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
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
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
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.
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.
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
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
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
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
36.
37.
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
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
49. Natural history of Hepatitis C
Acute HCV Infection
60-85 % Persistent infection15-40%
Recovery
20-40%
cirrhoses
4-5%
HCC
50.
51.
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
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.
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.
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
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
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.
Study was performed in 2001-2002. population-based cross-sectional survey of the adult population of Tbilisi. Number of study participants were 2000 persond
In 2008 study of hepatitis C prevalence was conducted in HIV infected Georgian cohort of patients. The aim of the study was to determine the prevalence of hepatitis C among HIV positive patients and to identify most relevant risk factors of co-infection . Total 175 patients were included in analysis. The study revealed high prevalence of hepatitis C among HIV positive patients. Almost half (48.57%) HIV positive patients were co-infected with HCV. Major risk factor of co-infection was related to drug use, needle and injection equipment sharing. Prevalence of HCV among injecting drug users was (73.40%).
GT, genotype; HCV, hepatitis C virus; IFN, interferon; LLOQ, lower limit of quantification; P/R, peginterferon/ribavirin; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; Tx, treatment; UII, Unwilling/Intolerant/Ineligible.
Paul Y. Kwo, MD:
To summarize our discussion of the phase III trials of sofosbuvir, the NEUTRINO study demonstrated high SVR rates with a 12-week regimen of sofosbuvir plus peginterferon/ribavirin in genotypes 1, 4, 5, and 6 HCV, and I think this will become the new gold standard for treatment-naive individuals with genotype 1 HCV infection when it is approved. Although many patients are reluctant to embark on interferon-based therapy, there are also many individuals who will not be daunted by a short 12-week course of peginterferon/ribavirin when combined with sofosbuvir, which has minimal additional adverse events. Moreover, if these patients fail, they will likely fail with virologic relapse, and it is encouraging that in this setting the likelihood of resistance associated variants will be minimal, if at all.
Regarding genotypes 4, 5, and 6 HCV, there is a very high SVR rate, and it will be important to still explore this combination further in larger studies. There are not yet data in patients with genotypes 1, 4, 5, or 6 HCV infection who have previously failed interferon-based therapy, although I suspect that these areas will be explored once this combination is available.
David R. Nelson, MD:
All of the phase III studies suggest that sofosbuvir is a potent, safe treatment option, and consequently, sofosbuvir is likely to gain approval in the coming months, at least in North America, for patients infected with genotype 1 HCV in combination with peginterferon/ribavirin and for patients infected with genotypes 2 and 3 HCV as the first all-oral, interferon-free regimen.
Stefan Zeuzem, MD:
Once sofosbuvir is initially approved in combination with peginterferon/ribavirin, I will be curious to see how many patients infected with genotype 1 HCV will request to be treated with only sofosbuvir and ribavirin (without peginterferon). There is a very heterogeneous data set in the literature of small phase II studies with sofosbuvir and ribavirin. In some of these studies, although a small number of patients were included, genotype 1 HCV demonstrated SVR rates in the range of 70% or more.[1,2] I would not be surprised if some physicians and patients reviewing those data decide to attempt treatment with sofosbuvir and ribavirin dual therapy in genotype 1 HCV infection.
David R. Nelson, MD:
There are certainly many patients who would rather not receive interferon-based treatment. Once simeprevir is also approved—which is discussed below—and physicians will have the opportunity to offer an off-label regimen such as sofosbuvir plus simeprevir; alternatively, some might consider an extended duration of sofosbuvir/ribavirin treatment, which has been evaluated in phase II trials.[2] However, I think that for patients with the IL28B CC genotype, peginterferon is a very potent drug and, for cost reasons and for the very short 12-week duration, peginterferon will continue to play a significant role.
Paul Y. Kwo, MD:
In our clinic, we certainly have patients who, for SVR rates approaching 90%, will be willing to undergo 12 weeks of treatment with peginterferon/ribavirin combined with sofosbuvir. I certainly recognize, however, that there is a strong desire to move away from peginterferon-based therapies, such that all individuals with hepatitis C will be candidates for all-oral therapy.
David R. Nelson, MD:
I can also envision a hybrid model, in which one might encourage genotype 1 HCV–infected patients to start treatment with sofosbuvir plus peginterferon/ribavirin, since this offers the highest current SVR rates, but if patients have a difficult time tolerating peginterferon, one might discontinue peginterferon if necessary and continue therapy with an all-oral peginterferon-free regimen.
References
1. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks post-treatment results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT 1 null responders. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia; March 3-6, 2013. Abstract 155LB.
2. Osinusi A, Bon D, Herrmann E, et al. High efficacy of sofosbuvir with weight-based ribavirin for 24 weeks in difficult-to-treat patients. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia; March 3-6, 2013. Abstract 157LB.
DAA, direct-acting antiviral; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain; NS5A/B, nonstructural protein 5A/B.
Now, one of the advantages of direct-antivirals for hepatitis C virus is that, unlike some of other virus, like HBV, for example, hepatitis C has a number of potential targets for drug development, and this has led to multiple classes of direct-acting antivirals being developed. So, if we look at this schematic of the HCV life cycle, you can see that after the virus enters the cell, the viral RNA is translated to lead to the viral proteins and then these are chopped up by the virally encoded protease. And of course, the first direct-acting antivirals were inhibitors of the NS3/4A protease. Subsequently, the viral RNA is replicated, and again, the HCV NS5B polymerase has been a target for inhibition, with both nucleotide polymerase inhibitors and nonnucleotide or nonnucleoside polymerase inhibitors, which act by a different mechanism of action but target the same enzyme. In addition, after viral replication occurs, the virus must be assembled and part of the replication complex involved in assembly is the nonstructural 5A protein—or NS5A—and a number of direct-acting antivirals target the NS5A protein. So, at least to date, the DAAs that have gone through clinical development include protease inhibitors, nucleotide and nonnucleotide polymerase inhibitors, and NS5A inhibitors.