Hepatitis Update Brendan M. McGuire, MD UAB Liver Center

Transcription

1 Hepatitis Update 2013 Brendan M. McGuire, MD UAB Liver Center

2 Introduction Hepatitis - Inflammation of the liver Five types A B C D E

3 Characteristics of Hepatitis Viruses Virus Genome Family Major mode of Transmission Chronicity HAV RNA Picornavirus Fecal - oral No HBV DNA Hepadnavirus Blood Yes HCV RNA Flaviviridae Blood Yes HDV RNA Satellite Blood Yes HEV RNA Caliciviridae? Fecal - oral No

4 Cases / 100,000 population US Incidence of Reported Cases of Acute 16 Viral Hepatitis, Hepatitis A Hepatitis C Hepatitis B Mortality Rate for acute hepatitis is approximately 0.2%

5 US Esimates of Acute & Chronic Disease Burden for Viral Hepatitis HAV HBV HCV New Infections 25,000 43,000 17,000 Chronic Infections million 3.2 million Chronic liver disease deaths/year 0 3,000 12,000 Based on CDC estimated annual incidence 2007

6 Transmission is fecal-oral Rarely transmitted by blood to blood transfer Incubation period is about 28 days Diagnosis by anti-hav IgM Hepatitis A Usually a self-limiting disease Severity of illness increases with age

7 Geographic Distribution of HAV Infection

8 Symptoms & Signs of HAV Infection Some persons, particularly young children, are asymptomatic. When symptoms are present, can include: Constitutional: fever, fatigue & joint pain Gastrointestinal: loss of appetite, nausea & emesis Hyperbilirubinemia: jaundice, dark urine & claycolored bowel movements

9 Body Fluids Concentration of HAV in Various Body Fluids Feces Serum Saliva Urine Infectious Doses per ml Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:

10 Risk Factors Associated with Reported HAV in the US ( ) Source: National Notifiable Diseases Surveillance System Unknown 45% Other 8% Personal contact 14% Food/waterborne outbreaks 4% IVD use 6% International travel 5% Daycare centers 8% Men who have sex with men 10%

11 Relative Concentration Sequence of Serologic Changes in Jaundice Symptoms Acute HAV ALT Anti-HAV HAV Stool Anti-HAV IgG Anti-HAV IgM Viremia TIME

12 Persons at Risk for Acquiring HAV Travelers to regions with intermediate or high rates of HAV Sex contacts of infected persons Household members or caregivers of infected persons Injection & non-injection illegal drug users Persons working with nonhuman primates susceptible to HAV infection

13 Prevention of HAV Hygiene Hand washing Sanitation Clean water source Immune globulin Pre-exposure Post-exposure Hepatitis A vaccine

14 HAV Prevention Immune Globulin Pre-exposure Travelers to intermediate & high HAVendemic regions without enough time for HAV vaccine Post-exposure (within 14 days) Household & other intimate contacts Selected situations in institutions & common source exposure

15 HAV Vaccine Two single-antigen vaccines are available (HAVRIX & VAQTA ) A combination vaccine, TWINRIX, contains both HAV & HBV antigens All are inactivated vaccines Schedule is 0 and 6 months Not recommended for children < 1 years old

16 Persons Currently Considered to Have an Indication for HAV Vaccine by ACIP All children ages months Travelers to countries with intermediate & high rates of disease Individuals who engage in high risk behaviors Homosexual activities Intravenous drug use Chronic liver disease Individuals with occupational risk of disease Primate handlers Advisory Committee on Immunization Practices (ACIP) Recommendations 2006

17 Advisory Committee on Immunization Practices = ACIP

18 Hepatitis B Virus (HBV) DNA virus Worldwide: 350 million infected & 620,000 die annually from HBV-related liver disease 1.2 million persons in the US with chronic HBV infection Incubation period is 120 days Causes acute & chronic disease

19 Prevalence of Chronic HBV Infection

20 Symptoms & Signs of HBV Infection Most children < 5 years old are asymptomatic % of persons > 5 years of age have signs & symptoms. Symptoms when present can include: Constitutional: fever, fatigue & joint pain Gastrointestinal: loss of appetite, nausea & emesis Hyperbilirubinemia: jaundice, dark urine & claycolored bowel movements Decompensated cirrhosis

