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

Epidemiology

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) .

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

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

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

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

HCV Nucleocapsid Single stranded, positive sense RNA virus 10 kb long 50 nm in size Nucleocapsid RNA Protective protein coating Protective lipid coating http://www.rit.edu/~japfaa/infectious.html http://www.epidemic.org/cgi-bin/hepcglossary.cgi?query=HepatitisC2&caller=theFacts/hepatitisC/anatomy.html

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).

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

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.

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. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16. 15

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

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

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

HCV: Genotypes in the USA 17% Type 3 10% Type 1 72% All others 1% McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

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

Transmission How is hepatitis C being transmitted?

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, 2007. Verucchi G, et al. Infection. 2004;32:33-46. 23

Modes of HCV Transmission HCV can probably survive on environmental surfaces at room temperature for 16-72 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

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

Diagnosis

HCV Testing Who should be tested?

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

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

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

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.

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.

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).

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:

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.

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.

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 .

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).

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.

Genotyping Genotyping There are at least six different genotypes of HCV. Genotype 1 - 70 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.

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.

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

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

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

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

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.

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

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

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;9:383-398 Strader DB, et al. Eur J Gastroenterol Hepatol. 1996;8:324-328. 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;132:296-305. Fattovich G, et al. Gastroenterology. 1997;112:463-472.

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;23:1334-1340.

I hope I don’t have Hepatitis C

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. 1998:28:805-809.

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;349:825-832.

Current Treatment

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.

Treatment Who should be treated?

Goal of Therapy

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