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 necro-inflammatory liver process •On the opposite bacterial infections lead to formation of liver abscesses •Division of viral hepatitis 1.Enterically transmissible •VH A – only acute •VH E – chronic in immunosuppressed pts. 2.Parenterally transmissible – possible chronic stage •VH B •VH C •VH 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 CIH-VHC-caput medusae 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 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 VH A 1104 862 264 284 348 673 723 930 772 211 acute VH B 247 244 192 154 133 105 90 73 85 54 chronic VH B 201 136 162 147 147 193 193 208 248 269 VH C 836 709 812 794 873 867 945 1103 992 1050 VH E 99 72 163 258 218 299 409 339 344 272 j0178242 Viral hepatitis in CR 2008-2017 Source: EPIDAT 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) 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 dlane 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 ü686 000 deaths anually due to LC or HCC (2013, increase about one third since 1990) üIndication for 5-10 % liver transplantations globally ü50 thousand death annually due to fulminant hepatitis üGlobal vaccination in 177 countries • • j0186004 Chronic HBV infection (CDC 2017) Zdroj: WHO 2008 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) HBeAg Anti-HBe Phases of chronic HBV infection Phase 2 Phase 3 Phase 1 Phase 4 HBeAg-positive chronic hepatitis B HBeAg-negative chronic HBV infection HBeAg-positive chronic HBV infection HBeAg-negative chronic hepatitis B Nomenclature treatment treatment ALT, alanine aminotransferase; HBeAg, hepatitis B ‘e’ antigen; HBsAg, hepatitis B surface antigen Hepatitis C virus (HCV) Family Flaviviridae, genus Hepacivirus, enveloped RNA virus 60 nm, 6 (7) genotypů (1-6), minimally 67 subtypes (a…) http://upload.wikimedia.org/wikipedia/commons/3/3b/HCV_EM_picture_2.png Chronic HCV infection (CDC 2017) • Distribution of HCV genotypes 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 • Patients with higher risk of HCV infection PIntravenous drug abusers (sharing of injection needles and syringes) PRecipients of blood transfusions before the year 1992 (especially hemophiliacs) PPersons with tattoo or piercing 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 45 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 Virus (HDV) Satelite virus, family Deltaviridae, genus Deltavirus, enveloped RNA, 36 nm, 8 genotypes (I-VIII), genotype 1 the most common worldvide Hepatitis D •Ability of replication only in presence of HBV infection (vaccination against HBV is potent against HDV as well) üCo-infection (better prognosis) üSuper-infection (worse prognosis) •Globally gradually decreasing HDV prevalence due to massive vaccination against HBV •Very low prevalence in CR • Drug addicts Rizzetto M. EASL 2009 Diapositiva1 2010s : • immigrants 2009 Rizzetto M. EASL 2009 Significant incidence and prevalence (since 2006) PAKISTANI1 INDIA2 MONGOLIA3 IRAN4 VIETNAM5 TAJIKISTAN6 TUNISIA7 MAURETANIA8 1. Zuberi BF, 2006; 2. Acharya SK, 2006; 3.Tsatsralt-Od B, 2006; 4. Roshandel G, 2007; 5. Nguyen VT, 2007; 6. Khan A, 2008; 7. Djebbi A, 2009; 8. Lunel F, personal communication 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 HEV0002 HEV genotypes Purcell RH, Emerson SU. J Hepatol 48 (2008) 494-503 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 •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) (?) • 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 disoproxil üentecavir ütenofovir alafenamid (?) ülamivudin ü •Interferon alfa (standard or pegylated) is absolutely contra-indicated –danger of acute liver failure! Current possibilities of treatment of chronic HEP B •tenofovir disoproxil or alafenamide – both for naive and lamivudine-resistant patients •entecavir – for naive patients •pegylated interferon alfa-2a – 48 weeks • • IFN-free regimens for HCV infection •Current standard of HCV therapy •Combination of oral drugs – DAA – direct-acting antivirals •High efficacy – minimally 95 % •Almost no adverse events •Short duration of therapy – 8-12 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 Direct Acting Antivirals against HCV Lék zkratka třída Glecaprevir GLE NS3/4A protease inhibitor Pibrentasvir PIP NS5A inhibitor Voxilaprevir VOX NS3/4A protease inhibitor Daclatasvir DCV NS5A inhibitor Dasabuvir DSV Non-nucleoside NS5B polymerase inhibitorázy Elbasvir EBR NS5A inhibitor Grazoprevir GZR NS3/4A protease inhibitor Ledipasvir LDV NS5A inhibitor Ombitasvir OBV NS5A inhibitor Paritaprevir PTV NS3/4A protease inhibitor Sofosbuvir SOF Nucleotide NS5B polymerase inhibitor Velpatasvir VEL NS5A inhibitor Hepatitis D therapy •very problematic – low efficacy •PEG-IFN long-term (more than 1 year) •ETV, TDF, TAF – not effective (absence of target enzyme – reverse transcriptase) Chronic 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