Similarities,differences, and possible interactions between hepatitis E and hepatitis C viruses: Relevance for research and clinical practice

Hepatitis E virus (HEV) and hepatitis C virus (HCV) are both RNA viruses with a tropism for liver parenchyma but are also capable of extrahepatic manifestations. Hepatitis E is usually a viral acute fecal-oral transmitted and self-limiting disease presenting with malaise, jaundice, nausea and vomiting. Rarely, HEV causes a chronic infection in immunocompromised persons and severe fulminant hepatitis in pregnant women. Parenteral HCV infection is typically asymptomatic for decades until chronic complications, such as cirrhosis and cancer, occur. Despite being two very different viruses in terms of phylogenetic and clinical presentations, HEV and HCV show many similarities regarding possible transmission through organ transplantation and blood transfusion, pathogenesis (production of antinuclear antibodies and cryoglobulins) and response to treatment with some direct-acting antiviral drugs. Although both HEV and HCV are well studied individually, there is a lack of knowledge about coinfection and its consequences. The aim of this review is to analyze current literature by evaluating original articles and case reports and to hypothesize some interactions that can be useful for research and clinical practice.     

Clinical features of hepatitis d

Hepatitis D is caused by infection with hepatitis D virus (HDV), a defective RNA virus that requires the obligatory helper function of hepatitis B virus (HBV) for its in vivo transmission. Thus, HDV is acquired only by coinfection with HBV or by superinfection of an HBV carrier. The clinical outcome of hepatitis D differs according to the modality of infection. Whereas coinfection evolves to chronicity in only 2% of the cases, superinfection results in chronic infection in over 90% of the cases. HDV is a highly pathogenic virus that causes acute, often fulminant hepatitis, as well as a rapidly progressive form of chronic viral hepatitis, leading to cirrhosis in 70 to 80% of the cases. The clinical picture of HDV disease is evolving as a consequence of a significant change in the epidemiology of HDV infection, which has led to a significant decline in incidence in Western countries, mainly as a result of universal HBV vaccination programs. However, in the face of a declining prevalence in areas of old endemicity like Europe, immigration poses a threat of HDV resurgence. The interaction of HDV with other hepatitis viruses or human immunodeficiency virus is complex and may lead to different patterns in terms of virologic expression and immunologic responses. Multiple viral infections are associated with rapid progression of liver fibrosis and eventually with the development of hepatocellular carcinoma. Hepatitis D is not a vanishing disease, and continuous efforts should be made to improve its prevention and treatment.     

Hepatitis E and chronic liver damage in apparently immunocompetent individuals: Now what?

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide, accounting for 20 million infections per year and 70,000 deaths. In developed regions, sporadic locally acquired infections are most commonly caused by HEV3, and in this setting Hepatitis E is mainly asymptomatic. However, certain group of patients HEV infection may present as a fulminant disease or progressive fibrosis. Chronic HEV infection can occur in immunocompromised individuals, including transplant recipients. A high proportion of solid-organ transplant recipients exposed to HEV are at risk of developing a chronic infection, frequently associated to extrahepatic manifestations. However, clinical phenotype of sporadic cases of HEV infection is still poorly characterized.A recent work, focused on the retrospective study of HEV as a causative agent of viral hepatitis in adults form Mexico, pose novel challenges to understanding the HEV threat to human health. Main findings are brought into discussion herein, in light of the current knowledge concerning viral pathogenesis and host–pathogen interaction. The role of HEV infection in the development of chronic liver disease is also discussed. Hepatitis E is a cause of mortality and morbidity which negatively impacts the prognosis of patients with chronic liver disease. Recognition of HEV infection must be improved, by increasing awareness and knowledge of the clinical phenotype of the disease.     

