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Part 2 > Hepatits B > Flashcards

Hepatits B Flashcards

1
Q

Occult Hep B & it’s complications

A

Occult hepatitis B infection (OBI) is defined as the existence of low-level HBV DNA in the serum (<200 IU/mL), cells of the lymphatic (immune) system, and/or hepatic tissue in patients with serological markers of previous infection (anti-HBc and/or anti-HBs positive) and the absence of serum HBsAg.

replication-competent viral DNA is present in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing negative for the HBV surface antigen (HBsAg). In this peculiar phase of HBV infection, the covalently closed circular DNA (cccDNA) is in a low state of replication.

a) it can be transmitted, causing a classic form of hepatitis B, through blood transfusion or liver transplantation; (b) it may reactivate in the case of immunosuppression, leading to the possible development of even fulminant hepatitis; (c) it may accelerate the progression of chronic liver disease due to different causes toward cirrhosis; (d) it maintains the pro-oncogenic properties of the “overt” infection, favoring the development of hepatocellular carcinoma.

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2
Q

HBV structure, virology, and classification

A

Enveloped circular partially ds DNA virus.

rcDNA- relaxed circular DNA
cccDNA - covalently closed circular DNA

SEE IMAGE IN ALBUM

spherical virion comprises an envelope that is outside a nucleocapsid that encloses a circular DNA genome.

The lipid bilayer of the virion envelope incorporates the large (42-kD) hepatitis B virus surface protein (LHBs), the medium (33-kD) surface protein (MHBs), and the small (26-kD) surface protein (SHBs).

LIFE CYCLE:

  1. Viral cell entry using receptor NTCP
  2. Partial dsDNA moves into cell nucleus
  3. Viral DdDP (aka reverse transcriptase) AND HUMAN POLYMERASES creates full dsDNA inside the nucleus - cccDNA
  4. From this dsDNA, DdRP creates pgRNA (pre-genomic) - this is done by human cellular machinery
  5. This pgRNA is the template for both capsid protein translation and nee partial dsDNA reverse transcription
  6. Some of the cccDNA also integrates into the host genome

10 genotypes (A to J) and 24 subtypes
Genotype C more severe disease

Baltimore class: VII

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3
Q

HBeAg in Hep B

A

HBeAg positive infection - usually in young adults. High VL > 10^7 log but normal ALTs.

HBeAg positive disease - VL between 10^5 to 10^7. High ALTs. Exacerbations leading to necroin-
flammation and hepatic fibrosis.

Spontaneous HBeAg seroconversion occurs in approximately 15% of cases per annum. Transition to HBeAg-negative, inactive infection reduces the risk of progression, but the
disease necessitates longitudinal monitoring.

Conversely, HBeAg seroconversion can augur a change to HBeAg-negative disease, with mutations in the precore or basal core promoter down-regulating HBeAg, despite continued HBV replication. PRE-CORE MUTANT. HBsAg levels can remain high(>1000 IU per milliliter), which reflects expression predominantly from integrated HBV genomes.

Spontaneous seroclearance of HBsAg
has been associated with improved clinical outcomes but is infrequent (accounting for an estimated 1 to 2% of cases per year)

Although there is a linear rela-
tionship between HBV DNA levels and the risks of cirrhosis and HCC among
HBeAg-negative patients, among HBeAg-positive patients, the immediate risk is lower for those
with HBV DNA levels exceeding 8 log10 IU per ML than for those with HBV DNA levels of 5 to 7 log10 IU per ML.

In HBeAg-positive patients with active disease, the infection is likely to be transitioning from a low inflamma-
tory–high replicative state to a different immunologic phenotype and phase. The transition is characterized by a decrease in HBV DNA levels and an increase in necroinflammatory damage,
which lead to an increase in hepatocyte turnover (and to the gradual selection of HBeAg-negative
variants).

HBeAg is a secreted HBV protein, derived from the HBcAg reading frame with the use of the first of the two start codons, but is not required
to maintain infection. HBeAg in serum
signals high levels of replication and infectivity, but since HBeAg expression is affected at the transcriptional, translational, and post-translational levels, it may not necessarily correlate with HBV DNA levels.

