HBV Flashcards
What type of virus is HBV?
Family: Hepadnaviridae
Genus: Orthohepadnavirus
Small (42nm), Enveloped, Partially dsDNA
What is 5Y cumulative incidence of cirrhosis in an untreated CHB pt?
8-20%.
Among those with cirrhosis; the 5Y risk of decompensation is 20%.
What is the annual risk of HCC in pts with cirrhosis?
2-5%
What are the host related risk factors for developing HCC in untreated CHB pt?
Chronic hepatitis necroinflamfmation/Cirrhosis
Co-infection with other hepatitis viruses or HIV
Male/older age/ African origin/FH of HCC
Alcohol abuse/Active smoking
DM/Metabolic syndrome
What are HBV properties that increase risk of HCC in untreated CHB pt?
High HBV DNA &/or
HBV genotype C > B*
Specific mutations
- C for cancer
What are the components of the initial assessment of pts with chronic HBV infection?
1)Complete history + physical examination
2)Assessment of liver disease activity and severity > identify pts for ttt and HCC surveillance.
-physical exam
-biochemical tests (AST/ALT/GGT/ALP/bilirubin/Albumin/gamma globulin/FBC/PT)
-liver USS
* if above inconclusive: liver biopsy or non-invasive (Elastography)
3)Assessment of markers of HBV infection.
-HBaAg and Anti-HBe
-HBV DNA serum level
-HBsAg quantification
4) Exclude other causes of CLD (AI/Metabolic/alcohol..)
5) Exclude co-infection with HDV/HCV/HIV.
6) Check anti-HAV IgG ( if negative > vaccinate)
** ALL 1st degree relatives/sexual partners should be tested (HBsAg/HBsAb/HBcAb) +/- vaccination
Define the following in relation to HBV ttt:
1)Main endpoint?
2)Valuable endpoint?
3)Additional endpoint?
4)Optimal endpoint?
1)The induction of LT suppression of HBV DNA levels.
2)The induction of HBeAg loss +/- Anti-HBe sero-conversion (in HBeAg pos CHB pts)
3)Biochemical response; normalisation of ALT
4) HBsAg loss +/- Anti-HBs sero-conversion (Functional cure).
What are the indications for ttt?
Should be treated:
1) All pts with chronic Hepatitis HBV DNA > 2000 IU/ml and
ALT > ULN and/OR
At least moderate necroinflmmation/fibrosis
2)Cirrhosis (comp/decomp) with any detectable HBV DNA *Regardless of ALT
3)HBV DNA > 20,000 and
ALT > 2ULN
*Regardless of fibrosis degree
May be treated ( Have infection NOT hepatitis):
4)HBeAg-pos + persistent normal ALT + high HBV DNA + > 30Y
*Regardless of fibrosis degree
5)FH of HCC/Cirrhosis and Extra-hepatic manifestation
What A) monitoring and B) how frequent is required for pts NOT on ttt?
A) HBV DNA, ALT, fibrosis (noninvasive).
B)
HBeAg-pos + <30Y = 3-6M
HBeAg-neg + HBV DNA < 2000iu/ml = 6-12M
HbeAg-neg + HBV DNA =/>2000iu/ml = 3M for the 1st Y, then 6M
What is A) the rationale for pegIFNa ttt and B) what is the main disadvantage?
A) Is to induce LT immunological control with finite duration ttt.
B) High variability of response and side effects.
What are the types of ttt response?
Virological
Serological
Biochemical
Histological
Define Virological response to NA ttt?
1)During ttt:
Virological response: HBV DNA ND using PCR with LOD of 10iu/ml
1ry non-response: <1log10 decrease in HBV DNA after 3M of ttt
Partial response: decrease in HBV DNA >1log 10 BUT still detected after 12M of ttt.
Virological breakthrough: increase in HBV DNA >1log10 compared to nadir level on ttt
2)After stopping ttt:
SVR: HBV DNA <2000iu/ml at least 12M post-stopping.
Define virological response to pegIFNa ttt?
