Hepatitis A, B, and Mostly C

Transcription

1 Hepatitis A, B, and Mostly C Blaire E Burman, MD Virginia Mason Gastroenterology & Hepatology

2 Leaning Objectives Burden of viral hepatitis Hepatitis A A little bit about hepatitis E Hepatitis B Hepatitis C 2

3 Viral Hepatitis Scope of Disease 500 million people have chronic viral hepatits globally 6-10 million newly infected per year 1.4 million die each year from viral hepatitis 60% of cirrhosis and 80% of primary liver cancer cases are related to viral hepatitis Disease Prevalence Worldwide US HIV 31 million 860,000 HBV (chronic) 300 million 1 million HCV (chronic) 170 million 4 million 3

4 Viral Hepatitis A virus that has a particular tropism for hepatocytes and replicates in liver cells In contrast, viruses such as EBV and CMV cause liver inflammation but cause systemic inflammation as well All hepatitis viruses can cause acute hepatitis; types B and C can cause chronic hepatitis. Symptoms of acute viral hepatitis include flu-like symptoms, fatigue, jaundice, dark urine, light-colored stools; rarely, acute hepatitis causes liver failure Symptoms of chronic viral hepatitis often are mild and nonspecific, and diagnosis is often is delayed 4

5 Differences in Hepatitis A, B, C How they are transmitted Whether they cause chronic infection Treatment Vaccination 5

6 Alphabet Soup Transmission Causative Agent Chronic liver disease Vaccine Treatment A Fecal-oral Picornaviridae ssrna No Inactivated virus None required B Parenteral Sexual Hepadnaviridae dsdna Yes Recombinant Case by case Not curative C Parenteral Filloviridae ssrna Yes None Curative D Parenteral HBV co-infection Deltaviridae ssrna Yes HBV vaccine Interferon E Fecal-oral Calciviridae ssrna No Not available in US None required 6

7 Hepatitis A Causes mild to severe acute illness Epidemics can be explosive and costly Risk of hep A associated with lack of safe water, poor sanitation, and hygiene Transmitted through ingestion of contaminated food and water or direct contact with infected person Almost everyone fully recovers from hep A and develops lifelong immunity Safe and effective vaccine available 7

8 Case #1 Pete is a 34 yo man who develops malaise, diarrhea, nausea, and jaundice, and symptoms have persisted for a week Several of his friends who shared a Mexican meal 3 weeks ago are also ill 8

9 Hepatitis A In 2003, 555 cases of acute HAV occurred in a small town in Pennsylvania All linked to a Mexican restaurant Mean age 34 22% hospitalized;3 deaths Average 27 days of missed work Cases Mild salsa 94% 39% Child con queso 15% 3% Controls In 2016, multistate outbreak linked to frozen strawberries imported from Egypt 9

10 Hepatitis A Diagnosis? HAV-specific IgM antibodies Treatment? None. Supportive care and recovery over weeks to months Prevention? Sanitation, food safety, and immunization 10

11 HAV Vaccination 2 doses given 6 months apart All children at age 1 year Travelers to (endemic) countries that have high rates of hep A Men who have sexual contact with other men Injection drug users People with chronic liver disease People with clotting factor disorders 11

12 What about hepatitis E? Usually self-limited acute infection, though some cases may develop into acute liver failure Fecal-oral transmission, principally contaminated water Found worldwide but highest prevalence in Mexico, Africa, East and SE Asia 20 mill infections worldwide, 3.3 mill symptomatic cases, and 60,000 deaths per year 12

13 What about hepatitis E? Typical symptoms of acute hepatitis, last 1-6 weeks Acute HEV can be severe and fatal during pregnancy (25% case fatality rate with 3 rd T transmission) Chronic HEV can occur in immune suppressed, in particular transplant patients Diagnosis? IgM antibodies, RNA testing of blood/stool Treatment? Usually not necessary ribavirin if chronic Prevention? Water safety, sanitation, hygiene; vaccine available only in China 13

14 Chronic Viral Hepatitis (B and C) What percent of patients with chronic viral hepatitis will develop cirrhosis? A. 5% B. 25% C. 50% D. 75% 14