Genetic diversity of hepatitis viruses in West-African countries from 1996 to 2018

The severity of hepatic pathology and the response to treatment depend on the hepatitis virus genotype in the infected host. The objective of this review was to determine the distribution of hepatitis virus genotypes in West African countries. A systematic review of the literature in PubMed, Google Scholar and Science Direct was performed to identify 52 relevant articles reporting hepatitis A, B, C, D, E and G viruses genotypes. Hepatitis B virus (HBV) genotype E with a prevalence of 90.6% (95%CI: 0.891-0.920) found in this review, is characterized by low genetic diversity. Hepatitis C virus (HCV) genotypes 1 and 2 represented 96.4% of HCV infections in West African countries, while hepatitis delta virus, hepatitis A virus, hepatitis G virus genotypes 1 and HEV genotype 3 were reported in some studies in Ghana and Nigeria. HBV genotype E is characterized by high prevalence, low genetic diversity and wide geographical distribution. Further studies on the clinical implications of HBV genotype E and HCV genotypes 1 and 2 are needed for the development of an effective treatment against this viral hepatitis in West African countries. Surveillance of the distribution of different genotypes is also needed to reduce recombination rates and prevent the emergence of more virulent viral strains.     

Prevention of virus hepatitis A to E

Infection with hepatitis viruses can lead to acute hepatitis with the risk of developing liver failure. Chronic viral hepatitis may evolve into liver cirrhosis and hepatocellular carcinoma. Thus, prevention of viral hepatitis and its sequels is essential. Vaccination against hepatitis A is successful in almost all individuals. Protective antibodies maintain for at least 20?years. Booster vaccinations are not necessary. Since the introduction of hepatitis A vaccines, the incidence of new HAV-infections has declined significantly. Hepatitis B vaccines are safe and highly effective. Special populations such as dialysis patients or immunocompromised patients require special vaccine schedules. New vaccines with improved adjuvants are currently being tested in clinical trials. So far there is no hepatitis C vaccine on the horizon. Prophylaxis of HCV-infections relies primarily on hygiene measures. Early therapy of acute hepatitis C can prevent chronic hepatitis?C. HDV-infection can only be established if HBsAg is present. Thus, prevention of hepatitis B or elimination of HBsAg means prevention of hepatitis delta. Hepatitis E vaccines have been evaluated in phase III studies. The development of HEV vaccines becomes more relevant since chronic HEV infections have been reported in immunosuppressed individuals.     

Spontaneous elimination of hepatitis C virus infection： A retrospective study on demographic, clinical, and serological correlates

To find correlates to spontaneous clearance of hepatitis C virus （HCV） infection, this study compared individuals with self-limited and chronic infection with regard to clinical, demographic, and serological pa- rameters. METHODS： Sixty-seven anti-HCV positive and repeatedly HCV RNA negative individuals were considered to have resolved HCV infection spontaneously. To determine the viral genotype these patients had been infected with HCV serotyping was performed. For comparison reasons, 62 consecutive patients with chronic hepatitis C were enrolled. Cases and controls were compared stratified for age and sex. RESULTS： Retrospective analysis showed （1） a lower humoral reactivity to HCV in patients with self-limited compared to chronic HCV-infection and （2） that younger age, history of iv drug use, and acute/post-acute hepatitis A or B co-infections, but not viral genotypes, are independent correlates for spontaneous HCV clearance. CONCLUSION： The stronger humoral reactivity to HCV in patients with persistent infections and in those with a history of iv drug use is supposed to be due to continuous or repeated contact（s） to the antigen. Metachronous hepatitis A or hepatitis B infections might favor HCV clearance.     

Hepatitis E: Discovery,global impact,control and cure

Hepatitis E was identified as an epidemic of non-A, non-B hepatitis from Kashmir, India in 1978. Hepatitis E virus(HEV), the etiological agent is the sole member of family Hepeviridae. The virus has marked heterogeneity and infects many animals like bats, camel, chicken, deer, boar, mongoose, pigs, rats, rabbit and cutthroat trout. Hepatitis E is a disease with a major global impact and has two distinct epidemiological patterns. Hepatitis E is an imperative health issue in developing nations, transmitted through sullied water and happens most every now in young adults. The disease is particularly severe during pregnancy and in people with underlying liver cirrhosis. Autochthonous hepatitis E is increasingly recognized in developed countries. The virus infects domestic pigs, wild boar and Sika deer in these countries. HEV infections in humans occur by eating the undercooked game flesh, raw liver from supermarkets and Figatelli sausages. Blood transfusion-associated HEV infections occur in many countries and screening of donors for HEV RNA is under consideration. Hepatitis E causes a number of extrahepatic diseases, including a wide spectrum of neurological syndromes. HEV genotype 3 causes prolonged viremia, chronic hepatitis, liver fibrosis and cirrhosis in organ transplant patients. The virus is amenable to ribavirin monotherapy and most patients clear the virus in a few weeks. Hepatitis E vaccine-239, marketed in China, has shown high efficacy with sustained protection for over four years.     