On ttt: HBV DNA <2000iu/ml at 6M and at end of ttt
After stopping: HBV DNA <2000iu/ml for at least 12M
Define Histological response to ttt?
Decrease in necroinflammation activity* without worsening in fibrosis compared to pre-ttt findings.
*by =/> 2 points in histologic activity index or Ishaks system🤷🏻♀️
Define sustained biochemical response?
Normal ALT on a minimum follow up 3 monthly for a year post ttt.
Define serological response to ttt?
1) for HBeAg-pos pts: loss + Anti-HBe.
2) for all pts: loss of HBsAg + Anti-HBs
What sort of virus is HBV? What size is it
Hepadnavirus, small enveloped partly ds relaxed circular DNA
42 nm
Where does HBV replicate?
Exclusively in hepatocytes
How many genotypes of HBV are there? What gene is sequenced for genotyping
10 (A-J) sequencing S gene
What does the HBsAg assay detect in relation to virus?
Infected cells usually secrete 100-1000 times as many empty polymers of envelope protein as they do infectious virus - this is what is detected in HBsAg assays
What is cccDNA?
Covalently closed circular DNA
Conversion of rcDNA into cccDNA requires completion of the +DNA strand
cccDNA remains in the nucleus as an episomal minichromosome
cccDNA is transcribed into 4 viral RNAS
Pre-Core mRNA, pregenomic RNA, L mRNA
M mRNA and S mRNA
X mRNA
What is the pre-core protein cleaved into?
What is the relevance of this?
HBeAg, therefore HBeAg is directly related to the level of cccDNA transcription and hence viral load
Where is each HBV genotype most commonly from geographically?
B & C = Asia (and vertical transmission)
A, D & E = Africa
G, H & F = America
A = UK
Incubation period of HBV
Approx 12 weeks (range 40-160 d)
What % of acute HBV is symptomatic?
One third
In what situation should patients with acute HBV be treated?
Only in severe disease i.e. coagulopathy INR >1.5 or protracted course
Symptoms of acute HBV
Anorexia
Nausea
Upper right quadrant pain
Severe fatigue
Jaundice (not always present)
Remember to inform PH!
Definition of chronic HBV?
Rate of chronicity in:
a) Perinatally infected children
b) Children infected at 1-5 years
c) Healthy adults
a) 90%
b) 20-50%
c) 5%
HBeAg, HBV DNA, ALT in:
a) HBeAg+ chronic infection
b) HBeAg+ chronic hepatitis
c) HBeAg- chronic infection
d) HBeAg- chronic hepatitis
e) HBsAg- phase
a) HBeAg, very high DNA, normal ALT
b) HBeAg, very high DNA, raised ALT
c) Anti-HBe, <2000 IU/ml, normal ALT
d) Anti-Hbe, moderate-high DNA, raised ALT and fibrosis
e) HBsAg negative, undetectable DNA (not always), cccDNA in the liver
What proportion of patients with chronic HBV will develop progressive liver disease?
25%
Cirrhosis > 20% annual risk of decompensated liver disease >5 year survival rates can be as low as 15%
Cirrhosis > 5% risk of HBV related hepatocellular carcinoma
Extrahepatic manifestations of HBV
Serum-sickness like immunological syndrome
Cervical
NHL
Cryoglobulinaemia
Polyarteritis
Define occult hep B
Presence of replication competent cccDNA in the liver and/or HBV DNA in blood in patients with no detectable HBsAg
DNA negative or very low (<200 IU/ml) and intermitently detected
Gold standard is detection of relication competent HBV DNA in liver
‘S-escape mutants’ in which HBsAg is not detected by current assays - may look like occult HBV
Why is occult HBV an issue for the blood supply and how can it be protected?
Infectious dose of HBV is below the limit of detection of NAATs
Methods of screening donors to reduce HBV transmission would be:
Excluding anti-HBc positive donors
Reducing LOD to 0.15 IU/ml
Testing samples individually by NAAT rather than in minipools
What are the risk factors for HBV related HCC?
