Chronic Hepatitis E: Comparison
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Hepatitis E is an inflammation of the liver caused by infection with the hepatitis E virus (HEV), and it is a major cause of acute viral hepatitis worldwide, the virus is usually transmitted via the fecal–oral route, principally via contaminated water. Chronic hepatitis E (CHE) has been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7—usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. 

  • chronic hepatitis E
  • immunocompromised
  • immunocompetent
  • HEV RNA

1. Definition of CHE and Its Historical Occurrence

Although acute hepatitis E has usually been recognized as having a favorable prognosis without prolonged viremia, hepatitis E virus (HEV) genotypes 3, 4, and 7 can cause chronic infection in immunocompromised individuals [1][2][3]. Most cases of CHE have been caused by genotypes 3 and 4, with only one case report of genotype-7-induced chronic hepatitis E (CHE) [4], which usually infects camels and is not expected to infect humans. According to this case report [4], a liver transplant recipient from the Middle East who regularly consumed camel meat and milk was chronically infected with genotype 7 HEV [3]. Chronic HEV infection is usually defined as the persistence of HEV replication for six months [5]. In contrast, CHE is defined as the presence of persistently elevated liver enzyme levels and a viremic status for more than three months [6].
However, in a small number of cases, spontaneous clearance has been observed between three and six months [7]. A quarter of a century has passed since the discovery of HEV [2]. As immunocompromised causes of persistent HEV infection, organ transplantation, HIV infection, and chemotherapy have been reported.

2. Pathogenesis of CHE

Chronic HEV infection can occur in immunocompromised hosts in whom the adaptive immune system is impaired. Regarding the clinical course of transplant patients, approximately 70% of solid organ transplant patients infected with HEV develop chronic hepatitis [8]. Individual differences in the immune response to HEV exist, as not all transplant patients treated with the same immunosuppressant develop chronic HEV infection; indeed, many anti-HEV-antibody-positive and HEV-RNA-positive organ transplant patients receive the same immunosuppressant regimen. HEV-specific CD4 and CD8 T-cell responses were reported to be undetectable in chronically HEV-infected patients but manifested after viral clearance [9]. In a unique macaque model, HEV clearance was accompanied by a neutralizing antibody response and liver infiltration of functional HEV-specific CD4 and CD8 T cells [10]. Innate immune responses to hepatitis E viral proteins translated from several ORFs have been demonstrated, and the persistence of HEV may be caused by these individual immunological differences [11].
As an immunosuppressant used in transplant patients, the use of tacrolimus rather than cyclosporine and a low lymphocyte count at diagnosis are associated with chronic infection after exposure to HEV [12]. A subsequent case report documented persistent HEV infection in a patient with HIV [13], but another study revealed that HIV-positive patients were not a risk group for HEV coinfection [14]. This may explain why chronic HEV infection is rare in patients with HIV, who typically experience a progressive loss of CD4 T cells in isolation. Patients with cancer receiving chemotherapy and/or immunotherapy [15], as well as those with autoimmune diseases (e.g., rheumatic diseases) receiving immunosuppressive or immunomodulatory therapies [16], are also at risk of developing CHE.
It should be noted that CHE in immunocompetent patients has rarely but occasionally been reported in several countries, including the USA [17], Germany [18], France [19], China [20], and Japan [21]. These cases were not organ-transplant- or cancer-related; instead, most had been administered immunosuppressants such as glucocorticoids and mycophenolate mofetil, except for the Chinese case [20]. This patient had a purely immunocompetent condition, rarely complicated with chronic HEV infection [20]. The Japanese case was also administered prednisolone and azathioprine, but the presence of a long-lasting high titer of HEV RNA before the administration of these drugs resulted in her diagnosis with CHE despite her immunocompetent condition and older age (late 70s) with underweight status (body mass index: 19.8 kg/m2) and without any immunocompromised comorbidities [21]. These two patients seemed to be immunocompetent but, nevertheless, developed CHE. As shown in the Japanese case [21], the patient’s age (>70 years) and low body mass index (<20 kg/m2) correspond to a severely undernourished status according to the Global Leadership Initiative on Malnutrition (GLIM) criteria [22]. Immune responses are reportedly decreased in undernourished elderly individuals, along with the CD4+ population [23]. Protein–energy malnutrition (PEM) and aging lead to severe immunodeficiency in the elderly population, affecting not only specific immunity (B and T lymphocytes) but also nonspecific immunity (polymorphonuclear cells and monocytes). PEM patients release fewer monokines, which leads to reduced stimulation of lymphocytes, the functions of which are already diminished. PEM patients are therefore unable to raise effective immune reactions [23].
It has been reported that HEV clearance is mainly dependent on T-cell responses, because lymphocyte subset counts—mainly CD4+ lymphocyte counts—have been found to be significantly lower at the diagnosis of HEV infection in patients who develop chronicity in comparison to those who clear the virus within 6 months [12]. In patients with HCV infection, HCV-specific CD4+ and CD8+ T lymphocytes play a crucial role in the eradication of the HCV in the liver [24]. Another study demonstrated that the number of IFN-γ–producing HCV-specific CD8+ T cells during the first 6 months after the onset of disease was associated with the eradication of HCV infection [25]. HEV eradication was also dependent on the IFN-γ sequence of HEV-specific CD8+ T cells [26]. Although the frequency of persistent viremia and the route of infection are quite different between HCV and HEV, both are hepatotrophic RNA viruses, and the immunological approach to HCV could be analogously applied for HEV. COVID-19 has also been reported to cause CHE [27], but no additional convincing reports regarding the relationships between COVID-19 and chronic HEV infection have been documented recently. Further studies are needed to elucidate the mechanism of CHE and to document the many hidden cases of undiscovered CHE.

