Viral Hepatitis prof. MUDr. Petr Husa, CSc. Klinika infekčních chorob, FN Brno C:\Users\33550\AppData\Local\Microsoft\Windows\Temporary Internet Files\Content.IE5\9H6TIIOV\Virus-Vaccinia[1].jpg Viral Hepatitis •Diffuse necrotic and inflammatory liver process •On the opposite bacterial infections lead to formation of liver abscesses •Division of viral hepatitis 1.Enterically transmissible •HEP A – only acute •HEP E – chronic in immunosuppressed pts. 2.Parenterally transmissible – possible chronic stage •HEP B •HEP C •HEP D Healthy liver Healthy Liver small Drawn Liver prezenční listina květen0011 Liver fibrosis Fibrosis small Drawn Fibrosis prezenční listina květen0009 prezenční listina květen0010 Liver cirrhosis Drawn Cirrhosis Cirrhosis prezenční listina květen0013 varixy6 varixy5 prezenční listina květen0014 C:\Users\33550\Pictures\Image Library One\My Images\Lékařské\Cirhotici\IMG_0717.JPG cirhotik1 cirhotik5 Hepatocellular carcinoma small Drawn Cancer Carcinoma j0178242 Viral hepatitis in CR 2011-2020 Source: ISIN 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 VH A 264 284 348 673 723 930 772 211 240 183 acute VH B 192 154 133 105 90 73 85 54 41 27 chronic VH B 162 147 147 193 193 208 248 269 276 142 VH C 812 794 873 867 945 1103 992 1050 1138 771 VH E 163 258 218 299 409 339 344 272 268 223 Hepatitis A virus (HAV) Family Picornaviridae, genus Hepatovirus – non-enveloped RNA, 27 nm 3 human genotypes (I-III), worldwide G-I dominates, subtypes A a B, 3 exclusively simian genotypes (IV-VI), 1 serotype hepatitis a virus http://gamapserver.who.int/mapLibrary/Files/Maps/Global_HepA_ITHRiskMap.png HAV epidemic in the South Moravia 2016-2017 Epidemiology •Fecal –oral route of transmission üContaminated hands or daily used instruments üContaminated drinking water üContaminated food • •Vaccination available, recommended especially fore travelers to countries with lower standard of hygiene Concentration of Hepatitis A Virus graph hepatitis a virus infection graph Hepatisi B Virus Hepatitis B Virus (HBV) Family Hepadnaviridae, genus Orthohepadnavirus, enveloped DNA, 42 nm, 9 genotypes (A-I), Europe A,D, Asie B,C, several subtypes Global significance of HEP B •One of the biggest global health problems üMore than 2 billions of infections during the life ü240 million chronic carriers üIndication for 5-10 % liver transplantations globally üGlobal vaccination in 184 countries • • Chronic HBV infection (CDC 2020) Zdroj: WHO 2008 HBV genotypes (A-I) slide08.jpg slide06.png Hepatitis B in Czech Republic •Still important infection but incidence and prevalence are gradually decreasing üPrevalence of chronic carriers was 0.56 % (2001) …0.064 % (2013) üDecrease of prevalence and incidence due to vaccination of high-risk persons (health care workers, newborns of HBsAg-positive mothers, before hemodialysis) üGlobal vaccination of all newborns and 12-years old children 2001-2013, now only newborns (hexavaccine) • • Epidemiology of HBV •HBV transmission üsexual intercourse üvertically from mother to newborn during delivery or in the last trimester üsharing of instruments among IUDs üblood and blood products üorgan and tissue transplant recipients Clinical findings in acute HEP B •IP: 30–180 days (mostly 2–3 months) •Prodromal stage - flu-like syndrome •Fulminant hepatitis: < 1 % •Chronic HBV infection mortality: 15 – 25 % C:\Documents and Settings\admin\Desktop\slide_lib\png\Slide10.jpg Outcome of Hepatitis B Virus Infection by Age at Infection (graph) Hepatitis C Virus (HCV) Family Flaviviridae, genus Hepacivirus, enveloped RNA virus 60 nm, 8 genotypes (1-8), many subtypes (a…) http://upload.wikimedia.org/wikipedia/commons/3/3b/HCV_EM_picture_2.png Chronic HCV infection (CDC 2020) • HCV genotypes distribution Hepatitis C •Significant global health problem ü70-80 million persons worldwide are chronically infected with HCV üIn well-developed countries about 20 % of all acute hepatitis, 70 % chronic