What is a marker used to monitor risk?
Host factors: cirrhosis, comorbidity, age
Viral factors: DNA and HBsAg level, genotype (C higher risk?)
Alpha-fetoprotein
Initial work up for new diagnosis of HBV
LFTs
FBC
Prothrombin time
Hepatic ultrasound
Fibroscan (transient elastography)
HBeAg/HBeAb, DNA, HBsAg, HDV
HAV IgG (if neg offer vaccine)
FIB-4 (Age, ALT, AST, platelets)
What is HBsAb directed against?
A range of epitopes on the ‘a’ determinant of the surface protein - it is considered a neutralizing antibody
What is the minimum level of HBsAb considered protective?
10 IU/ml confers protection but 100 IU/ml is preferable as per DHSC
What antigen can cross the placenta and act as a ‘tolerogen’?
HBeAg
Possible causes of isolated anti-HBc?
False positive
Occult HBV
Early resolving infection when HBsAb about to come up
Resolved HBV with waning HBsAb (HBeAb can sometimes be positive)
What quant HBV assays are available?
What POC HBV assays are available
Alinity m and Realtime HBV (Abbott)
Artus HBV (Qiagen)
AccuPower HBV (Bioneer)
Cobas HBV (Roche)
Aptima HBV (Hologic)
Cepheid GeneXpert
Truenat HBV (Molbio)
What is HBV core related antigen (HBcrAg)
New biomarker containing several antigens HBcAg, HBeAg, prec22 protein
Can be detected in Dane particles and DNA neg particles which contain the pre core protein and are 100x more prevalent than Dane particles
May provide info on the translational activity of HBV
May reflect amount of cccDNA in hepatocytes and predict risk of HCC
When would you use sequencing in HBV infection?
Can be used to determine vaccine escape mutants (esp in mother to child transmission post vaccine)
Can identify pre-core mutants (e-null mutants) caused by premature stop codon in precore region (less common in GTA)
Phylogenetic analysis can be used in outbreaks
Detecting HBcAg mutants with mutations in basal core promotor region
What is the goal of HBV treatment?
What is the main endpoint?
What is the optimal endpoint?
Reduce progression to liver damage and therefore HCC
Main endpoint is long term suppression of replication
Optimal endpoint is HBsAg loss
Which patients are eligible for HBV treatment as per EASL?
1) Patients with cirrhosis (and ALT, any DNA)
2) DNA >2000 IU/ml, raised ALT and/or at least moderate fibrosis
3) Patients with HBV DNA >20,000 and ALT >2xULN
4) >30 y and HBeAg+ CHB with normal ALT and high DNA
5) Family history of HCC or cirrhosis/extrahepatic manisfestations
What are first line treatments for chronic HBV?
Entecavir or tenofovir
Peg-IFN can be considered for mild to moderate CHB
What are four endpoints of HBV treatment?
Long term suppression of HBV DNA (biomarker most associated with disease progression)
HBeAg loss (represents some immune control)
ALT normalisation
Optimal endpoint - HBsAg loss (functional cure)
Name 3 NAs used for HBV with low barrier to resistance and 2 with high barrier to resistance
Low barrier to resistance
Lamivudine
Adefovir
Telbivudine
High barrier to resistance
Tenofovir (TDF and TAF)
Entecavir
What are the two NAs recommended for HBV treatment in EASL?
Tenofovir or entecavir monotherapy
What two issues do you need to be aware of in NA treatment of HBV?
Dose reduction for renal disease (and monitor)
Bone and renal issues with TDF
What are the stopping rules for NA treatment of HBV?
1) Stop after HBsAg loss
2) In non-cirrhotic HBeAg+ can stop if HBeAb and undetectable DNA and 12 months of consolidation therapy
3) In non-cirrhotic HBeAg - patients, can stop if undetectable DNA for >3 y (but close monitoring)
HBV/HIV co-infection - what should their cART regimen contain?
Tenofovir
What needs to continue after cessation of HBV treatment?