DNA-guided hepatitis B treatment, viral load is essential, but not sufficient

Hepatitis B virus （HBV） infection is a global public health problem that concerns 350 million people worldwide. Individuals with chronic hepatitis B （CriB） are at increased risk of developing liver cirrhosis, hepatic de-compensation and hepatocellular carcinoma. To maintain undetectable viral load reduces chronic infection complications. There is no treatment that eradicates HBV infection. Current drugs are expensive, are associated with adverse events, and are of limited efficacy. Current guidelines try to standardize the clinical practice. Nevertheless, controversy remains about management of asymptomatic patients with CriB who are hepatitis B e antigen （HBeAg）-positive with normal alanine aminotransferase, and what is the cut-off value of viral load to distinguish HBeAg- negative CriB patients and inactive carriers. We discuss in detail why DNA level alone is not sufficient to begin treatment of CriB.     

Hepatitis viruses (other than hepatitis B and C viruses) as causes of hepatocellular carcinoma: an update

Chronic hepatitis B and C virus infections are universally accepted as causes of hepatocellular carcinoma in humans. Hepatitis A and E viruses cause only acute self‐limiting infections of the liver. Of the remaining hepatitis viruses ‐ Delta hepatitis, hepatitis G (GB‐C), TT and SEN ‐ all have at some time been incriminated as causes of hepatocellular carcinoma. Delta hepatitis virus requires helper functions from hepatitis B virus to become invasive. Chronic Delta/hepatitis B viral co‐infection runs a more severe course than that resulting from chronic hepatitis B virus infection alone, with progression to cirrhosis being more likely and more rapid. A substantial majority of the early studies did not find an increased incidence of hepatocellular carcinoma in co‐infected individuals. But more recently, an increased incidence of the tumour has been recorded more often than no increase. Further studies are needed to draw a firm conclusion with regard to the hepatocarcinogenic effect of dual Delta/hepatitis B virus co‐infection. With one exception, no published study (of 13) has incriminated chronic infection with hepatitis G virus as a cause of hepatocellular carcinoma. The dissenting study, published in 1999, was the only one performed in the United States. Fewer studies of the hepatocarcinogenic effect of TT virus have been performed. Apart from one study, published in 1999, no convincing evidence is available that supports a causal role for TT virus in hepatocarcinogenesis. The exception was in Japanese patients with high hepatitis C viral loads but independent of chronic hepatitis C virus infection. No evidence has been produced to indicate that SEN virus causes hepatocellular carcinoma.     

Human hepatitis viruses-associated cutaneous and systemic vasculitis

Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.     

妊娠期暴发型肝功能衰竭的研究

目的探讨妊娠期暴发型肝功能衰竭(FHFP)的临床,生化,病原学特点。方法观察21例FHFP临床表现,并分析实验室资料,13例作肝组织学检查。结果乙型肝炎病毒感染7例,乙型肝炎病毒、戊型肝炎病毒重叠感染2例。FHFP血清白蛋白极显著低于妊娠期急性肝炎和慢性肝炎,分别为(25.19±6．95)、(33．17±3．44)及(33．80±3．78)g/L(均P＜0.01)。肝组织学诊断为,存活的6例中,急性肝炎1例,慢性肝炎4例,瘀胆型肝炎1例。死亡7例中,慢性肝炎4例,瘀胆型肝炎2例,产前子痫肝损害1例。结论肝炎病毒是FHFP的病因之一。低蛋白血症在FHFP发病中起着重要作用;FHFP可能是一种独特的综合征。     

