2. Dr.mousavi GI Ward , Abadan Khordad. 1397
Hepatitis C
Dr.mousavi
GI Ward ,
Abadan Khordad. 1397

3. Epidemiology

4. Globally, it was estimated that in 2005, more than 185 million people had hepatitis C virus (HCV) antibodies (prevalence of 2.8 percent) (figure 1) .

6. Areas with high prevalences (>3.5 percent) included:
●Central and East Asia
●North Africa
●The Middle East

7. Moderate prevalences (1.5 to 3.percent)
●South and Southeast Asia
●Sub-Saharan Africa
●Andean, Central, and Southern Latin America
●The Caribbean
●Oceania
●Australasia (Australia, New Zealand, New Guinea, and neighboring Pacific islands)
●Western, Central, and Eastern Europe

8. Low prevalences (<1.5 percent)
●The Asia Pacific
●Tropical Latin America
●North America

9. Hepatitis C Virus Single stranded, positive sense, RNA
Flaviviridae family
Spherical, enveloped
Great genetic diversity
Six genotypes: 1 through 6
Multiple subtypes: a, b, c, etc
Viral sequences can be used to track a common source of infection
~ 50 nm 9

10. HCV Nucleocapsid Single stranded, positive sense RNA virus 10 kb long
50 nm in size
Nucleocapsid
RNA
Protective protein coating
Protective lipid coating

11. Illustration of the proposed structure of the hepatitis C virus
Illustration of the proposed structure of the hepatitis C virus. The lipid envelope contains glycoproteins E1 and E2 (as a heterodimer). Inside the envelope is the viral capsid which contains the HCV genome (Penin et al, 2004).

12. Hepatitis C Virus capsid envelope protein protease/helicase
RNA-dependent
RNA polymerase
c22
33c
c-100 5’ 3’
core E1 E2
NS2
NS3
NS4
NS5
hypervariable
region 12 7 7 7

14. HCV: Magnitude of the Problem
Nearly 4 million persons in United States infected
Approximately 35,000 new cases yearly
85% of new cases become chronic
Leading cause of
Chronic liver disease
Cirrhosis
Liver cancer
Liver transplantation
Centers for Disease Control and Prevention. Hepatitis C fact sheet. February 1, 2006.

15. Hepatitis C: A Worldwide Epidemic
Estimated ~ 185 million (3.1%) globally (2005)
Europe
8.9 million
(1.03%) 1
Western Pacific
62.2 million
(3.9%)
1, 2, 3
1, 3 3
The Americas
13.1 million
(1.7%) 4
Asia: 6 4 3
1,3
Southeast Asia
32.3 million
(2.15%)
Eastern Mediterranean
21.3 million
(4.6%)
Africa
31.9 million
(5.3%) 4 1
4,5
Common Genotype
Worldwide: 6
World Health Organization. Hepatitis C: global prevalence: update Farci P, et al. Semin Liver Dis. 2000;20: Wasley A, et al. Semin Liver Dis. 2000;20:1-16. 15

16. Burden of diseases in Iran Studies in Iran have found HCV:
46% among liver cancer patients
63.8%among beta thalassemia major patients
30.4% among chronic liver disease patients (
18% among cirrhotic patients
In hemodialysis patients from 5.5% to 55.9% in different cities

17. The prevalence of HCV infection in Iranian hemophilic patients is from 15.65% in Fars, a southern district of Iran to 76.7% in North-West of Iran in different studies
0.12% among blood donors

18. In Iranian patients with anti-HCV Ab positive from Tehran and five cities from different locations of Iran, showed that genotype 1a was predominant (47%), and 3a, 1b, and 4 were 36%, 8%, and 7%, respectively

19. HCV: Genotypes in the USA
17%
Type 3
10%
Type 1
72%
All others 1%
McHutchinson JG, et al. N Engl J Med. 1998;339:

20. Determination of HCV Genotype INNOLiPA Assay
Best pretreatment predictor of response
Determines duration of therapy
All patients should have genotype determined prior to initiating therapy

21. Transmission
How is hepatitis C
being transmitted?

23. HCV Infection: High-Risk Populations in Which Screening Is Indicated
Injection drug use
Nasal inhalation of cocaine
Chronic renal failure on dialysis
Incarceration
Multiple sexual partners, MSM, HIV positive
Transplantation or transfusion of blood products before 1992
Occupational exposure to blood products
Body piercing and possibly tattoo
Children born to HCV-positive women
Centers for Disease Control and Prevention. April 10, Verucchi G, et al. Infection. 2004;32:33-46. 23

24. Modes of HCV Transmission
HCV can probably survive on environmental surfaces at room temperature for hours
Do not exchange blood
Razors, toothbrushes, nail clippers
Sexual transmission rate is low
Condoms recommended for multiple sexual partners
Not transmitted by casual contact (eg, hugging) 24

