Viral Hepatitis

Question 1

Virology of Hepatitis C

Answer 1

• RNA virus
• Copying errors during replication → viral diversity → no vaccine, allows virus to escape host’s immune system
• Seven genotypes
  
  • Genotype 1 most common in the US and Europe
  • Genotype 3 most common in Australia, most difficult to treat with direct acting antivirals

Question 2

Examples of extra-hepatic manifestations of Hepatitis C infection

Answer 2

1. Membrano-proliferative GN
2. Porphyria cutanea tarda
3. Cryroglobulinaemia
4. Rheumatological - arthralgias
5. Sjogren’s

Hepatic complications

• Cirrhosis
• HCC

Question 3

Natural history of Hepatitis C infection e.g. outcomes

Answer 3

Question 4

Risk factors for Hepatitis C infection

Answer 4

• IVDU (inc. ever IVDU)
• Aboriginal & Torres Strait Islanders
• Migrants from high prevalence countries (Egypt, Pakistan, Mediterranean and Eastern Europe, Africa, Asia)
• People in custodial settings (prisons)
• Sex workers
• Tattoos/body piercings
• People who received blood products/organ transplant before 1990
• Babies born to HCV infected mothers (risk <1%)
• Sexual partners of HCV infected persons
• People infected with HIV or Hepatitis B
• People with evidence of liver disease
• Needlestick injury

Question 5

How to diagnose Hepatitis C

Answer 5

• Hepatitis C antibody (indicates prior exposure) - if positive test HCV RNA (indicates current infection)
• Can get false negative antibody tests in severely immunocompromised - should do HCV RNA anyway
• If +ve antibody and no RNA BUT ongoing risk → test yearly for HCV RNA

Other investigations

• HCV genotype
• HIV, Hepatitis A & B serology
• U&Es, LFTs, CBC, INR
• Evaluate for cirrhosis - ultrasound and AFP if concerns re cirrhosis
• Notify regional public health

Question 6

Methods for assessing for liver cirrhosis:

Answer 6

• Clinical features - ascites, jaundice, spider naevi
• Ultrasound features of cirrhosis or portal hypertension
• APRI score - only need AST and platelet count
  
  • Very high negative predictive value - any score <1 unlikely to be cirrhosis
• Fibroscan → assess the “stiffness” of the liver

Question 7

Principles of treatment Hepatitis C and classes of drugs used

Answer 7

• All people living with HCV should be treated
• 8-12 weeks combination therapy with duration of treatment 8-12 weeks
• Goal is sustained virological response (SVR) defined as pCR negative 12 weeks after completion date of hepatitis C therapy

Classes of drugs

• NS3 /4a protease inhibitors (can’t be used in decompensated cirrhosis)
• NS5A inhibitors
• Nucleoside polymerase inhibitors
• Non-nucleoside polymerase inhibitors
• Ribavarin

Question 8

Potential drug interactions with DAAs for Hepatitis C

Answer 8

• PPIs - reduce effectiveness, should stop or dose reduce (or dose at different time of day to Hep C therapy)
• Higher dose statins → rhabdomyolysis
• Amiodarone - can precipitate heart block
• Anti-epileptics - note cytochrome P450 interactions

Question 9

Notes on resistance-associated substitutions in Hepatitis C

Answer 9

• Most clinically significant is T93H - associated with decreased response to common DAA regiments
• Vosevi regimen effective in many with resistant mutations

Question 10

Notes on hepatitis C with decompensated cirrhosis

Answer 10

• Require specialist assessment
• Genotype 3 cirrhotics - most challenging population to treat
• Protease inhibitors relatively contraindicated
• Risk of liver failure
• Consider transplant referral.