15 Why does this matter? About 25% of people with chronic hepatitis develop cirrhosis HCV remains the #1 indication for liver transplant About 3% of people with cirrhosis develop liver cancer (HCC) each year Rising incidence of HCC related to aging of HCVinfected patients and NASH epidemic 15

16 Hepatitis B Talking Points Natural history Diagnosis Management case based Prevention 16

17 Outcomes of HBV Infection Acute liver failure 2% Acute HBV infection Chronic HBV infection 5% adult 95% vertical 20% Progressive liver injury Risk of infection after needlestick exposure: HIV: 1 in 300 HCV: 1 in 30 HBV: 1 in 3 Cirrhosis HCC Death of Transplant 17

18 Diagnosis Case 27 yo woman presents to urgent care with new onset nausea and jaundice. Pt has been regularly injecting crystal methamphetamine, and 6 weeks ago she shared needles. Two years ago, she had negative antibody tests for hepatitis A, B, and C, but did not return for follow-up and vaccinations. Labs: total bilirubin 6.8 mg/dl, AST 1,906 U/L, and ALT 2,086 U/L. 18

19 Diagnosis Case Which of the following serologic profiles would be most consistent with acute HBV infection? A. HBsAg (-), anti-hbs (+), Total anti-hbc (+), HBeAg (-), anti-hbe (+) B. HBsAg (+), anti-hbs (-), Total anti-hbc (-), HBeAg (-), anti-hbe (+) C. HBsAg (+), anti-hbs (-), Total anti-hbc (+), HBeAg (+), anti-hbe (-) D. HBsAg (-), anti-hbs (+), Total anti-hbc (-), HBeAg (-), anti-hbe (-) 19

20 Diagnosis Case Which of the following serologic profiles would be most consistent with acute HBV infection? A. HBsAg (-), anti-hbs (+), Total anti-hbc (+), HBeAg (-), anti-hbe (+) Self-limited, cleared B. HBsAg (+), anti-hbs (-), Total anti-hbc (-), HBeAg (-), anti-hbe (+) Chronic infection C. HBsAg (+), anti-hbs (-), Total anti-hbc (+), HBeAg (+), anti-hbe (-) Acute or chronic send anti-hbc IgM D. HBsAg (-), anti-hbs (+), Total anti-hbc (-), HBeAg (-), anti-hbe (-) Vaccinated 20

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23 Natural History Case A 32-year-old Chinese American woman whose mother was born in China presents to clinic. Her mother was recently informed she had chronic hepatitis B, so the patient asks to be tested for HBV: Hepatitis B surface antigen (HBsAg): positive Hepatitis B core antibody (total anti-hbc): positive Hepatitis B core antibody (IgM anti-hbc): negative Hepatitis B surface antibody (anti-hbs): negative Hepatitis e antigen (HBeAg): positive Hepatitis e antibody (anti-hbe): negative HBV DNA: 1.1 x 10 7 IU/ml Alanine aminotransferase (ALT): 16 U/L (normal = less than 19 U/L in women) The provider elects to measure repeat aminotransferase levels in 3 months. At that point, both the ALT and the AST are within the normal range. 23

24 What is the phase of HBV infection and what should be done? A. The patient has acute HBV infection and she should be followed closely to see if chronic infection develops. B. The patient is in the immune tolerant phase and should be followed on a regular basis with ALT levels every 3 to 6 months. C. The patient has evidence of hepatic inflammation and is in the immune active phase of chronic viral hepatitis; she should immediately start on therapy for HBV. D. The patient is in the inactive chronic carrier phase and she does not need evaluation again unless she develops an increase in ALT and AST. 24

25 What is the phase of HBV infection and what should be done? A. The patient is in the immune tolerant phase and should be followed on a regular basis with ALT levels every 3 to 6 months. 25

26 Phases of Chronic HBV Infection 26

27 Approach to HBsAg-positive Patients Complete HBV serologic profile (eag, eab) HBV DNA level Liver enzymes and liver function panel HIV, HAV, HCV screen Alcohol and fatty liver screen Need for HCC screening? 27

28 Who should be referred? eag positive patients High liver enzymes High viral loads Inactive carriers that need reassurance Suspect fibrosis or cirrhosis Pregnancy HIV or HCV co-infection 28

