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Hepatitis c

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Hepatitis C
Is a Viral infection of the liver caused by the hepatitis C virus.

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Hepatitis c

  1. 1. Lali Sharvadze Associated Professor Viral Hepatitis Hepatitis C Infectious Diseases, AIDS & Clinical Immunology Research Center 2016
  2. 2. Viral Hepatitis AlphabetViral Hepatitis Alphabet Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis F Hepatitis GHepatitis G Hepatitis TTVHepatitis TTV
  3. 3. Viral hepatitisViral hepatitis Hepatitis AHepatitis A Hepatitis BHepatitis B Hepatitis CHepatitis C Hepatitis DHepatitis D Enteral rout of transmission Parenteral rout of transmission By ways of transmission Hepatitis EHepatitis E
  4. 4. Hepatitis C
  5. 5. Hepatitis C Is a Viral infection of the liver caused by the hepatitis C virus.  Definition
  6. 6. EPIDEMIOLOGY
  7. 7. Global Burden of Hepatitis C Hepatitis C is major public health problem worldwide. About 180 million people are infected with hepatitis C virus It account for 3 percent of global population 3-4 million people become infected with HCV annually About 25 million people are infected in Europe HCV prevalence 5 times exceeds HIV prevalence
  8. 8. Global Burden of Hepatitis C More then 350 000-500 000 people die every year from Hepatitis C related end-stage liver disease (cirrhoses, HCC, liver failure) Hepatitis C infection is top priority problem for Georgia as well.
  9. 9. • Infection with the hepatitis C virus (HCV) remains chronic in 70-85% of infected individuals. • In 20-40% cases of chronic hepatitis C infection leads to end-stage liver diseases: cirrhoses, hepatocellular carcinoma and liver failure after 20-30 years of HCV infection. • Liver failure from chronic hepatitis C is one of the most common reasons for liver transplantation. • Infection with the hepatitis C virus (HCV) remains chronic in 70-85% of infected individuals. • In 20-40% cases of chronic hepatitis C infection leads to end-stage liver diseases: cirrhoses, hepatocellular carcinoma and liver failure after 20-30 years of HCV infection. • Liver failure from chronic hepatitis C is one of the most common reasons for liver transplantation.
  10. 10.    There is no prophylactic vaccine and/or specific immunoglobulin against hepatitis C    But effective antiviral treatment exist, which is disease prophylaxis as well
  11. 11. Epidemiology of hepatitis C in Georgia Epidemiology of hepatitis C in Georgia
  12. 12. 6.7% (≈150, 000 adults) − General population (age: 18-65) − Patients with HCV Prevalence of HCVPrevalence of HCV in General Population of Georgiain General Population of Georgia Data of 2001-2002Data of 2001-2002 population-based cross-sectional survey of the adult population of Tbilisi.
  13. 13. 14  Primary Objectives 1. Estimate HCV prevalence in Georgia • Nation-wide • In 6 major cities (including Tbilisi) • Several specific geographical  regions • Urban vs. rural 2. Determine HCV genotype distribution and risk factors of HCV transmission Anti-HCV positive 7.1% HCV RNA positive 5.16% HCV prevalence and Genotype distributions  According new survey-2015  30.9%30.9% 23.8%23.8%
  14. 14. HCV Infection in Key Populations Tsertsvadze T. In: Frontiers in Research. Humana Press. 2008:257-261. Shapatava et al. Drug Alcohol Depend. 2006 Apr;82 Suppl 1:S35-8. Richards et al. Int J Tuberc Lung Dis. 2006;10:396-401. CIF, Tanadgoma. BSS Survey among MSM in Tbilisi, 2010.
  15. 15. Study of Prevalence of Hepatitis C among HIV infected patients Badridze et al. Prevalence of hepatitis B and C among HIV positive patients in Georgia and it's associated risk factors. Georgian Med News. 2008;(165):54-60. 49% of patients were HIV/HCV co-infected. 49% of patients were HIV/HCV co-infected. 2008 73.4
  16. 16. Etiology
  17. 17. RNA virus Family- Flaviviridae Genus - Hepacivirus Hepatitis C virus is a linear, single-strand, 9600-nucleotide RNA virus.  
