Hepatitis C, D, and E PDF

1 HEPATITIS C, HEPATITIS D, AND HEPATITIS E By Prof. Hoda El Aggan Professor of Internal Medicine (Hepato-Biliary Pancreatic Unit) Faculty of Medicine, Alexandria...

1 HEPATITIS C, HEPATITIS D, AND HEPATITIS E By Prof. Hoda El Aggan Professor of Internal Medicine (Hepato-Biliary Pancreatic Unit) Faculty of Medicine, Alexandria University ILOs At the end of this session, the student will be able to: ▪ Review hepatitis C. hepatitis D, and hepatitis E as regards virology, pathogenesis, clinical presentation, diagnosis, outcome, prevention, and treatment. HEPATITIS C Virology HCV is a small, single‐stranded positive‐sense enveloped RNA virus belonging to the genus Hepacivirus within the family Flaviviridae. The HCV particle is composed of an envelope (E1 and E2 glycoproteins, a lipid membrane, the nucleocapsid, and the RNA Figure 1: Hepatitis C virus. genome (Figure 1). The RNA genome encodes a polyprotein of 3010–3033 amino acids that is cleaved into structural and non‐structural (NS) proteins (Figure 2). The structural proteins include the core (capsid) protein, two envelope glycoproteins (E1 and E2), and the p7 viroporin.  2 The nonstructural (NS) proteins include the NS2, NS3 (protease/helicase), NS- 4A (protease co-factor), NS4B, NS5A, and NS5B (RNA-dependent RNA polymerase (RdRp) proteins. Figure 2: The hepatitis C virus genome. There are seven genotypes of HCV based on their nucleotide variability in HCV sequences recovered from multiple geographic regions. The dominant genotype in Egypt is genotype 4. There is a very high level of virion turnover by the NS5B RNA polymerase resulting in the generation of viral mutants, also known as "quasispecies". Unlike hepatitis B virus (HBV), the HCV RNA genome cannot integrate into the host's genome. Mode of transmission The most common route for HCV infection is parenteral transmission (usually by intravenous drug use or blood product transfusion). HCV may also be transmitted via tattooing, sharing razors, and acupuncture. Perinatal (Maternal-fetal transmission) and sexual transmission can occur, and inhaled drug use can also result in transmission. Breastfeeding is not associated with HCV transmission. The incubation period ranges from 2 to 12 weeks (average 7 weeks). Pathogenesis HCV is not considered directly cytopathic in virus-infected hepatocytes. The innate immune response plays a major role as a first line of defense against the invading virus. Secretion of Type I and Type III interferons induces an antiviral state in infected cells and activates the cellular components of innate and adaptive immunity. Progression to chronic infection can be considered a failure of the innate and adaptive immune responses to control viral replication.  3 Chronic inflammatory response triggers liver fibrogenesis and cirrhosis. with increased risk of hepatocellular carcinoma (HCC). Histopathology The basic morphologic features of acute and chronic hepatitis C are similar to those of other causes of hepatitis. However, hepatitis C is characterized by the histologic triad of lymphoid aggregates in portal tracts, macrovesicular steatosis, and epithelial damage of small bile ducts (Figure 3). The outcome of HCV infection Figure 3: Chronic hepatitis C showing lymphoid aggregates in portal tract Only 15-45% of patients infected with (arrow) and macrovesicular steatosis HCV have a self-limited infection with of hepatocytes (arrow heads). virus clearance. HCV infection becomes persistent in 55-85% of patients and leads to chronic hepatitis. 20-30% of chronic HCV-infected individuals develop liver cirrhosis within 20– 30 years. Once cirrhosis is established, the risk of hepatic decompensation is 2-5% annually and the rate of HCC development is 1-4% annually. Clinical presentation Acute hepatitis C Acute hepatitis C is usually asymptomatic, and typically unrecognized. Generally, acute hepatitis C is therefore relatively infrequently diagnosed. About 25% of patients present with jaundice (icteric attack) (more likely to clear the virus) while most symptomatic patients (75% of patients) are not jaundiced (anicteric attack) and present with non‐specific symptoms including fatigue, anorexia, mild or moderate abdominal pain, low-grade fever, nausea, and/or vomiting. Fulminant hepatitis is rare but has been reported. Chronic hepatitis C Patients with chronic hepatitis C are asymptomatic or have nonspecific symptoms. These may include fatigue or malaise, intermittent right upper  4 quadrant pain, nausea, diarrhea, anorexia, sleep disturbances, myalgia, arthralgia, weakness, depression