21 Concentration of HBV in Body Fluids High Blood Serum Wound exudate Moderate Semen Vaginal fluid Saliva Low/not detectable Urine Feces Sweat Tears Breast milk

22 Reported Risk Factors for Acute HBV in the US ( ) Heterosexual activity 45% Men who have sex with men 13% Other 6% IVD use 21% Unknown 15% Other include household contact, institutionalization, hemodialysis, blood transfusion, occupational exposure Source: CDC

23 Natural History of HBV in Infants Acute HBV infection 5% 95% Recovery and immunity Chronic HBV Replication High Low Progressive liver injury Asymptomatic infection Fibrosis and cirrhosis Hepatocellular carcinoma

24 Natural History of HBV in Adults Acute HBV infection 95% 5% Recovery and immunity Chronic HBV Replication High Low Progressive liver injury Asymptomatic infection Fibrosis and cirrhosis Hepatocellular carcinoma

25 Cellular Immune Responses to HBV NEJM 2004;350:1118

26 Acute HBV with Recovery Symptoms Titer HBeAg HBsAg anti-hbe Total anti-hbc IgM anti-hbc anti-hbs Weeks after Exposure

27 Serological Markers of Acute HBV Infection Clinical Significance Early Window Recovery HBsAg HBsAb HBeAg HBeAb HBcAb IgM HBcAb IgG HBV DNA

28 Progression to Chronic HBV Infection Acute (6 months) HBeAg Chronic (Years) HBsAg anti-hbe Titer Total anti-hbc IgM anti-hbc Weeks after Exposure Years

29 Chronic HBV Disease Types HBeAg positive Also known as wild type Antibody to HBeAg is negative HBV DNA > 20,000 IU/mL (> 10 5 copies/ml) HBeAg negative Also known as precore mutant Antibody to HBeAg is positive HBV DNA > 2000 IU/mL (> 10 4 copies/ml) Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2: Chu CJ, et al. Gastroenterology. 2003;125:

30 4 Phases of Chronic HBV Current Understanding of HBV Infection HBeAg Anti-HBeAg ALT activity HBV DNA Phase Immune Tolerant Immune Clearance Inactive Carrier State Reactivation Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation Yim HJ, et al. Hepatology. 2006;43:S173-S181. Optimal treatment times

31 Hepatitis B Viral (HBV) Markers Laboratory Results HBsAg + HBsAb + HBeAg + HBeAb + Comments Active viral replication Prior exposure or immunity Active viral replication Acute or prior exposure or chronic infection HBcAb IgM + HBcAb IgG + HBV DNA + Acute or prior exposure Prior exposure Active viral replication

32 Phase Markers of Chronic HBV Infection Replicative or Reactivation Clinical Significance Low, nonreplicative, or inactive carrier Flare of chronic HBV Precore/core promotor mutants HBsAg HBsAb HBeAg + +/- +/- - HBeAb - -/+ -/+ + HBcAb IgM - - +/- - HBcAb IgG + + -/+ + HBV DNA +++ +/- ++ +

33 The Replication Cycle of HBV NEJM 2004;350:1118

34 Therapeutic Approaches to HBV Interferon Nucleoside analogues Lamivudine & Entecavir Nucloetide analogues Adefovir & Tenofovir Monoclonal antibody to HBsAg Vaccination for prevention

35 Hepatitis B Immune Globulin (HBIG) Prepared from plasma containing high titers of antibody to HBsAg Used for post-exposure prophylaxis to prevent infection from: Perinatal Sexual Occupational Must be given within 2 weeks of exposure to be effective Confers no protection against future exposure

36 Hepatitis B Vaccine Became available in All are produced with yeast & recombinant techniques to generate the HBsAg protein. Advisory Committee on Immunization Practices recommended universal vaccinations of All infants, in All adolescents, in All persons up to age 18, in 1999.

