GI & Hepatology JC057: I Am A Hepatitis B Carrier Flashcards
Hepatitis B structure
Structure of virion (Dane particle)
- 42 nm (tiny)
- Circular surface
- Hexagonal core (HBcAg)
- Double-stranded DNA, long Minus strand, short Plus strand
- Excessive HBsAg in Circular (22nm) / Tubular form
Hepatitis B molecular virology
- smallest DNA virus
- approx. 3,200 nucleotides
- overlapping ***open reading frame for “economical” manufacture of proteins
- regulatory sequences within the genes, i.e. nucleotide both encode for proteins + regulate their production e.g. Glucocorticoid responsive element (GRE), Enhancer (enhance replication of virus)
Proteins + Regulatory sequences
- Gene S
- produces HBsAg - Pre-S2
- encodes polyalbumin-binding sites
- encodes peptides ***binding to cell surface receptors —> allow virus to enter host cell
- Pre-S2 + S produces “middle” protein - Pre-S1
- encodes peptides ***recognised by cell surface receptors for HBV
- Pre-S1 + Pre-S2 + S produces “large” protein
3 different types of HBsAg:
1. Pure S
2. Middle protein (Pre-S2 + S)
3. Large protein (Pre-S1 + Pre-S2 + S)
- Role in hepatocarcinogenesis of pre-S1 / S2 uncertain (probable)
- Gene C
- encodes HBcAg
- HBcAg found inside virus / hepatocytes, **NOT in serum (∴ can only detect Ab against HBcAg but not HBcAg itself)
- **HBeAg, its “derivative” —> secreted in serum (can be detected) - Pre-C
- 1st 19 a.a. constitutes signal peptide to change Pre-core to **HBeAg via ER, Golgi —> secreted in serum (can be detected)
- Mutant strain (Pre-C mutation) with stop codon (TAG) causes inability to produce HBeAg —> even when virus is replicating, but cannot detect level of HBeAg
- Mutant strain exist around **e-seroconversion ∵ host immune response act against HBeAg —> select for mutant strains which does not produce HBeAg —> HBeAg-deficient mutants emerge —> so host immune response cannot recognise virus, virus can reproduce without attacked by host immune response
- IMPORTANT: patients with be HBeAg -ve, **Anti-HBe +ve, HBV DNA +ve —> but virus still replicating: “*False e-seroconversion”
- among Anti-HBe patients, >90% in Mediterranean countries, ~55% in HK, China, TW - Gene P
- encodes **polymerase (exactly identical to RT) + **reverse transcriptase (RT)
- overlap with most reading frames - Glucocorticoid responsive element
- regulates the “Enhancer” and is stimulated by **steroid (i.e. Steroid stimulates replication of HBV)
—> **Enhancer 1 stimulates **protein expression (esp. **Core protein) - Enhancer 2
- stimulates ***Surface gene promoters - Region X
- encodes products for ***transactivation (activate adjacent genes when incorporated into host DNA)
- ?related to carcinogenesis (e.g. insert near oncogene) - Direct repeat 1 (DR1)
- 11 nucleotides (exactly same as DR2), initiates **long strand synthesis
- together with DR2 are preferential sites for **integration into host DNA
(NB DR1, 2 coincide with Region X) - Direct repeat 2 (DR2)
- 11 nucleotides (exactly same as DR1), initiates ***short strand synthesis
***Replication of HBV
Virion envelop surrounds nucleocapsid which contains:
- ***Relaxed circular HBV DNA
—> partially double-stranded
—> Minus strand: full length
—> Plus strand: variable length
Process:
- Entrance of virus by Adsorption via cell surface receptors
—> release of relaxed circular HBV DNA
—> **completion of Plus strand DNA (complete double-stranded circular DNA / cccDNA)
—> transport to nucleus
—> conversion of relaxed circular DNA to **supercoiled covalently closed circular DNA (cccDNA) exclusively inside the **nucleus of hepatocytes (make virus very hard to be attacked directly)