and anxiety. Development of cirrhosis is evidenced by the manifestations of portal hypertension (esophageal varices, splenomegaly, caput medusae, venous hum) and hepatic decompensation (ascites, coagulopathy, encephalopathy, jaundice, and other stigmata of decompensated cirrhosis) (refer to cirrhosis). The majority of HCV-associated HCCs occur in cirrhotic livers. Fibrosing cholestatic hepatitis (FCH) is recognized in patients with chronic hepatitis C who are under immunosuppression particularly those co-infected with human immunodeficiency virus (HIV). Extrahepatic manifestations include hematologic abnormalities (essential mixed cryoglobulinemia (type 2 cryoglobulinemia) and B cell lymphoma), membranoproliferative glomerulonephritis, dermatologic disorders (porphyria cutanea tarda and lichen planus), rheumatologic complaints (arthralgias/myalgias), neurocognitive changes with sensory or motor neuropathy, metabolic disorders (insulin resistance, type 2 diabetes), and autoimmune conditions such as thyroiditis. Diagnosis Serological markers The diagnosis of HCV infection is based on the detection of antibodies to HCV (anti-HCV) and HCV RNA in serum when HCV infection is suspected due to exposure, clinical presentation, or elevated aminotransferase levels (Figure 4). Figure 4: Serologic markers in acute HCV infection. Anti-HCV is directed against antigens from the capsid region (C22) and non‐ structural regions; NS3 (C33) and NS5 and are detected by enzyme immunoassay.  5 - Anti-HCV becomes positive within 8–10 weeks of exposure by the time serum alanine aminotransferase (ALT) levels peak and decline within 30 to 60 days of infection. - Following viral clearance, anti-HCV antibodies usually persist in the absence of HCV RNA, but titers may wane and finally disappear in some individuals. - Anti-HCV antibodies cannot differentiate between past or current HCV infection. - False negative results of antibody testing (i.e the antibodies are undetectable during HCV infection) occur in the early phase of acute infection as well as in patients on hemodialysis and immunocompromised patients. - The HCV Rapid Antibody Test with rapid turnover can be an essential public health tool as results can be obtained in 20 to 40 min. HCV RNA testing by real time polymerase chain reaction (RT-PCR) is necessary to distinguish between ongoing or prior infection in patients with positive HCV antibodies. An assay with a lower limit of detection ≤ 15 IU/ml is recommended. - HCV RNA is detected early in serum within 2 weeks of exposure. Viremia peaks in the first 8 to 12 weeks of infection, and then plateaus or drops to undetectable levels if viral clearance occurs. - However, elevated HCV RNA persists in the majority of patients (75% to 85%). - Chronic hepatitis C is defined as persistence of HCV RNA in serum for 6 months or more. HCV core antigen (HCVcAg) is a marker of HCV replication and is detected in serum a few days after HCV RNA becomes detectable during acute HCV infection. HCVcAg testing has good sensitivity to identify patients with active infection but less than that of HCV RNA assays (lower limit of detection equivalent to approximately 500 to 3,000 HCV RNA IU/ml). HCV genotyping is helpful for predicting the likelihood of response and duration of treatment. Current treatment with pangenotypic regimens can be initiated without knowledge of the genotype and subtype with a high probability of success. Other laboratory tests Serum ALT levels rise between weeks 4 and 10 weeks peaking around week 6 in acute hepatitis C. About two thirds of patients with chronic hepatitis C have elevated ALT while approximately 30% of patients have persistently normal ALT levels.  6 Complete blood count (CBC), hepatic function panel, estimated glomerular filtration rate (eGFR), serology for other hepatitis viruses, cryoglobulins, rheumatoid factor, and thyroid function. Liver biopsy A liver biopsy is not routine, but it may help determine the severity of the disease (grading and staging) (refer to chronic hepatitis). Imaging Imaging modalities (transient elastography) with or without noninvasive fibrosis scores can assist in the assessment of liver fibrosis (refer to cirrhosis). Screening tests All patients with cirrhosis should undergo endoscopic screening for esophageal varices and screening for HCC. Occult HCV infection Occult HCV infection (OCI) is defined by the presence of HCV RNA in hepatocytes and/or peripheral blood mononuclear cells in the absence of HCV RNA in serum. Depending on the presence of anti-HCV in serum, two types of OCI are distinguished: seronegative and seropositive. OCI is a milder form of infection associated with less hepatic injury and extrahepatic manifestations. Prevention Since there is no vaccine for HCV, HCV screening is recommended because of the known benefits of care and early treatment in reducing the risk of decompensated cirrhosis, HCC, all-cause mortality, and HCV transmission. One-time, routine HCV testing is recommended for all individuals aged 18 years or older. Prenatal HCV testing as part of routine prenatal care is recommended with each pregnancy. Periodic repeat HCV testing should be offered to all persons with an increased risk of HCV exposure (Table 1).  