Hepatitis C Virus 1/24/ :34 AM. Objectives. University of Chicago March 25, 2006 , MD. Nancy Reau, Reau. HCV Facts.

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1 Hepatitis C Virus Historical Perspective, Epidemiology, and Natural History Nancy Reau, Reau, MD University of Chicago March 5, 6 HCV Facts At least 3.9 million Americans are infected with HCV.7 million are chronically infected (HCV RNA +) Most patients have not yet been diagnosed Most common chronic blood-borne borne infection HCV is one of the leading causes of liver disease in the United States NIH Consensus Development Conference Statement: Management of Hepatitis C:. Hepatology. ;36:S3-S. S. Objectives Review the epidemiology and natural history of hepatitis C virus (HCV) Review the role of liver biopsy in HCV Review co-infection with hepatitis A and hepatitis B and the role of vaccination HCV Facts Progressive damage from HCV can lead to serious consequences, cirrhosis of the liver Liver cancer (HCC) HCV is the #1 reason for liver transplant Approximately 13, people die from the disease every year 1

2 New Infections/1, HCV Epidemiology and Natural History Estimated Incidence of Acute HCV Infection; United States, Decline in transfusion recipients Decline in injection drug users Year Adapted from CDC Hepatitis Slide Kit. Accessed 7/1/5. HCV: A Global Challenge USA 3.9 M West Europe 9 M East Mediterranean M South East Asia 3 M Far East Asia 6 M South America 1 M Africa 3 M Australia. M WHO, Prevalence of HCV by Age Groups are now ~ - 63 Prevalence of Anti-HCV Antibodies (%) Age Group (Years) Alter MJ et al. N Engl J Med ;31;556.

3 Prevalence of HCV Infection by Age and Gender; United States, Males Total Females Age in Years CDC, NHANES III. Accessed 7/1/5. Prevalence of HCV Infection by Age and Race/Ethnicity United States, White Black Mexican- American Age Group (Years) MMWR, 1998;7: Anti-HCV Positive, % Anti-HCV Positive (%) Estimated Prevalence of HCV Infection at Age 6, by Year of Birth 5.%.% 3.%.% 1.% Prevalence at Age 6.% Birth year of cohort Armstrong GL et al. Hepatology. ;31: Future Prevalence of HCV Prevalence of HCV Infection (%) 3 1 Individuals infected at any time Individuals infected for > years Armstrong GL et al. Hepatology. ;31:

4 Future Prevalence of HCV 3 1 Individuals infected at any time Prevalence of HCV Infection (%) Individuals infected for > years Armstrong GL et al. Hepatology. ;31: HCV Prevalence by Selected Groups, United States Hemophilia Injecting drug users Hemodialysis STD clients Gen population adults Surgeons, PSWs Pregnant women Military personnel Average Percent Anti-HCV Positive Accessed 7//5. Sources of Infection for Persons with Hepatitis C Injecting Drug Use 6% Sexually Transmitted 15% Transfusion 1% (before screening) Occupational % Other* 1% Unknown 1% *Nosocomial; iatrogenic; perinatal. Adapted from et/index.htm. Accessed 1/8/. Injecting Drug Use and HCV Transmission Highly efficient Contamination of drug paraphernalia, Contamination of drug paraphernalia, not just needles and syringes Rapidly acquired after initiation 3% prevalence after 3 years >5% after 5 years x more common than HIV Accessed 7/1/5.

5 Sexual Transmission of HCV Occurs, but efficiency is low Rare between long-term steady partners Factors that facilitate transmission between partners unknown (eg, viral titer) Accounts for 15%-% of acute and chronic infections in the United States Sex is a common behavior Large chronic reservoir provides multiple opportunities for exposure to potentially infectious partners Accessed 7/1/5. Occupational Transmission of HCV Inefficient incidence 1.8% after needlestick from HCV- positive source increased with hollow-bore needles Case reports of transmission from blood splash to eye; one from exposure to non-intact skin Prevalence 1%-% among healthcare workers Lower than adults in the general population 1x lower than for HBV infection Accessed 7/1/5. Sexual Transmission of HCV (cont) Case-control, cross-sectional sectional studies Increased risk: Infected partner multiple partners non-use of condoms other STDs sex with trauma MSM no higher risk than heterosexuals Partner studies Accessed 7/1/5. Low prevalence (1.5%) among long-term partners Male-to to-female transmission more efficient More indicative of sexual transmission HCV Related to Healthcare Procedures, United States Recognized primarily in context of outbreaks Unsafe injection practices Reuse of syringes and needles Contaminated multiple-dose medication vials Accessed 7/1/5. 5

