Hepatitis B Virus

Factors related to progression to Cirrhosis/HCC

  • – Annual risk of HCC in patients with cirrhosis 2-5%
  • ⇒Factors related to host
  •              – Cirrhosis
  •              – Chronic necroinflammation
  •              – Older age
  •              – Male sex
  •              – African origin
  •              – Alcohol abuse
  •              – Co-infection (HCV, HIV)
  •              – DM
  •             – Active smoking
  •             – Positive family history
  • ⇒ Factors related to HBV
  •              – High HBV DNA, HBsAg level
  •             – HBV genotype C>B
  •            – Specific mutation

 

Histopathological features of Chronic HBV

  • – Mononuclear cell infiltrate in periportal area
  • – Interface hepatitis ( disruption of limiting plates of hepatocytes)
  • – During reactivation: Lobular inflammation is more intense and reminiscent of acute HBV
  • In light microscopy: ground glass appearance of hepatocytes due to HBsAg particle deposition

Treatment of acute severe hepatitis due to HBV

  • – Some experts recommend NA therapy when
  •                       •  HBeAg remain detectable for >10-12 weeks
  •                       • INR>1.5
  •                       • Deep jaundice >4 weeks
  • Duration of therapy: Not established
  •                • 3 months after HBs Ag seroconversion
  •                • 12 months after HBeAg seroconversion if HBsAg loss does not occur

                                 

                               DIAGNOSIS OF HBV

HBsAg

  • • Appear 2-10 weeks after exposure
  • • Undetectable within 4-6 weeks
  • •HBsAg + Anti HBsAb: 10-20% HBV carrier
  • • Isolated Anti HBc
  • • Found in 50% patients of highly endemic region of the world
  • • 10-30% patients with this finding may have HBV DNA detectable in serum

Interpretation of isolated anti HBcAb

  • • Recent infection
  • • False positive infection
  • • Window period of acute HBV infection
  • • Occult HBV

HBV DNA

  • • Quantitative PCR method can detect <400 copies/ml
  • • High HBV DNA (>109 copies/ml) respond less commonly to IFN therapy

Indications for treatment:

 

  • • HBV DNA>2,000 + Moderate Fibrosis-
  •         -Start treatment even if ALT is normal
  • • In compensated/ decompensated cirrhosis
  •         -Treat at any detectable DNA level and regardless of ALT level
  • •  HBeAg positive Chronic HBV infection (persistently normal ALT + High DNA)
  •        – Start treatment if patient is older than 30 years without biopsy
  • • HBeAg positive/ negative Chronic HBV infection + family H/O HCC/Cirrhosis/extrahepatic manifestatios
  •          – Start treatment even if typical indications are not fulfilled

Follow-up of patients on NA

  • 1. At Baseline
  •              • CBC
  •              • LFT
  •               Renal function test (eGFR, S. Phosphate)
  •               HBV DNA by sensitive PCR
  • 2. After initiating therapy
  •         LFT
  • • Every 3-4 month in first year
  • • Then 6 monthly
  •       HBV DNA
  • • 3-4 monthly in first year
  • • Then 6-12 monthly
  •           HBsAg
  • • 12 monthly if HBV DNA undetectable
  • • Test for anti HBsAb if HBsAg cleared

                  Renal function test:

  • Patients at risk of renal disease and all patients regardless of renal status treated with TDF
  •                 • RFT 3 monthly in first year
  •                 •Then 6 monthly if no deterioration
  •                 • Monitor closely if CCR <60ml/min or S. Phosphate <2 mg/dl

 

                            Monitoring of Patients Who are not Candidates for Anti-Viral Drugs

 

  •                             1. HBeAg-positive chronic HBV infection
  •                                                   – ALT : Every 3 months
  •                                                   – HBV DNA  :  Every 6–12 months and
  •                                                   – Liver fibrosis assessment  : Every 12 months
  •                              2. HBeAg-negative chronic HBV infection and HBV DNA <2,000 IU/ml
  •                                                  – ALT : Every 6-12 monthly
  •                                                 – HBV DNA  :  Every 2-3 years
  •                                                 – Liver fibrosis assessment  : Every 2-3 years
  •                             3.  HBeAg-negative chronic HBV infection and HBV DNA  ≥ 2,000 IU/ml
  •                                              – ALT : Every 3 months for the first year and every 6 months thereafter
  •                                              – HBV DNA  :  Every year for at least 3 years
  •                                             – Liver fibrosis assessment  : Every year for at least 3 years non-invasively

 

                                      Nucleos(t)ide analog  discontinuation:

  • – Discontinuation is discouraged in cirrhotic patients (both compensated, decompensated)
  • – Non cirrhotic + HBeAg seroconversion patients may discontinue who
  • – Achieve stable HBeAg seroconversion
  • – Achieve HBV DNA undetectable and who completed at least 12 months of consolidation therapy
  • – Close post NA monitoring is warranted
  •            • In HBeAg negative non cirrhotic patients who achieve long term (³3 yr) virological suppression under NA may be considered for discontinuation if post-NA monitoring can be guaranteed

 

 

Nucleos(t)ide analog drugs

  • – 70-85% of HBeAg positive patients become HBV DNA negative during the first year of treatment. 85-95 % at 2 year
  • – HBeAg seroconversion occur slowly and often require treatment for years or an indefinite duration
  • – Despite rapid decline in HBV DNA level on nucleos(t)ide analog therapy, only 20-25% patients achieve HBeAg seroconversion after 1 year of therapy. 40% at 5 year
  • – 15-20% HBeAg positive patients develop virologic relapse 1 year after discontinuation of therapy
  • – Treatment for a minimum of 6 months after HBeAg seroconversion is recommended

Peg-IFN therapy in CHB

                                  Indication:

  • – Mild to moderate CHB hepatitis (HBeAg +ve/ HbeAg –Ve patients
  • – Selected patients with compensated cirrhosis but no portal HTN
  • Duration of therapy:
  •              • 48 weeks
  •              • Beyond 48 weeks in selected HBeAg –Ve CHB patients
  • – HBsAg loss rate increases after the end of PegIFNα therapy in initially HBeAg positive CHB patients with sustained virological response
  • – Rate of HBsAg loss after 12 months of therapy is 3-7%
  • – Patients with initial HBeag loss HBsAg loss 3 year after therapy  is 30%
  • – In HBeAg –Ve patients, HBsAg loss progressively increase after PegIFN discontinuation
  •                    • 3% at 6 months of discontinuation
  •                    • 9% at 3 year of discontinuation
  •                    • 12% at 5 year of discontinuation

Monitoring of Patients receiving PegIFN-α

  • In patients with undetectable HBV DNA (-Ve HBeAg) HBsAg should be checked at 12 months interval, as the rate of HBsAg loss increase over time
  • – Patients who become HBsAg negative should be tested for anti HBs

Desired treatment end point

  • – HBV DNA<2000 IU/ml
  • – HBSAg loss
  • – HBeAg seroconversion

Long term outcome after PegIFN

  • – Rates of HBsAg loss in sustained responders are gradually increasing approaching 50% at 5 year after the end of thearpy

 

 

                                                            Main concepts and features of current treatment strategies of chronic hepatitis B

 

Features PegIFNa

ETV, TDF, TAF

 

Route of administration Subcutaneous injection Oral
Treatment duration 48 weeks Long-term until HBsAg loss (stopping NA after some years might be considered in selected cases)
Tolerability Low High
Long-term safety concerns Very rarely persistence of on-treatment adverse events(psychiatric, neurological, endocrinological) Probably not (uncertainties regarding kidney function, bone diseases for some NA)
Contraindications Many (i.e., decompensated disease, co-morbidities etc.) None (dose adjustment according to eGFR)
Strategy Induction of a long-term immune control by finite treatment Stopping hepatitis and disease progression by inhibiting viral
replication
Level of viral
suppression
Moderate (variable response pattern) Universally high
Effect on HBeAg loss Moderate, depending on baseline characteristics Low in the first year, increases to moderate during long-term
treatment
Effect on HBsAg levels Variable, depending on baseline characteristics (overall
higher as compared to NA)
Low: slowly increases with treatment time in HBeAg-positive
patients3; usually very low in HBeAg-negative patients
Risk of relapse after treatment cessation Low for those with sustained response 6–12 months after
therapy
Moderate if consolidation treatment provided after HBeAg seroconversion.
Early stopping rules Yes No
Risk of viral resistance
development
No Minimal to none

 

HBV Infection in Pregnancy

  (EASL- 2017)

 

  • – Screening for HBsAg in the 1st trimester is strongly recommended
  • – Pregnant woman with CHB and advanced fibrosis or cirrhosis, therapy with Tenofovir (TDF) is recommended
  • – If pregnant woman already on NA therapy TDF should be continued, while Entecavir or other NA should be switched to TDF
  • – In a woman of child bearing age without advanced fibrosis who plans a pregnancy in near future, it may be prudent to delay therapy until the child is born
  • – In all pregnant women with high HBV DNA level (200,000 IU/ml) or HBsAg level > 4 log IU/ml, antiviral prophylaxis with TDF should start at week 24-28 of gestation and continue for upto 3 months after delivery
  • – Peg IFN is contraindicated during pregnancy
  • To prevent perinatal transmission: HBIG and vaccination of the new born within 12 hours of delivery
  • – Safety of NA during lactation is uncertain
  • – HBsAg is detected in breast milk but breast feeding is not contraindicated in HBsAg positive mothers