7 Table 1: High-risk populations for hepatitis C virus infection Intravenous drug users Healthcare, emergency medical, and public safety workers after needlestick, sharps, or mucosal exposure to HCV-infected blood Individuals on long-term hemodialysis Those who engage in high‐risk sexual practices Persons who received blood transfusion or infusion of clotting factor concentrates before 1992 Solid organ transplant recipients Human immunodeficiency virus (HIV)‐positive homosexuals Infants born to HCV‐infected mothers with high HCV RNA (1– 5%) Individuals with HCV infection should be counseled to reduce high-risk behaviors that could result in virus transmission. Vaccination against HAV and HBV is recommended for patients with chronic hepatitis C. Treatment Treatment of acute hepatitis C Management of acute hepatitis C includes conventional supportive treatment and specific antiviral therapy. Acetaminophen (paracetamol) and alcohol consumption should be avoided during acute HCV infection. All patients with acute hepatitis C should be treated upon initial diagnosis without awaiting spontaneous resolution to minimize the risk of chronicity and of HCV transmission. Direct acting antivirals (DAAs) in patients with acute hepatitis C are the same combination regimens recommended for chronic HCV infection (as will be discussed later). Treatment of chronic hepatitis C virus infection The goal of HCV treatment is to eliminate the virus and thus stop inflammation and prevent fibrosis, progression to cirrhosis and associated complications, the need for liver transplantation, and death. Before the development of the all-oral DAAs, the mainstay of HCV therapy was injectable pegylated interferon alpha (PEG-IFN) and ribavirin. This form of treatment only has a cure rate of 40% to 60%.  8 - PEG-IFN is given as 180 mcg subcutaneously weekly for 48 weeks and leads to numerous adverse effects (refer to Hepatitis B). - Ribavirin is an oral guanosine analog with activity against both RNA and DNA viruses. Ribavirin is given in combination with PEG-IFN as weight-based dose (1000 mg/day for ≤75 kg or 1200 mg/day for >75 kg for 48 weeks). - Ribavirin is usually well tolerated but may produce hemolytic anemia, especially in patients with renal disease given its excretion in the kidney. It should be avoided in patients with a creatinine clearance less than 50 ml/min. In addition, ribavirin is teratogenic. - PEG-IFN and ribavirin treatment is not recommended in patients with decompensated cirrhosis, pregnant patients, and patients with less than 12 months of life expectancy. Direct acting antivirals With the advent of oral DAAs, the duration of treatment is shortened from 48 weeks to 8-12 weeks with less adverse effects, increasing cure rates to 90-97%, and elimination of the need for injectable agents. Treatment with DAAs is recommended for all patients with acute and chronic HCV infection, unless their life expectancy is very short. Sustained virological response (SVR) (virologic cure) is defined as the absence of HCV RNA in serum 12 weeks after antiviral treatment completion. SVR has been associated with improvement in liver inflammation, aminotransferase levels, the rate of liver fibrosis progression, hepatic decompensation, HCC, and liver- related deaths. DAA classes DAAs inhibit replication of HCV by targeting HCV proteins. Currently, three classes of DAAs are available: - The NS3/4 protease inhibitors inhibit the NS3/4 serine proteases. Their names end in the suffix “-previr” (e.g. glecaprevir, grazoprevir, voxilaprevir, simeprevir, and paritaprevir). - The NS5A inhibitors interfere with the structural protein NS5A, a crucial element in viral replication. Their names end in the suffix “-asvir” (e.g. daclatasvir, ledipasvir, elbasvir, velpatasvir, and pibrentasvir). - The NS5B polymerase inhibitors inhibit the enzyme responsible for transcription of a negative-strand intermediate for future viral progeny. Their names end in the suffix “-buvir” and are either nucleoside/nucleotide (sofosbuvir), or non-nucleoside (dasabuvir).  