3. The Diagnosis and Clinical Course of CHE

Anti-HEV antibodies are often undetectable in immunosuppressed patients who are chronically infected with the virus [21][28][29][30][31]. To diagnose HEV infection based on an antibody response, HEV IgM has been used worldwide, while HEV IgA is mainly used in Japan [32]. However, these antibody responses have demonstrated limited sensitivity, especially in immunocompromised situations [33][34]. The nucleic acid amplification technique-based detection of viral RNA in blood and/or stool samples is the only reliable method for making a diagnosis. Chronic HEV infection is defined by the detection of viral RNA for more than three months. The viral load calculated from the quantification of HEV RNA is also used to evaluate the treatment response [5]. The diagnosis is usually only considered when infection is clinically suspected, but this is clearly insufficient to fully recognize the burden of HEV infection in immunocompromised patients. HEV RNA is not always evaluable everywhere in the world, but recent advancements in polymerase chain reaction (PCR) for the diagnosis of COVID-19 have improved the commercial availability. Clinicians must therefore not overlook the possibility of chronic HEV infection based on one-time-negative anti-HEV antibody findings.
Questions have been raised as to whether or not structured systematic screening of HEV infection for transplant recipients living in endemic areas should be considered [35], but further research—especially cost-effectiveness analyses—will be required to address this issue [2].
CHE may progress to liver cirrhosis [2][36], but the hepatocarcinogenic potential of persistent HEV infection has yet to be clarified, due to the rarity of HCC in cases of advanced CHE [37][38]. Epidemiological studies have shown both a positive and a negative relationship between HEV and HCC [38]. A Chinese group showed that HEV infection was not an independent risk factor for HCC, but that HBV and HEV coinfection might be positively associated with the development of HCC [39]. Another group in Cameroon demonstrated that HCC patients had a higher seroprevalence of HEV IgG in comparison to patients with chronic liver disease [40]. Superinfection of hepatitis B or C and HEV may enhance hepatocarcinogenesis; however, at this time, researchers do not consider simple HEV infection to be sufficient to induce HCC. Large amounts of experimental data have also been accumulated on the relationship between HEV and hepatocarcinogenic pathways such as angiogenesis, apoptosis, oxidative stress, and chronic hepatic inflammation with fibrosis [41], which are seen in CHE, and which could cause HCC [37][38]—the same as it is caused by chronic HCV and HBV infection, habitual alcohol intake, genetic disorders such as hemochromatosis, and other conditions [41][42]. At any rate, further evidence must be accumulated for HEV to be accepted as a cause of HCC.