  18. 18. Electron micrograph of hepatitis C virus
  19. 19.  The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further covered in a lipid (fatty) envelope of cellular origin.  Two viral envelope glycoproteins, E1 and E2, are surrounded in the lipid envelope.
  20. 20. Etiology
  21. 21. At least six distinct major genotypes, as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing. At least six distinct major genotypes, as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing.
  22. 22. HCV 1a HCV 1b HCV 1c HCV 2a HCV 2b HCV 2c HCV 3a HCV 3b HCV 4 HCV 5 HCV 6 I II III IV V VI HCV Genetic Types
  23. 23. HCVHCV GGGGenotypesenotypes HCVHCV SubtypesSubtypes 1 a, b, c, d, e, f, g, h, i, j, k, l, ma, b, c, d, e, f, g, h, i, j, k, l, m 2 a, b, c, d, e, f, g, h, i, k, l, m, n, o, p, q, ra, b, c, d, e, f, g, h, i, k, l, m, n, o, p, q, r 3 a, b, c, d, e, f, g, h, i, ka, b, c, d, e, f, g, h, i, k 4 a, c, d, e, f, g, h, k, l, m, n, o, p, q, r, s, t, ua, c, d, e, f, g, h, k, l, m, n, o, p, q, r, s, t, u 5 aa 6 a, b, d, f, g, h, i, j, k, l, m, n, o, p, q, r, sa, b, d, f, g, h, i, j, k, l, m, n, o, p, q, r, s HCV genotypesHCV genotypes
  24. 24. HCVHCV genotipebis gavrcelebagenotipebis gavrceleba msoflioSimsoflioSi
  25. 25. HCVHCV GenotypeGenotype 1. HCV Genetic type is very strong prognostic marker for HCV antiviral Treatment 1. HCV Genetic type is very strong prognostic marker for HCV antiviral Treatment Clinical significance of HCV genotype
  26. 26. TRANSMISSION
  27. 27. Transmission routes of HCV Transfussion of infected blood or its products, using nonsterile syringes, needles and medical instruments, transplantation of infected donor organs or tissues, occupasional exposure with infected blood Parenteral Risk of sexual tramission of HCV is very low. In monogamous partners about 2 %. The risk is higher among persons having multiple sexual partners about 4-6% (commercial sex workers, men who have sex with men etc.) Sexual Mother to child Chance of Vertical transmission of HCV is about 5-7 %. The risk is increased if HCV viral load in mother’s blood is high. HCV is not transmitted HCV is not transmitted by air, dropltes, vectors or from animals.
  28. 28. Persons who shoud be teste for HCV infection • Intravenous drug users • HIV-infected persons • Hemophilia patients • Patients on dialysis • Blood recipients • Organ transplant patients • Children born from HCV infected mothers • Healthcare professionals who had exposure to infected blood (needle stick, cut, blood contact on mucosa). • Sex partners of HCV infected persons • Persons with elevated liver enzymes
  29. 29. PATHOGENESIS
  30. 30.  The virus replicates mainly in the hepatocytes of the liver, where it is estimated that daily each infected cell produces approximately fifty virions (virus particles)  The virus may also replicate in peripheral blood mononuclear cells, potentially accounting for the high levels of immunological disorders found in chronically infected HCV patients
  31. 31. Because HCV does not replicate via a DNA intermediate, it does not integrate into the host genome.
  32. 32. To enter the host cell, HCV E2 and E1 proteins recognize and bond with the CD81 receptors present on the surface of hepatocytes and lymphocytes After the interaction of the virus envelope with the host cell membrane, HCV enters the cell through endocytosis. In the cytoplasm, the messenger RNA then undergoes translation, and polyproteins are processed; the HCV RNA then replicates, after which the new viral 'RNA's are packaged and transported to the surface of the host cell so that they can disseminate and complete a new cycle
  33. 33. Pathogenesis of HCV infection Why HCV infection is predominantly chronic? Why HCV infection is predominantly chronic?