—> transcription of **4 mRNA classes including **“pregenomic mRNA” of greater than one unit length of virus
—> mRNA transportation to cytoplasm
—> cytoplasmic mRNA translated into **viral proteins (e.g. HBsAg, HBcAg) (which hide inside ER)
—> pregenomic mRNA translated to form **HBV DNA polymerase (DNA pol) / reverse transcriptase (RT)
—> **encapsidation of DNA pol bound to pregenomic mRNA
—> reverse transcription of pregenomic mRNA to produce full length Minus strand DNA (造翻d viral DNA出黎)
—> Plus strand DNA synthesis by HBV DNA polymerase (RT act as DNA pol as well)
—> partially double-stranded relaxed circular DNA
—>
1. migration to ER to collect viral proteins (e.g. HBsAg, HBcAg)
—> forms whole virion
—> acquisition of envelops
—> exocytosis
- Migration to nucleus and completion of Plus strand DNA
—> cccDNA
—> amplification / replenishment of cccDNA
—> whole reproductive process all over again
—> virion multiply rapidly
cccDNA:
- 10-50 copies per cell
- no. of copies probably regulated by viral envelop protein(s)
- no direct replication (only replicates when form pregenomic mRNA) + hide inside nucleus —> ∴ difficult to attack cccDNA
簡單而言:
Transport to nucleus
—> relaxed circular HBV DNA conversion to cccDNA
—> transcription of mRNA
—> some mRNA form HBsAg, HBcAG
—> pregenomic RNA encapsidated in cytoplasm
—> formation of Minus-strand HBV DNA by RT
—> formation of Plus-strand HBV DNA by DNA pol
—> double-stranded DNA acquires HBsAg —> exocytosis
OR
—> double-stranded DNA replenishes cccDNA
Epidemiology of HBV
- 257 million chronic HBV carrier
- ***75% Chinese
- high prevalence in China, Africa, Australia
- estimated HBsAg carrier in China: 83,864,139
- **very low prevalence in younger subjects currently (∵ **vaccination at birth)
Transmission of HBV
***Parenteral only (i.e. ∵ at least require mucosal breach —> saliva cannot transmit HBV)
- At birth
- Early postnatal period
- Playmates
- Needles: IV addicts, Acupuncture (disposable needles now), Tattoo
- Sexual contact
- Other instruments e.g. toothbrushes, razors
HBsAg +ve mothers
—> HBsAg +ve infants (50%) (father can also transmit to infants)
—> Daughters
—> becomes HBsAg +ve mothers
—> transmit to next generation
—> 14% HBsAg +ve mothers die of liver death (cirrhosis / liver cancer)
—> Sons
—> 50% die of liver death (cirrhosis / liver cancer)
Transmission by Saliva
- Report of high levels of HBV DNA in saliva of HBeAg +ve children / adults (though still lower than in plasma)
- Potential modes of transmission include premastication of food, sharing sweets
- No definite proof of transmission
Level of saliva required to transmit HIV: 1L
Amount of saliva produced per day: 1.5L
***Immune response to HBV
Virion uptake by Hepatocyte (i.e. infected)
—> Replication
—> Viral peptide display on surface of Hepatocyte (in infants covered up by maternal Anti-HBc)
—> T-cell response
—> T-cell cytolysis / Anti-virion Ab —> Phagocytosis
Chances of chronicity in HBV infection
- Neonates and 1st year: 90%
- 1-6 yo: 30%
- > 6 yo: 2% (probably <1%)
Possible reasons for Chronicity in Neonates
Host factors:
1. Failure of host to recognise infected hepatocytes (e.g. covering of viral Ag by maternal Anti-HBc —> fetal T cells cannot detect the hepatocyte as being infected —> maternal Anti-HBc can exist in infants for up to 1 year)
Viral factors:
1. Excessive production of HBsAg
- acts as “decoy” for HBV specific humoral + T cell response
- leads to modulation of immune signalling pathways with suppression of inflammatory cytokines (T cells cannot recognise hepatocytes as being infected)
- ***HBx protein