hepatitis, 40 % cirrhosis, 60 % HCC and indication to 30 % liver transplantations •In Czech Republic üprevalence 0.2 % (2001), current estimations 0.4-0.5 % •No vaccine, no hyper-immune immunoglobulin Epidemiology of HEP C •Transmission: ü blood and blood products ü sharing of used injection needles and syringes ü sexually (rare) ü vertically (rare) •Who is in the highest risk of HCV infection at present? ü intravenous drug abusers •Infection is frequently diagnosed in chronic stage • Source: ECDC reports - Hepatitis B and C epidemiology in Selected Populations and Systematic review on Hepatitis B and C prevalence in the EU/EEA https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/systematic-review-hepa titis-B-C-prevalence.pdf HCV prevalence in risk groups of inhabitants in EU/EEA countries Problematic drug abusers in the CR (2017) Zdroj: Národní monitorovací středisko pro drogy a závislosti (2018) About 44 000 intravenous drug abusers (cca 90 % of all) Odhadovaný celkový počet problémových uživatelů drog je dlouhodobě stabilní, v posledních letech se pohybuje mezi 45 a 48 tis. uživatelů. V posledních 5 letech vidíme pokles odhadovaného počtu uživatelů pervitinu a nárůst odhadovaného počtu uživatelů opioidů. V ČR je odhadováno celkem 43 700 injekčních uživatelů drog, tj. odhadem 90 % všech problémových uživatelů drog užívá drogy injekčně. V podílu injekčních uživatelů mezi problémovými uživateli drog je ČR nad průměrem evropských zemí. Problematic drug abusers in the CR (2017) 2017 - Estimation in the CR - 47 800 problematic drug abusers, about 90 % intravenous –fentanyl –Vendal® Retard (morfin) –Palladone® (hydromorfon) –oxycodon • Zdroj: Národní monitorovací středisko pro drogy a závislosti (2018) Vrátíme se zpátky k situaci v oblasti užívání drog. V ČR je odhadováno celkem 47 800 problémových uživatelů drog, tj. dlouhodobých nebo pravidelných nebo injekčních uživatelů opiátů nebo pervitinu. Je odhadováno celkem 35 tis. uživatelů pervitinu a 13 tis. uživatelů opioidů. V posledních letech zaznamenáváme nárůst počtu problémových uživatelů opioidů – zejména se jedná o nárůst užívání opioidních analgetik. Příkladem je zneužívání fentanylu nebo užívání léků na bázi morfinu, hydromorfonu a oxykodonu, které mohou lokálně představovat nejrozšířenější opioid mezi problémovými uživateli drog. Současně dlouhodobě sledujeme pokles odhadovaného počtu uživatelů pervitinu. Odhadovaný celkový počet problémových uživatelů drog je dlouhodobě stabilní. V ČR je odhadováno celkem 43 700 injekčních uživatelů drog, tj. odhadem 90 % všech problémových uživatelů drog užívá drogy injekčně. V podílu injekčních uživatelů mezi problémovými uživateli drog je ČR nad průměrem evropských zemí. Opiates and pervitin abusus 44 Odhadovaný počet problémových uživatelů drog v ČR v r. 2016 podle drog a krajů Zdroj: Národní monitorovací středisko pro drogy a závislosti (2018) Infectious diseases in IUDs – new cases 1996-2016 Acute HBV Acute and chronic HCV Zdroj: SZÚ Praha Infectious diseases in IUD in prison (%) Matavir 3.. 00000010Ramonet ABA78158: ch 00000010Ramonet ABA78158: fig82x.jpg 00000010Ramonet ABA78158: Acute infection Chronic infection 80% Chronic hepatitis 80% Cirrhosis 20% Fibrosis 0...........1........2.......3......4 HCC 1-5%/year > 30 years Alcohol, co-infection (HBV,HIV), < 20 years WERWER 00000010Ramonet ABA78158: Clinical course of HCV infection Anti-HCV are total antibodies against HCV – not division into IgM and IgG class ! Serologic Pattern of Acute HCV Infection w/ Recovery Diagnosis of HCV infection Hepatitis D (Delta) Virus (photo and diagram) Hepatitis D (Delta) Virus (HDV) Satelite virus, family Deltaviridae, genus Deltavirus, enveloped RNA, 36 nm, 8 genotypes (I-VIII), genotype I the most common worldvide Hepatitis D: fast facts •Hughes SA, et al. Lancet 2011;378:73-85; Koh C, et al. Gastroenterology 2019;156:461-7; Miao Z, et al. J Infect Dis 2020;221:1677-87; Stockdale AJ, et