Viral Hepatitis Prof. MUDr. Petr Husa, CSc. Klinika infekčních chorob, FN Brno j0115884 Viral Hepatitis 1.Enterically transmitted – no chronic stage •VH A •VH E – extremely rare (IS) 2.Parenterally transmitted – 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 květen0012 prezenční listina květen0013 prezenční listina květen0014 varixy6 varixy5 cirhotik1 cirhotik2 cirhotik3 cirhotik4 cirhotik5 CIH-VHC-caput medusae ascites1 ascites2 Hepatocellular carcinoma small Drawn Cancer Carcinoma 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 VH A 127 114 70 322 132 128 1648 1104 862 264 VH B 413 370 392 361 307 307 306 247 244 192 VH C 858 846 868 844 1022 980 974 836 709 812 VH E 12 21 36 37 35 43 65 99 72 163 Viral Hepatitis in CR 2002-2011 j0178242 A B C D E Genom RNA DNA RNA RNA RNA Incubation 15-50 30-180 15-180 30-180 15-60 Enteral Yes No No No Yes Parenteral Rare Yes Yes Yes No Sexual Rare Yes Rare Yes Rare Vertical No Yes Rare Yes Yes Chronicity No Yes Yes Yes Very rare Vaccination Yes Yes No VH B No Imunoglob. Yes Yes No VH B No hepatitis a virus Hepatitis A family Picornaviridae, genus Hepatovirus – non-enveloped RNA, 27 nm Global_HepA_ITHRiskMap Hepatitis A 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 family Hepadnaviridae, enveloped DNA virus, 42 nm Global significance of HEP B •One of the biggest global health problems üMore than 2 billions of infections during the life ü350-400 million chronic carriers - China (125 million), Brazil (3,7 million), South Korea (2,6 million), Japan (1,7 million), USA (more than 1 million), Italy (900 thousand). ü25-40 % chronic carriers have LC or HCC, 0,5-1,0 million death due to decompensated LC or HCC ü50 thousand death annually due to fulminant hepatitis üGlobal vaccination in 177 countries (2008) • • j0186004 Hepatitis B slide08.jpg slide06.png slide16.jpg slide17.png Hepatitis B in Czech Republic •Still important infection but incidence and prevalence are gradually decreasing üPrevalence of chronic carriers was 0.56 % (2001) üPrevalence of historical antibodies anti-HBc total was 5,59% (2001) 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 since 2001 • • Epidemiology of HEP B •Transmission ü blood and blood products ü sexual intercourse ü organ and tissue transplant recipients ü vertically from mother to newborn •Who is in the highest risk in well-developed countries? ü intravenous drug abusers ü persons with multiple sexual partners • HM00316_ playmate_01 Clinical pictures of acute HEP B •IP: 30–180 days (mostly 2–3 months) •Prodromal stage - flu-like syndrome •Icteric form: < 5 years < 10 %, > 5 years (30–50 %) •Chronicity: newborns > 90 %, children 30-40 %, adults 5–10 % •Fulminant hepatitis: < 1 % •Chronic HBV infection mortality: 15 – 25 % j0136801 C:\Documents and Settings\admin\Desktop\slide_lib\png\Slide10.jpg Outcome of Hepatitis B Virus Infection by Age at Infection (graph) C:\Documents and Settings\admin\Desktop\slide_lib\png\Slide11.jpg C:\Documents and Settings\admin\Desktop\slide_lib\png\Slide12.jpg c_virus Hepatitis C family Flaviviridae, genus Hepacivirus, enveloped RNA virus 60 nm • Hepatitis C World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C: Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16. Europe 8.9 million (1.03%) Americas 13.1 million (1.7%) Africa 31.9 million (5.3%) Western Pacific 62.2 million (3.9%) Eastern Mediterranean 21.3 million (4.6%) Southeast Asia 32.3 million (2.15%) HCV, hepatitis C virus. The World Health Organization has estimated that approximately 170 million persons are infected with HCV worldwide. The distribution of HCV infection is not uniform around the world. In most places, approximately 1% to 2% of the population is infected with HCV, but some regions, such as Egypt, are burdened with rates that range from 10% to 20%. HCV screening is the first step in identifying the 170 million HCV-infected persons worldwide. Distribution of HCV genotypes Hepatitis C •Significant global health problem üabout 3 % of the world population 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) •No vaccine, no hyper-immune immunoglobulin j0286672 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 • j0281051 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 Clinical course of HEP C •Acute hepatitis is mostly asymptomatic •Probability of chronicity is high (40-50% till 90-100%). •Higher probability of chronicity: aOlder persons aHigher initial infection dose (transfusion versus needles) aHBV, HIV co-infection aabusus of alcohol aimmunodeficiency Clinical course of HEP C •LC in about 20 % patients with chronic HCV infection •HCC annually in 1-4 % patients with LC •Progression to HCC depends on: üage (more rapid progression in older persons) üalcohol abuse üHIV co-infection üHBV co-infection j0084356 Serologic Pattern of Acute HCV Infection w/ Recovery Serologic Pattern of Acute HCV