HBV Flashcards
What are the five phases of chronic HBV infection?
(I) HBeAg-positive chronic infection
(II) HBeAg-positive chronic hepatitis
(III) HBeAg-negative chronic infection
(IV) HBeAg-negative chronic hepatitis
(V) HBsAg-negative phase (occult infection)
Not all patients with chronic HBV infection have hepatitis
Evaluation depends on HBeAg, HBV DNA level, and ALT
What are goals of HBV therapy?
Improve survival/ quality of life by reducing disease progression -
liver failure
HCC
Extra-hepatic manifestations
Prevent transmisson to others
What are drug options to treat HBV?
entecavir
tenofovir
PEG-IFN
HBV DNA has 4 ORFs, producing 7 proteins
What are they?
HBV Pol/ RT
PreS1/ PreS2/ HBsAg
HBcAg/ HBeAg
HBx
What is HBV viral life cycle once uptaken by hepatocytes?
- nucleocapsid transported to nucelus - release the relaxed circular DNA (rcDNA)
- rcDNA converting into covalently closed circular DNA, which is wrapped by histones to form an episomal chromatinized structure. Acts as transcription template for all viral proteins
- pregenomic RNA is reverse transcribed into new rcDNA within the viral capsid. The DNA containing nucleocapsids in the cytoplasm are either recycled into the nucleus to maintain cccDNA reservoir, or enveloped and secreted via the endoplasmic reticulum
- In addition to complete infectious virions (Dane particles diameter of 42 nm), infected cells produce a large excess of genome-free, non-infectious sub-viral spherical or filamentous particles of 22 nm
Viral genome integration in the host genome can occur randomly; it is not required for viral replication, but is one of the important mechanisms involved in hepatocyte transformation.
Why does HBV develop mutations frequently?
Reverse transcriptase has low fidelity, and no proof-reading mechanism
can produce genetically distinct viral species in infected individuals - also called viral quasispecies
How many HBV genotypes exist currently?
Nine genotypes
A
B
C
D
E
F
G
H
I
Several sub-genotypes exist
Chronic HBV infection
What HBV DNA level would be concerning that chronic hepatitis will occur?
Usually > 20 000 IU/ml
However patients may have viral load between 2000 - 20 000 without signs of hepatitis
Why might occult HBV infection not be detected?
HBsAg negative patients
- low sensitivity of HBsAg assay
- HBsAg mutation not picked up by HBsAg assay
What are risk factors for developing HCC in chronic HBV infection?
cirrhosis
HCV/ HIV co-infection
alcohol use
diabetes
smoking
older age
high HBV DNA levels
HBV genotype - C causes more HCC
Patient with new HBV diagnosis
Who should be screened and immunised?
first degree relatives
sexual partners
Patient with new HBV diagnosis
What other infections to screen for?
HAV - immunity
HCV
HIV
STI screen if sexually acquired
What are end point goals of HBV treatment?
Level of HBV replication is strongest predictive biomarker associated with disease progression, and long-term outcome of chronic HBV infection
HBsAg
HBeAg
HBV DNA
ALT
Long term suppression of HBV DNA - ideally zero, but lower viral loads are better. Suppression of viral load is associated with normalisation of ALT levels. Although there is no evidence what low level viral load is an acceptable cut-off to prevent complications
HBeAg loss, with/without anti-HBe seroconversion is valuable end point, as often represents a partial immune control of the chronic HBV infection. Less reliable, as after stopping treatment sero-reversion back to HBeAg pos can occur. So sometimes continue treatment until HBsAg neg
HBsAg loss - represents functional cure. As HBsAg sero-reversion is rare, so patient may have reactivation in future, but unlikely to have liver inflammation. Allows cessation of treatment, as they are unlikely to run into significant problems in future. Small risk of HCC remains
Biochemical response - ALT normalisation can be considered additional end point
What are indications for HBV treatment?
Combination of 3 criteria:
- HBV DNA level
- Serum ALT level
- Severity of liver disease
Scenario 1
- HBeAg pos
- HBV DNA >2000 IU/ml
- ALT >50
- moderate fibrosis
Scenario 2
- HBV DNA > 20 000 IU/ml
- ALT >100
- any stage of fibrosis
Scenario 3
- HBV DNA - any level
- Cirrhosis
Scenario 4
- HBeAg pos
- HBV DNA - any level
- ALT - normal
- no fibrosis
- may be treated depending on local policy, risk to others, or risk progression to HCC
Scenario 5
- extra-hepatic manifestations
Patients with chronic HBV infection who do not meet treatment criteria.
How often should they be followed up?
- HBeAg pos + age <30
- HBeAg neg + HBV DNA <2000
- HBeAg neg + HBV DNA >2000
- HBeAg pos + age <30 - follow up in 3-6 months
- HBeAg neg + HBV DNA <2000 - follow up in 6-12 months
- HBeAg neg + HBV DNA >2000 - follow up 3 months
What drugs are approved from treatment of HBV in Europe?
Adefovir dipivoxil
Entecavir
Lamivudine
Telbivudine
Tenofovir disoproxil/ alafenamid
Pegylated- IFN alpha
Which HBV drugs have a low barrier to resistance?
low barrier against HBV resistance
- adefovir dipivoxil
- lamivudine
- telbivudine
high barrier to HBV resistance
- entecavir
- tenofovir disoproxil/ alafenamide
Avoid using drugs with low barrier to resistance.
Pegylated-IFN alpha aims to induce immunological control .
However can only be used for a finite time
What is benefits of combining with an antiviral drug for dual-treatment approach?