al. J Hepatol 2020;73:523-3. Defective RNA virus, requiring HBV for infection Most severe form of viral hepatitis Increased risk of cirrhosis/HCC and higher mortality vs HBV Until recently, no approved therapeutic options 9-60 million people infected with HDV globally 4.5-13% of HBV carriers co-infected with HDV Progression to cirrhosis within 5 years and to HCC within 10 years Eight HDV genotypes Warning with solid fill World with solid fill Covid-19 with solid fill Transition: This is an introductory slide that provides a brief overview of the burden associated with HDV infection. Main Messages: •Despite being the most severe form of viral hepatitis, resulting in rapid progression to cirrhosis and HCC, until recently there have been no approved therapeutic options for HDV. •It has been estimated that up to 60 million people globally are infected with HDV. •Progression to cirrhosis is anticipated within 5 years of infection and progression to hepatocellular carcinoma occurs approximately 10 years after infection. References: 1.Hughes SA, et al. Lancet 2011;378:73-85; 2.Koh C, et al. Gastroenterology 2019;156:461-7; 3.Miao Z, et al. J Infect Dis 2020;221:1677-87; 4.Stockdale AJ, et al. J Hepatol 2020;73:523-3. • Drug addicts Rizzetto M. EASL 2009 Diapositiva1 2010s Immigrants 2009 Rizzetto M. EASL 2009 Prevalence rate (%) >20 0 No data available Estimated number of individuals with HDV in selected countries •Miao Z, et al. J Infect Dis 2020;221:1677-87. •Numbers shown are patient numbers, ie prevalence of HDV in HBsAg-positive patients. •HBsAg: hepatitis B surface antigen; HDV: hepatitis delta virus. An estimated 48-60 million people are infected with HDV worldwide Transition: This slide shows the number of individuals estimated to have HDV in the Miao analysis where data are available. Main Messages: •The number of individuals infected with HDV varies substantially between countries (note: numbers shown on figure have not been validated locally). •The prevalence of HDV is unknown in many areas of the world. Background: A total of 332,155 individuals from general populations of 48 countries and regions and 271,629 HBsAg-positive carriers from 83 countries were included in this analysis of HDV prevalence (Miao et al. 2020). China, India and Nigeria are the countries most affected by HDV but HDV is also highly prevalent in certain regions including central Asia, eastern Europe, tropical and central Latin America, and central and west sub-Saharan Africa. The burden was estimated to be greatest in Asia (44.41-56.55%) followed by Africa (22.30-38.37%). HDV is especially prevalent in low-income and lower middle-income countries, but it is important to note that data are relatively limited from these countries. Reference: Miao Z, et al. J Infect Dis 2020;221:1677-87. •Miao Z, et al. J Infect Dis 2020;221:1677-87 •Data presented are based on estimates of HDV prevalence and disease progression rates determined in a large global epidemiology analysis. HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HDV: hepatitis delta virus. A picture containing diagram Description automatically generated Clinical course of HBV/HDV infection depends on timing of HDV infection Transition: This slide highlights that the clinical course of HBV/HDV infection is dependent on the timing of infection. Main Messages: •Patients simultaneously infected with HBV and HDV - HBV/HDV co-infection - have a lower chance of progressing to severe liver disease than those infected initially with HBV and subsequently being infected with HDV - HBV/HDV superinfection. Background Data presented are based on estimates of HDV prevalence and disease progression rates determined in a large global epidemiology analysis. The majority (81%) of HBV/HDV co-infected patients have a short-lived (acute) infection and spontaneously recover. Where co-infected patients develop chronic HDV infection, progression to severe liver