The ABCDE of Viral Hepatitis Phase 2a Liver Symposium Dr Ben Stone Consultant in Infectious Diseases Sheffield Teaching Hospitals NHS Foundation Trust

Viral hepatitis HAV HBV HCV HDV ‘Δ’ HEV Epidemiology Natural History Management Presentation Diagnosis Prevention

What is “hepatitis”? Inflammation of the liver Acute Chronic time 6 months time onset

“Acute hepatitis” patient Can be asymptomatic General malaise Myalgia GI upset Abdominal pain +/- Jaundice (pale stools, dark urine) Tender hepatomegaly Raised AST, ALT (GGT, ALP) +/- Bili

Causes of acute hepatitis Infection Non-Infection Viral Alcohol Drugs Toxins / Poisoning Pregnancy Autoimmune Hereditary metabolic Hepatitis A to E Herpes viruses, e.g. EBV, CMV, VZV Non-viral Leptospirosis Toxoplasmosis Coxiella (Q fever)

“Chronic hepatitis” patient Can be asymptomatic (e.g. acute HCV infection) +/- Signs of chronic liver disease: clubbing, palmar erythema, Dupuytren’s contracture, spider naevi, etc. LFTs can be normal Compensated – liver function maintained Decompensated – jaundice, ascites, low albumin, coagulopathy, encephalopathy Complications: hepatocellular carcinoma (HCC); portal hypertension – varices, bleeding

Causes of chronic hepatitis Infection Non-Infection Hepatitis B (+/-D) Hepatitis C (Hepatitis E) Alcohol Drugs Autoimmune Hereditary metabolic

Viral hepatitis HAV Epidemiology Natural History Management Presentation Diagnosis Prevention

Hepatitis A RNA virus Commonest viral hepatitis World wide distribution Faeco-oral transmission Contaminated food or water shellfish travellers food handlers

Hepatitis A epidemiology Source: CDC

Hepatitis A: Clinical Short incubation period: 2 to 3 weeks Acute hepatitis only - no chronic disease Usually self limiting (3 to 6 weeks) very rarely causes fulminant hepatitis 100% immunity after infection

Hepatitis A serological response Total anti-HAV antibody = IgM + IgG Titre anti-HAV IgM anti-HAV IgG Exposure to HAV Time

Hepatitis A management Supportive Monitor liver function Fulminant hepatitic failure (0.35%) Management of close contacts (HNIG, vaccine) Primary prevention: vaccination (travel) Prevention – Human Normal Immunoglobulin (HNIG), within 14 days to close contacts +/or vaccine (given within 1 week); notifiable to public health

Viral hepatitis HEV Epidemiology Natural History Management Presentation Diagnosis Prevention

Hepatitis E epidemiology Source: CDC

Hepatitis E genotype comparison Source: CDC

Hepatitis E Small RNA virus Faeco-oral transmission (water or food-borne) Usually self-limiting acute hepatitis Can cause fulminant hepatitis Mortality 1-2% (pregnant women 10-20%) Chronic disease in immunosuppressed patients Serology: similar to Hepatitis A (HEV IgM, IgG) Use HEV RNA to detect chronic infection Vaccine in development

Viral hepatitis HBV HDV ‘Δ’ Epidemiology Natural History Management Presentation Diagnosis Prevention

Hepatitis B Hepadnavirus - DNA virus Transmission – blood-borne Needle stick (6-20%) Tattoos Sexual Vertical Highly infectious: <0.00004ml blood Incubation: 1 to 6 months

HBV epidemiology >350 million carriers worldwide

Hepatitis B acute serology Total anti-HB core antibody = IgM + IgG Titre anti-HB core IgM anti-HB core IgG Hepatitis B surface antigen Exposure to HBV Time

Acute hepatitis B management Supportive Monitor liver function Fulminant hepatic failure (0.1 to 0.5%) Management of contacts (vaccine +/- HBIG) Follow up: HBsAg @ 6 mths Primary prevention: vaccination (e.g. 0, 1 ,6 mths) tenofovir entecavir Prevention – super accelerated vaccine in non-immune (0,7,21 days) +/- HBIG (asap, ideally 48h, up to 1 week) if very high risk exposure +/or known vaccine non-responder; notifiable to public health

Hepatitis B: acute clearance Anti-HBs Titre HBsAg Exposure to HBV Time 6 months

Hepatitis B: failure to clear (chronic) Anti-HBs Titre HBsAg Exposure to HBV Time 6 months

Chronic Hepatitis B Who to treat? Nature Reviews Gastroenterology & Hepatology 8, 275-284 (May 2011) doi:10.1038/nrgastro.2011.33

Chronic Hepatitis B Why treat? Acute HBV infection Chronic HBV infection Spontaneous resolution* Cirrhosis Decompensated cirrhosis Hepatocellular carcinoma * risk of re-activation 95-99% 1-5% % figures for immunocompetent adults; more chronicity in immunocompromised including neonates and infants