6 HCW-to to-patient Transmission of HCV Rare US none related to performing invasive procedures HCW substance abuse Reuse of needles or sharing narcotics used for self-injection No restrictions recommended for HCV-infected HCWs Accessed 7/1/5. Household Transmission of HCV Rare but not absent percutaneous/mucosal exposures to blood Contaminated equipment used for home therapies IV therapy, injections Through sharing of contaminated personal articles (razors, toothbrushes) Accessed 7/1/5. Perinatal Transmission of HCV Transmission only from women HCV-RNA positive at delivery Average rate of infection 6% Higher (17%) if woman co-infected with HIV No association with Delivery method Breastfeeding Infected infants do well Severe hepatitis is rare Accessed 7/1/5. HCV: Other Potential Exposures to Blood Insufficient data Intranasal cocaine use tattooing body piercing acupuncture military service Accessed 7/3/5. 6

7 Reduce or Eliminate Risks for Acquiring HCV Infection Screen and test donors Risk-reduction counseling and services high-risk drug and sex behaviors Safe injection and infection control practices Accessed 7//5. MMWR. 1998;7(no. RR-19). HCV Testing Routinely Recommended increased risk for infection Ever injected illegal drugs Received clotting factors made before 1987 Received blood/organs before July 199 Ever on chronic hemodialysis Evidence of liver disease exposure needlestick/mucosal exposures to HCV-positive blood Children born to HCV-positive women Accessed 7//5. HCV: Reduce Risks for Disease Progression and Further Transmission Identify persons at risk for HCV and test to determine infection status Provide HCV-positive persons Medical evaluation and management Counseling Prevent further harm to liver Prevent transmission to others Treatment options Accessed 7//5. MMWR. 1998;7(no. RR-19). Preventing HCV Transmission to Others Avoid direct exposure to blood Do not donate blood, body organs, other tissue or semen Do not share items that might have blood on them personal care (eg, razor, toothbrush) home therapy (eg, needles) Cover exposed cuts and sores IVDU: do not share needles, paraphernalia Accessed 7//5. 7

8 HCV: Mother-to to-infant Transmission Post-exposure prophylaxis not available No need to avoid pregnancy or breastfeeding Consider bottle feeding if nipples cracked/bleeding No need to determine mode of delivery based on HCV-infection status Test infants born to HCV-positive women > months old Consider testing any children born since woman became infected Accessed 7//5. Sexual Transmission of HCV Persons with high-risk sexual behaviors At risk for sexually transmitted diseases, eg,, HIV, HBV, gonorrhea, chlamydia, etc Reduce risk Limit number of partners Use latex condoms Get vaccinated against hepatitis B MSMs also get vaccinated against hepatitis A Accessed 7//5. Sexual Transmission of HCV 1 long-term steady sex partner No need to change sexual practices Discuss with partner Risk low but not absent testing of partner should be individualized May provide couple with reassurance barrier precautions reduce risk Accessed 7//5. HCV: Other Transmission Issues HCV not spread by kissing, hugging, sneezing, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact Do not exclude from work, school, play, child-care care or other settings based on HCV infection status Accessed 7//5. 8

9 HCV: Natural History Serologic Pattern of Acute HCV Infection with Recovery Symptoms +/1 HCV RNA Pathogenesis of HCV A Clinical Timeline HCV RNA first detected in blood weeks Time until symptoms (if any) Average weeks Range -6 6 weeks Antibody first detected in blood In 5-7% at onset of symptoms; in 9% by 3 months Acute illness (jaundice) Chronic infection Cirrhosis Mild (%) 75-85% >% Mortality from Chronic Liver Disease (CLD) 1-5% Adapted from NIH Consensus Development Conference Statement: Management agement of Hepatitis C:. Hepatology. ;36:S3-S S and dex.htm. Accessed 1/8/. 9 Titer Titer ALT Normal Months Years Time After Exposure Accessed 7/1/5. anti-hcv Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Anti-HCV Symptoms +/- HCV RNA ALT Normal Months Time After Exposure Years Adapted from et/index.htm. Accessed 1/8/.