- inhibits degradation of viral protein thus ↓ Ag presentation (Ag require degradation of viral protein first) on surface of hepatocytes - ***Polymerase protein
- suppress myeloid differentiation protein —> ↓ Toll-like receptor (TLR) function - ***Pre-core / HBeAg
- down-regulate TLR-2 expressions on Kupffer cells, hepatocytes, monocytes (of infant)
- down-regulate CD28 on T cells, CD86 on monocytes, Kupffer cells (of infant)
Typical profile of Hep B serological markers
- Incubation period (4-12 weeks)
—> Acute infection (2-12 weeks) (Symptoms occur)
—> HBsAg ↑ then ↓
—> HBeAg ↑ then ↓
—> Anti-HBc ↑ - Recent acute infection (12-16 weeks)
—> Anti-HBc level off
—> Anti-HBe ↑
—> Anti-HBs ↑ (~16 weeks)
—> Recovery
(NB: Anti-HBs is protective, Anti-HBc is not protective)
Hep B ***Chronic carrier serological markers profile
No seroconversion at all (***No Anti-HBs)
- HBsAg ↑ + remains high
- HBeAg ↑ + remains high before **Anti-HBe ↑ after **several decades (e-seroconversion)
- Anti-HBc ↑ + remains
- Anti-HBc IgM ↑ then ↓
***Serological markers for HBV
HBsAg: +
Anti-HBs: -
Anti-HBc: +
1. Acute infection —> check IgM Anti-HBc
2. Chronic carrier (Anti-HBs not appear at all even after decades, Anti-HBe appear decades later)
HBsAg: +
Anti-HBs: -
Anti-HBc: -
- Uncommon, in very early phase of incubation period of acute infection (before production of Anti-HBc)
HBsAg: -
Anti-HBs: +
Anti-HBc: -
1. Past infection
2. Post vaccination
HBsAg: -
Anti-HBs: -
Anti-HBc: +
1. If IgM Anti-HBc +ve —> Acute infection (acute exacerbation of chronic Hep B —> IgM Anti-HBc can also become +)
2. Past infection
3. ***Occult Hep B infection (more common with use of potent immunosuppressants e.g. Anti-CD20)
HBsAg: -
Anti-HBs: +
Anti-HBc: +
1. Past infection
2. ***Occult Hep B infection (more common with use of potent immunosuppressants e.g. Anti-CD20)
(Occult Hep B: HBsAg -ve but have HBV DNA in serum / liver tissue)
(記住: different types of Hep B Ag are just markers!!! No specific indication and less sensitive than HBV DNA (most sensitive))
Hepatitis B pathogenesis
Damage to liver:
- HBV **NOT directly cytopathic
- Damage to liver through **cytolytic T cells + **cytokines (TNFα, IL1β)
- Proteolytic cleavage of viral proteins in infected hepatocytes (probably HBcAg) —> peptides carried and presented to cell surface by **class 1 HLA —> T cell response
Chronic HBsAg carrier:
- 25% die of liver diseases
—> 50% for male
—> 14% for female
***Natural history of Chronic Hepatitis B
- Viral tolerance phase
- **minimal host reaction
- **high EBV DNA, HBeAg +ve
- **normal AST, ALT (∵ very little reaction from host against virus —> little damage to liver)
- only mild histologic abnormality
- **lasts 2-3 decades - Viral clearance phase
- host tolerance suddenly decrease (?∵ HBV-specific thymocytes from thymus)
- **cytotoxic T cells kill HBV-infected hepatocytes
- **fluctuating HBV DNA
- **fluctuating AST, ALT
- histology shows **intermittent active hepatitis (aka chronic active hepatitis) +/- **cirrhosis onset
- T cell kill hepatocytes —> AST, ALT ↑ —> no. of infected cell ↓ —> immune reaction ↓ —> no. of infected hepatocyte ↑ (reinfection of hepatocytes) —> T cell kill hepatocyte ↑ (aka **exacerbation of chronic Hep B)
- multiple exacerbations before e-seroconversion - Late / Residual phase
- **e-seroconversion: HBeAg -ve, Anti-HBe +ve
- host response variable
- **HBV DNA levels relatively low
- ALT levels normal with ~30% having reactivation (HBeAg-negative hepatitis)
- **>70% of HCC / cirrhosis complications occur in Anti-HBe +ve phase, even with “normal” ALT