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4
Q

HBSAg marker in HBV

A

Serologic assays for HBsAg de-
tect virion and subviral particles in blood.

Non–DNA-containing subviral HBsAg particles greatly outnumber virions. SHBs antigen is the pre-dominant component of 22-nm spherical parti-
cles; virion particles are enriched in LHBs antigen. The isoforms cannot be identified by current immunoassays, which target the common antigenic epitope within the “a” determi-
nant of HBsAg protein.

Neither can current HBsAg assays distinguish between HBsAg origi-
nating from covalently closed circular DNA (cccDNA) and HBsAg derived from integrated viral genomes.

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5
Q

Diagnostics to quantify HBV cccDNA

A
  1. HBV RNA: During HBV replication, pgRNA is reversely transcribed to minus-strand DNA. However, a minority of pgRNA transcripts are not transcribed but are encapsidated, releasing HBV RNA–containing capsids into serum. Several methods are available for quantitating pgRNA; two higher-throughput assays have been developed
  2. HBV core-related antigen (HBcrAg): HBcrAg measures a composite of HBeAg, HBcAg, and p22cr protein (a 22-kD truncated core protein). The components of HBcrAg thus originate
    exclusively from HBV cccDNA. Serum
    HBcrAg is measured by means of a chemiluminescent enzyme immunoassay (Lumipulse G sys-
    tem, Fujirebio).
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6
Q

Nucleoside analogues in HBV

A

Nucleoside analogues: Tenofovir, Tenofovir alafenamide, & entecavir.

Compete with endogenous nucleotide substrate to bind the active site of HBV polymerase and disrupts 5’ to 3’ phosphodiester linkage - terminates DNA chain elongation.

ADR: Renal impairment and bone mineral density lowering with Tenofovir.
High LDL and cholesterol with Tenofovir alafenamide.

NAs target late stage of life cycle - act on RT step with no effect on pgRNA transcription and do not directly affect HBsAg expression from integrated genomes. Thus HBeAg loss is uncommon (20-30% in 1-2 years) and HBsAg seroclearance is VERY LOW (0.22% per year).

NAs also do not reduce risk of HCC.

Resistance rates - for entecavir after 5 years, 1%.

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7
Q

Entecavir resistance

A

1% resistance in 5 years

rtL180M
T184L
M204V

Also confers resistance to Tenofovir when in combinations

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8
Q

Peg IF alpha in Hep B

A

IF alpha - pleotropic cytokine

Can be used in Mild-moderate eAg pos or neg disease.

Inhibits transcription of pgRNA from cccDNA.

Tenofovir + IF alpha trial showed HBsAg loss in 9% patients (higher than mono therapy)

TEST THESE 4 before starting:
1. Genotype
2. quantitative surface Ag testing before starting IF alpha. (>20,000 IU/mL in genotype B&C OR no decline of levels at 12 weeks in genotype A&D @12 weeks associated with treatment failure).
3. eAg
4. DNA VL

DURING THERAPY, monitor:
1. FBC
2. ALT
3. TSH
4. DNA
5. sAg levels

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9
Q

Newer agents in HBV

A
  1. Entry inhibitors - Buleviritide - inhibits entry of HBV & HDV
  2. Nucleic acid polymers - REP 2139 (Replicor)
  3. Capsid assembly modulators - disrupts encapsulation of pgRNA
  4. RNA interference
  5. siRNA: Binds to complementary target mRNA leading to cleavage.
  6. ASOs: synthetic single stranded oligonucleotodes that bind to complementary HBV RNA transcripts to form ASO-RNA complexes causing cleavage.
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10
Q

Natural history of chronic HBV

A
  1. Immune tolerance phase: HBeAg pos, high DNA, low ALT
  2. Immune clearance phase: HBeAg pos, low DNA, high ALT- High risk of CLD
  3. Immune control phase: HBeAg neg, DNA neg, ALT normal
  4. Immune escape phase: HBeAg neg, DNA high, ALT high - High risk of cirrhosis
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11
Q