10 Why Do We Treat Chronic HCV? 1 8 ALT 1+ 6 HCC Fibrosis Cirrhosis Anti-HCV Years After Exposure Hoofnagle JH. Hepatology. ;36:S1-S9. 1 ALT (U/L) HCV RNA+ Natural History of HCV 1- Years Acute HCV Chronic HCV 75%-85% Cirrhosis % Slide courtesy of Kris Kowdley, MD, 5. Hoofnagle JH. Hepatology. 1997;6(suppl 1):15S-S. Di Bisceglie. Hepatology.. Why Do We Treat Chronic HCV?* Acute HCV (3.9 million) ~85% 1 Chronic HCV (.7 million; low est) %-5% Cirrhosis (5,-1,35,) ~% ~ % 3 Hepatic Failure (18,-7,) Liver Cancer (18,-7,) Liver Transplant Candidates *Adapted from Brown RS. Epidemiology and Natural History of Hepatitis C. Presented at the ACG Clinical Implications meeting, April 6,, Dallas, TX. 1. NIH Consensus Development Conference Statement; March -6, 6, Davis GL et al. Gastroenterol Clin North Am.. 199;3: Koretz RL et al. Ann Intern Med ;119: Takahashi M et al. Am J Gastroenterol ;88: Natural History of HCV Annual Rate Cirrhosis % Decompensation 6% HCC % Death ~% Slide courtesy of Kris Kowdley, MD, 5. Hoofnagle JH. Hepatology. 1997;6(suppl 1):15S-S. Di Bisceglie. Hepatology..

11 Chronic HCV: Factors Promoting Progression or Severity Increased alcohol intake Age > years at time of infection HIV co-infection Other Male gender Chronic HBV co-infection Insulin resistance (obesity, diabetes, etc) Adapted from Accessed 3/31/5. Estimated Cost of HCV 7, deaths from hepatocellular carcinoma $1.7 billion in direct medical expenditures 7,7 years of decompensated cirrhosis and hepatocellular carcinoma at a cost of $1. billion Loss of 1.83 million years of life in those <65 years of age at a cost of $5. billion Wong JB et al. Am J Public Health.. ;9: Future Estimated HCV Disease Burden -3 3 The number of patients with cirrhosis will almost double (7, - 879,) Liver-related related deaths will more than triple (13, - 39,875) Davis GL et al. Liver Transpl. 3;9: HCV in the United States Summary 3.9 million Americans are infected with HCV IDU is the biggest risk factor for HCV Of the 3.9 million infected in the United States >% will develop cirrhosis 5-1% may die of complications of liver disease Liver-related related deaths will triple by 3 if left untreated 11

12 HCV Further Evaluation of the Chronic Hepatitis C Patient Liver Biopsy Regardless of the level of ALT, a liver biopsy should be done when the results will influence whether treatment is recommended, but a biopsy is not mandatory in order to initiate therapy. A liver biopsy may be obtained to provide information on prognosis. Strader DB et al. Hepatology. ;39: HCV Testing: Molecular Tests Performed Prior to and During Therapy HCV-RNA Quantitative Prior to treatment to establish viral load During therapy to determine response Qualitative To monitor for continued response after therapy has been stopped Genotype HCV: Liver Biopsy 1

13 Histological Data: Normal vs. Elevated ALT Histological Scoring System Cirrhosis Bridging Portal 6% Normal ALT 6% 6% 3% No Fibrosis Mild % Bridging Cirrhosis Portal Elevated ALT 16% % % 19% 19% Mild No Fibrosis Grade 1 3 Inflammation Fibrosis Description No activity Minimal Mild Moderate Severe Stage 1 3 Description No fibrosis Portal fibrosis Periportal fibrosis Septal fibrosis Cirrhosis ML Shiffman et al. J Infect Dis. ; 18: Batts KP, Ludwig J. Am J Surg Pathol. 1995;19: HCV: Utility of Liver Biopsy Liver Biopsy Confirm Clinical Diagnosis Evaluate Possible Concomitant Disease Processes Role of Liver Biopsy Assess Fibrosis Assess Severity of Necroinflammation Assess Therapeutic Intervention Advantages ID most likely to benefit from therapy Evaluate for prognostic information Inflammation Fibrosis Steatosis Exclude alternative diagnosis Limitations Sampling error Complications >3% pain.3% sever complications.3% Mortality Slide courtesy of Kris Kowdley, MD, 5. Brunt EM. Hepatology. ;31:

14 HCV: Is Biopsy Always Necessary? Consider foregoing biopsy in: Treatment candidates with genotype or 3 Motivated patients with genotype 1 Clinical evidence of cirrhosis Thrombocytopenia Splenomegaly Portal hypertension on imaging Treatment for extrahepatic manifestations HCV: Noninvasive Markers of Fibrosis Noninvasive alternatives to liver biopsy FibroScan (transient elastography): Measures liver stiffness Fibrotest: Evaluates serologic markers of fibrosis Most accurate in predicting advanced fibrosis or minimal disease Accuracy for intermediate degrees of fibrosis poor Adapted from slide courtesy of Kris Kowdley, MD, 5. HCV: Noninvasive Markers of Fibrosis Liver biopsy is the standard approach for assessment of HCV-related histologic lesions Noninvasive alternatives to liver biopsy Fibrotest Fibrospect FibroScan Adapted from slide courtesy of Kris Kowdley, MD, 5. Summary: Liver Biopsy Biopsy should be performed if it will change disease management Biopsy is not needed in every patient Non-invasive fibrosis markers may have a role in evaluating for level of fibrosis and disease progression 1