Hepatitis B and hepatitis C viruses: a review of viral genomes,viral induced host immune responses,genotypic distributions and worldwide epidemiology

Hepatitis B and hepatitis C viruses (HCV) are frequently propagating blood borne pathogens in global community. Viral hepatitis is primarily associated with severe health complications, such as liver cirrhosis, hepatocellular carcinoma, hepatic fibrosis and steatosis. A literature review was conducted on hepatitis B virus (HBV), HBV genome, genotypic distribution and global epidemiology of HBV, HCV, HCV genome, HCV and host immune responses, HCV genotypic distribution and global epidemiology. The valued information was subjected for review. HBV has strict tissue tropism to liver. The virus infecting hepatocytes produces large amount of hepatitis B surface antigen particles which lack the DNA. It has capability to integrate into host genome. It has been found that genotype C is most emerging genotype associated with more severe liver diseases (cirrhosis). The approximate prevalence rate of genotype C is 27.7% which represents a major threat to future generations. Approximately 8% of population is chronic carrier of HBV in developing countries. The chronic carrier rate of HBV is 2%-7% in Middle East, Eastern and Southern Europe, South America and Japan. Among HCV infected individuals, 15% usually have natural tendency to overcome acute viral infection, where as 85% of individuals were unable to control HCV infection. The internal ribosomal entry site contains highly conserved structures important for binding and appropriate positioning of viral genome inside the host cell. HCV infects only in 1%-10% of hepatocytes, but production of tumor necrosis factor alpha (from CD8+ cells) and interferon-gamma cause destruction of both infected cells and non-infected surrounding cells. Almost 11 genotypes and above 100 subtypes of HCV exists worldwide with different geographical distribution. Many efforts are still needed to minimize global burden of these infections. For the complete eradication of HBV (just like small pox and polio) via vaccination strategies, sincere efforts would be required from government and nongovernmental organizations.     

Update on the management and treatment of viral hepatitis

This review aims to summarize the current evidence on the treatment of viral hepatitis, focusing on its clinical management. Also, future treatment options and areas of potential research interest are detailed. PubMed and Scopus databases were searched for primary studies published within the last ten years. Keywords included hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus, hepatitis D virus (HDV), hepatitis E virus, and treatment. Outcomes reported in the studies were summarized, tabulated, and synthesized. Significant advances in viral hepatitis treatment were accomplished, such as the advent of curative therapies for hepatitis C and the development and improvement of hepatitis A, hepatitis B, and hepatitis E vaccination. Drugs that cure hepatitis B, going beyond viral suppression, are so far unavailable; however, targeted antiviral drugs against HBV (immunomodulatory therapies and gene silencing technologies) are promising approaches to eradicating the virus. Ultimately, high vaccination coverage and large-scale test-and-treat programmes with high screening rates may eliminate viral hepatitis and mitigate their burden on health systems. The development of curative hepatitis C treatment renewed the enthusiasm for curing hepatitis B, albeit further investigation is required. Novel therapeutic options targeting HDV life cycle are currently under clinical investigation.     

丙型肝炎病毒感染个体的准种源于感染过程中的病毒核酸突变

目的研究丙型肝炎病毒(HCV)准种特性与感染慢性化的关系,以及个体准种特性的来源形式。方法收集HCVRNA阳性的10例急性丙肝、20例慢性丙型肝炎(丙肝)和11例肝细胞癌(HCC)患者,采用单链构型多态性分析(SSCP)方法进行HCV准种检测。结果急性丙肝、慢性丙肝和HCC患者中,SSCP电泳条带数分别为2．7±1．16、4．8±1．68和5．2±2．85。慢性丙肝和HCC的条带数显著高于急性丙肝(P＜0．05)。进行DNA序列分析研究发现,准种高变区间的变异性显著低于本地株间和异地株间的变异性(P＜0．01)。结论SSCP是检测准种相对简便而有效的方法。HCV准种特性与其感染慢性化相关。HCV感染个体准种的来源主要为感染过程中的核酸突变。     

Hepatitis E in Latin America

Hepatitis E virus produces an emerging health problem, knowledge about epidemiology of hepatitis E virus infections in the USA and Latin America is still limited. The wide-ranging clinical manifestations lead to an extensive underestimation of the global seroprevalence. Clinical and diagnostic accuracy are critical to improve patient management.     