Treatment in HBeAg pos + compensated liver disease

A
  1. Tenofovir
  2. Entecavir second line
  3. Peg IF alpha for 48 weeks. CI in pregnancy.
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12
Q

HBeAg neg + compensated liver disease treatment

A
  1. Tenofovir
  2. Entecavir second line
  3. Peg IF alpha for 48 weeks. CI in pregnancy.
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13
Q

HBV treatment in pregnancy

A

Tenofovir disoproxil if DNA > 200,000 IU/mL OR sAg > 10^4 IU/mL in 3rd trimester to reduce transmission

Repeat DNA after 2 months and ALT monthly after birth

Stop Tenofovir 4-12 weeks after birth UNLESS mum fits criteria for long term treatment

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14
Q

Chronic HBV prophylaxis in immunosuppression

A
  1. sAg pos + DNA > 2000: Tenofovir or entecavir - start before immunosuppression and continue for 6 months after seroconversion and DNA neg.
  2. sAg pos + DNA < 2000: Lamivudine if immunosuppression expected to be more than 6 months. Check VL in 3 months and switch to entecavir/Tenofovir if DNA detectable.

Duration- start before go 6 months after stopping immunosuppression

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15
Q

Fibroscanning indications and cut-offs in HBV

A
  1. New diagnosis
  2. Antivirals if elastography score > 11KPa
  3. Antivirals & Liver biopsy if score 6-10 KPa
  4. Antivirals & liver biopsy if score < 6 BUT age < 30 + DNA > 2000 + ALT >30/19 twice 3 months apart
  5. Offer scan annually if not on antivirals
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16
Q

Indications & antivirals in chronic HBV

A
  1. > 30 years + DNA > 2000 + ALT >30/19 TWICE
  2. <30 years + DNA >2000 + ALT >30/19 TWICE + biopsy/fibroscan s/o inflammation (>6 KPa)
  3. DNA > 20,000 + ALT >30/19 TWICE
  4. CLD + detectable DNA
  5. DNA > 2000 + biopsy showing inflammation
  6. Family H/O HCC
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17
Q

HBV treatment in DCLD

A

NO IF
1. Entecavir first line
2. Tenofovir if lamivudine resistance

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18
Q

Treatment in HBV + HCV

A

DAAs for HCV + NA prophylaxis until 12 weeks post DAA for HBV.

Monitor for sAg in core Ab positive patients on DAAs.

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19
Q

HBV + HDV treatment

A

48 weeks peg IF 2a if evidence of fibrosis

Stop if no decrease in HDV RNA after 6 months.

If responding as they should, Stop treatment when HBsAg seroconverts

50% relapse risk. If ongoing viral load - consider NAs.

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20
Q

Immunosuppression - HBV prophylaxis in cleared infection

A
  1. The NICE recommendations for Core Ab +/sAg - individuals who are undergoing immunosuppressive therapy is:

A. Rituximab - give Lamivudine for at least 6 months after last dose

B. NOT ritux/B cell depletion - monitor and pre-emptiest treat. They’ve subdivided this into:

HBV DNA <2000 IU/ml - Lamivudine
HBV DNA > 2000 - TDF/ETV

  1. EASL on the other hand says:

A. High risk (>10% risk) - ritux/HSCT - give lamivudine for at least 18 months post immunosuppression followed by 12 months monitoring after stopping LAM.

B. Medium/low risk - monitor and pre-emptively treat. First line is ETV/TDF.

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21
Q

Surveillance for HCC in HBV

A
  1. 6 monthly USG & AFP in patients with fibrosis or CLD
  2. 6 monthly USG & AFP with no fibrosis if >40 years + family h/o HCC + DNA > 20,000
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22
Q

PAGE B calculator in HBV

A

Platelet
Age
Gender
HBV

Other score - REACH B - also accounts for ALT & eAg

23
Q

Hep B natural outcome percentages & transmission rates in pregnancy

A

Younger age of infection: greater risk of chronic infection:

90% in infancy
20% upto 5 years
10% after that

Perinatal transmission 90% if baby not immunised and mum high infectivity

<5% with intervention

Perinatal transmission 20-40% if baby not immunised and mum low infectivity

24
Q

HBV incubation

A

30 to 150 days

25
Q

Normal & accelerated HBV vaccination schedule

A

Normal (3 doses):

Hexavalent vaccine (DTaP, IPV, Hib, HBV) @ 8,12,16 weeks

Accelerated (6 doses):

Monovalent HBV vaccine @ birth, 4 weeks, Hexavalent @ 8,12,16, and final monovalent at 1 year

Test @ 1 year old with a dried blood spot test

26
Q

Indications for HBIG

A
  1. Mum sAg + eAg positive
  2. Mum sAg positive but eAb negative
  3. Mum sAg positive but e markers UNKNOWN
  4. Mum has acute HBV in pregnancy
  5. Baby <1500g birth weight
  6. Mum VL > 10^6 in any antenatal sample
27
Q

Timeframes for antenatal HBV referral

A
  1. Specialist team (hepatology) within 6 weeks of positive result or by 24 weeks gestation
  2. F2F appointment in 3rd trimester around 34 weeks to decide on HBIG based on various factors
28
Q

Testing HBV post natally

A
  1. Maternal DNA after delivery
  2. Neonatal DBS before vaccine
  3. Baby DBS at 1 year of age - sAg + anti HBc
29
Q

Women presenting to delivery without HBV screening

A
  1. Facilitate urgent testing
  2. If no further info, give monovalent vaccine.
  3. NO HBIG without a confirmed diagnosis.
30
Q

Missed HBV doses

A
  1. Give immediately
  2. If 4 week dose is late by > 2 weeks, bring 8 week dose forward. Maintain 4 week gap for further doses.
31
Q

Management of babies whose mum is HBV neg but household member is HBV positive

A

Newborn infants given a monovalent HBV vaccine prior to discharge. Then usual course of Hexavalent vaccine.

32
Q

HBV vertical transmission risk with HBIG and vaccine

A

<5% in highly infective mothers

90% without intervention

33
Q

HBV vaccine escape mutant

A

Coexisting HBsAg + anti-HBs

G145R mutation resulting in breakthrough infections despite vaccine/HBIG - this is the most stable mutant

As HBV replicates through an RNA intermediate synthesised by RT, mutant viral genomes and quasi species are generated resulting in production of viral mutants during natural infection. Vaccination and HBIG, antivirals exert evolutionary pressure to select these mutants

34
Q

Antenatal HBV reporting and patient follow up

A
  1. Antenatal HBV results should be reported within 8 working days of receipt
  2. Positive HBV - screening assessment within 10 working days of result
  3. New diagnosis:
    A. High risk: specialist review within 6 weeks or before 24 weeks gestation
    B. Low risk: 18 weeks specialist review
  4. Offer DNA & quantitative sAg before 24 weeks.
  5. Offer treatment with Tenofovir @24-28 weeks if DNA>200,000 or sAg>4log 10

Sequencing of new diagnosis HBV is offered by UKHSA to look for vaccine escape mutants

35
Q

Postnatal care of mum in HBV

A
  1. Stop antivirals at 12 weeks post delivery
  2. Postnatal hepatitis follow up at 3 months
36
Q

Breast feeding in HBV & whilst on TDF

A

No contraindications to either UNLESS co-infection with HIV

37
Q

HBIG dosing

A

250 IU IM

38
Q

Available HBV vaccines

A
  1. Monovalent - Engerix - 1ml dosing
  2. Bivalent HAV/HBV - Twinrix - 1ml
  3. Hexavalent - DTap/IPV/Hib/HBV - infarix hexa -0.5ml

Recombinant DNA from yeast cells. Exception being Trivalent PreHevbri which is a tri-antigenic vaccine comprising S, Pre-S1, and pre-S2 prepared on Chinese hamster ovary cells.