Infection w/ Progression to Chronic Infection Hepatitis D (Delta) Virus (photo and diagram) Hepatitis D Satelite virus, family Deltaviridae, enveloped RNA, 40 nm Hepatitis D •Ability of replication only in presence of HBV infection üCo-infection (better prognosis) üSuper-infection (worse prognosis) •Endemic in South America, Mediterranean Region, Romania, Central Africa •Very low prevalence in CR j0109667 Anti-HDV prevalence in HBsAg-positive (approximately 15 000 000 persons) Rizzetto M. EASL 2009 • Drug addicts Rizzetto M. EASL 2009 Diapositiva1 2010s : • immigrants 2009 Rizzetto M. EASL 2009 koinfekce superinfekce Hepatitis E Virus (photo) Family Hepeviridae, genus Hepevirus, non-enveloped RNA virus, 27-34 nm hepatitida E Hepatitis E Source: CDC HEV0002 HEV genotypes Purcell RH, Emerson SU. J Hepatol 48 (2008) 494-503 HEV0003 Genotypes of swine HEV Purcell RH, Emerson SU. J Hepatol 48 (2008) 494-503 Hepatitis E •Travel-related disease especially •Infection is possible to acquire in CR as well (pork, sea food) •Main route of transmission by drinking water •Extremely serious clinical course in late pregnancy (mortality above 20 %) •Repeated infection may be possible •Rare cases of chronic hepatitis E in seriously immunosuppressed patients (organ recipients…) • • j0262752 HEV Serology (graph) Treatment of acute hepatitis •Symptomatic for all types ü physical and mental rest ü diet ü no alcohol, no hepatoxic drugs ü supportive treatment (silymarin, essential phosholipids) • j0318804 Current possibilities of treatment of chronic HBV infection •pegylated interferon alfa-2a – 48 weeks •lamivudine - only in severe acute HEP B or protection of reactivation or recurence •telbivudine – for naive patients •entecavir – for naive patients •adefovir dipivoxil – for lamivudine-resistant mutants in combination with lamivudine •tenofovir – both for naive and lamivudine-resistant patients • Resistance to NUCs Current possibilities of treatment of chronic HCV infection •Pegylated interferon alfa-2a or alfa-2b + ribavirin üGenotype 1 or 4 – 48 weeks, SVR about 60 % üGenotype 2 or 3 – 24 weeks, SVR about 85 % Standard chronic hepatitis C therapy •genotypes 1,4 üPEG-IFN + RBV (1000-1200mg) - 48 weeks üPEG-IFN + RBV + DAA (boceprevir or telaprevir) – response guided therapy – 24-48 weeks •genotypes 2-3 üPEG-IFN+RBV (800 mg) – 24 weeks • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen • • • • • • • • • • LD • • • LD • • • • • • • • ER lumen LD • NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain. The elucidation of the life cycle of the hepatitis C virus (HCV) allowed for the identification of potential targets of antivirals that directly interrupt HCV replication. From the binding of the virus to the plasma membrane and its endocytosis through the membrane, all the way through uncoating and generating the membranous web to translation and replication, viral assembly, and transport and release again into the extracellular space, one may envision a variety of potential targets. The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase. Therefore, our first DAAs have been protease inhibitors and nucleoside or nonnucleoside polymerase inhibitors. Also interesting was the recent discovery of NS5A inhibitors that are inhibitors of the NS5A protein. However, the function of this protein in the hepatitis C life cycle is not yet well understood. Therefore, the inhibitory drugs may help to elucidate the involvement of this protein in the HCV life cycle rather than vice versa. Efficacy of chronic hepatitis C therapy 0 20 40 60 80 100 naive experienced 38-44[1-2] 17-21[3-4] PEG IFN/RBV 0 20 40 60 80 100 63-75[1-2] 59-66[3-4] PEG IFN/RBV+TVR, BOC 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon BR, et al. AASLD 2010. Abstract 216. 4. Foster GR, et al. APASL 2011. Abstract 1529. naive experienced BOC, boceprevir; GT1, genotype 1; SOC, standard of care; SVR, sustained virologic response; TPV, telaprevir. This slide is a summary of data. It is clearly not a head-to-head comparison but an illustration of the data for boceprevir and telaprevir in patients who were treatment naive or previous nonresponders. If one compares the blue box on the left with the blue box on the right, one can see that in treatment-naive patients, approximately 30% more patients can be cured with the addition of either boceprevir or telaprevir to peginterferon/ribavirin. The difference is even more pronounced in previous nonresponders. Here one can see success rates of 17% to 21% with repeat peginterferon/ribavirin treatment; however, a 59% to 66% SVR rate can be attained in these previous nonresponders when a protease inhibitor is added. So you clearly see how important, especially for patients who have been previously unsuccessfully treated, the addition of a protease inhibitor will be. husa-tenisky Thank you for your attention! phusa@fnbrno.cz