Monitoring for HCC
Pros and cons of Peg IFNa for HBV
Pros:
Finite treatment duration (48 w)
Long term immune control
No risk of resistance
Low risk of relapse
Cons:
Subcut injection(weekly)
Many contraindications
Poorly tolerated
When can Peg-IFN? not be used for HBV treatment?
Patients with decompensated cirrhosis
Pregnancy
What is the duration of Peg-IFNa for HBV?
48 weeks
Early stopping rules in place for non-responders
Which patients have most success with Peg-IFNa treatment in HBV?
HBeAg+ patients 20-30% HBsAg loss
What is one of the main side effects of Peg-IFN? treatment?
Thyroid dysfunction
What is first line HBV treatment as per NICE? What is second line?
Peg-IFN?
TDF (entecavir is an alternative)
What does NICE receommend if HBV DNA detectable at 96 weeks of NA treatment?
1) check adherence
2) add lamivudine if no history of lamivudine resistance (HB
3) add entecavir if history of lamivudine resistance (HBsAg+)
Main updates in WHO 2024 HBV guidelines
Treat all with significant fibrosis (>7kPa) previously only cirrhosis
Treat all with DNA >2000, previously >20,000 IU/ml and ALT above ULN
Treat all patients with coinfections, comorbidities, immunosuppression or extra hepatic manifestations
What is the risk of HBV transmission in pregnancy without prophylaxis?
70-90% for HBeAg+
40% for HBeAg-
When should testing for e markers and DNA be performed by during pregnancy?
By 24 weeks gestation
What are risk factors for HBV transmission in pregnancy?
IgM positive
eAg positive
Anti-HBe negative
DNA >200,000 IU/ml
HBsAg >4 log
Which women should be treated for HBV during pregnancy?
All patients eligible for treatment due to liver disease etc
Women who aren’t eligible for treatment, should still be treated in last trimester if >200,000 IU/ml to to reduce VL at delivery as 10% transmission risk of HBV if VL >200,000 despite HBIG and vaccination
When should women be treated for HBV in pregnancy? And what is the treatment?
TDF from week 24-28 weeks
If women are being treated for HBV what should this treatment be changed to when pregnant?
Tenofovir
If women are treated for HBV to reduce perinatal transmission, when should their treatment be stopped? What should be monitored?
Treatment should be stopped by 12 weeks post partum, and they should be monitored for HBV flares
Should women with HBV have a C-section? Can they breastfeed?
No (although can be considered for Asian women with >6.14 log viral load!)
Women should breastfeed (unless cracked nipples or infant has oral ulcers)
What test is collected on babies born to HBV positive mothers and when?
DBS at birth (pre-PEP) for neonates born to high risk mothers
HBsAg tested at 12 months
Risk of HBV infection in pregnancy?
Risk of transmission to foetus
High VL but low ALT during pregnancy
Flares in pregnancy are common, close follow up for 6 m post partum
More likely to eAg seroconvert
Definition of reactivation in:
a) HBsAg+ DNA+
b) HBsAg+ DNA-
c) HBsAg- DNA-
d) HBsAg- DNA+
a) >2log increase in VL
b) DNA > 100 on 2 occasions
c) detectable HBsAg or DNA
d) ?occult HBV (as per a)
Which treatments are considered a) high risk b) moderate risk or c) low risk for HBV reactivation?
a) >10% risk eg rituximab, JAK inhibitors, HSCT
b) 1-10% risk CAR-T
c) <1% eg methotrexate, azathioprine
Actions for patients with a) HBsAg+ CHB b) anti-HBc +, HBsAg- treated with agents causing HBV reactivation with:
a) high risk
b) moderate risk
c) low risk
a) NA prophylaxis for both
b) NA prophylaxis for a) and either NA prophylaxis or monitoring for b)
c) monitoring
What prophylaxis is given when patients are at risk of HBV reactivation?
If not on prophylaxis, what monitoring is performed?
Lamivudine or entecavir or tenofovir
HBsAg/DNA/ALT every 1-3 months with pre-emptive therapy with ETV/TDF/TAF
In immunosuppressed patients being treated/prophylaxed for HBV reactivation, when should NAs be stopped post immunosuppression?