disease, including cirrhosis and HCC, occurs infrequently. In contrast, the vast majority (70%) of patients with HBV/HDV superinfection will develop chronic infection. For these patients, a high proportion will go on to develop the long-term sequelae of liver disease including cirrhosis and HCC. Reference: Miao Z, et al. J Infect Dis 2020;221:1677-87. Clinical course of hepatitis delta •Miao Z, et al. J Infect Dis 2020;221:1677-87 World Health Organization. Hepatitis delta fact sheet. July 2020. https://www.who.int/news-room/fact-sheets/detail/hepatitis-d. Accessed March 2021. •HBV: hepatitis B virus; HCV: hepatitis C virus; HCC: hepatocellular carcinoma; HDV: hepatitis delta virus. 55 HDV exposure Chronic disease Death Spontaneous clearance Virus persists Acute HDV Fibrosis HCC Cirrhosis Icon Description automatically generated Icon Description automatically generated with medium confidence A picture containing shape Description automatically generated Covid-19 with solid fill Covid-19 with solid fill Covid-19 with solid fill Covid-19 with solid fill HCC development can occur independently of cirrhosis in some individuals 76.5% 3.1 years 29.7% 3.1 years 5.6% 5.4 years 51.9% HDV/HBV vs HBV monoinfection: more rapid progression to cirrhosis and HCC Transition: This slide highlights the clinical course of HDV infection. Main Messages: •HBV/HDV infection can be either a short-lived (acute) infection or a persistent (chronic) infection. •Patients spontaneously recover from acute infection. •Patients with chronic HDV infection are at risk of rapid disease progression resulting in cirrhosis, HCC and death. Background: Following HDV exposure, infection can resolve spontaneously within 6 months. However, if the virus persists for more than 6 months, chronic infection has been established. The impact of persistent infection is that patients progress to liver disease which can ultimately lead to fibrosis (scarring of the liver), cirrhosis (severe scarring), hepatocellular carcinoma and death. The disease pathway is not necessarily linear in HDV and patients without fibrosis or cirrhosis can still present with hepatocellular carcinoma. In a large global epidemiology analysis, Miao et al. determined the rate of disease progression in patients with HBV/HDV. They demonstrated that 76.5% of individuals with chronic HDV infection were likely to progress to chronic hepatitis/disease within 3 years of infection. This group were then at high risk of rapid progression to cirrhosis, as 29.7% of individuals had cirrhosis within 3.1 years. Finally, 5.6% of individuals with chronic HDV were shown to have HCC within 5.4 years. References: 1.Miao Z, et al. J Infect Dis 2020;221:1677-87; 2.World Health Organization. Hepatitis delta fact sheet. July 2020. https://www.who.int/news-room/fact-sheets/detail/hepatitis-d. Accessed March 2021. Increased risk of long-term consequences of viral hepatitis in HBV/HDV patients versus HBV monoinfection •Da BL, et al. Gastroenterol Rep 2019;7:231-45. •Disease progression in chronic hepatitis B is not linear and HCC can develop in the absence of cirrhosis. HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HDV: hepatitis delta virus Cirrhosis HCC Liver transplant Hepatic decompensation 2−3 x 3−6 x 2 x 2 x Reference = 1 Minimum Maximum Risk of long-term consequence in HDV/HBV patients: Risk in HBV patients: 2 x Mortality Transition: This slide highlights that HBV/HDV patients are at higher risk of severe liver disease than those with HBV monoinfection. Main Messages: •HBV/HDV is more severe than HBV. Background: In a recent review, Da and colleagues summarised the relative risk of liver disease sequelae in patients with HBV/HDV co-infection versus HBV monoinfection. HBV/HDV infection is associated an increased risk of poor long-term outcomes (cirrhosis, HCC and death) than HBV monoinfection. Compared with HBV monoinfection, the risk of progression to most phases of severe disease