- e-seroconversion median age: **35, onset of all types of complications: **57 (already Anti-HBe +ve, in fact most complications occur **after e-seroconversion (∵ liver damaged during e-seroconversion))
Development of Cirrhosis
Occur more frequently with
1. Age
- Hepatic ***decompensation
- ***Repeated severe acute exacerbation
- AFP >100 ng/ml (produced by young liver cells, high level when regeneration of new liver cells)
- Bridging necrosis on biopsy
- Unsuccessful / Prolonged HBeAg seroconversion - HBV reactivation with ***HBeAg reversion after e-seroconversion (uncommon)
***Hepatitis episodes in Chronic Hep B
Can be with / without symptoms (symptoms of acute hepatitis)
Causes:
1. HBV-related
- “Spontaneous” reactivation: IgM Anti-HBc ↑ (but not as high as in Acute Hep B)
—> HBeAg clearance (spontaneous / during therapy)
OR
—> e-seroreversion (HBeAg -ve / Anti-HBe +ve/-ve —> HBeAg +ve) (uncommon)
- ***Emergence of resistant variants / Non-compliance during nucleoside analogue therapy
- ***Corticosteroid / other immune suppressants, esp. anti-CD20 —> withdrawal
- Superinfection by ***Hepatitis D
- Superinfection by other viral agents (e.g. HAV, HEV)
- Drug-induced hepatic injury (e.g. alcohol, TCM, herbal tea (涼茶))
***Factors associated with disease progression
- HBeAg seroconversion (Anti-HBe development)
- ALT levels
- HBV DNA levels
- HBsAg seroclearance +/- seroconversion (Anti-HBs development)
- 記住: HBsAg跌唔代表Anti-HBs一定出現
***1. HBeAg seroconversion (Anti-HBe development)
- Acute exacerbation probably triggered off by viral replication + viral protein
- ***Disease progresses after HBeAg seroconversion in patients who acquire HBV infection at birth / early childhood (i.e. Asians / some Mediterraneans)
—> Development of cirrhosis complications / HCC - Patients acquiring disease at birth / early childhood: disease progresses after e-seroconversion in a proportion of patients
—> Majority of complications occur after e-seroconversion - ***HBeAg-negative disease (active viral replication despite HBeAg -ve, Anti-HBe +ve)
—> Mediterraneans >90% precore mutation
—> Asian: 45-56.5% precore mutation; 41-69.5% core promoter mutations, ~10% precore + core promoter wild type
記住: 就算係唔係hidden Hep B (HBeAg-negative disease) —> disease都會progress —> 都會有complications
Conclusion:
- Disease can continue to progress after e-seroconversion
- Cirrhosis-related complications and HCC:
—> peak age ~55
—> >2/3 Anti-HBe +ve
- Disease progression likely related to ***prolonged continuing inflammatory destruction even at low-viral levels
- ALT levels
Normal (QMH):
- Male: <53
- Female: <45
Normal (American Liver Association 2018):
- Male: **<35
- Female: **<25
Except when ALT levels too high (100-300) / extremely high (>300)
—> Risk of complications is less than that of ALT 50-100 (∵ ?stronger immune response to clear away virus more rapidly)
Conclusions:
- ***Lower ALT levels —> Lower risk of complications
- ALT 25-50 has increased risk
- ALT 50-100 has highest risk
—> Implications: decide when to treat patients
- HBV DNA levels
REVEAL (Risk Evaluation of Viral Load Elevation Associated Liver Disease / Cancer) study
Conclusions:
- Higher HBV DNA levels —> Higher risk of developing Cirrhosis / HCC
- 80% of them even have HBeAg -ve + normal ALT
—> HBV DNA levels recognised as important for disease progression
Problems:
- Patients in immune tolerance phase has very high HBV DNA levels —> but disease not yet progressive —> liver has very little damage
—> so when to start treatment?
—> when patients are in ***immune clearance phase (HBe clearance phase) (but hard to define)
When to stop treatment?