25. Transmission No Known Risk Exposures in Other Settings (CDC)
In 10 percent of cases, no known risk is identified.
Exposures in Other Settings (CDC)
No data or insufficient data to show transmission through:
Intranasal cocaine use
Tattooing
Piercing

26. Diagnosis

27. HCV Testing
Who should
be tested?

28. CDC Testing Recommendations
Testing Routinely Recommended Based on Risk of Infection
Person who ever injected illegal drugs
Persons with selected medical conditions
Persons who received clotting factor concentrates produced before 1987

29. Persons who were ever on long-term hemodialysis
Persons with persistently abnormal alanine aminotransferace levels (persons with chronic liver disease)

30. Prior recipients of transfusions or solid organs
Persons who were notified that they received blood from a donor who later tested positive for HCV infection
Persons who received a transfusion of blood or blood components before July 1992
Persons who received an organ transplant before July 1992

31. HCV Testing HCVAb(screening) HCV RNA PCR(Qualitative&Quantitative)
HCV core antigen(Alternative NAT)
CDC MMWR on Guidelines for laboratory testing of hepatitis C. “Persons being tested for anti-HCV are entitled to accurate and correctly interpreted test results.

32. DIAGNOSIS :
(HCV) RNA by polymerase chain reaction (PCR) in the setting of undetectable anti-HCV antibodies that subsequently become detectable within 12 weeks is generally considered definitive proof of acute HCV infection.
Alternately, newly detectable HCV RNA and anti-HCV antibodies with documentation of negative tests within the prior six months is also diagnostic of acute HCV infection.

33. Diagnostic approach:
Acute HCV infection should be suspected in patients with clinical manifestations of acute hepatitis or with possible recent exposure to HCV (eg, needle-stick injury, recent injection drug use).
Such patients should be tested for the presence of HCV RNA and antibodies in the serum. The timing of testing is influenced by when HCV RNA and antibodies become detectable in the blood (figure 2 and figure 3).

36. Patients with acute hepatitis:
We immediately obtain HCV RNA by PCR and anti-HCV antibody testing by enzyme-linked immunosorbent assay (ELISA) (algorithm 1).
Establishing the diagnosis of acute hepatitis C or the need for further testing for acute HCV depends on results of these tests:

39. Regimen selection — Our approach to regimen selection for acute HCV infection depends on the genotype:
●For patients with genotype 1 or 4 infection, we suggest sofosbuvir-ledipasvir.

40. For patients with genotypes 2, 3, 5, or 6 infection, we generally wait to confirm persistent viremia at six months and promptly initiate genotype-appropriate DAA therapy for chronic infection at that point.
For those who have pressing need for more prompt therapy, we attempt to treat them in the acute setting with one of the genotype-appropriate DAA regimens that are used for chronic infection.

41. For interferon-based regimens for acute HCV infection, we usually initiate peginterferon weekly at 12 weeks after infection.
Treatment duration is 24 weeks for genotype 1 infection and 12 weeks for other genotypes. The addition of ribavirin is recommended for patients with HIV coinfection and may be considered in other individuals .

42. ASSESSING TREATMENT RESPONSE:
Virologic response to treatment is assessed by checking the viral load at 12 weeks following the cessation of therapy.
For those with ongoing risk exposures, it is important to promote harm-reduction strategies to avoid reinfection, and screening with repeat HCV RNA every 6 to 12 months should continue post-sustained virologic response (SVR).

43. If a person is chronically infected
Testing
If a person is chronically infected
what other tests
will they do?
Although there are both acute and chronic infections, in general clinical practice, however, acute hepatitis is uncommonly recognized; the majority of patients already have chronic hepatitis.

44. Genotyping Genotyping
There are at least six different genotypes of HCV.
Genotype to 75 percent of persons infected in the US.
Genotypes 2 and 3 – 10 to 15 percent of persons infected in the US.
Genotype testing should be done on all HCV positive people considering treatment.
Often determines length of treatment.
Is also a predictor of response to treatment.

45. Liver Enzyme Tests Liver Enzyme Tests
Elevated ALT levels are an indirect measure of liver cell inflammation and damage.
In patients with risk factors and elevated liver enzymes, HCV infection is probable.
However, the absence of elevation does not rule out significant liver damage.
One-third to one-half of HCV infected individuals will have a normal ALT level.