4. Prevention and Treatment for CHE

The hope for better prevention of HEV infection lies in the availability of safe and effective vaccines [2]. The only approved vaccine (Hecolin) was licensed in China in 2011. It is well tolerated and effective in the prevention of HEV genotypes 1 and 4 in the general population, with long-lasting protective immunity [43][44]. Although these findings cannot be directly applied to HEV genotype 3, immunization with Hecolin in a rabbit model has been shown to confer full protection against HEV genotype 3 [45]. In addition, the World Health Organization (WHO) calls for studies to evaluate the safety and immunogenicity of Hecolin in special populations such as immunocompromised patients and pregnant women, and an ongoing phase IV trial is testing protection in pregnant women in Bangladesh [46]. On the other hand, the vaccination with Hecolin in rabbits prior to the administration of immunosuppressive medication fully protected them against HEV genotypes 3 and 4, whereas only partial protection was achieved when the animals were already receiving immunosuppressants [47]. From a clinical practice perspective, one could argue in favor of preferentially vaccinating patients on the waiting list for organ transplantation [2].
Regarding the treatment for CHE, in immunocompromised cases, the first-line therapeutic option for chronic HEV infection is a reduction in immunosuppressive therapy [48]. HEV clearance was reportedly observed in 30% of solid organ transplant patients with chronic HEV infection after reducing immunosuppressive therapies that principally targeted T cells [8]. It has been recommended that if HEV infection is not cleared within three months after starting dose reduction of immunosuppressants, antiviral therapy should be considered [8].
Ribavirin (RBV) has been reported to show excellent efficacy and safety in treating CHE. In a multicenter retrospective study including 59 solid organ transplant recipients treated with RBV, a sustained virologic response (SVR)—defined as an undetectable serum HEV RNA level for at least 6 months after the cessation of medication—was achieved in 78% of initial treatment cases, 85% of overall cases (including retreatment cases [49]), and 83% of liver transplant recipients [50]. The exact mechanism of RBV on HEV clearance remains unclear. RBV could act both directly on viral replication and as an immunomodulatory agent [49]. The effect of RBV on HEV was demonstrated in another mechanism through natural killer (NK) cells [51]. An in vitro study demonstrated that RBV has an immunomodulatory effect on the IL-12R pathway of NK cells via tyrosine kinase (TYK)-2. This subsequently leads to an enhanced IFN-γ response as an additive antiviral effect in the context of HEV infection [51].
Although the optimal dose of RBV for CHE has not yet been established in both immunocompromised and immunocompetent cases, RBV was initiated at a median dose of 600 mg/day and achieved high rates of SVR, and the dose was often adjusted in response to adverse events such as RBV-induced anemia [49][52]. It was also reported that no statistically significant difference in the SVR rate was observed between patients treated for three months or less and those who received RBV for more than three months [49]. In contrast, however, 6 of 10 relapsed patients who had been initially treated for 3 months were retreated with RBV for 6 months, and an SVR was achieved in 4 of these patients [49]. Therefore, three months of RBV administration is considered appropriate as the initial treatment, but it should be extended to six months at retreatment. Regarding the mechanism underlying the effect of RBV on HEV, RBV inhibits HEV replication through the depletion of guanosine triphosphate (GTP) [53]. It was also recently shown that although RBV increases viral heterogeneity, RBV-induced metagenesis seems to be reversible after therapy is stopped [54]. Another study showed that an RBV-failure-associated mutation (Y1320H) in the RNA-dependent RNA polymerase of HEV genotype 3 enhanced viral replication in a rabbit HEV infection model [55]. A more precise investigation is needed to clarify the effect and the reason for failure of the RBV treatment.