37 Adults Considered to Have an Indication for HBV Vaccine By ACIP Sexual or household contacts of people infected with HBV Multiple sexual partners IVD user Job that involves contact with blood or blood products Prisoner in a correctional facility Residents/staff in institutions for the developmentally disabled Travelers to countries with high rates of HBV HIV positive Chronic liver disease, renal failure or dialysis Unvaccinated adults with diabetes ages years

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39 HCV: RNA Genomic Organization NEJM 2001;345:41

40 Hepatitis C Virus (HCV) RNA virus 17,000 cases new annually in the US (2007) Approximately 12,000 deaths each year in the US secondary to chronic HCV

41 World Health Organization (WHO). Wkly Epid Rec.1999;74: WHO. 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. Identifying Estimated 170 Million Persons With HCV Infection Worldwide Americas 13.1 million (1.7%) Europe 8.9 million (1.03%) Africa 31.9 million (5.3%) E Mediterranean 21.3 million (4.6%) SE Asia 32.3 million (2.15%) W Pacific 62.2 million (3.9%)

42 CDC & Prevention. HCV. Available at: Accessed June 26, Institute of Medicine. Hepatitis & Liver Cancer: A National Strategy for Prevention & Control of Hepatitis B & C; Prevalence of Chronic HCV Infection In the US, million people are living with chronic HCV infection; 75% are unaware they are infected

43 Epidemiology of HCV in the US M Americans infected (2%) High prevalence rates 2.5% of males 3.2% of African Americans 2.1% of Hispanic Americans People born between

44 Individuals (n) Two-Thirds of Those With Chronic HCV in the U.S. Were Born Between 1946 & 1964 Estimated Prevalence by Age Group 1.6M 1.4M 1.2M 1M 800k 600k 400k 200K 0 < Birth Year Group Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009.

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46 Natural History of HCV Infection Acute HCV Infection (100) Recovery & Clearance of HCV (20) Chronic Infection (80) Mild (24) Moderate (32) Chronic Hepatitis Severe (24) Cirrhosis End-Stage Liver Disease Hepatocellular CA Clin Liver Dis 2005;9: Eur J Gastroenterol Hepatol 1996;8: Hepatology 2002;36(suppl):S1-S2. Hepatology 2002;36(suppl):S35-S46. Ann Intern Med 2000;132: Gastroenterology 1997;112:

47 Immunopathogenesis of HCV CD4 HCV Antigen IL-12 T-Helper Cells APC Th1 Th0 Th2 INF-g CD-4 MHC Class II TCR/CD3 IL-4 Th3 TGF-b, IL-10 IL-2, TNF-a/b, IFN-g Greater Immunopathology IL-4, IL-6, IL-6, IL-10 Lesser Immunopathology

48 Number of cases Gastroenterology 2010;138: Projected Cases of Hepatocellular Carcinoma & 160, , , ,000 Decompensated Cirrhosis Due to HCV 80,000 60,000 40,000 20,000 Decompensated cirrhosis Hepatocellular cancer Year

49 Patient Survival Rates with HCV (+) & HCV ( ) After Liver Transplantation HCV (+) HCV (-) Gastro 2002;122(4):889.

50 Risk Factors for HCV Transfusion of blood or blood products before 1992 Intravenous drug use Intranasal cocaine Hemodialysis High-risk sexual contact Tattooing or body piercing Occupational exposure to blood or blood products An organ, graft, or tissue transplant from an HCV+ donor

51 Reported Risk Factors for Acute HCV in the US, 2007 Injection drug use 48% Multiple sex partners 42% Men who have sex with men 10% Sex with someone known to have HCV -10% Risk factors are not mutually exclusive

52 Low Risk of HCV Transmission Between Monogamous Sexual Partners 776 serodiscordant spouses followed for 10 yrs Intercourse mean: 1.8/wk No condom use, no anal sex 3 new infections (incidence 0.37/1000 pt-yrs), but all 3 differed from partner s strain Net incidence of transmission: 0 Vandelli C, et al. Am J Gastroenterol. 2004;99:

53 Counseling HCV Patients Potentially infectious Keep cuts and skin lesions covered Potential for sexual transmission Potential for perinatal transmission no evidence to advise against pregnancy or breastfeeding Should not Donate blood, organs, tissue, or semen Share household articles (e.g., toothbrushes, razors)

54 Titer Typical Course for Resolution of Acute HCV Symptoms anti-hcv Normal Months Time after exposure Years ALT HCV RNA Hepatology. 2002;36:S65-S73.

55 Titer Typical Course for Chronic HCV Infection Symptoms HCV RNA anti-hcv Normal Months Time after exposure Years ALT Hepatology. 2002;36:S65-S73.