39
Q

HBV standard, accelerated & super accelerated courses

A

Standard: 0,1,6 months
Accelerated: 0,1,2,12 months with Engerix
Super accelerated: 0,7,21 plus 12 if ongoing risk (for travel) - Enger

40
Q

HBV vaccine in renal insufficiency and HD

A

Renal insufficiency: 0,1,2,6 months - Engerix B double dose

HD/gfr<30 : 0,1,2,4 months - HEPLISAV B

41
Q

Indications for prep with HBV vaccine

A
  1. PWID
  2. Frequent sexual partner change & GBMSM
  3. Close contact of HBV
  4. Families adopting children from high/intermediate prevalence areas
  5. Foster caters
  6. People receiving regular blood products
  7. SOT recipients
  8. CKD
  9. CLD
  10. Prisoners & asylum seekers
  11. Residential care
  12. Travellers to highly endemic countries
  13. Occupational risk: HCWs, Lab staff, residential care staff, tattoo artists, embalmers, police etc.
42
Q

Indications for reinforcing/booster dose HBV

A

NOT routinely recommended in people who have completed a primary course

  1. CKD
  2. Significant exposure
  3. Non responders
43
Q

PEP schedule for HBV

A

Accelerated schedule monovalent vaccine @ 0,1,2 months. HBIG if indicated within 24 hours but upto 7 days.

Test for sAg immediately and at 6 months.

Scenarios: SEE FIGURE IN ALBUM

44
Q

Indications to test for immunity after HBV vaccine & non-responders

A
  1. Occupational exposure - HCWs and lab workers

> 10 IU/ml gives protection but >100 is preferable.

If between 10 to 100, offer booster and no further testing or booster needed.

Non responder: sAb <10 taken 1-2 months (CORRECT INTERVAL) after primary course. REPEAT COURSE of vaccine followed by RETESTING after 2 months. If still <10, they are non responders and will need HBIG if exposed.

  1. CKD - threshold for boosting is 10 IU/ml and check annually.
45
Q

HBIG & live vaccines

A

Interferes with immunity generation to live vaccines EXCEPT yellow fever.

Wait 3 months after HBIG ago give live vaccines.

46
Q

Quantitative HBSAg

A

This test measures the level of hepatitis B surface antigen in the serum of patients being monitored for progression of chronic hepatitis B and their response to antiviral therapy. Such measurement is especially useful in those individuals who have negative HBe antigen and positive HBe antibody results with relatively low hepatitis B viral DNA levels (eg, <2000 IU/mL) in serum.

47
Q

HBV receptor

A

GPC5 & NTCP

48
Q

End points of HBV treatment with NA

A
  1. NAs should be discontinued after confirmed HBsAg loss, with or with out anti- HBs seroconversion.
  2. NAs can be discontinued in non-cirrhotic HBeAg positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy.
  3. Discontinuation of NAs in selected non-cirrhotic HBeAg-negative patients who have achieved longterm (3 years) virological suppression under NA(s) may be considered if close post-NA monitoring can be guaranteed.
  4. Normalisation of ALT.
49
Q

HBV liver transplant indications

A
  1. Fulminant liver failure
  2. DCLD
  3. HCC

Note - start tenofovir in all 3 above first before transplant

50
Q

Pre-transplant treatment in HBV

A

Start tenofovir with aim for undetectable DNA

51
Q

HBV core Ab or surface Ag organ donors

A

Match donor and recipient as far as possible

LIVER:

  1. Core Ab liver in Core Ab pos OR immune naive patients - Lamivudine indefinitely
  2. SAg liver in ANY patient - Tenofovir indefinitely

NON-LIVER:

  1. Core Ab pos - Lamivudine for 6 months
  2. SAg pos - individual risk assessment - ?Tenofovir how long?
52
Q

Post transplant HBV prophylaxis & treatment of reactivation

A
  1. High risk of recurrence (eAg, HCC, HIV co-infection) - HBIG + NA lifelong
  2. Low risk - consider stopping HBIG AFTER 1 year, continue NA lifelong
  3. Isolated Core Ab - 6 months Lamivudine OR MONITOR alone
  4. Recurrence - Lifelong Tenofovir
53
Q

Post transplant HBV monitoring

A

Every 3 months for a year and 6 monthly thereafter in SAg all organs and cAb liver.

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