For other treatments for CHE, the efficacy of pegylated interferon (Peg-IFN) has been reported [56][57]. However, the number of cases investigated for the effect and safety has been small, and Peg-IFN may cause immunological adverse events. Although Peg-IFN can be used in liver transplant patients and non-transplant patients with CHE [56], Peg-IFN-alpha increases the risk of acute rejection in other transplant patients with CHE [58]. Regarding sofosbuvir (SOF), it was reported that SOF monotherapy had only modest antiviral efficacy in CHE patients and failed to achieve viral elimination [59]. Additional effects of SOF in combination with RBV have also not yet been established in vivo. However, a synergistic effect of 2′-methylcytidine or 2′-C-methylguanosine with RBV in inhibiting HEV replication in a reporter assay and cultured cells was recently reported [60]. Due to a lack of information demonstrating the efficacy and safety these medicines in clinical practice, large-scale clinical trials should be conducted in the future.
At present, RBV is the first-choice antiviral agent to treat CHE in both immunocompromised and immunocompetent cases. It is essential that the WHO continues to include RBV in the List of Essential Medicines, and the development of additional therapies is crucial [34].
HEV infection can cause some disorders in other organ systems. Neurological disorders such as Guillain–Barré syndrome associated with HEV infection have been reported [61]. Antibodies that are produced against gangliosides through molecular mimicry after culprit infections have been shown to lead to Guillain–Barré syndrome. As a severe case of Guillain–Barré syndrome successfully treated with intravenous immunoglobulin has been reported [62], treatments by immunological approaches could be preferable to antiviral therapy in such patients. In addition, glomerulonephritis cases such as membranoproliferative glomerulonephritis, IgA glomerulonephritis, and membranous nephropathy caused by HEV infection have also occasionally been reported [63][64][65][66]. The patients with spontaneous HEV clearance subsequently show improved glomerulonephritis and renal function as well [64][65]. On the other hand, in patients who develop CHE, glomerulonephritis may also continue. Antiviral therapy with RBV is useful not only for the eradication of HEV, but also for the remission of glomerulonephritis and renal function in such patients [63][65][66]. Both neurological disorders and renal disorders may be attributed to the direct cytopathic effects of HEV and/or immune-mediated mechanisms. Although the question of whether antiviral therapy with RBV or immunological therapies such as corticosteroids or immunoglobulin should be preferentially given is still controversial, treatment should be selected considering the pathophysiological mechanisms, titer of HEV RNA, liver function, and the severity of neurological and/or renal disorder in each patient. Most acute pancreatitis cases associated with HEV have been reported from the Southern Asia region, suggesting that these were possibly caused by HEV genotype 1 infection [67]. It is possible that genotype 1 has high tropism for the pancreas, because no cases of acute pancreatitis have been reported in patients infected with other HEV genotypes [67]. Bazerbachi F et al. reported that of the 53 acute pancreatitis patients associated with HEV infection, 44 patients (83%) had mild and 9 (17%) had moderate–severe acute pancreatitis [67]. Although acute pancreatitis associated with HEV usually resolves with supportive treatments, early diagnosis may help in reducing morbidity and mortality [67]. Thus, clinicians should consider the complication of acute pancreatitis in patients with severe abdominal pain in the course of HEV infection. Although mild thrombocytopenia may coexist with HEV infection, it does not generally require any specific treatments [68].

5. Prognosis of CHE

The prognosis of CHE depends on the primary disease complicating immunosuppression, such as organ transplant, positive HIV, cancers (e.g., hematological malignancies), autoimmune diseases (e.g., rheumatoid arthritis, usually treated with immunosuppressants such as steroids, tacrolimus, etc.), and so on. Because the first-choice treatment for CHE in such situations should be the dose reduction of immunosuppressants, the control of the primary disease would be more important. Secondarily, the impact of drugs for CHE such as ribavirin would influence the prognosis of CHE. The effect of ribavirin on CHE has been reported to be adequate—around 80% of the rate of sustained viral response [49][69] and a meta-analysis of liver transplant recipients [50]. CHE could progress to cirrhosis [37][38] if the diagnosis and treatment are delayed. It must be obvious that the early recognition and diagnosis of CHE should be mandatory to obtain a good prognosis.

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