- see “treatment” section
- HBsAg seroclearance +/- seroconversion (Anti-HBs development)
Spontaneous HBsAg seroclearance associated with:
- progressively more patients with undetectable HBV DNA (only 13.4% detectable after 1 year)
- majority have normal ALT levels
- near normal histology
- 100% had intrahepatic HBV DNA, but only 1 had detectable mRNA —> signifying low transcriptional level
Study showed:
- HBsAg clearance <50 yo —> almost 0% develop HCC (∵ less significant fibrosis of liver)
- HBsAg clearance >=50 yo —> higher risk of developing HCC (∵ significant fibrosis of liver)
—> although HBV can still cause HCC without going through cirrhosis stage (∵ Oncogenic virus itself: Region X, Pre-S2, Pre-S1)
(vs HCV / Alcoholic liver disease: must go through cirrhosis before HCC (CL Lai))
Conclusion:
- HBsAg seroclearance is the ideal end-point but still require HCC monitoring
Aims for Treatment of Chronic Hep B
Prevent / Decrease cirrhotic complications + HCC
Objectives:
1. Viral suppression + reduce liver damage
- maximal suppression of HBV DNA (PCR undetectable level)
- ↓ AST, ALT
- improvement in liver histology
- Viral eradication
- difficult ∵ cccDNA and Viral integration (hide inside host cell nucleus)
- loss of HBsAg occurs in <10% —> esp. difficult for carriers acquiring disease early in childhood (loss of HBsAg: commonly known as “functional endpoint”)
- loss of cccDNA
Current guidelines for indications of treatment
NEJM:
Patients with
1. Active viral replication (HBV DNA)
- HBV DNA levels indicated for treatment currently progressively lowered
- Active disease (↑ ALT levels)
- currently recognised that disease may be active with relatively low ALT level
—> recommended ALT levels for treatment: male >35, female >25
European Liver Association 2017 (least restrictive)
1. (**記) ALL patients
- e +ve / -ve
- with **ALT > ULN
- **DNA >2000 IU/ml
- with **moderate necroinflammation / fibrosis
- (**記) Patients with **cirrhosis with any detectable HBV DNA irrespective of ALT levels
- Patients with family history of HCC / Cirrhosis
- HBeAg +ve patients (not yet e-seroconversion) with high HBV DNA but persistently normal ALT, if ***>30 yo (∵ damage start to be done)
Current endpoints for treatment
記: 4個criteria: HBeAg seroconversion, HBsAg clearance, HBV DNA, ALT level
- HBeAg seroconversion for HBeAg +ve patients
- NOT sufficient as sole endpoint (not very useful) - HBsAg loss
- Ideal (so-called “functional endpoint”)
- but only achieved in <10% - HBV DNA undetectable by PCR
- ideally permanently - ALT normalisation
- ideally <50% ULN
Treatment of Chronic Hep B
Model for treatment of Chronic Hep B
1. Stimulate immune response
- Immunomodulators: IFNα, Therapeutic polypeptide vaccines
(To be effective must also inhibit reinfection (see below) + allow sufficient hepatocyte regeneration)
- Block reinfection of healthy hepatocyte (i.e. HBV production)
- Viral suppressors: Lamivudine, Adefovir, Entecavir, Telbivudine, Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide (TAF)
(To be effective must also clear the pool of infected cells —> ∴ have to be given long-term)
IFN (for HBV, HCV)
MOA:
Immunomodulation:
- protects uninfected hepatocytes from virus entry + replication
- ↑ display of both viral Ag (HBsAg) and HLA-1 on infected hepatocytes
- accelerates specific cytotoxic T cell response
- ↑ non-specific NK cell activity
- inhibits Ab production e.g. Anti-HBc
Administration:
- Conventional IFNα 3 times / week for 16-24 weeks SC
- Pegylated IFNα once / week for 48 weeks SC
—> similar efficacy
SE (many):
- Flu syndrome (but rapid tachyphylaxis)
- Fatigue
- Myalgia
- Nausea
- Diarrhoea
- Alopecia (not severe)
- Depression (may be suicidal)
- Neuropsychiatric complications in HIV patients
- Marrow suppression (usually not severe, usually only take 3-4 days for WBC / Plt count to recover)
- Activation of autoimmune disease e.g. Thyroid, Plt (immune complex thrombocytopenia)
- ***Hepatotoxicity if LFT borderline (∵ IFN attacks hepatocyte, if not allow sufficient regeneration —> liver can die even quicker!)