46. Liver Biopsy Most sensitive measure of disease severity.
Used to determine stage of fibrosis.
Can be used to help predict natural history of disease.
Often used to determine the need for treatment.
Can also be used to predict response to treatment.
May not be indicted for patients with genotypes 2/3.
Fibrosis is scarring of the liver.
Pathohistology – Inflammation/necrosis.
There are a number of different scales for grading cirrhosis – The Metavir Scale 0 = Fibrosis, 1 Portal Fibrosis, 2 = Bridging Fibrosis, slight, 3 = bridging fibrosis, marked, 4 = cirrohsis
Example: A person with genotype 1, persistently normal or slightly elevated ALTs, and minimal or no fibrosis may chose to delay treatment. An interval of 4 to 5 years between biopsies may be needed to measure a change in such patients.
The presence of advanced fibrosis or cirrhosis markedly decreases response to treatment
There is controversy to doing liver biopsy in all patients. Most clinicians routinely obtain a biopsy in patients with genotype 1.
AASDL – After weighing the risks, benefits, and cost of existing HCV treatments and liver biopsies, most experienced clinicians routinely obtain a liver biopsy in patients with genotype 1 infection to guide recommendations for treatment. Patients with genotypes 2 and 3, however, have a high likelihood of response and therefore, some advocate treating all such patients regardless of severity of liver disease without resorting to liver biopsy.
Liver biopsies may also be used to monitor progression of disease. Progress of fibrosis is non-linear. Four to five years intervals for those with mild disease? May still miss some progression.
Invasive procedures – May experience pain, small number = bleeding. Death is rate.
There are other laboratory tests that contribute to the monitoring of patients with HCV.
There are new serum markers of fibrosis and inflammation that are currently under development. These markers are not yet able to accurately predict the severity of liver damage but they may be useful in the future

47. Is Liver Biopsy Necessary?NO
Patient wants treatment even if no fibrosis
Patient does not want treatment or treatment contraindicated even if advanced fibrosis
Labs and radiographic studies do not suggest cirrhosis
Patient achieves SVR
YES
Patient would only accept treatment if advanced fibrosis
Labs or radiographic studies suggest cirrhosis may be present
Patient fails to achieve SVR and no recent biopsy available

48. Making the diagnosis Natural History - Acute Infection Symptoms
Are uncommon (body aches, flu-like symptoms, etc)
On average, appear 6 to 7 weeks after infection.
Testing
6 to 8 weeks: Average time antibodies can be detected.
1 to 3 weeks: Average time virus can be detected.
4 to 12 weeks: Often elevation in ALT

49. Serologic Pattern of Acute HCV Infection with Recovery
Symptoms +/-
anti-HCV
HCV RNA
Titer
ALT
Normal 1 2 3 4 5 6 1 2 3 4
Months
Years
Time after Exposure

50. Chronic HCV Symptoms Percentage of Patients Fatigue Symptomatic 100
37%
Cirrhosis 80 7% 60
Percentage of Patients 40 20
56%
Asymptomatic
Fatigue
Unpublished data from MCV Hepatitis Program, 1995.

51. Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection
Symptoms +/-
anti-HCV
HCV RNA
Titer
Normal 1 2 3 4 5 6 1 2 3 4
Months
Years
Time after Exposure

52. Hepatitis C Virus Host Production of HCV Antibodies
HCV infects cell
HCV proteins expressed on surface of hepatocytes
Antibodies to HCV proteins produced by host
HCV antibodies DO NOT convey immunity Y Y Y Y Y Y Y Y

53. HCC or Decompensation 1% to 3%/yr
Natural History
Acute HCV
Resolved 15%
Chronic HCV 85%
Stable 75% to 95%
Cirrhosis 5% to 25%
Stable 97% to 99%/yr
HCC or Decompensation 1% to 3%/yr
Thomas DL, et al. Clin Liver Dis. 2005;9: Strader DB, et al. Eur J Gastroenterol Hepatol. 1996;8: Seeff LB, et al. Hepatology. 2002;36(suppl):S1-S2. Seeff LB, et al. Hepatology. 2002;36(suppl):S35-S46. Liang TJ, et al. Ann Intern Med. 2000;132: Fattovich G, et al. Gastroenterology. 1997;112:

54. Chronic HCV: Progression to Cirrhosis
Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis
Approximate Percentage of
Patients With Cirrhosis
100 80
Bridging 60
Portal 40
None 20 5 10 15 20
Time (Years)
Yano M, et al. Hepatology. 1996;23:

55. I hope I don’t have Hepatitis C

56. HCV and Alcohol Cirrhosis (%) Years Following Exposure 100 80 60 HCV
HCV + alcohol 40 20 10 20 30 40
Years Following Exposure
Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.
Wiley TE, et al. Hepatology. 1998:28:

57. HCV Fibrosis Progression: Effect of Age
4.0
3.0
Age at time
of infection
Fibrosis Score
2.0
> 40 years
< 40 years
1.0 .
< 10
11-20
21-30
31-40
> 40
Duration of Infection (Years)
Poynard T, et al. Lancet. 1997;349:

58. Current Treatment

61. GENERAL MANAGEMENT :
Antiviral therapy is the cornerstone of treatment of chronic hepatitis C virus (HCV) infection (see 'Antiviral therapy' below).
With current antiviral therapies, HCV is relatively easily treated and can be eliminated in almost all patients.
Other general measures in the management of patients with chronic HCV include symptom management, dose adjustment of medications, and preventing complications of cirrhosis if present.

62. Treatment
Who should
be treated?

64. Goal of Therapy

67. Thank you