Question 11

Non-pharmacological principles of Hepatitis C management

Answer 11

• Address IVDU if present
• Counsel re transmission risk
• Avoid factors that accelerate liver disease → avoid alcohol, weight loss if obese, cessation of cigarette and marijauna smoking
• 2-3 cups of coffee a day apparently reduced risk of hospitalisation & mortality in CLDs (inc. chronic viral hepatitis, alcoholic liver disease and NASH)
• Dose adjust medications e.g. 2g paracetamol/day if liver disease, avoid NSAIDs, statins probable ok
• Vaccination → hepatitis A and B if not immune, pneumococcal vaccine if CLD
• Monitor for cirrhosis: If cirrhosis present → needs monitoring for varices and 6 monthly ultrasound for HCC

Question 12

Significance of Hepatitis C treatment and hepatitis B infection:

Answer 12

• Risk of hepatitis B reactivation during treatment for Hep C
• Hep BsAg positive - check PCR at baseline and treat if meet criteria
• Hep B cAb positive: check LFTs week 4-8 and test PCR if increase

Question 13

Notes on vertical transmission of Hepatitis C infection:

Answer 13

• Risk if 5% in HCV monoinfected women, 10% if HIV co-inection
• Risk factors for vertical transmission:
  
  • High HCV viral load
  • IVDU
  • Prolonged rupture of membranes and obstetrics procedures
• Factors not associated with vertical transmission:
  
  • Viral genotype
  • Mode of delivery (have have vaginal delivery)
  • Breastfeeding → viral RNA passed in breast milk but no disease transmission
• Note DAA safety not assessed in pregnancy → women should be counselled to avoid pregnancy prior to starting DAA therapy
• Testing for HCV antibodies immediately after birth can lead to false positive → test at 15-18 months

Question 14

At risk individuals who should be tested for Hepatitis B

Answer 14

• People born in Asia, Africa, Middle East, Pacific Islanders Eastern and Southern Europe
• Aboriginal and Torres Strait Islanders
• Maori
• Pregnant women
• MSM
• Sex workers
• Haemodialysis patients
• IVDU
• People with another STI, hepatitis C or HIV
• Sexual, household contacts and family members of a positive case
• Everyone prior to receiving immunosuppressive therapy or chemotherapy
• People with elevated ALT/AST of unknown aetiology

Question 15

Transmission of HBV infection

Answer 15

• Vertical/perinatal → most common
  
  • HBeAg +/- high HBV viral load → increases risk of vaginal transmission
  • No protective effect C section, breast feeding does not increase risk
• Horizontal → skin, mucosal breaks, schoolchildren
• Sexually acquired
• Percutaneous → IVDU, tattoos, acupuncture, body piercing, household inc. toothbrush, razors
• Blood transfusion/medically acquired/nosocomial
  
  • Surgery, dentistry, dialysis, finger pricks

Question 16

Notes on Hepatitis B disease progression

Answer 16

• Can cause HCC without cirrhosis

Question 17

Notes on HBV structure

Answer 17

• DNA virus - incoorporated into genome - not currently curable
• Partially double stranded
• Surrounded by nucleocapsis = core antigen
  
  • Positive core antigen = exposure to Hepatitis B
• Surrounded by envelope - Hepatitis B surface antigen
• E antigen = surface antigen = highly infectious

Question 18

Tests to order when hepatitis B suspected

Answer 18

• Generally don’t routinely order genotypes
  
  • A& B → better response to pegylated interferon
  • C & D → generally more severe disease and more likely to progress to cirrhosis

Question 19

Interpreting results of Hepatitis B tests

Answer 19

HbsAg negative, anti-HBc positive, anti-HBs negative

• Distant quiescent HBV infection → most common scenario, especially in people born in HBV endemic areas
• False positive result
• Resolving acute HBV infection
• Occult HBV infection

If HepB sAg positive → refer to speciality clinic → HBV DNA and markers of liver disease

If Hep B cAb positive → risk of reactivation with immunosuppression

If all negative immunise

Question 20

Risk factors for progression of Hepatitis B

Answer 20

• Male
• Family history HCC
• Co-infection with HDV
• >45 years
• Co-infection with HIV, HCV
• Cirrhosis
• Long duration of infection
• Heavy alcohol intake (>40-50g daily)

Question 21

Initial assessment of patients with chronic HBV infection (known HBsAg positive)

Answer 21

Viral markers

• Hepatitis B e-antigen (HBeAg); anti-HBe
• Serum hepatitis B virus DNA (HBV DNA)
• Hepatitis A IgG, Hepatitis C Ab, anti-HDV, anti-HIV

Markers of liver disease

• Liver enzymes - ALT, AST
• Liver function → bilirubin, albumin, INR
• AFP

Imaging

• Ultrasound
• Assessment of fibrosis
  
  • Transient elastography (Fibroscan) most common → does not give cause of fibrosis, good to determine normal liver and cirrhosis, reduced need for liver biopsy, non-invasive, simple and quick. CAP score can identify those that need NASH management (concimitant NASH and Hep B → more advanced fibrosis and shorter time to development of HCC and death)