56 Enzyme Immunoassay (EIA) anti-hcv Main screening test Detects circulating antibodies 2 months after exposure Advantages are ease of use, low variability, ease of automation & relatively low expense Sensitivity is % Positive predictive value varies on prevalence 95% with risk factors & elevated ALT 50% without risk factors & normal ALT

57 Quantitative HCV RNA by PCR Important for measuring the level of circulating HCV RNA (viral load) Diagnosis within 1 to 2 weeks after exposure Evaluation of patients with false positive EIA Diagnosis of patients who fail to develop antibodies Detection limit > 12 IU/ml Hepatology. 2009;49:

58 False Negative Molecular Tests Ribonucleases are ubiquitous & makes RNA inherently unstable Serum specimens should be separated from whole blood < 4 hours of venipuncture Rapid storage of serum specimens at -70 o C Minimal freezing & thawing

59 Nucleic Acid Testing For HCV Allows very small amounts of RNA to be detected by a process of massive copying of a gene fragment. A rapid test to determine RNA in the blood. Can identify RNA in the blood 12 days after exposure. Used by organ and blood banks for identifying acute cases of HCV from donors. Transfusion 2010; 50:

60 Prevalence of HCV Genotypes & 2a 1a & 1b Subtypes in the USA 1 & 2 2b 3 4 1a (36%) 1b (39%)

61 HCV RNA (log 10 IU/mL) Patterns of Virologic Response 7 6 PegIFN alfa & RBV Null Response* 5 4 Partial Response* 3 2 Relapse 1 Undetectable RVR EVR ETR SVR *Subset of Nonresponse Wks After Start of Therapy 4 weeks - RVR: rapid virological response 12 weeks - ervr: extended RVR & EVR: early virological response weeks - ETR: end of treatment response 24 weeks after treatment - SVR: sustained virological response Hepatology 2009;49:

62 Treatment Evolution of HCV Sustained Viral Response (SVR) % % 40 34% 42% 39% % IFN 6m 16% IFN 12m IFN/RBV 6m IFN/RBV 12m Peg-IFN 12m Peg-IFN/ RBV 12m Peg-IFN/ RBV + PI 6-12m IFN: Interferon; m: months; RBV: Ribavirin; Peg: Pegylated; PI: Protease inhibitor Adapted from Strader DB et al. Hepatology 2004;39:

63 Guidelines for HCV Testing: Acute Infection Suspected Baseline HCV Ab 4-6 weeks - HCV antibody & HCV RNA 2-3 months HCV RNA If positive, consider treatment 4-6 months - HCV antibody & HCV RNA JAMA. 2007;297:

64 Spontaneous Clearance for Symptomatic Acute HCV High, Justifies Treatment Delay 60 patients with acute HCV (36 genotype 1) followed [1] Spontaneous clearance in 52% of 51 symptomatic cases No asymptomatic patient cleared virus spontaneously SVR achieved in 81% of symptomatic patients without spontaneous clearance who were treated > 3 mos after symptom onset with IFN ± RBV Recent study showed similar SVR rates in symptomatic adherent patients who delayed therapy for 12 wks vs those who received immediate treatment [2] 1. Gerlach JT, et al. Gastroenterol. 2003;125: Deterding K, et al. EASL Abstract 1047.

65 SVR (%) Randomized Trial of Treatment for Acute HCV at Variable Times After Onset 129 patients entered treatment for lack of spontaneous clearance within 8 wks of presentation 37% genotype 1 41% genotype 4 Randomized to treatment at Wk 8, 12, or 20 Treatment with pegifn alfa- 2b 1.5 µg/kg/wk x 12 wks * wks 12 wks 20 wks Time of Treatment Initiation *SVR rates significantly higher for genotype 1 patients who received treatment after 8 wks vs either 12 or 20 wks (P =.01 and P =.004, respectively). Gastroenterol. 2006;130:

66 Acute HCV Infection: Summary of Recommendations Patients with acute HCV infection should be considered for IFN-based therapy (either standard or pegifn). Treatment can be delayed 8-12 weeks after acute onset to allow for spontaneous resolution No definitive recommendation about optimal duration of treatment for acute HCV; however, it is reasonable to treat for 12 weeks, & 24 weeks may be considered Decision to use RBV made on a case-by-case basis Ghany MG, et al. Hepatology. 2009;49: