Overview

Hepatitis E virus (HEV) is the most common cause of acute hepatitis. Over 2 billion people live in endemic areas for HEV and are hence at risk of infection. Since the symptoms are non-specific and the disease is self-limited, it is not routinely diagnosed.

The most common mode of transmission is the faecal-oral route, stemming from water systems in developing countries, owing to a lack of hygiene. Person-to-person transmission is rare, but HEV can be transmitted by blood transfusion. Similarly, it can be transmitted from a mother to their infant.¹

This article will explore the severity of HEV and the current antiviral medications that are used to combat this virus. Since none are Food and Drug Administration (FDA)-approved, this article will also examine emerging drugs that appear to exhibit prospective antiviral properties.

What is hepatitis?

Hepatitis is inflammation of the liver and can be caused by alcohol, substance abuse, viruses, and other diseases. Inflammation can cause your liver cells to look and behave abnormally, which in turn causes these cells to replicate, contributing to the development of more serious diseases, such as cirrhosis, liver cancer, liver failure, acute renal failure, renal impairment, and death.

Viral hepatitis is specifically caused by viruses that target the liver. There are five main types, hepatitis A, B, C, D, and E, each caused by a different virus. These types differ in how they are transmitted, where they are most common in the world, the symptoms they produce, and the severity of illness they cause. The reason there are multiple types is simply that these are distinct viral strains that independently affect liver function in different ways.²

How can hepatitis E virus be contracted?

Hepatitis E virus (HEV) is primarily transmitted through the faecal-oral route, most commonly via contaminated water or food. This mode of transmission is particularly prevalent in regions with inadequate sanitation, such as parts of Asia, Central America, and Africa.

HEV can also be zoonotic, meaning it can spread from animals to humans, particularly through the consumption of raw or undercooked meat from boars, deer, or pigs. The virus can remain infectious at temperatures up to 60°C.

Less commonly, HEV may be transmitted through blood transfusions or organ transplants, especially in healthcare settings where screening protocols are lacking.³

What are the symptoms of hepatitis E virus?

Generally, HEV infections are asymptomatic or mildly symptomatic, which makes diagnosing this disease very difficult.³ When symptoms do occur, they may include:

• Fever
• Body aches
• Nausea
• Vomiting
• Malaise

The vast majority of acute HEV infections are self-limiting and therefore do not need any special treatment. However, people with weakened immune systems, such as elderly people, pregnant women, infants and young children, are more likely to experience a more severe illness and can succumb to HEV.¹

Antiviral medications for hepatitis E virus

Since HEV can cause more severe diseases, such as liver failure or liver cancer, the following antiviral medications have been tested in these contexts, rather than on HEV-infected patients alone. Therefore, these medications may be effective against HEV but not against the other consequential diseases. 

Ribavirin

Ribavirin is used for off-label treatment because there are currently no drugs that have been approved for HEV infection. It is a broad-spectrum antiviral that has been shown to benefit other infections, such as respiratory syncytial virus (RSV) infection and Lassa fever.

A retrospective study determined that a three-month course was the most appropriate length of therapy for most patients. This was because:⁴

• HEV was cleared from 95% of transplant recipients following the administration of ribavirin
• HEV was cleared from 87.5% of immunocompromised patients 

Therefore, ribavirin seems to be an effective treatment option for immunocompromised patients.⁴

Pegylated interferon alpha

Like ribavirin, pegylated interferon alpha has also shown some promise as a treatment for HEV, especially in transplant recipients with chronic hepatitis. It has already demonstrated antiviral effects against two types of HEV (B and C).

This drug functions by clearing the genetic material of the virus (RNA) following three months of therapy. However, this drug has been associated with some severe side effects, such as psychosis, autoimmune disorders, and blood clot infections.⁵

Emerging hepatitis E virus antivirals

Since HEV, a global health problem, does not currently have any drugs approved by the FDA on the market, there is a great interest in developing more antivirals for HEV.

Please be aware that the following examples have not entered clinical trials or the drug market to treat HEV. Sample sizes from these studies are small, and cell models (cell culture) may not represent the true efficacy of these drugs.

Azithromycin

Azithromycin has so far only been used in cell models but has been shown to inhibit the replication of HEV within liver cells. It has proved to be effective against genotypes 1 and 3 of HEV. Since HEV can also cause kidney injuries, studies have demonstrated that azithromycin can substantially inhibit the viral replication in human kidney cells.

As azithromycin is already FDA-approved to treat bacterial infections and sexually transmitted diseases, it could potentially be repurposed as an antiviral drug.⁶

Sofosbuvir

Sofosbuvir is a well-established treatment for Hepatitis C Virus (HCV) and has emerged as a potential option for chronic HEV infections in immunocompromised individuals. It is hypothesised that sofosbuvir interferes with viral replication.

In studies using human hepatocellular carcinoma, or human liver cancer cell lines, sofosbuvir has been shown to effectively inhibit HEV replication. The combination of sofosbuvir and ribavirin has yielded the best results in reducing HEV replication.

Also, an individual affected by HEV involved in a study achieved viral clearance when treated with both medications, an outcome not seen when ribavirin was used alone, so there is renewed hope for the use of sofosbuvir in combination with ribavirin.⁷

Summary

Hepatitis E is generally a self-limiting viral infection, particularly in healthy individuals. However, it can progress to severe liver or kidney disease in vulnerable populations. Because no FDA-approved antivirals currently exist for HEV, maintaining good hygiene, especially in endemic areas, remains critical.

Medications such as ribavirin and pegylated interferon alpha offer hope in treating chronic cases, particularly in immunocompromised individuals. Furthermore, emerging drugs like azithromycin and sofosbuvir show promise in early studies but require further clinical research before approval. This further reinforces the importance of hygiene and a healthy lifestyle, which would favour a self-limiting infection rather than one that leads to a more severe illness.