Chronic Hepatitis B Treatment Option 1 Pegylated interferon-α 2a Option 2 Nucleos(t)ide analogues tenofovir entecavir Prevention – super accelerated vaccine in non-immune (0,7,21 days) +/- HBIG (asap, ideally 48h, up to 1 week) if very high risk exposure +/or known vaccine non-responder; notifiable to public health

Option 1 Pegylated interferon-α 2a Immunomodulatory – stimulates immune response Weekly subcutaneous injection 48 weeks Offers best chance of treatment-free control up to 30% @ 1 year (eAg+) up to 8% HBsAg loss @ 3 years Side effects & need for monitoring Stopping rules

Option 1 Pegylated interferon-α 2a

Option 2 Nucleos(t)ide analogues Inhibit viral replication One tablet once a day High barrier to resistance Minimal side effects Renal monitoring (tenofovir) May be required lifelong tenofovir entecavir

Hepatitis D (delta)

http://www.stanford.edu/group/virus/delta/2004hammon/Taxonomy_files/image003.jpg

Hepatitis D (delta) Defective RNA virus – requires presence of HBsAg Transmitted via blood and body fluids – particularly IVDUs If acquired simultaneously with HBV causes increased severity of acute infection

Chronic Hepatitis B + D Increased rate of fibrosis progression Hepatitis D usually “dominant” (HBsAg+, HBV DNA low, HDV RNA high) 30% patients respond to prolonged course of pegylated interferon-α Super-infection in patients with chronic HBV secondary acute hepatitis increases risk of fulminant hepatitis

Viral hepatitis HCV Epidemiology Natural History Management Presentation Diagnosis Prevention

Hepatitis C Flavivirus (RNA) Genotypes 1 to 6 (1 > 3 > 2,4,5,6) Transmission – Blood-borne

HCV testing Current infection Acute infection diagnosis Infection exposure: current or past Median 90 days to detection False negatives: acute infection immunosuppressed HCV antibody HCV RNA Current infection Acute infection diagnosis Delayed anti-HCV seroconversion in HIV+ - median 91 days (0-1206 days) from HCV RNA detection, 10% failure to seroconvert at 9 months

HCV natural history Acute HCV infection Chronic HCV infection Spontaneous resolution* Cirrhosis Decompensated cirrhosis Hepatocellular carcinoma 30% 70% * risk of re-infection Depending on the presence of co-factors, between 10% and 40% of patients with chronic HCV infection will develop cirrhosis [10]. Death related to the complications of cirrhosis may occur, at an incidence of approximately 4% per year, whereas HCC occurs in this population at an estimated incidence of 1–5% per year [11]. % figures for immunocompetent adults; more chronicity in immunocompromised including HIV co-infected

HCV treatment – recent “past” Pegylated interferon-α 2a/b / Ribavirin twice daily tablets

Pegylated interferon-α / RBV Genotype 2: 80% SVR* 24 weeks Genotype 3: 75% SVR* Genotype 1: 40% SVR* 48 weeks *SVR = sustained virological response = undetectable HCV RNA at 12 or 24 wks after end of treatment = cure

Pegylated interferon-α 2a + RBV

NS3/4A protease inhibitors (PIs) DAA 1st generation – G1 only: Telaprevir Boceprevir Given as “triple therapy” Genotype 1: 70% SVR* 24 or 48 weeks DAA = directly-acting antiviral

New DAA-based “triple therapy” PegIFN + RBV + simeprevir (G1&4) 24 to 48 weeks PegIFN + RBV + sofosbuvir (G1–6) NS5B inhibitor 12 weeks (PegIFN-free for G2) SVR up to 85-90%

DAA-based interferon-free Rx Ledipasvir/sofosbuvir (Harvoni®) +/- RBV (G1-6) Ledipasvir = NS5A inhibitor

DAA-based interferon-free Rx Ledipasvir/sofosbuvir (Harvoni®) +/- RBV (G1-6) Ombitasvir/paritaprevir/ritonavir (Viekirax®) +/- dasabuvir (Exviera®) +/- RBV, 12–24 wks (G1&4)* *not licensed for decompensated cirrhotics

Hepatitis C prevention No vaccine Previous infection does not confer immunity Can be re-infected Screening blood products (in UK since 1991) Lifestyle modification, e.g. needle exchanges, etc. Universal precautions handling bodily fluids

Viral hepatitis - Summary A is Acquired by mouth from Anus, is Always cleared Acutely and only ever Appears once E is Even in England and can be Eaten, if not always beaten B is Blood-Borne and if not Beaten can Be Bad B and D is DastarDly C is usually Chronic but Can be Cured – at a Cost