15 HCV: HAV Superinfection and HBV Coinfection/Superinfection Outcome of HAV Superinfection in Patients with Chronic HCV 595 Italian patients with chronic HBV (n=163) or HCV (n=3) infection were prospectively followed for 7 years 7 patients acquired HAV, 17 of whom were in HCV group 7 out of 17 developed fulminant hepatitis % Fulminant Hepatitis A, % Prevalence of HBV Infection in CLD HBV markers detected in 6% of subjects positive for anti-hcv (NHANES III) 1% to 5% of patients with advanced liver disease Patients with HAV+HCV % Patients with HAV alone Adapted from Vento S et al. N Engl J Med. 1998;338:86-9. Impact of Acute HBV in Patients with Chronic HCV Frequency of liver failure: (ascites,encephalopathy ascites,encephalopathy,, PT <5%) 5 Frequency of Liver Failure, (%) 3 1 9% % Pre-existing HCV No HCV n=1 n= Sagnelli E et al. Hepatology. ;36:

16 Risk of HCC With HBV/HCV Coinfection in Cirrhotic Patients 1 HCC developed in 3/9 cirrhotic patients during follow-up of 6.3 years ± 1. months % 1.% 19.6% % No Risk HCV HBV HBV + HCV Factors 1. Koff RS. J Clin Gastroenterol. 1;33:-6.. Benvegnu L et al. Cancer. 199;7:-8. More Severe Complications of CLD with HBV/HCV Coinfection 9 consecutive patients with HCV seen in Hadassah Medical Center Liver Unit (Jerusalem, Israel) HBV coinfection observed in 66% Coinfection associated with more complications Bleeding esophageal varices Hepatic encephalopathy Spontaneous bacterial peritonitis Hepatocellular carcinoma Ilan Y et al. Isr J Med Sci. 199;3: Patients with Cirrhosis, % Patients, % Incidence of Cirrhosis in HBV/HCV Coinfection vs HCV Alone % HCV+/HBV- (n=5) 56.% HCV+/HBV+ (n=3) Fuiano B et al. Ital J Gastroenterol. 199;:9-11. Commercially Available Hepatitis Vaccines Monovalent: Hepatitis A Vaccine, Inactivated HAVRIX VAQTA Hepatitis B Vaccine (Recombinant) ENGERIX-B RECOMBIVAX HB Bivalent: Hepatitis A Inactivated and Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine TWINRIX 5 Physician s Desk Reference; Medical Economics: Montvale, NJ.

17 Monovalent Hepatitis A Vaccine, Inactivated Dose and Schedule for Adults 19 Years Dose Schedule Havrix 1 1 EL.U. in 1. ml IM, 6 to 1 months Vaqta ~5 U in 1 ml IM, 6 to 1 months 1. Havrix Prescribing Information. SmithKline Beecham Pharmaceuticals. Philadelphia, PA. August 3.. Vaqta Prescribing Information. Merck & Co, Inc. West Point, PA; January. Bivalent Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine Dose and Schedule for Adults Dose Schedule TWINRIX Adults 18 years 1. ml (contains 7 EL.U. of inactivated HAV virus and mcg of HBV surface antigen), 1, and 6 months Twinrix Prescribing Information. SmithKline Beecham Pharmaceuticals. Philadelphia, PA; August 3. Monovalent Hepatitis B Vaccine (Recombinant) Dose and Schedule for Adults Engerix-B Adults >19 > years 1 Dose mcg in 1. ml IM Schedule, 1, and 6 months or, 1,, and 1* months Recombivax HB Adults > years 1 mcg in 1. ml IM, 1, and 6 months * For certain subpopulations please refer to PI for prescribing information. 1. Engerix-B Prescribing Information. SmithKline Beecham Pharmaceuticals. Philadelphia, PA; August, 3.. Recombivax HB Prescribing Information. Merck & Co, Inc. West West Point, PA; June. HCV: Conclusions At least.7 million Americans are chronically infected with HCV (HCV +); only a small percentage of these patients have been diagnosed HCV progresses slowly over a period of - years and can result in cirrhosis, liver failure, the need for liver transplantation, or death Individuals who have been infected for > years are expected to peak around 1 17

18 Suggested Reading National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C:. Hepatology. ;36:S3-S. S. Available without charge at Web site: Strader DB et al. AASLD Practice Guideline: Diagnosis, Management, and Treatment of Hepatitis C. Hepatology. ;39: Available without charge at Web site: 18