9 Combinations of DAAs classes are typically used as daily fixed-dose to make a treatment regimen against various genotypes of hepatitis C. Resistance-associated substitutions (RASs) are alterations in the amino acid sequence that leads to increased resistance to DAA drugs. They can emerge as a result of exposure to DAA therapy or can also exist in DAA-naïve patients. RASs are more common in genotype 1a and 3 particularly in the NS3 gene (e.g. Q80K) and NS5A gene (e.g. Y93H). Initial DAA treatment for treatment-naïve patients A) Patients with and without compensated cirrhosis Pangenotypic DAA regimens are effective as the first-line treatment for all genotype 1-6 (except genotype 3 with NS5A resistance-associated RASs as will be discussed later) and include: - Glecaprevir (300 mg) / pibrentasvir (120 mg) to be taken with food for 8 weeks (administered as three 100 mg/40 mg fixed-dose combination pills). - Sofosbuvir (400 mg) / velpatasvir (100 mg) for 12 weeks. Other alternative regimens for genotypes 1 and 4 include: - Elbasvir (50 mg) / grazoprevir (100 mg) for 12 weeks. - Sofosbuvir (400 mg) / ledipasvir (90 mg) for 8 weeks (non-cirrhotic) or 12 weeks (compensated cirrhosis). Patients with genotype 3 require baseline NS5A RAS testing before DAA treatment. - In patients with compensated cirrhosis and a baseline NS5A RAS Y93H, weight-based ribavirin or voxilaprevir (100 mg) is added to sofosbuvir (400 mg) / velpatasvir (100 mg) for a duration of 12 weeks. B) Patients with decompensated cirrhosis NS3/4 protease inhibitors are primarily hepatically excreted and thus, protease inhibitor-containing regimens are not recommended in patients with decompensated cirrhosis (Child-Pugh B and C). Sofosbuvir-based regimens are used with or without low initial dose of ribavirin (600 mg, increase as tolerated to weight-based dose) for 12 weeks and 24 weeks respectively. C) Patients with hepatocellular carcinoma Patients with HCV-associated HCC are recommended to start treatment 3–6 months after complete treatment of their HCC, given lower rates of SVR with active HCC.  10 D) Patients with renal impairment No dose adjustment in DAAs is required when using recommended regimens in patients with renal impairment. A ribavirin dose reduction may be required for patients with chronic kidney disease (CKD) stage 3, 4, or 5. Retreatment of persons in whom prior DAA therapy has failed Re-treatment must be optimized in treatment-experienced patients (with past DAA therapy) through prolongation of therapy (often to 24 weeks), the addition of ribavirin to prior DAA regimen, switch to other drug class regimen, or the use of regimens combining triple or quadruple drug with unique mechanisms of action to overcome RASs. Post-DAA treatment assessment Quantitative HCV RNA measurement is recommended 12 weeks following completion of therapy to confirm that HCV RNA is undetectable (virologic cure) No liver-related follow-up is recommended for noncirrhotic patients who achieve SVR. Continued ultrasound surveillance for HCC (with or without alpha-fetoprotein testing) every 6 months and upper endoscopic surveillance for esophageal varices are recommended for patients with cirrhosis. Liver transplantation Patients with HCV infection who have decompensated cirrhosis—moderate or severe hepatic impairment, i.e, Child class B or class C—should be referred to a liver transplant center. Timing of DAA treatment before or after liver transplantation does not affect cure rates. Drug-drug interactions between DAA agents and calcineurin inhibitors can be expected. The coadministration of elbasvir / grazoprevir with cyclosporine should be avoided. HEPATITIS D Virology Hepatitis D virus or delta virus (HDV) is a satellite or defective RNA virus because it requires the helper function of HBV for its replication cycle.  