Lack of evidence of benefit when using dual-treatment
Peg-IFN has high variability in treatment response, so not used as often
Patient on anti-viral treatment can be monitored by virological, serological, biochemical and histological methods
What are accepted definitions of:
Primary non-response
Full response (on therapy)
Full response (off therapy)
Partial response
Primary non-response
- check patient compliance
Full response (on therapy)
- undetectable HBV DNA (<10 IU/ml)
Full response (off therapy)
- HBV DNA <2000 IU/ml after 12 months off therapy
Partial response
- 1log10 IU/ml HBV DNA decrease, but still detectable HBV DNA, after 12 months therapy
Patient on anti-viral treatment can be monitored by virological, serological, biochemical and histological methods
What are accepted definitions of:
Non-response
Virological breakthrough
Biochemical breakthrough
Non-response
- <1log10 IU/ml HBV DNA decrease, still detectable HBV DNA, after 3 months therapy
Virological breakthrough
- increase in HBV DNA by >1log10 IU/ml compared to nadir (lowest value), whilst on therapy
- usually related to viral resistance mutation
Biochemical breakthrough
- increase in ALT levels
What is accepted virological response to PegIFNa
Virological response
Sustained virological response off therapy
Virological response -
- HBV DNA level <2000 IU/ml - at 12 months and end of therapy
Sustained virological response - off therapy
- HBV DNA level <2000 IU/ml - 12 months after completion of therapy
Patient of tenofovir disoproxil for chronic HBV
They have developed osteoporosis and renal disease
What are other drug options to switch to?
Entecavir
Tenofovir alafenamide
Renal disease includes gradual reduction in function, or more severe such as Fanconi syndrome
What is the approximate treatment success rate of each of these drugs in chronic HBV infection
Rank from highest to lowest
- adefovir dipivoxil
- entecavir
- lamivudine
- telbivudine
- tenofovir disoproxil/ alafenamide
- tenofovir disoproxil/ alafenamide
- entecavir
- telbivudine
- lamivudine
- adefovir dipivoxil
All drugs vary from 60-95% success, depending on whether patient is HBeAg positive or not.
Success is not not HBV eradication, and nucleoside/ nucleotide treatment is unlikely to eradicate. So patient will need long term treatment
Which drugs are nucleotide analogues, and nucleoside analogues
- adefovir dipivoxil
- entecavir
- lamivudine
- telbivudine
- tenofovir disoproxil/ alafenamide
Nucleoside
- entecavir
- lamivudine
- telbivudine
Nucleotide
- adefovir dipivoxil
- tenofovir disoproxil/ alafenamide
What is difference between nucleotide and nucleoside analogue?
Nucleosides have a nitrogenous base and a five-carbon carbohydrate group, usually a ribose molecule (see Chapter 2). Nucleotides are simply a nucleoside with one or more phosphate groups attached (Figure 4-1). The resulting molecule is found in ribonucleic acid or RNA.
Patient on nucleoside/nucleotide anti-viral treatment.
When can this be discontinued?
- HBsAg loss (with or without anti-HBs)
- HBeAg pos who seroconvert, with undetectactable HBV DNA, and had 12 months of treatment completed
What are reasons to pick entecavir or tenfovir disproxil/ alafenamid?
Age >60
Bone disease
Renal disease
Patient with chronic HBV on treatment with drug with low barrier to resistance.
Viral load not responding.
What steps would you take?
- check patient compliance
- switch to drug with high barrier to resistance e.g entecavir/ tenofovir
Peg-IFN-alpha duration is normally 48 weeks
Which types of patients may be suitable for this?
mild-mod chronic HBV infection
HBeAg neg - success rate if HBeAg pos is 20-30%
What monitoring is required for patients of Peg-IFN-alpha treatment?
FBC
ALT
TSH
every 3 months
What are successful endpoints of Peg-IFN-alpha treatment?
HBV DNA <2000
HBsAg loss
ALT normalisation
Peg-IFN-alpha may not be effective, and may be stopped early.
What are the stopping rules?
Week 12
Week 12 used, as if no response by then, high predictor of treatment failure
Use quantitiate HBsAg as marker
At 12 weeks, stop if:
HBsAg >20 000
HBV DNA has not decreased by 2log10
The most important on-treatment predictor of response to PegIFNa is serum HBsAg levels, although they are influenced by HBV genotype
What are side effects of PegIFNa?
Mild
- Flu-like illness
- myalgia
- headache
- fatigue
- depression
- hair loss
Severe
- Myelosuppression - can be managed with dose reduction
- hepatitis flares can result in decompensation - so contraindicated in patients with decompensated cirrhosis
- Hypothyroidism
Why is PegIFNa contraindicated in combination with telbivudine?
The combination of PegIFNa with telbivudine is contraindicated due to a high risk of neuropathy.
Why are combinations of entecavir/ TDF/ TAF not used in clinical practice?
Minimal/ no benefit to dual therapy on outcomes
However, if patient has HBV DNA viral load between 50 - 2000 whilst on monotherapy, there may be a small benefit to adding a second agent. And may help reduce risk of HCC. But more studies required
Why are anti-virals not used in combination with PegIFNa?
No evidence that combination therapy is better that either therapy alone
Small study showed 9% vs 3% reduction in HBsAg seroconversion. So not worth recommending
Patient with decompensated liver disease, due to chronic HBV
What are treatment options?
- Patients with decompensated cirrhosis should be immediately treated with a NA with high barrier to resistance, irrespective of the level of HBV replication. Aim to achieve rapid viral suppression
- Assess for liver transplantation
- PegIFNa is contraindicated in patients with decompensated cirrhosis
- Patients should be closely monitored for tolerability of the drugs and the development of rare side effects like lactic acidosis or kidney dysfunction
lactic acidosis is a class effect of anti-virals
What is most common HBV genotype UK?
A 55%
C 20%
D 20%
