Introduction to hepatitis E

Hepatitis E, caused by the resilient hepatitis E virus (HEV), remains a silent yet formidable threat to global health, historically linked to outbreaks during tumultuous times. As many infected individuals remain asymptomatic, the potential for acute liver failure especially in vulnerable populations like pregnant women underscores the urgency for effective treatments. With emerging therapies like ribavirin and the promising HEV 239 vaccine on the horizon, the battle against this often-overlooked virus is evolving, highlighting both the challenges and hope in tackling hepatitis E worldwide.

Overview

Hepatitis E is a type of liver inflammation triggered by the hepatitis E virus (HEV), which is the fifth identified form of viral hepatitis.¹ It was discovered during the Soviet occupation in Afghanistan, where a hepatitis outbreak led to the discovery of the virus. It is the most common cause of viral hepatitis, and it belongs to the genus Orthohepevirus, Hepeviridae family.

To microbiologically characterise it, it is a non-enveloped virus (it lacks a lipid bilayer), making it more resistant to specific agents, such as detergents and even disinfectants. With a small size of 27-34 nm, it has a single-stranded RNA genome, capped at the 5’ end and polyadenylated at the 3’ end, which makes the RNA molecule more stable, preventing its degradation. The genome has three open reading frames (ORFs), ORF1 encodes non-structural proteins with enzymatic functions, ORF2 encodes the viral capsid protein responsible for virion assembly and immunogenicity, and ORF3 encodes a small protein involved in virion morphogenesis and release.

It can be diagnosed either directly via the detection of its nucleic acid or indirectly, by detection of the host immune response. Post-incubation, the immune response is reflected by a short IgM response (which are immunoglobulins that appear in response to initial antigen exposure), followed by a more durable IgG response (immunoglobulins reflecting an infection has occurred, protecting against the viral infection). Serum analysis that reveals the presence of HEV RNA for more than 6 months means chronic infection.² There are seven HEV genotypes, but only HEV 1-4 affects humans.

Symptoms

Infected individuals often have no symptoms. When present, they resemble acute hepatitis symptoms: 

• Malaise
• Nausea and vomiting
• Abdominal pain
• Fever
• Jaundice
• Itching

In rare cases, it can result in acute liver failure, especially when it occurs during pregnancy.

Epidemiology

HEV epidemics can occur throughout the world, and sporadic cases occur through endemic regions. It is mainly transmitted through water contaminated with faeces, while the person-to-person transmission is uncommon. It primarily affects young adults, with the highest clinical attack rate being at 15-35 years. Although there are no sex differences in HEV exposure, men seem to be more clinically affected by hepatitis.³ Statistically, there are more asymptomatic infections, but it is important to know that HEV infection is a significant burden. 

Antiviral treatment 

Ribavirin

Most HEV cases are self-limiting and do not require medical treatment, but acute cases are treated with ribavirin monotherapy, an antiviral medication. Even if there are no present specific Hepatitis E treatments, it has been reported to be effective in acute cases because of the higher mortality rate associated with Hepatitis A or B. Moreover, HEV infections while having an underlying liver disease lead to a poor prognosis. Ribavirin monotherapy effectively inhibits HEV replication in vivo and may result in a sustained virological response in patients with chronic HEV infections.⁴ However, additional research is needed to establish the optimal treatment duration. It usually lasts three weeks.

Interferon therapy

Unfortunately, treatment options for chronic HEV infections are limited, and the immunological factors contributing to viral persistence are still largely unexamined.

• In case of ribavirin resistance, PEGylated interferon-alpha can be used as a treatment option. It is used in combination therapy with other antiviral medications for treating chronic HEV infection⁵ 
• Interferons are clinically used to treat viral infections, and interferon-alpha is a laboratory-made copy of naturally produced interferons. Interferon-alpha is a protein generated by immune cells in response to pathogens, activating a T-cell response⁶ 

Preventive strategies

The establishment of effective sanitation and hygiene practices significantly mitigates the risk of fecal-oral transmission of hepatitis E. 

Contaminated drinking water and water supplies, tainted by human waste, are recognised vectors for the virus, while the consumption of raw or undercooked meat and shellfish also poses a transmission risk, emphasising the necessity of thorough cooking with sanitised kitchen utensils. The presence of functional latrines, accompanied by proper faecal sludge management and accessible handwashing facilities, is critical for reducing transmission risks.⁷

Hepatitis E outbreaks are particularly concerning in contexts characterised by population displacement and movement, necessitating targeted public health interventions.

Vaccination

Prevention through vaccination is now a realistic and successful prevention method. The clinical trials are currently investigating two candidate vaccines.

• HEV 239 (Hecolin) has been licensed in China, and it is a protein encoded by HEV1
• The recombinant vaccine is effective against both symptomatic and asymptomatic infections, even though its efficacy and safety in certain high-risk populations are still under investigation⁸ 
• A full three-dose regimen of HEV 239 triggered antibody responses in 99.9% of individuals who were seronegative at the start. Fifty-five months after the initial vaccination, 87% of these individuals remained seropositive⁹
• Since its approval in China in 2011, the Hecolin vaccine has not been used outside of China, except for an ongoing study in Bangladesh
• Despite strong interest from humanitarian agencies to deploy the vaccine in high-risk camps and hepatitis E outbreaks, several obstacles persist
• One key barrier is the lack of World Health Organization (WHO) prequalification, a necessary step for United Nations procurement
• The WHO recently held its first meeting to develop the technical standards required for prequalification, but challenges remain, including limited clinical data on protection against certain HEV genotypes and its use in specific populations such as children, pregnant women, and immunocompromised individuals
• Additionally, the vaccine's current packaging and three-dose schedule make widespread deployment difficult in high-need areas¹⁰

Summary

While there are gaps in fully understanding the global burden of the Hepatitis E virus. The available data clearly show its significant prevalence and serious impact, particularly on vulnerable groups like pregnant women and displaced populations. With a safe and effective vaccine already available, it is crucial to address the barriers hindering its use in outbreaks and endemic areas, urging public health authorities to take action and direct research and funding towards reducing the preventable toll of hepatitis E worldwide.

As we confront the persistent challenge of hepatitis E, the development of effective treatments and vaccines is crucial to mitigating its impact, particularly on vulnerable populations. By addressing, the barriers to vaccination and enhancing public health strategies, we can pave the way for a future where hepatitis E is no longer a silent threat but a preventable disease.