBV clears virus in ~80% (mutations may cause failure). PEG-IFN-a is for liver-transplant recipients. Sofosbuvir (NS5B inhibitor) inhibits HEV replication in vitro, but clinical effect is controversial.

Conclusion and Perspectives

HEV was neglected but is now recognized as a major health issue. Its pathogenic mechanism is unclear. Studies on animal hosts and epidemiology are significant. Robust cell culture and more animal models are needed. Transmission routes are diverse. Testing blood and organ donors is under discussion. Extrahepatic manifestations’ range and mechanisms need study. Screening for anti-HEV drugs and new therapies is urgent.

doi: 10.1097/CM9.0000000000001998

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