are at least doubled, with the risk of cirrhosis and HCC being substantially higher than for HBV. Reference: Da BL, et al. Gastroenterol Rep 2019;7:231-45. Non-enveloped RNA virus, family Hepeviridae, genus Orthohepevirus, 27-34 nm, 8 genotypes (1-8), human infections by G1-4 nm Hepatitis E Virus (photo) Hepatitis E virus Phylogenetic relationship of hepeviruses identified in various hosts •Debing Y, et al. J Hepatol 2016;65:200–12 Screen Clipping Mostly Asia, Africa China and Southeast Asia GT, genotype HEV genotypes (1-4) Sources of HEV infection Infection with G-1,2 HEV •Only human infection •Mostly Asia, Africa •Extremely serious clinical course in late pregnancy (mortality about 25 %) •No chronicity •Possibility of acute-on-chronic liver failure • Infection with G-3,4 HEV •Both human and zoonotic infection •Pigs are the main reservoir (venison as well) •G-3 – worldwide distribution, G-4 – China a southeast Asia •≥ 2 million locally acquired HEV infections/year in Europe (G-3), mostly asymptomatic (minimally 95 %), tend to affect older males •Possibility od chronic infection in persons with immunosuppression (after solid organ transplantation 50-66% probability of chronicity, patients with haematological disorders, individuals living with HIV, patients with rheumatic disorders receiving heavy immunosuppression) •High mortality in patients with liver cirrhosis (60-70 %) - acute-on-chronic liver failure • Covance 7 Figatellu – sausage with raw pork liver Kliknutím na obrázek zavřete okno HEV Serology (graph) Covance 7 Rapid progression of chronic hepatitis E Treatment of acute hepatitis (all types) •Symptomatic for all hepatitis types ü physical and mental rest üno alcohol, no hepatoxic drugs üdiet (?) üsupportive treatment (silymarin, essential phosholipids) (?) üantivirals for complicated acute HEP B and E • Therapy of acute HEP B •Antiviral therapy is indicated only in serious (INR > 1,5) or prolongated (pronounced icterus > 4 weeks) clinical course od acute hepatitis B •Therapy only with oral virostatics (NA) ütenofovir üentecavir • Current possibilities of treatment of chronic HEP B •tenofovir •entecavir • • IFN-free regimens for HCV infection •Current standard of HCV therapy •Combination of oral drugs – DAA – direct-acting antivirals •High efficacy – minimally 99 % •Almost no adverse events •Short duration of therapy – 8 or 12 weeks • • HCV infection is curable in majority of patients •SVR – sustained virological response = the definite eradication of HCV infection •1. Pawlotsky JM. J Hepatol 2006;44:S10–3; 2. Siliciano JD, et al. J Antimicrob Chemother 2004;54:6–9; 3. Lucas GM. J Antimicrob Chemother 2005;55:413–6; 4. van der Meer AJ, et al. JAMA 2014;312:1927–8; 5. Burki T. Lancet Infect Dis 2014;14:452–3 Long-life suppression Long-life suppressione HCV elimination “Vzhľadom k tomu, že neexistuje účinná vakcína, optimálna liečba chronickej HCV infekcie sa dnes považuje za ‘nutnú’ jednak z hľadiska stratégie verejného zdravotníctva, jednak z hľadiska klinického vývoja jednotlivých pacientov.” od Yu a Chuang J Gastro Hep 2009 Popis obrázku: Hostiteľská bunka cccDNA Hostiteľská DNA Jadro Liečba Provírusová DNA Liečba Vírusová RNA Liečba Hepatitis D treatment •PEG-IFN – 1 × weekly s.c. üduration of therapy minimally 1 year üIn most cases only temporary effect – frequent relapses after treatment discontinuation •LAM, ETV, TDF, TAF – non-effective – HDV has no target enzyme – reverse transcriptase •Bulevirtid (entry inhibitor) s.c. 1× daily, duration of therapy was not definitely established Hepatitis E therapy •Acute hepatitis E üSpontaneous infection elimination without therapy üfulminant course – ribavirin – mortality lowering • •Chronic hepatitis E üReduction of immunosupression – infection elimination in about 30 % patients üribavirin for 3-6 months üPEG-IFN for 3 months – only after liver transplantation ü ü husa-tenisky Thank you for your attention! phusa@fnbrno.cz