29 What to tell patients about treatment Not every patient needs to be treated Treatment controls disease, but does not cure disease Treatment is easy with few side effects Most people will need treatment long term Medication adherence is important 29

30 Who should be treated? AASLD recommendations: Advanced fibrosis or cirrhosis Immune active eag+ with ALT 2X normal and DNA > 20,000 IU/mL eag- with ALT 2X normal and DNA > 2,000 ALT elevations should be persistent over 3-6 mo Older age, family hx of HCC, extrahepatic complications 30

31 HBV Antivirals Vemlidy! 31

32 Who should be vaccinated for HBV? All children Household / sexual contacts Healthcare workers Dialysis patients Chronic liver disease patients International travelers IVDU MSM or multiple sexual partners Prisoners 32

33 Vaccination Question Your patient who is a 54 yo nurse is non-immune to hepatitis B so you vaccinate her. A post-vaccination titer is undetectable. What should you do next? A. Give a fourth shot and check a titer B. Give another 3 shot series and check a titer C. Vaccinate with TwinRx the next time around D. Tell her to get HBIG in case of a needlestick E. B, C, and D are all correct 33

34 Hep B Vaccine Non-Responders 5-15% of persons may not respond to HBV vaccination Post-vaccination titer testing is not routine except for infants born to HBVinfected mothers, immune-compromised persons, healthcare workers, sexual partners of HBV-infected persons For adults, titer should be drawn 1-2 months after completing series For infants, test 3-9 months after Persons who do not respond to initial 3-dose series have a 30-50% chance of responding to second Non-responders should be considered susceptible to infection and counseled about precautions, and need HBIG ppx for any probable exposures, then restart vaccine series ASAP 34

35 Chronic Hepatitis C Update 2017 and Beyond 35

36 What you should know about HCV How big is this problem? How do we evaluate patients with HCV? What treatment options are currently available? How about the future? Will HCV be managed by primary care? Eradicated? 36

37 Burden of Chronic Hepatitis C (HCV) Chronic HCV affects over 185 million worldwide Substantial geographic variability United States prevalence estimated at ~3 million Based on most recent NHANES data Accounting for high risk populations, >5 million people are HCV-infected 2% overall population prevalence Majority infected in 1960s through 1980s prevalence among baby boomers 3.5% 2014 Virginia Mason

38 Prevalence of Chronic Active HCV Up to 5 Million Persons Living with Chronic HCV Unware 50% Aware 50%

39 HCV: What s the Big Deal? While incidence has declined, rates of more advanced HCV liver disease and associated healthcare costs are rising - WHY? Population most affected is aging Progressive liver disease and co-morbid conditions 2-fold increase in cases of HCV cirrhosis 30% risk of cirrhosis over time 5% risk of hepatic decompensation and ESLD per year Leading indication for liver transplant in the US 3-fold increase in hepatocellular carcinoma HCC is the fastest growing cancer in the US 75% of HCC cases are associated with HCV 3-5% annual risk of HCC once bridging fibrosis established Projected cases of decompensated cirrhosis, liver cancer, and death are projected to continue to increase through Virginia Mason

40 HCV Incidence New HCV Cases Alarming Facts After years of declining incidence, identification of rising incidence ,000 acute cases occurring annually, majority not diagnosed Most significant rise among young adults aged 18-29, with a 200% overall increase Crossover opiate heroin epidemics Non-urban white youth highest rates 40

41 Improving HCV outcomes and preventing associated morbidity and mortality starts with screening and referral for care 2014 Virginia Mason

42 Who should be Screened for HCV? Probably everyone ER based screening Definitely baby boomers Universal 1-time screening of baby boomers has been endorsed by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force as of 2013 Definitely patients with risk factors: any history of IVDU, incarceration, percutaneous exposure, blood transfusion before 1992, hemodialysis, HIV/HBV 42

43 Case 1: HCV antibody positive You see your 63 yo male diabetic patient Larry in follow up. He saw a commercial for Harvoni and requests screening. HCV antibody is positive. What next? A. This confirms active infection, refer to hepatology B. Send a HCV viral load and genotype C. Assume false positive given lack of risk factors D. Send for liver biopsy 43