11 HDV is 35–37 nm in diameter and the only one to possess a circular RNA genome, which is coated by HBsAg as its envelope protein. The HDV genome encodes a single structural protein, the HDV antigen (HDAg) (Figure 5). HDV and HBV share the same receptor, the sodium-taurocholate co-transporting polypeptide (NTCP) receptor for entry Figure 5: Structure of hepatitis D virus. into human hepatocytes. Unlike all RNA viruses, HDV lacks its own RNA polymerase. Therefore, it uses the host RNA polymerase II to transcribe its messenger RNA. Mode of transmission HDV is only able to infect patients that concomitantly harbor the HBV. It is mainly transmitted via the parenteral route through exposure to blood or blood products. While sexual transmission is infrequent and vertical transmission is rare. High-risk populations include health‐care workers, transfusion recipients, and intravenous drug users. There are two distinct patterns of infection for HDV: - “Co-infection” which involves simultaneous infection with HBV and HDV and - “Superinfection”, which involves the infection of an HBV-infected patient with HDV. HBV replication is suppressed in HDV-infected individuals. Clinical presentation The pattern of HBV/HDV infections typically influences the clinical outcome. Co-infection with both HBV and HDV resembles classic acute hepatitis B. It is transient and usually self-limited. Most patients are typically able to clear both viruses as HDV cannot outlive the transient HBs antigenaemia. In some cases, more severe hepatitis than acute HBV mono-infection may be seen with an increased risk for acute liver failure. Less than 5% of the patients develop chronic hepatitis (defined as persistence of HDV RNA beyond 6 months). Superinfection caused by HDV infection of a chronically HBV-infected patient, results in severe acute hepatitis that can be self-limited, but in most cases progresses to chronic hepatitis D in 80-90% of patients.  12 HDV superinfection may exacerbate liver injury caused by a pre‐existing chronic hepatitis B resulting in acute liver failure in 5% of patients. Chronic HDV infection causes more severe morbidity and complications (progressive fibrosis, cirrhosis, HCC, and hepatic decompensation) than chronic HBV infection. Autoimmune manifestations often develop including antinuclear antibodies and smooth muscle antibodies. Diagnosis Since hepatitis D only occurs in HBV infection, serological testing for HDV should be considered in patients with hepatitis B. Anti-HDV antibody, namely anti-HDV immunoglobulin (Ig)M and IgG, is the first-line screening test for HDV infection. Anti‐HDV IgM appears within 1–2 weeks from the clinical onset and disappears by 5–6 weeks, but may last up to 12 weeks. When serum anti‐HDV IgM disappears, serum anti‐HDV IgG becomes detectable. HDV RNA detection in serum is considered the most sensitive and practical test for the early diagnosis of HDV infection before antibody seroconversion. HDAg may be transiently detected in serum before the appearance of anti‐HDV IgM, However, the detection of HDAg in serum is not practical owing to antigen sequestration in immune complexes with high titer circulating antibodies. HDAg may be shown in the nuclei of hepatocytes. HDV/HBV co-infection HDV/HBV co-infection is diagnosed by the simultaneous presence of serological markers of primary HBV and HDV infection (Figure 6). The most specific of acute HDV infection is the finding of HDAg (early and transient), anti‐HDV IgM, and HDV RNA in serum in the presence of HBsAg, high‐titer Figure 6: Viral markers in HBV/HDV co- anti‐HBc IgM, and HBV RNA in infection. serum. The anti‐HBc IgM precedes anti‐HDV IgM and appears concomitant with the clinical onset of acute hepatitis. This is because HBV infection must be established first during the acute coinfection before HDV starts to spread.  13 Co-infection is characterized by a biphasic course of two peaks of serum ALT seen several weeks apart. Loss of anti‐HDV IgM confirms the resolution of acute HDV infection, whereas persistence predicts chronicity. Anti‐HBs and anti‐HBc IgG become detectable later, during convalescence. HDV superinfection In HDV superinfection, the pre‐ existing HBV infection is indicated by the finding of HBsAg, anti‐HBc IgG and anti‐ HBe while anti-HBc IgM is absent (Figure 7). Superinfection with HDV is marked by the early transient presence of serum HDAg along with HDV RNA and anti-HDV Figure 7: Viral markers in HDV superinfection IgM. in a chronically HBV-infected patient. Suppression of markers of HBV replication occurs during the acute phase. Progression to chronicity is characterized by Increasing titer of anti‐HDV IgM and IgG as well as HDV RNA in serum and HDAg in the liver. Prognosis The prognosis is worse in individuals with HBV-HDV co-infection compared with HBV infection alone. Acute hepatitis D infection superimposed on chronic HBV infection may result in chronic hepatitis, which may progress rapidly to cirrhosis. Prevention Although no vaccine is available for hepatitis D, vaccination with the hepatitis B vaccine can protect from HDV infection particularly in individuals likely to contract HDV infection. HBV carriers must be educated about the risks of acquiring HDV through injection drug use, sexual or household transmission, and contact with HDV‐ infected patients to avoid the risk of HDV superinfection.  