  34. 34. HCV has ability to “escape” immune response of the host Pathogenesis 1
  35. 35. HCV is characterized by rapid and permanent changes in its antigenic structure; antigenic structure changes occur multiple times per minute; Such antigenic variability of this virus makes T and B lymphocytes unable to identify and respond to these permanently changed antigens. HCV is characterized by rapid and permanent changes in its antigenic structure; antigenic structure changes occur multiple times per minute; Such antigenic variability of this virus makes T and B lymphocytes unable to identify and respond to these permanently changed antigens. Pathogenesis 2
  36. 36. Pathogenesis 3 Antigenic variations of HCV in the same host is called (quasispecies). Number of Such quasispecies reaches about 1010 – 1011 per day
  37. 37. Due to variability of HCV “Time competition” between new antigenic strains and the speed of neutralizing antibodies develops Due to variability of HCV “Time competition” between new antigenic strains and the speed of neutralizing antibodies develops HCV wins this competitionHCV wins this competition Pathogenesis 4
  38. 38. Natural History and Disease Outcome Natural History and Disease Outcome
  39. 39. CLINICAL FEATURES 2 forms of Hepatitis C exists: • Acute Hepatitis C • Chronic Hepatitis C
  40. 40. Acute Hepatitis C Definition Acute hepatitis C is an infectious disease caused by hepatitis C virus, which developes within 6 months after entering virus to the organizm. Disease has symptomatic (with jaundice and without jaundice) and asymptomatic course. In case of symptomatic Acute HCV disease is self limited In 50% of cases.
  41. 41. Acute hepatitisAcute hepatitis CCAcute hepatitisAcute hepatitis CC With symptomsWith symptoms infeqciuri paTologiis, Sidsisa da klinikuri imunologiis samecniero-praqtikuli centri Without symptomsWithout symptoms
  42. 42. With JaundiceWith Jaundice infeqciuri paTologiis, Sidsisa da klinikuri imunologiis samecniero-praqtikuli centri Without JaundiceWithout Jaundice Symptomatic Acute Hepatitis c Symptomatic Acute Hepatitis c
  43. 43. Acute HCVAcute HCV Asymptomatic 75% Asymptomatic 75% Without JouncesWithout Jounces JouncesJouncesJouncesJounces recovery 10% ? ? ? recovery 10% ? ? ? Chronic Infection 70-85% Chronic Infection 70-85% Recovery 50%-52% Recovery 50%-52% Symptomatic 25% Symptomatic 25% recovery 15-30% recovery 15-30% Natural History
  44. 44. Natural history of Hepatitis C Acute HCV Infection 60-85 % Persistent infection15-40% Recovery 20-40% cirrhoses 4-5% HCC
  45. 45.  Fatigue  Fever  Nausea and vomiting  Abdominal pain or discomfort, especially in the area of liver on right side under your lower ribs  Clay-colored bowel movements  Loss of appetite  Low-grade fever  Dark urine  Joint pain  Yellowing of the skin and eyes (jaundice) Main symptoms of Hepatitis C
  46. 46. Incubation period (Phase): (range, 6-12 weeks) after exposed to the virus. During these period patient has no symptoms
  47. 47. Chronic Hepatitis C Definition Chronic hepatitis C is a chronic infection caused by HCV which developes after 6 months from acute phase of infection. Chronic hepatitis C is the main form of HCV infection. It is chronic in 70-85% of infected individuals. usually progresses slowly and is characterised with non-specific clinical symptoms.
  48. 48. Diagnosis
  49. 49. Anti HCVAnti HCV HCV RNA qualitative and quantitative HCV RNA qualitative and quantitative Serologic and virologic markers of HBV infection
  50. 50. Major laboratory methods for HCV diagnosis  1984- ELISA  1985 -Western blot  1995 -Qualitative and quantitative PCR  2003 -HCV genotyping (INNO Lipa)  2007- HCV quantit. test – using Real Time PCR ( TaqMan technology)  2010 -HCV NS5B and 5’UTR/Core region sequencing
  51. 51. HCV RNA can be detected even before acute elevation of aminotransferase activity and before the appearance of anti-HCV in patients with acute hepatitis C. HCV RNA can be detected even before acute elevation of aminotransferase activity and before the appearance of anti-HCV in patients with acute hepatitis C.