12 months (18 months for rituximab 12-24 m for HSCT) monitoring for late reactivation is essential
Management of HSCT recipient whose donor is anti-HBc positive?
Lamivudine prophylaxis for 12-24 m
How are HBV positive patients managed when on dialysis?
Separate machines required
How are HBV negative patients managed when on dialysis?
Vaccination - <100 IU/ml is considered non responder
HBsAg testing every 3 m (or 6 m if known to be HBsAb >100)
HBV vaccine schedules:
Childhood
Standard
Accelerated
a) 8,12, 16 weeks
b) 0, 1, 6 months
c) 0, 1, 2, 12 months
HBV vaccines, what is special about:
Fendrix
PreHevbri
HEPLISAV B
Fendrix - for renal insufficiency
PreHevbri - tri-antigenic monovalent vaccine in cell culture. Good for poor responders
HEPLISAV B - two dose schedule
Which patients get antibody testing post HBV vaccine? When does testing occur and what if non-response?
Only HCW, organ recipients or dialysis patients
Tested 1-2 m post final dose
If 10-100 IU/ml give one more booster dose (no Ab testing)
If <10 test for current and past infection and rpt course
How often are renal dialysis patients tested for anti-HBs?
In which situations would they get a booster dose?
Annually or prior to dialysing in high risk country
Boosted if <100 mIU/ml
When should HBV vaccine and HBIG be administered to neonates born to HBV infected mothers?
First dose of vaccine within 24 h and HBIG within 24 h of vaccine - given at different sites
Which neonates get HBV vaccine at birth? Which vaccine?
All neonates born to HBsAg+ mothers and those who will be going home to someone with HBV
Engerix or HBVaxPro
What situations would require HBIG at birth?
1) acute HBV in pregnancy
2) HBeAb neg
3) HBeAg pos
4) VL of >1x10^6 at any point in pregnancy
5) <1500 g at birth
What is the HBV vaccine schedule for neonates born to HBV infected mothers?
1) birth (monovalent)
2) 4 weeks (monovalent)
3) 8 weeks (hexavalent)
4) 12 weeks (hexavalent)
5) 16 weeks (hexavalent)
6) 12 months (monovalent)
When can HBIG be administered in relation to vaccine?
Ideally within 24 h but can give up to a week post exposure
What might occur if HBIG given after infection has occurred?
May reduce the chance of chronic infection
If you test anti-HBs titres in a patient one month after vaccine AND HBIG, what indicates an adequate vaccine response?
> 50 mIU/ml likely reflects vaccine response and not circulating HBIG
Dose of HBIG for a) newborns b) adults
a) 200-250 iu
b) 500 IU
HBV PEP post sexual exposure.
What 4 actions?
1) baseline testing prior to PEPSE
2) accelerated vaccine course
3) HBIG if within 1 week of last exposure
4) condom use until 3rd dose
Can donors with chronic HBV donate tissues?
No, donation is contraindicated
HBV testing in organ recipients?
What additional tests if anti-HBc positive?
HBsAg, anti-HBc, anti-HBs
HBV DNA and HDV serology (also confirmation of core?)
Three indications for liver transplant due to HBV?
What is required prior to transplant and what is the aim?
1) Severe acute HBV (ALF/fulminant hepatitis /INR >6.5)
2) Decompensated liver disease
3) HCC
All patients should be treated with NAs before transplant with the aim of having an undetectable VL prior to transplant
Which patients can receive anti-HBc positive liver?
What prophylaxis?
HBV immune or non-immune recipients - lifelong lamivudine
HBsAg+ recipient - NA and HBIG
Which patients can receive HBsAg positive liver?
What prophylaxis?
Ideally a HBsAg+ recipient
If urgent then HBsAg neg recipient and treat with ETV/TDF
Which patients can receive HBV/HDV coinfected liver?
What prophylaxis?