Question 22

Notes on APRI score and Fib-4 score in Hepatitis B

Answer 22

May be used to exclude presence of cirrhosis in settings where Fibroscan not available

APRI

AST to platelet ratio index → high negative predictive value → any score <1 unlikely to be cirrhosis

65% sensitivity, 75% specificity

Fib-4 score

Uses age, AST, ALT and platelets

Question 23

Phases of Hepatitis B

Answer 23

Question 24

Management of HbeAg positive patients

Answer 24

Question 25

Management of HbeAg negative patients

Answer 25

Question 26

Monitoring in Hepatitis B and frequency

Answer 26

Question 27

Aims of Hepatitis B treatment

Answer 27

• Achieve sustained suppression of viral replication
• Limit liver damage due to immune-mediated inflammation and fibrosis
• Achieve HBeAg seroconversion in HbeAg positive patients
• Achieve HBsAg loss/seroconversion (functional cure) → rare
• Reduce risk of progession to cirrhosis and HCC
• Reduce morbidity and mortality
• Minimise toxicity, minimise resistance, maximise adherence

Question 28

Treatment options for Hepatitis B

Answer 28

First line oral antivirals

• Entecavir → possible increased risk lactic acidosis. Avoid if previously developed resistance to lamivudine.
• Tenofovir fumarate (TDF) → renal toxicity, bone mineral density loss
• Tenofovir alafenamide (not on PBS)
• Generally held to be equivalent

50-75% reduction in HCC risk over 5 years

• Cost effective cancer prevention intervention
• Virological suppression common. HBsAg seroconversion rare.
• Indefinite treatment. Adherence important

Question 29

Pegylated interferon vs oral antivirals in hepatitis B

Answer 29

Question 30

HCC surveillence in chronic hepatitis B

Answer 30

Groups at increased risk HCC

• Cirrhosis
• Anyone with a first degree relative
• Asian men > 40, Asian women > 50
• ATSI > 50 years
• African men and women >20 years

Surveillence

• Ultrasound +/- AFP every 6 months

Question 31

Notes on management Hepatitis B in pregnancy

Answer 31

• TDF (tenofovir) → 3 rd trimester with vaccination and HBIG → significantly lower mother-to-child transmission of HBV than vaccination and HBIG alone
• Threshold → HBV viral load in 2nd trimester 10 million IU/ml generally used
• Mother to infant transmission high as 90% if baby does not receive HBIG within 12 hours and vaccination at birth (3 courses) → reduces up to 95% perinatal infection

Question 32

Notes on co-infection hepatitis b

Answer 32

Hepatitis B/D

• 5% of all people with chronic HBV in Australia - PEG-IFN
• HBV/HCV → HBsAg positive may flare post HCV treatment

Question 33

Notes on hepatitis D

Answer 33

• Smallest virus known to infect himans → 71% cases born overseas in endemic areas
  
  • Found in 20% HBsAg positive NZ of Pacific Island ethnicity
• Defective virus → requires presence of Hepatitis B to fully express pathogenicity (needs HBsAg to replicate)
• HBV nucleoside treatment does not treat HDV as sAg remains
• Infection varies from benign acute hepatitis to fulminant hepatitis
  
  • Can be most aggressive hepatitis virus
• Ranges from asymptomatic carrier state to rapidly progressive chronic liver disease
• Diagnosis
  
  • HDC sAg and sAb
  • HDV viral load

Question 34

Risk of reactivation Hepatitis B according to therapy

Answer 34

Most risky → least risky

• Stem cell and solid organ transplant
• B-cell depleting agents → rituximab, ofatumumab, ustekinumab, natalizumab, alemtuzumab
• Corticosteroids
• Local therapy for HCC
• TNF-alpha inhibitors → infliximab, adalimumab, certolizumab, golimumab, etanercept
• Systemic chemo
• Antimetabolites, azathioprine, 6MP, methotrexate

Management

• Treat everyone who is HbsAg positive
• HBsAg negative but core positive and higher risk e.g. stem cell transplant, B cell depleting agents, active leukaemia or high grade lymphoma → treat
• If core positive and lower risk chemo no treatment required