  52. 52. COMPLICATIONS
  53. 53. Liver cirrhosis H HCC healthy lever Liver fibrosis COMPLICATIONS
  54. 54. Evaluation of liver disease severity Invasive methodInvasive methodInvasive methodInvasive method Non invasive methodsNon invasive methodsNon invasive methodsNon invasive methods
  55. 55. Invasive methodInvasive methodInvasive methodInvasive method Liver biopsyLiver biopsy Advantages Disadvantages
  56. 56. Noninvasive methodsNoninvasive methodsNoninvasive methodsNoninvasive methods Instrumental methodsInstrumental methodsInstrumental methodsInstrumental methods Laboratory MethodsLaboratory Methods
  57. 57. ultrasonographyultrasonography Computed tomographyComputed tomography KTKT Magnetic ResonanceMagnetic Resonance InvestigationsInvestigations- MRI- MRI Liver ElastrographyLiver ElastrographyLiver ElastrographyLiver Elastrography Instrumental methods for diagnosis of HepatitisInstrumental methods for diagnosis of Hepatitis
  58. 58. Liver Elastrography by Fibroscan Elasticity (KPA) <5.5 5.5-8 8-10 10-12.5 12.5-14 >14 Metavir F0-F1 F2 F2-F3 F3 F3-F4 F4 Correlation between the KPA and METAVIR scores The method is based on ultrasound principle. A mechanical pulse (wave) is spread through the liver. The velocity of the wave is measured by ultrasound. The velocity is directly correlated to the stiffness of liver, which in turn reflects the degree of fibrosis. Non invasive method for evaluation liver Fibrosis /Cirrhosis Fibroscan
  59. 59. Liver Elastography Stifnness (kpa) <5.5 5.5-8 8-10 10-12.5 12.5-14 >14 Metavir F0-F1 F2 F2-F3 F3 F3-F4 F4 results by Fibroscan measured in kpa is correlated to Metavir score in the following way The method is based on ultrasound principle. Velocity of share wave in the liver is measured by ultrasound sensor, which than corresponds to the stiffness of the liver tissue. The stifnness correlates to the degree of liver fibrosis. New and most precise method for the measurement of liver fibrosis
  60. 60. Was implemented since 2007 Non invasive method for evaluation liver Fibrosis /Cirrhosis Liver Elastrography by Fibroscan
  61. 61. FibroScan 2.5 cm 4 cm 1 cm ∅ Explored volume The probe induces an elastic wave through the liver The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface
  62. 62. TREATMENT
  63. 63. The 19The 19thth international Conference of the APASLinternational Conference of the APASL 13-16 February 2009 Hong Kong Michael P. Manns, Hanover Chronic HCV is the first and currently only chronic infection, which became curable. Announcement Michael P. Manns. APASL 2009 Hong Kong
  64. 64. HCV infection Curable diseases SVR =Cure
  65. 65. 6 16 34 42 39 56 75 >97>90 0 20 40 60 80 100 1986 19981991 2001 2002 2011 INF 6m INF 12m INF/RBV 6m INF/RBV 12m PEG 12m REG/RBV 12m SOF + REG/RBV 2014 REG/RBV + DAA SVR% SOF + REG/RBV Boceprevir Telaprevir 2013 HARVONI Milestones of hepatitis C treatment
  66. 66. 2001 – 2011 years Standard of care (SOC) Dual therapy PEG-Interferon + Ribavirin
  67. 67. 2011 DAA (direct acting antiviral) Telaprevir and Boceprevir
  68. 68. Triple therapy PEG-Interferon + Ribavirin Telaprevir or Boceprevir + For HCV genotype 1
  69. 69. DAA (direct acting antiviral) Direct-acting antivirals (DAAs), are medications targeted at specific steps within the HCV life cycle. DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection.
  70. 70. Classes of DAAs 1. NS3/4A - protease (serin) inhibitors P 3. NS5B- polymerase inhibitors 2. NS5A- inhibitors • nucleoside polymerase inhibitors • non-nucleoside polymerase inhibitors .