44 Case 1 A. This confirms active infection, refer to hepatology 25% of cases HCV is cleared spontaneously and no chronic infection B. Send a HCV viral load and genotype Very helpful! C. Assume false positive given lack of risk factors Forgot about the lost day at college in Berkley in 1972, and that hidden tattoo, and that blood transfusion in 1988 D. Send for liver biopsy There are better options! 44

45 HCV Genotypes in the US Genotype All others 45

46 Genotype Worldwide 46

47 HCV Initial Evaluation Patient education and counseling Transmission, natural history, complications Determine duration of infection and co-factors for fibrosis progression Age, gender, alcohol use, NAFLD (BMI, DMII, metabolic syndrome) Rule out viral co-infections (HIV, HBV); assess immunity and vaccinate (HAV, HBV) Establish genotype, sub-genotype, and baseline viral load Identify disease activity and stage Activity = inflammation Stage = degree of fibrosis 2014 Virginia Mason

48 HCV Evaluation: Staging Staging underlies all HCV management and is the most critical aspect of clinical evaluation Liver biopsy has long been the gold standard but has many disadvantages FibroScan is our standard of care Performed in <10 minutes, non-invasive, painless Accurate point-of-care results allows for decision making during clinical visits Less reliable for lower degrees of fibrosis (F1-F2) Often not possible with obesity or ascites Can incur $300 out-of-pocket fee Interpretation is liver-disease specific Alternatives: HCV FibroSure, APRI score 2014 Virginia Mason

49 2014 Virginia Mason FibroScan Scorecard

50 When to biopsy? Rarely Unable to obtain accurate FibroScan score (obesity) Concern for overlap with NASH, alcohol, iron overload 50

51 Management of Advanced Fibrosis If bridging fibrosis or cirrhosis (F3-4): Determine timely treatment plan Which medication and for how long? Process of waiting for approval Screen for complications of cirrhosis and portal hypertension Upper endoscopy to identify and treat varices Assess hepatic synthetic function, renal function, etc Manage co-factors for disease progression Identify need for transplant referral (ie: MELD >16) Initiate HCC surveillance program 2014 Virginia Mason

52 Benefits of HCV Therapy Eradication of HCV virus confers: Halted progression of liver disease Prevention of hepatic decompensation Potential reversal of fibrosis; improvement in synthetic function Reduced liver-related morbidity and mortality Lower but not eliminated risk of HCC Reduced all-cause mortality CVD, DMII Enhanced quality of life Less fatigue, improved depression scores, piece of mind 2014 Virginia Mason

53 Who Should be Treated NOW? Highest Priority Owing to Highest Risk for Severe Complications Advanced fibrosis (F3) or compensated cirrhosis (F4) Organ transplant, pre- or post Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations Proteinuria, nephrotic syndrome, membranoproliferative glomerulonephritis High Priority Owing to High Risk for Complications Presence of fibrosis (Metavir F2) HBV or HIV-1 co-infection Other coexistent liver disease (eg, NASH) Type 2 Diabetes mellitus (insulin resistant) Debilitating fatigue Porphyria cutanea tarda 2014 Virginia Mason

54 Other Treatment Considerations Persons At Elevated Risk of HCV Transmission (in whom treatment may yield transmission reduction benefits) Active injection drug users Incarcerated persons MSM with high-risk sexual practices Women of child-bearing potential wishing to get pregnant Factors associated with Fibrosis Progression Older age at time of infection Male sex Alcohol consumption NAFLD, Obesity, Insulin resistance Genotype 3 Post-organ transplant 2014 Virginia Mason

55 HCV Therapy

56 HCV: Major progress! HCV Cure Rates (% SVR) Virginia Mason

57 2014 Virginia Mason HCV Genome and Potential Drug Targets

58 Basics of HCV Treatment What do I need to know? HCV genotype Baseline HCV viral load Prior treatment experience Cirrhotic or non-cirrhotic if cirrhotic, Child A, B, or C Renal failure Concurrent HBV or HIV Current medication, herb, supplement list 2014 Virginia Mason

59 Case 1 continued Larry s PCP sent further labs and he was found to have genotype 1a with an HCV viral load of 7,562,803 IU/mL. He is sent to hepatology clinic for treatment evaluation. Labs: AST 65, ALT 124, total bili 1.2, albumin 4.1, INR 1.1, creatinine 0.8, platelet count 135,000 HBV non-immune, HIV negative Ultrasound: Normal appearing liver and spleen FibroScan: 13.5 kpa What are his treatment options? 2014 Virginia Mason