Advantages:
- Finite period of treatment (partly related to SE)
- More durable HBeAg seroconversion
- More HBsAg seroconversion (NOT for patients with early childhood infection)
- ***No resistant mutations
Disadvantages (many):
- SE moderate to severe
- **NOT suitable for patients with significant cirrhosis
- **Most patients have HBV DNA detectable by PCR assays even after HBeAg seroconversion
- ***Multiple meta-analyses not consistent in ↓ incidence of HCC, may be useful in cirrhosis patients who are sustained responders (~30%) —> but IFN potentially dangerous in cirrhotic patients
Nucleoside/tide analogues
Nucleoside analogues
L-nucleoside (unnatural nucleoside)
- ***Lamivudine (1st ever drug)
- Telbivudine
- Emtricitabine
Cyclopentane
- ***Entecavir
Nucleotide analogues (Nucleoside + Phosphate)
- Adefovir
- **Tenofovir disoproxil fumarate (TDF)
- **Tenofovir alafenamide (TAF)
Lamivudine
Oral nucleoside analogue (Cytidine analogue) (2’3’-dideoxy-3’-thiacytidine)
MOA:
- inhibits DNA synthesis by chain termination of Minus strand HBV DNA
- potent RT inhibitor
Effectiveness:
- Also effective against HIV
- Rapid >95% suppression of HBV DNA in 1-2 weeks
- Almost without SE
- ↓ Necroinflammation, Fibrosis
- ↑ HBeAg seroconversion
- Continuous HBV DNA suppression
- Emergence of resistant virus (**YMDD mutation HBV) from 9 months onwards —> problem: 15% in 1 year, >70% in 5 years
—> **NOT advocated as 1st line agent
Entecavir
Guanosine analogue (NB: animal carcinogenicity)
Effectiveness:
- Much more potent than Lamivudine
- Almost **no SE
- Resistance only **1.2% in 8 years in treatment naive patients
- 5 year continuous Entecavir: ~100% **undetectable HBV DNA
- In Lamivudine-resistant patients —> much less effective —> 50% resistance in 6 years
—> ∵ Entecavir require 3 mutations to be become resistant: YMDD + 2 other mutations
—> if already Lamivudine-resistant (YMDD): only need another 2 mutations to be resistant
—> Recommended as **1st line agent for treatment naive patients
TDF, TAF
Nucleotide:
- Different group than Nucleoside —> Different resistance pattern (no need to be worried of Lamivudine-resistance)
TDF:
- Adenosine analogue
- Potential **renal toxicity with PO4 loss in urine (∵ short plasma t1/2 —> very quickly excreted by kidney)
—> hypophosphataemia and osteomalacia secondary to proximal renal tubulopathy can also occur
- Bone mineral density (BMD) decline —> suggest increased bone turnover
- Effective against both wild type + Lamivudine resistant HBV
- Resistance 0% up to 10 years
- Recommended as **1st line agent
- Still prescribed for pregnancy (no published studies for TAF)
TAF:
- Novel prodrug of Tenofovir (TFV cannot be absorbed in GI tract)
- Potent antiviral activity against HBV
- Longer t1/2, more stable in plasma than TDF —> most enter hepatocytes (only small amount excreted by kidney —> **much less renal toxicity (almost none))
- Almost no decline in BMD
- 25mg daily
—> **NOW recommended as ***1st line agent for Chronic Hep B
Long-term effects of Nucleoside/tide analogues
Continuous Entecavir / Tenofovir:
- ~100% undetectable HBV DNA in long-term
Effect on HCC / Fibrosis:
1. Long-term Lamivudine
- improve fibrosis + cirrhosis
- improve Child-Pugh score in cirrhotic patients
- ↓ complications of cirrhosis + liver cancer in both early + late stage disease
- effect ↓ with YMDD resistance (but still better than placebo)
- Long-term Entecavir, Tenofovir
- reversal of fibrosis / cirrhosis (***cirrhosis actually partly reversible!!!)
- >95% HBV DNA undetectable by PCR
Current nucleoside/tide analogues require long-term treatment (except ~10% who achieve HBsAg seroclearance: functional cure)
- Main problems:
—> **Inability to clear cccDNA
—> **Viral integration into host genome
Newer agents aim to ↑ HBsAg seroclearance (e.g. siRNA targeting S region, X region)
Hepatitis B reactivation with Immunosuppression
- Steroid
- Anti-CD20, Anti-CD52
簡單而言: 當比immunosuppressants —> 降低抵抗力 —> 當抵抗力回復 —> 立刻攻擊Liver
- Steroid
Effect of Steroid on Chronic HB carriers:
During steroid therapy
- ↑ Viral replication (∵ ***Glucocorticoid responsive element)
- ↑ HBV DNA
Following steroid withdrawal (~4-10 weeks)
- ***Immune rebound with ↑ cytotoxic suppressor T cells (?direct effect, ?secondary to ↑ viral load after steroid initiation)
- ↑ Immune attack on liver —> ↑ AST + ALT
- ↓ HBV DNA
Immune rebound:
- Potential dangerous + fatal
—> in patients with decompensated liver disease
—> in patients with abnormal immune system e.g. lymphoma, leukaemia
—> but occasionally seen in “normal” patients
- Anti-CD20, Anti-CD52
- Known to reactivate CMV, Parvovirus B19, Adenovirus, PCP
- First reported to **reactivate **Occult Hep B (OHB) in 2001
—> patient was ***Anti-HBs +ve with lymphoma on Rituximab - Subsequent reports for both CHB and OHB patients: mostly in patients with **haematological / **lymphoid malignancies
- Can be Fatal!