Treatment of hepatitis C

Hepatitis C virus is a leading cause of chronic liver disease, with over 170 million people infected worldwide. It is also the leading indication for liver transplantation. Complications from chronic hepatitis C infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma. As a result, treatment strategies to prevent such complications have been widely researched, although many questions remain unanswered. To date, the standard therapy for chronic hepatitis C infection is the combination of peginterferon and ribavirin. Treatment strategies differ based on factors such as genotype and liver biopsy results. Other strategies must be considered for special groups, such as patients with acute hepatitis C infection, hepatitis C/human immunodeficiency virus (HIV) coinfection, and prior nonresponse to interferon or relapse after its use. The goal of therapy is to achieve a sustained virologic response (ie, no detectable hepatitis C ribonucleic acid 6 months after completion of therapy). The substantial adverse effects associated with both interferon alfa and ribavirin often make it difficult for patients to continue with their therapies.     

Can we foresee the end of the alphabet in viral hepatitis?

There is a number of viruses which may cause acute or chronic liver damage. Only some of them belong into the group of hepatotropic viruses and only the latter are the cause of acute or chronic viral hepatitis. So far we know seven hepatotropic viruses. The virus of hepatitis A (HAV), virus of hepatitis B (HBV), virus of hepatitis C (HCV), virus of hepatitis D (HDV), virus of hepatitis E (HEV), virus of hepatitis G (HGV) and Transfusion-Transmitted-Virus (TTV). For HAV and HEV orofaecal transmission is typical, the others are transmitted by the parenteral route. All cause acute hepatitis. Only HAV and HEV infections develop into the chronic stage. The decisive finding for the dynamic development of the problem of viral hepatitis was the discovery of the Australian antigen (Au antigen) by B. Blumberg in 1965. The discovery made it possible to recognize viral hepatitis B and by the application of new biotechnologies the genes of other viruses were detected. Some of them were not visualized so far. A great advance was alpha interferon and lamivudine treatment in patients with chronic hepatitis B and alpha interferon treatment along with ribavirine in chronic hepatitis C.     

Role of viral factors in the natural course and therapy of chronic hepatitis B

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.     

Management of hepatitis C in patients with chronic kidney disease

Hepatitis C virus(HCV) infection is highly prevalent among chronic kidney disease(CKD) subjects under hemodialysis and in kidney transplantation(KT) recipients, being an important cause of morbidity and mortality in these patients. The vast majority of HCV chronic infections in the hemodialysis setting are currently attributable to nosocomial transmission. Acute and chronic hepatitis C exhibits distinct clinical and laboratorial features, which can impact on managementand treatment decisions. In hemodialysis subjects, acute infections are usually asymptomatic and anicteric; since spontaneous viral clearance is very uncommon in this context, acute infections should be treated as soon as possible. In KT recipients, the occurrence of acute hepatitis C can have a more severe course, with a rapid progression of liver fibrosis. In these patients, it is recommended to use pegylated interferon(PEG-IFN) in combination with ribavirin, with doses adjusted according to estimated glomerular filtration rate. There is no evidence suggesting that chronic hepatitis C exhibits a more aggressive course in CKD subjects under conservative management. In these subjects, indication of treatment with PEG-IFN plus ribavirin relies on the CKD stage, rate of progression of renal dysfunction and the possibility of a preemptive transplant. HCV infection has been associated with both liver disease-related deaths and cardiovascular mortality in hemodialysis patients. Among those individuals, low HCV viral loads and the phenomenon of intermittent HCV viremia are often observed, and sequential HCV RNA monitoring is needed. Despite the poor tolerability and suboptimal efficacy of antiviral therapy in CKD patients, many patients can achieve sustained virological response, which improve patient and graft outcomes. Hepatitis C eradication before KT theoretically improves survival and reduces the occurrence of chronic graft nephropathy, de novo glomerulonephritis and post-transplant diabetes mellitus.