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

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

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

4. “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

5. 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)

6. “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

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

8. Viral hepatitis HAV Epidemiology Natural History Management
Presentation Diagnosis Prevention

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

10. Hepatitis A epidemiology
Source: CDC

11. 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

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

13. 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

14. Viral hepatitis HEV Epidemiology Natural History Management
Presentation Diagnosis Prevention

15. Hepatitis E epidemiology
Source: CDC

16. Hepatitis E genotype comparison
Source: CDC

17. 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

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

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

20. HBV epidemiology
>350 million carriers worldwide

21. 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

22. Acute hepatitis B management
Supportive
Monitor liver function
Fulminant hepatic failure (0.1 to 0.5%)
Management of contacts (vaccine +/- HBIG)
Follow up: 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

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

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

25. Chronic Hepatitis B Who to treat?
Nature Reviews Gastroenterology & Hepatology 8, (May 2011)
doi: /nrgastro

26. 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

27. 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

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

29. Option 1 Pegylated interferon-α 2a

30. 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

31. Hepatitis D (delta)

33. 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

34. 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

35. Viral hepatitis HCV Epidemiology Natural History Management
Presentation Diagnosis Prevention

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

38. 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 ( days) from HCV RNA detection, 10% failure to seroconvert at 9 months

39. 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

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

41. 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

42. Pegylated interferon-α 2a + RBV

43. 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

44. 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%

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

46. 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

47. 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

48. 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