No-one - contraindicated in all circumstances
What livers can HBV/HDV co-infected patients receive?
What prophylaxis?
HBsAg negative livers only to avoid superinfection of transplanted liver
Lifelong NA and HBIG (can consider stopping HBIG at >24 m, the aim of HBIG is to keep anti-HBs >100 mIU/ml
Can anti-HBc positive, non-liver, organs be donated?
What prophylaxis?
Yes, de novo infection is rare
6 months of lamivudine, or consider none if anti-HBs positive
Can HBsAg positive, non-liver, organs be donated?
What prophylaxis?
HBsAg positive orgnas not usually used unless recipient HBsAg+
Can be used in urgent cases if recipient anti-HBs, and given lamivudine and HBIG post transplant
What makes HBV infected patients considered high risk if receiving a liver transplant due to HBV?
What prophylaxis is given to high risk patients?
What prophylaxis is given to low risk patients?
HCC
DNA positive pre-transplant
HBeAg+
HIV
HBIG and NAs
NAs only can be considered, or early withdrawal of HBIG
Management of anti-HBc positive recipients of a non-liver organ?
NA prophylaxis or monitoring for reactivation
Risk of de novo HBV infection in:
anti-HBc positive liver > naive recipient
anti-HBc positive liver > anti-HBc positive
anti-HBc positive liver > anti-HBc and anti-HBs positive
> 50%
10-20%
<10%
Treatment options for patient with de novo HBV, despite lamivudine prophylaxis, post organ transplant?
Tenofovir - do not use entecavir!
Treatment of HBV in patient who has been exposed to lamivudine?
Previous lamivudine exposure can pre-dispose to entecavir resistance, therefore in LAM experienced patients tenofovir should be used for treatment
Treatment of HBV in patient who has adefovir resistance?
Entecavir
The efficacy of which NA do YMDD mutations impact?
Lamivudine
Which two HBV mutations cause intermediate resistance to tenofovir?
A181T/V
N236T
Which two mutations cause resistance to lamivudine and intermediate resistance to entecavir and adefovir?
M204V/I
M204V + L180M
What monitoring should be done post organ transplant for:
a) HBsAg positive liver transplant recipient
b) Recipient with anti-HBc pos organ
Both get DNA and HBsAg monitoring 3 monthly for first year then 6 monthly after, regardless of prophylaxis (not sure if this is for core+ livers or all?)
What % of IgM positives are due to HBV flare rather than acute infection?
How can you differentiate?
20%
anti-HBc avidity testing
PH actions for case of acute HBV
Identify close contacts = household and sexual contacts
Sexual contacts (last 6 months)
Vaccine and HBIG if last sexual contact within 7 days
Condom use until third dose of vaccine
Test for HBV
Household contacts
Vaccine
Test for HBV
Actions for NSI from ?HBV pos source
Remember first aid first! Wash with soap and water
PEP within 24 h ideally, or at least within 7 d
HBsAg testing at 6, 12, 24 weeks (and storage bloods at d0)
No donating blood, and barrier contraception, until HBV ruled out
HBV PEP for HBsAg positive source in:
Unvaccinated
Partially vaccinated
Fully vaccinated with primary course
Non-responder
Accelerated course plus HBIG
One dose of vaccine and finish course
Booster dose if >1 y since last dose
Booster dose plus HBIG at d0 and d30
HBV PEP for unknown source in:
Unvaccinated
Partially vaccinated
Fully vaccinated with primary course
Non-responder
Accelerated course
One dose of vaccine and finish course
Consider booster dose if >1 y since last dose
Booster dose plus HBIG at d0 and d30
What are pre-core mutants, basal core mutants and Sgene mutations in HBV? What do they mean clinically?
Basal core mutations include double mutant A1762T and G1764A, which reduce HBeAg expression through transcriptional mechanisms. PC mutants have premature stop coding resulting in absent HBeAg expression.
These cause increased replication and faster disease progression.
S gene mutations include S-escape variants can be undetected by lab tests and immune escape. Causes my mutations in preS/S genomic region