14 Treatment Acute hepatitis D Most patients with acute hepatitis D improve with only supportive care, since HDV/HBV co-infection is usually self-limited. In cases of fulminant hepatitis, liver transplantation may be considered. In patients with HBV DNA positivity, early treatment with nucleoside and nucleotide analogs (NUCs) may be of benefit but NUC therapy does not have antiviral activity against HDV. Bulevirtide is available for treatment of hepatitis D as will be discussed later. Chronic hepatitis D Treatment options for chronic hepatitis D are limited. NUCs are generally not effective in treating chronic hepatitis D. PEG-IFN (administered 180 mcg subcutaneously once weekly for 48 weeks) has shown some efficacy in chronic hepatitis D with normalization of serum ALT levels, histologic improvement, and elimination of HDV RNA from serum. However, the sustained virologic response rate is low (25%). relapse may occur, and tolerance is poor. When the disease progresses to cirrhosis, liver transplantation is the only available option. Novel HDV therapies Bulevirtide Bulevirtide is a synthetic N-acylated pre-S1 lipopeptide that mimics a region of the pre-S1 HBsAg. It is able to inhibit HBV/HDV entry by competitive binding to the NTCP receptor, which is the cell entry receptor for both HBV and HDV, without interfering with bile salts transport at recommended doses, Bulevirtide is more effective than interferon-based therapy. A dose of 2 mg daily subcutaneous administration for 24 or 48 weeks as monotherapy or combined with PEG-IFNα reduces HDV viremia and normalizes ALT levels. The primary endpoint is undetectable HDV RNA at week 24. There was no recording of serious adverse events nor side effects leading to drug discontinuation. Mild symptoms/signs such as fatigue, nausea, headache, dizziness, leukopenia and thrombocytopenia may occur.  15 Lonafarnib Lonafarnib inhibits the host enzyme farnesyltransferase, which is required for prenylation step of HDV replication and blocks virus assembly inside the liver cells. Oral lonafernib boosted with low dose ritonavir is a promising all-oral therapy particularly with PEG-IFNα addition. The side effects are well tolerated mainly diarrhea and nausea. HEPATITIS E Virology Hepatitis E virus is an icosahedral, Enveloped HEV particle nonenveloped, single-stranded Non-enveloped RNA virus that is approximately 27 HEV particle to 34 nm in diameter and is classified in the genus Orthohepevirus of the Hepeviridae family of viruses. The virus has an outer capsid consisting of a single protein, existing in both non-enveloped form Figure 8: Non-enveloped and enveloped forms of hepatitis E virus. (in blood) and enveloped form (in stools). The capsid encloses the RNA genome of the virus (Figure 8). There are five genotypes of the virus (HEV-1, HEV-2, HEV-3, HEV-4 and recently HEV-7) cause hepatitis in humans. The epidemiology, transmission and clinical course differ between HEV genotypes. Mode of transmission As in the case of HAV, HEV is enterically transmitted and is excreted in the bile and in feces. HEV-1 and HEV-2 are transmitted in humans through the fecal-oral route usually by sewage‐contaminated water. HEV-3, HEV-4, and HEV-7 are mainly found in animals without causing a disease and are transmitted to humans (zoonotic transmission) via direct contact with infected animals (such as swine, pork, sheep, cows, goats, deer (HEV-3 and HEV-4) and camels (HEV-7)) or by consuming undercooked meat or infected cow’s milk, and environmental contamination (e.g. water) by using animal feces in agriculture.  16 After ingestion of HEV, the virus is absorbed through the gastrointestinal mucosa into the portal circulation to reach the liver. HEV can produce morphologic changes in the liver that resemble both classic and cholestatic acute hepatitis. Parenteral transmission of HEV is also a possibility following whole blood transfusion and transfusion of blood products, organ transplant, intravenous drug abuse, and hemodialysis. The incubation period of HEV infection ranges from 28 to 40 days. Clinical presentation There are distinct clinical manifestation patterns of acute hepatitis E with HEV-1 and HEV-2 infections (endemic) differing from HEV-3, HEV-4, and HEV-7 infections (sporadic). HEV-1 and HEV-2 infections are usually seen in young adults as part of outbreaks, causing asymptomatic anicteric hepatitis or present as icteric attack or prolonged cholestasis. Generally, HEV causes a self-limited infection in