Occult Hep B:
- HBsAg -ve but HBV DNA +ve in serum / liver tissue (need biopsy to confirm)
Mechanism of reactivation:
- Profound depletion of B cells when on drugs —> take 1 year to recover —> after recovery —> HBcAg-binding B cells prime specific cytotoxic T cells (~ Immune rebound) —> T cells destroy infected hepatocytes
Conclusion:
- If ***any evidence of past infection with HBV (就算Anti-HBs +ve) —> need to treat as if OHB patient if need to start potent immunosuppressants
—> using Entecavir to complete control reactivation
Signs of past infection:
- Anti-HBs +ve, Anti-HBc +ve (even though HBV DNA -ve)
- HBV DNA +ve (even though Anti-HBs +ve / HBsAg -ve)
Prevention + Management of Hep B reactivation
Before using Conventional immunosuppressants / Anti-TNFα
- Check HBsAg / Anti-HBs
—> HBsAg +ve —> Check baseline HBV DNA + LFT
Anti-CD20 / CD52:
- Check HBsAg, Anti-HBs, Anti-HBc
—> Any HBV marker +ve (驚OHB) —> Check baseline HBV DNA + LFT
3 組patients:
1. HBsAg +ve
2. HBsAg -ve, Anti-HBs / Anti-HBc +ve (and on Anti-CD20)
3. Anti-HBc +ve but Anti-HBs -ve
HBsAg +ve patients:
1. **Prophylactic Anti-viral therapy **irrespective of baseline HBV DNA levels
—> superior + safer than monitoring for reactivation / treating when reactivation occurs
—> Entecavir / TAF / TDF
- Frequent monitoring of LFT + HBV DNA (esp. when Lamivudine used)
- Duration of antiviral therapy
- when **Baseline HBV DNA <2000 —> continue for 6 months after completion of therapy (12 months for Anti-CD20 therapy) + monitor closely after stopping antiviral therapy
- when **Baseline HBV DNA >2000 —> continue for life
Patients on Anti-CD20, HBsAg -ve, Anti-HBs / Anti-HBc +ve (驚OHB):
1. When ***Baseline HBV DNA +ve
- Prophylactic antiviral therapy (same as for HBsAg +ve patients)
- When Baseline HBV DNA undetectable
- Monitor LFT + HBV DNA up to 12 months after stopping therapy
- Start antiviral treatment once HBV DNA detectable (actually may be wise to just start rather than wait for HBV DNA to rise)
(NB: rise in HBV DNA ***precedes rise of ALT by 2-3 weeks —> a better guide than ALT for reactivation)
Patients with Anti-HBc +ve but Anti-HBs -ve
1. May start antiviral even if HBV DNA undetectable (∵ they are at higher risk of reactivation)
Prevention of HBV infection
- Care in handling infected material
- treat every patient as potential carrier - Passive immunisation
- Hep B Immunoglobulin - Active immunisation
- Hep B vaccine
Hepatitis B Immunoglobulin (HBIG)
Indications:
- Babies of HB carrier mothers (give asap after birth)
- Needle prick by HB +ve blood (if Anti-HBs -ve staff)
- Any parenteral / mucosal contact with HB +ve subjects
Dose:
- 2 IM injections (Babies of HB carrier mothers: 1 dose of HBIG + vaccine)
- 1st dose within 24 hours of contact (definitely not >48 hours)
Efficacy:
- 75% protection only
Hepatitis B vaccine
Recombinant DNA Yeast Vaccine (1st of its kind)
- Cloning of gene S (226 a.a.) by recombinant DNA technique to the yeast, Saccharomyces cerevisiae
- 22nm particle isolated from yeast culture
- 1st subunit vaccine with ***no complete viral particles —> no risk for subjects becoming Hep B carrier
Dose:
- Given at 0, 1, 6 months
- ~95% develop Anti-HBs (immunogenicity)
- 100% protection if Anti-HBs +ve (protective efficacy)
Booster dose necessary?