  71. 71. HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. 2007 Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly NS3/4A protease inhibitors NS5B polymerase inhibitors NS5A inhibitors “Previr’s” Boceprevir, Telaprevir, Simeprevir, Faldaprevir “Buvir’s” Sofosbuvir, Deleobuvir “Asvir’s” Daclatasvir, Ledipasvir DAA Uncoating Receptor binding
  72. 72. Pagilated Interferon alpha 2a (Pegasys) Pagilated Interferon alpha 2b (PegIntron) Ribavirin (Copegus, Rebetol) Boceprevir (Victrelis) Telaprevir (Incivek, Incivo) Simeprevir (Olisio) Sofosbuvir (Sovaldi) Daclatasvir (Daklinza) Dasabuvir (Exviera) Sofosbuvir/ledipasvir (Harvoni) Ombitasvir/Paritaprevir/Ritonavir +dasabuvir (Viekira PaK) Ombotasvir/Paritaprevir/Ritonavir (Viekirax) Grazoprevir/Elbasvir (Zepatier) Sofosbuvir/Velpatasvir (Epclusa) 2016 July Drugs for HCV (FDA approved)
  73. 73. Direct Acting Antivirals DAAs Simeprevir (Olisio) Sofosbuvir (Sovaldi) Daclatasvir (Daklinza) Dasabuvir (Exviera) Sofosbuvir/ledipasvir (Harvoni) Ombitasvir/Paritaprevir/Ritonavir +dasabuvir (Viekira PaK) Ombotasvir/Paritaprevir/Ritonavir (Viekirax) Grazoprevir/Elbasvir (Zepatier) Sofosbuvir/Velpatasvir (Epclusa) 2016 July I Generation Boceprevir (Victrelis) Telaprevir (Incivek, Incivo) II Generation 2011 2013-2014-2015-2016
  74. 74. Treatment regimens
  75. 75. Treatment Regimens for HCV I Interferon Containing Regimens Interferon Free Regimens
  76. 76. April 20152015-2016 Treatment regimens Interferon Containing  PEG/RBV+SOF  PEG/RBV+SMV  PEG/RBV+SOF  PEG/RBV+SMV Interferon Free  SOF/LDP (Harvoni)  SOF/LDP + RBV  SOF+RBV  SOF+SMV  SOF+SMV+RBV  SOF+DCV  SOF+DCV + RBV  VIEKIRA PAK  VIEKIRA PAK +RBV  EBV/GZR  EBV/GZR +RBV  SOF/VEL (Epclusa)  SOF/VEL +RBV  SOF/LDP (Harvoni)  SOF/LDP + RBV  SOF+RBV  SOF+SMV  SOF+SMV+RBV  SOF+DCV  SOF+DCV + RBV  VIEKIRA PAK  VIEKIRA PAK +RBV  EBV/GZR  EBV/GZR +RBV  SOF/VEL (Epclusa)  SOF/VEL +RBV
  77. 77. April 20162016  PEG/RBV+SOF  PEG/RBV+SMV  PEG/RBV+SOF  PEG/RBV+SMV  SOF/LDP (Harvoni)  SOF/LDP + RBV  SOF+RBV  SOF+SMV  SOF+SMV+RBV  SOF+DCV  SOF+DCV + RBV  VIEKIRA PAK  VIEKIRA PAK +RBV  EBV/GZR  EBV/GZR +RBV  SOF/VEL (Epclusa)  SOF/VEL +RBV  SOF/LDP (Harvoni)  SOF/LDP + RBV  SOF+RBV  SOF+SMV  SOF+SMV+RBV  SOF+DCV  SOF+DCV + RBV  VIEKIRA PAK  VIEKIRA PAK +RBV  EBV/GZR  EBV/GZR +RBV  SOF/VEL (Epclusa)  SOF/VEL +RBV Treatment regimens Interferon Containing Interferon Free
  78. 78. Treatment regimens EASL 2016 2 Pangenotypic Regimens
  79. 79. EASL 2016 Treatment regimens 2 Pangenotypic Regimens
  80. 80. THENKS FOR ATTENTION

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