Realm of hepatitis E: Challenges and opportunities

Abstract

Hepatitis E virus (HEV), responsible for widespread viral hepatitis, infects approximately 2.3 billion individuals globally, with a significant mortality burden in Asia. The virus, primarily transmitted through contaminated water and undercooked meat, is often underdiagnosed, particularly in immunocompromised patients. Current HEV treatments, while effective, are limited by adverse effects, necessitating research into safer alternatives. Moreover, HEV’s extrahepatic manifestations, impacting the nervous and renal systems, remain poorly understood. This study underscores the imperative for enhanced HEV research, improved diagnostic methods, and more effective treatments, coupled with increased public health awareness and preventive strategies.

Core Tip: Diagnosing hepatitis E virus (HEV), especially in immunocompromised individuals, is challenging due to the limitations of standard serological markers, necessitating the use of more sensitive nucleic acid amplification techniques. Existing treatments, mainly ribavirin and interferon-α, play a certain role in controlling the progression of the disease but have notable side effects. There is a lack of safe treatment options for pregnant women and immunocompromised patients. Future research should continue to concentrate on understanding the global prevalence, enhancing surveillance and prevention measures, and exploring innovative treatment approaches for HEV. This focused effort is critical to address the World Health Organization’s urgent goal of eradicating viral hepatitis by 2030.

INTRODUCTION

The identification of hepatitis E virus (HEV), a positive-strand RNA virus, dates back 40 years ago[1], and in 1990, Reyes et al[2] successfully sequenced its genome. HEV is a major etiological factor for both chronic and acute viral hepatitis[3]. Among the eight genotypes identified so far, HEV1, HEV2, HEV3, and HEV4 are the predominant genotypes responsible for human infections. Seroprevalence studies indicate that approximately 2.3 billion individuals worldwide are infected with HEV[4], resulting in an annual death toll of 160000 due to hepatitis E solely in Asia[5]. However, the relative threat posed by hepatitis E compared to hepatitis B and C remains significantly underestimated. Limited awareness about this disease has contributed to substantial misdiagnosis or missed diagnosis cases being reported sporadically over time[6]. Given the World Health Organization’s vision for eliminating hepatitis by 2030, urgent attention must be given to promoting research on hepatitis E. Currently, there exist numerous challenges pertaining to its diagnosis and treatment including screening protocols management strategies prediction models for severe disease prevention measures addressing extrahepatic manifestations vaccine evaluation efforts as well as establishing suitable animal models.

The incubation period of HEV infection typically ranges from 2 to 6 wk, and the detection of anti-HEV immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in serum is commonly used as a diagnostic marker for HEV infection[7]. However, immunosuppressed patients with long-term viral infection often have undetectable levels of anti-HEV antibodies. In such cases, the reliable diagnostic method relies on detecting viral RNA in blood and/or stool samples using nucleic acid amplification techniques[8]. Wolski et al[9] recently conducted a meta-analysis on global blood donors to test for anti-HEV IgG/IgM or HEV presence. The analysis revealed significant regional variations in both the risk of exposure to HEV and blood-borne transmission rates. In addition, the detection of DNA biomarkers has been reported for clinical diagnosis of hepatitis virus, such as fluorescence[10], mass spectrometry[11], electrochemistry[12], flow tomography[13], etc., but there are drawbacks including low sensitivity, poor accuracy, and unsatisfactory stability. Using dark-field microscopic imaging, a novel approach for the simultaneous detection of hepatitis B virus and hepatitis C virus based on automated particle enumeration was established[14], offering a fresh perspective on HEV detection. Ribavirin and interferon-α are commonly used in the treatment of chronic HEV infection, but they are often accompanied by significant side effects. Targeting various stages of the viral life cycle, including attachment and internalization in the early stages, translation and RNA replication in the middle stages, and viral particle formation and release in the late stages, is a necessary prerequisite for the development of novel anti-HEV medications[15]. Netzler et al[16] employed a subgenomic replicon strategy to screen 16 compounds from the NA or NNI class of antivirals, leading to the identification of two novel HEV antiviral candidates, namely NITD008 and GPC-N114. These candidates exhibited potent antiviral activity against HEV in vitro and demonstrated synergistic effects when used in combination. The entry process of viral particles is also an attractive target for pharmaceutical intervention, and the epidermal growth factor receptor (EGFR) has recently been identified as a novel host factor for HEV, playing a crucial role during HEV infection. Application of EGFR modulators can effectively limit HEV infection[17]. However, there is still a lack of feasible drugs for the treatment of HEV in pregnant women and immunocompromised individuals. Zhang et al[18] conducted an unbiased compound library screening on human hepatocytes harboring HEV replications and successfully identified 17 inhibitors targeting HEV-HSP90, providing a promising perspective for the development of new clinical antiviral drugs.

HEV not only poses harm to the liver, but also has the potential to impact various other systems including the nervous system, kidney, and blood system[19-21]. While some cases suggest an incidental association between HEV and these extrahepatic manifestations, the underlying pathophysiological mechanism remains unestablished. Data reveals significant activation of inflammatory cytokines (such as tumor necrosis factor alpha and interleukin-1β) in HEV-infected brain tissue, which promotes mitochondria-mediated apoptosis and provides novel insights into the mechanism of central nervous system injury caused by extrahepatic involvement[22]. El-Mokhtar et al[23] demonstrated that renal manifestations associated with HEV infection may primarily be linked to an exacerbated inflammatory response induced by Interferon-gamma produced by peripheral blood mononuclear cells (PBMC), through analysis of inflammatory response markers and renal injury markers in PT cells co-cultured with or without PBMC. Furthermore, direct or indirect associations between HEV replication in human monocytes, macrophages, and human bone marrow derived macrophages may contribute to hematological manifestations associated with HEV infection[24]. Clinically, patients with systemic manifestations of HEV infection should be given priority to antiviral therapy to help eliminate or improve extrahepatic manifestations of HEV infection.

CONCLUSION

As previously mentioned, there are still numerous challenges and significant obstacles to overcome in the process of translating knowledge into disease prevention and improving clinical outcomes for HEV patients. In order to bridge the existing gap, it is imperative to foster collaboration between researchers specializing in basic science, translational research, and clinical practice while also leveraging the collective efforts of health authorities. This will further advance HEV research and enhance clinical practices. Simultaneously, preventive measures should be directed towards addressing the threat posed by HEV infections. Enhanced emphasis on fundamental hygiene practices and education can effectively contribute to achieving better prevention outcomes.