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

1. Lali Sharvadze
Associated Professor
Viral Hepatitis
Hepatitis C
Infectious Diseases, AIDS & Clinical Immunology Research Center
2016

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. 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. Hepatitis C

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

6. EPIDEMIOLOGY

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. 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. • 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. There is no prophylactic vaccine
and/or specific immunoglobulin
against hepatitis C
But effective antiviral treatment
exist, which is disease prophylaxis as
well

12. Epidemiology of hepatitis
C in Georgia
Epidemiology of hepatitis
C in Georgia

13. 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.

14. 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%

15. 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.

16. 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

17. Etiology

18. RNA virus
Family- Flaviviridae
Genus - Hepacivirus
Hepatitis C virus is a linear, single-strand,
9600-nucleotide RNA virus.

19. Electron micrograph of hepatitis C virus

20.  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.

22. Etiology

24. 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.

25. 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

26. 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

27. HCVHCV genotipebis gavrcelebagenotipebis gavrceleba
msoflioSimsoflioSi

28. 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

29. TRANSMISSION

30. 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.

31. 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

32. PATHOGENESIS

33.  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

34. Because HCV does not replicate
via a DNA intermediate, it does
not integrate into the host
genome.

35. 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

38. Pathogenesis of HCV infection
Why HCV infection is
predominantly chronic?
Why HCV infection is
predominantly chronic?

39. HCV has ability to “escape”
immune response of the host
Pathogenesis 1

40. 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

41. Pathogenesis 3
Antigenic variations of HCV in
the same host is called
(quasispecies).
Number of Such quasispecies
reaches about 1010
– 1011
per day

42. 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

43. Natural History
and Disease Outcome
Natural History
and Disease Outcome

44. CLINICAL FEATURES
2 forms of Hepatitis C exists:
• Acute Hepatitis C
• Chronic Hepatitis C

45. 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.

46. Acute hepatitisAcute hepatitis CCAcute hepatitisAcute hepatitis CC
With symptomsWith symptoms
infeqciuri paTologiis, Sidsisa da klinikuri imunologiis
samecniero-praqtikuli centri
Without symptomsWithout symptoms

47. With JaundiceWith Jaundice
infeqciuri paTologiis, Sidsisa da klinikuri imunologiis
samecniero-praqtikuli centri
Without JaundiceWithout Jaundice
Symptomatic Acute
Hepatitis c
Symptomatic Acute
Hepatitis c

48. 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

49. Natural history of Hepatitis C
Acute HCV Infection
60-85 % Persistent infection15-40%
Recovery
20-40%
cirrhoses
4-5%
HCC

52.  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

53. Incubation period (Phase):
(range, 6-12 weeks)
after exposed to the virus.
During these period patient has no symptoms

54. 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.

55. Diagnosis

56. Anti HCVAnti HCV HCV RNA
qualitative and quantitative
HCV RNA
qualitative and quantitative
Serologic and virologic markers of HBV infection

57. 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

58. 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.

59. COMPLICATIONS

60. Liver cirrhosis H HCC
healthy lever Liver fibrosis
COMPLICATIONS

61. Evaluation of liver disease severity
Invasive methodInvasive methodInvasive methodInvasive method
Non invasive methodsNon invasive methodsNon invasive methodsNon invasive methods

62. Invasive methodInvasive methodInvasive methodInvasive method
Liver biopsyLiver biopsy
Advantages
Disadvantages

63. Noninvasive methodsNoninvasive methodsNoninvasive methodsNoninvasive methods
Instrumental methodsInstrumental methodsInstrumental methodsInstrumental methods
Laboratory MethodsLaboratory Methods

64. 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

65. 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

66. 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

67. Was implemented
since 2007
Non invasive method for evaluation liver Fibrosis /Cirrhosis
Liver Elastrography by Fibroscan

68. 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

69. TREATMENT

70. 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

71. HCV infection
Curable diseases
SVR =Cure

72. 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

73. 2001 – 2011 years
Standard of care (SOC)
Dual therapy
PEG-Interferon + Ribavirin

74. 2011
DAA
(direct acting antiviral)
Telaprevir and Boceprevir

75. Triple therapy
PEG-Interferon + Ribavirin
Telaprevir or Boceprevir
+
For HCV genotype 1

76. 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.

77. Classes of DAAs
1. NS3/4A - protease (serin) inhibitors P
3. NS5B- polymerase inhibitors
2. NS5A- inhibitors
• nucleoside polymerase inhibitors
• non-nucleoside polymerase inhibitors
.

80. 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

81. 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)

82. 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

83. Treatment regimens

84. Treatment Regimens for HCV
I
Interferon Containing Regimens
Interferon Free Regimens

85. 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

86. 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

87. Treatment regimens
EASL 2016
2 Pangenotypic Regimens

88. EASL 2016
Treatment regimens
2 Pangenotypic Regimens

89. THENKS
FOR ATTENTION