No need for booster dose:
1. Healthy adults given a booster dose —> High Anti-HBs titre within 3-4 days (anamnestic response)
- 22 years FU from HK children
- still effective
- anamnestic responses demonstrated (when expose to HBV)
—> Conclusion: Probably no need for booster dose
Prevention in babies of HBsAg mothers
HBIG alone: 71%
Vaccine alone: 75%
HBIG + Vaccine: ~95%
For failure cases even after HBIG + Vaccine:
- related to maternal HBV DNA levels
- failure rate increases with DNA levels when >6 log10 copies / ml (<6 log10 0% failure rate)
—> solution: give mother nucleoside/tide analogue (e.g. TDF) in last trimester
Who to vaccinate?
High endemic areas:
1. Neonates of HB +ve mothers (together with HBIG)
2. All neonates
3. Preschool children
4. Medical + Paramedical personnel
5. Other subjects at high risk
- Family members of HB carriers
- Immunocompromised subjects e.g. transplant patients
- Promiscuous persons
- Drug addicts
Global eradication of HBV
Definitely possible
Universal vaccination esp. in high endemic areas:
- All newborns (preferably with HBIG if test for HBsAg done for mothers)
- All young children under 5
SpC Medicine Teaching Clinic: Fibrosing cholestatic hepatitis after liver transplant
Pathogenesis:
- Primary cytopathic effect of HBV dysregulation of viral transcription
—> ↑↑ HBV RNA
—> ↑↑ Viral Ag in endoplasmic reticulum
—> Cell death
Effect:
- Rapid graft failure after liver transplant —> death
- Rapid occurrence with re-transplant
Prevention of Recurrent HBV in Liver transplant
- Indefinite high dose HBIG
- 65-80% effective - Lamivudine
- depends on rate of resistance developing -
**Low dose HBIG + **Nucleoside analogue
- >90% effective
- current practice in most centres - Entecavir / Tenofovir monotherapy
- viable option
Hepatitis C
Transmission:
- **PARENTERAL only
1. **Transfusion of blood or blood products
2. **Intravenous drug addicts
3. Medical personnel
4. **Mother-to-child
- transmission possible but comparatively uncommon
- depends on viral titre in the mother
5. ***Sexual (heter- or homosexual)
- much (~10x) lower than HBV or HIV (∵ lower infectivity of HCV)
- more common with anal sex, or in HIV subjects
Diagnosis:
- Often delayed (Median time from infection to first review for HCV 26 years)
Clinical course:
- Hepatitis C chronicity: **50-85% (irrespective of age of subject)
—> **Rapid mutation (esp. in envelope protein) —> “Quasispecies” in the host simultaneously
—> Immune pressure on dominant strain —> Coexistent strain emerges to escape immune attack
- Immune attack
—> **Neutralising Ab develop but are **time limited + highly strain specific
—> Cell mediated responses cause liver damage
- Viraemia peaks at pre / early acute phase
- **Chronic hepatitis —> **Fluctuating AST + ALT —> Cirrhosis + HCC in 20-50 yr
Treatment of Hepatitis C
Indications:
1. **ALL patients with chronic HCV
- except those with short life expectancy due to non-HCV disease(s)
2. Patients with **end-stage liver disease due to HCV (should still be treated)
Treatment guideline:
- Simplified pangenotypic regimes recommended
- Ribavirin not used now (only needed for cirrhosis)
- IFN not used now
Pre-treatment assessment:
- Proof of HCV replication
- Assess presence / absence of cirrhosis by non-invasive methods, e.g. Fibroscan
Target (self notes):
- Sustained virologic response: **Undetectable HCV RNA **12w after completion
Direct Acting Antiviral (DAA)
1. Protease inhibitor
- Grazoprevir
2. NS5B (RNA polymerase) inhibitor (-buvir)
- Sofosbuvir
3. NS5A inhibitor (-asvir)
- Ledipasvir
- Elbasvir
- Velpatasvir
- Pibrentasvir
Licensed drugs:
Recommended treatment for GT1 a+b, GT4
1. Harvoni
- Ledipasvir (90mg) + Sofosbuvir (400mg)
2. Zapatier
- Grazoprevir (100mg) + Elbasvir (50mg)
Screening for resistance-associated substitutions (RAS) recommended before treatment
Recommended treatment for ALL genotypes
Pangenotypic agents:
3. **Epclusa
- Sofosbuvir (400mg) + Velpatasvir (100mg)
- **Once daily, Oral
- ***12-16 weeks
-
**Mavyret
- Glecaprevir (100mg) (NS3/4A protease inhibitor) + Pibrentasvir (40mg)
- **3 FDC tablets (i.e. 300mg/120mg) once daily, taken with food
- ***8-12 weeks