60 Genotype 1 Regimens HCV Genotype 1: Recommended Regimens and Estimated Cost Elbasvir-Grazoprevir (Zepatier) x 12 weeks $54,600 Elbasvir-Grazoprevir (Zepatier) x 16 weeks $72,800 Ledipasvir-Sofosbuvir (Harvoni) x 8 weeks $66,000 Ledipasvir-Sofosbuvir (Harvoni) x 12 weeks $94,500 Ledipasvir-Sofosbuvir (Harvoni) x 24 weeks $189,000 Ombitasvir-Paritaprevir-Ritonavir+Dasabuvir (Viekira) x 12 weeks $84,000 Sofosbuvir-Velpatasvir x 12 weeks $74,760 Sofosbuvir + daclatasvir x 12 weeks $147,000 Sofosbuvir + Simeprevir x 12 weeks` $150, Virginia Mason

61 Genotype 1 HCV AASLD-IDSA Guidelines For initial therapy of treatment-naive genotype 1a patients with compensated cirrhosis, three 12-week regimens with similar efficacy are recommended: (a) elbasvir-grazoprevir (Zepatier) with resistance testing (b) ledipasvir-sofosbuvir (Harvoni), (c) sofosbuvir-velpatasvir (Epclusa) Larry s insurance company denies Zepatier but approves 8 weeks of Harvoni 2014 Virginia Mason

62 Appeal! Insurance companies have HCV formularies and preferred medications They should NOT dictate your care 8 weeks of Harvoni is only appropriate for patients who are treatment naïve, non-cirrhotic, with HCV VL < 6 million Patient starts on 12 weeks of Harvoni. What can you expect? How do you monitor treatment? 2014 Virginia Mason

63 Treatment Monitoring Review med list stop PPIs (if possible), herbs, supplements Routine blood work and HCV viral load at week 4 and week 12 Anticipate mild side effects: 20% rate of fatigue, headache, nausea Repeat viral load 12 weeks after completing therapy = sustained virologic response (SVR) = cure If early stage, no follow up needed HCV antibodies will always be positive; NOT immune to re-infection If cirrhosis: ongoing monitoring, lifelong liver cancer surveillance 2014 Virginia Mason

64 What about genotype 2-6? Velpatasvir is a pan-genotypic NS5A inhibitor Sofosbuvir - Velpatasvir (Epclusa) is the standard of care for genotype % SVR for genotype 2-95% SVR for genotype 3 Sofosbuvir + Daclatasvir is also approved for genotype 2-3 Consider resistance testing (Y93H) and add ribavirin if positive 2014 Virginia Mason

65 ASTRAL-3 Trial: Epclusa for Genotype Virginia Mason

66 HCV Treatment Pipeline MOST HCV patient can be cured with current options A minority of patients remain difficult to cure and for this patient population, further R&D is needed Salvage regimens for DAA treatment failures likely to be approved in 2017 Voxilaprevir (NS3/4A) + Sofosbuvir Velpatasvir Glecaprevir (ABT-493) + Pibrentasvir (ABT-530) x 8-12 weeks MK-3682+MK-8408 (2 nd gen NS5A) 2014 Virginia Mason

67 HCV Therapy Remaining challenges? Difficult to treat and cure populations? End-stage renal disease (non-genotype 1) Resistance-associated variants (RAVs) Decompensated cirrhosis Pre-transplant Active substance abuse Lack of screening and referral Cost of treatment and insurance approval 67

68 Cascade of Care 68

69 Virginia Mason HCV Treatment Clinic Hepatitis C Treatment Clinic launched 2014 Blaire E Burman, MD, Clinic Director Asma Siddique, MD, Hepatology Alex Kuo, MD, Hepatology Houghton Lee, RN, Hepatology Weekly clinic aiming to provide: Diagnosis, comprehensive evaluation, staging, and liver disease management Focus on patient education and advocacy Timely access to therapy: #1 prescriber of HCV meds in the state Immediate access to clinical research trials To refer a patient or for more information, call GI/Hepatology at (206)

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