immunocompetent individuals. In a small percentage of patients, the acute icteric phase can be severe and progress to acute liver failure (ALF) particularly in pregnant women during their second and third trimester or lead to acute on chronic liver failure (ACLF) in patients with underlying chronic liver disease. HEV-3, HEV-4 and HEV-7 infections usually cause sporadic cases and is mainly seen in older adults (older than 40 years). Most infections are either asymptomatic or mildly symptomatic They may present as a rapidly progressive disease with a possibility of developing to chronic hepatitis mainly in immunocompromised patients such as solid organ transplant recipients on immunosuppressant drugs and, rarely, in patients with human immunodeficiency virus (HIV) infection, preexisting liver disease, or cancer undergoing chemotherapy. Extrahepatic manifestations of HEV Infection include: - Neurological manifestations (Guillain- Barré syndrome, neuralgic amyotrophy, encephalitis, myelitis, myositis, vestibular neuritis, peripheral neuritis, and Bell’s palsy). - Renal manifestations (pre-renal failure, membranoproliferative glomerulonephritis, tubular and interstitial injury, and cryoglobulinemia). - Hematological manifestations (thrombocytopenia, hemolysis, aplastic anemia).  17 - Other manifestations (autoimmune thyroiditis, myositis, polyarthritis, and acute pancreatitis). Diagnosis The diagnosis of hepatitis E includes serological antibody measurement and HEV RNA detection. Anti‐HEV IgM or IgA is indicative of acute infection. It appears with the onset of symptoms and disappears in the majority of cases in 3- 6 months. Anti‐HEV IgG appears at about 10–12 days of illness and persists for years confirming natural protection. HEV RNA can be detected by RT-PCR in serum or feces before the onset of symptoms. In immunocompetent patients, viraemia is transient and HEV RNA becomes undetectable in 3-6 weeks. In immunocompromised patients, testing for HEV RNA in blood is preferred if available, because of the low antibody response in the immunosuppressive conditions (false‐negative antibody tests) compared with the immunocompetent patients. Chronic hepatitis E is defined as persistent HEV replication with detectable HEV RNA in serum or stool for more than 3 months after the onset of infection. Prognosis Generally, HEV causes a self-limited infection in immunocompetent individuals. Acute hepatitis E in pregnant patients or patients with chronic liver disease can be severe with progression to fulminant liver failure with high mortality. Due to their ongoing immunosuppression, transplant patients are unable to clear the virus and develop chronic hepatitis E with a risk of eventually developing cirrhosis or even death. Prevention Prevention is based on the provision of clean water, better sanitation, and hygiene education and avoidance of raw or undercooked seafood, meat, and vegetables. HEV vaccine (Hecolin) is a recombinant vaccine based on a truncated form of the capsid protein (56 kDa) is only licensed in China. The vaccine has an 87% efficacy rate after three doses given at 0, 1, and 6 months and is well-tolerated with long-lasting protective immunity. HEV IgG confirms also vaccine efficacy.  18 Treatment Acute hepatitis E Acute hepatitis E is generally self-limited and requires only supportive and symptomatic treatment. Patients who do develop fulminant liver failure may need liver transplantation. Chronic hepatitis E Chronic hepatitis E in immunocompromised patients (solid organ transplant recipients) requires reduction of immunosuppressive medication (if feasible) and/or use of anti-viral drugs, such as ribavirin, pegylated interferon alpha (PEG-IFN) or a combination of both drugs. Ribavirin monotherapy (600–1000 mg/day) for at least 3 months is recommended and leads to sustained virological response (undetectable HEV RNA in serum 6 months after the completion of ribavirin treatment) in up to 90% of patients. Ribavirin should not be used in pregnant women who have acute HEV infection due to the risk of teratogenicity. PEG-IFN (180 mcg subcutaneously once weekly for 48 weeks) can be used in the event of ribavirin treatment failure if there is no contraindication and leads to viral clearance in about two-thirds of patients with chronic hepatitis E. In transplant recipients, treatment with PEG-IFN should be administered with caution especially those who have undergone heart, lung or kidney transplantation because of the risk of graft rejection. A combination of ribavirin and PEG-IFN may be used in non-transplant immunosuppressed patients.