Acute Flare of HBV 

Characteristics:

  • – Precipitous increase in ALT
  • – ALT 2-3 times from baseline and at least 100 IU/ml
  • – Leads to histologic progression

    Reactivation of Chronic HBV

  • – Marked increase in HBV replication (≥ 2 log increase from baseline levels or new appearance of HBV DNA to a level ≥ 100 IU/ml) in a person with previously stable or undetectable level

                                     Or,

          – Detection of HBV DNA with levels ≥ 20,000 IU/ml in a person with no baseline HBV DNA

 

Causes of hepatic flare:

  • – Spontaneous 
  • – Immunosuppressive therapy
  • – Super-infection with other hepatotrophic viruses
  • – Herbal medications
  • – HIV treatment (due to direct toxicity of HAART or immune reconstitution)
  • – Antiviral therapy for HBV
  • IFN: 30% patients in 2nd/3rd month of therapy
  • NA: Reappearance of wild-type HBV

 

Immunosuppressive induced flare:

  • – When reactivation occurs in the setting of cancer chemotherapy or systemic treatment for severe autoimmune disorder, patient may not be eligible for salvage liver transplantation
  • – Growing body suggests
  •                 Screening all patients in need of immunosuppressive drug therapy for HBsAg, anti HBc
  •                 Prophylactic treatment with antiviral for HBsAg positive patients
  • – Antiviral should be started 1 week before immunosuppressive drug therapy initiation
  • – NA therapy continue for 6-12 months after completion of immunosuppressive therapy
  • – ALT flare occur in approximately 20% patients after withdrawal of NA therapy

 

Occult Hepatitis B Virus Infection (OBI)

       

   Definition:

  • – Detectable DNA in serum/liver
  • – Negative HBsAg in serum
  • – Anti HBS (Anti-HBc may or may not positive)

1st Group:

  • – Window phase of HBV, exposed recently

2nd Group

  • – Persistently detectable HBV DNA without prior documentation of HBsAg positivity before presentation
  • – Window phase of HBV, exposed recently

3rd Group

  • – Known chronic HBV infection
  • – Previous documentation of HBsAg positivity for at least 6 months and subsequent HBsAg seroclearance
  • – 50-60% of these patients are anti-HBc positive

 

Serological classification of OBI

1.Seropositive OBI

  • – Anti HBs and or Anti-HBc positive

2.Seronegative OBI

  • – Both anti HBS and or anti-HBc negative
  • – These seronegative OBI patients may likely be infected with minute amount of HBV which are insufficient to mount intense and specific immune response

 

                                                 Who should be suspected for OBI?

  • – HBsAg negative patients with or without anti HBs Ab or Anti HBc
  • – Patients with cirrhosis/HCC who have no identifiable cause. in these patients HBV DNA should be measured by highly sensitive method

 

Who should be tested for HBV DNA to detect OBI?

  • – If HBsAg is negative before blood donation. Donation should be discarded if HBV DNA is detectable in these patients
  • – HBsAg negative, Anti HBc positive subjects with or without positive Anti HBs should be closely monitored by HBV DNA during and at least 12 months after immunosuppressive therapy
  • – Chronic HBV patients with HBsAg seroclearance still require follow up for the development of cirrhosis related complications and HCC

HBV in Special Groups

Patients undergoing immunosuppressive therapy/Chemotherapy

  • – All candidates for chemotherapy and immunosuppressive therapy should be screened for
  •                    • HBsAg
  •                    • Anti HBS Ab
  •                    • Anti HBc
  • – If these tests are negative then advice for vaccination
  • – All HBsAg positive Patients Should receive ETV,TDF or TAF as treatment or prophylaxis (without DNA report)

HBsAg positive patients

  • – Chronic HBV infection without chronic hepatitis
  •               • Prophylaxis should continue 12 months (18 months for Rituximab based regimen) after cessation of immunosuppressive treatment and discontinue only if underlying disease is under remission
  •               • LFT+ HBV DNA should be tested every 3-6 months during prophylaxis for at least 12 months after NA withdrawal

HBsAg -ve, Anti HBc +ve Patients

  • – Tests for HBV DNA before chemotherapy and if it is +ve should be treated similar to HBsAg positive patients
  • – High risk groups (Taking Rituximab, undergoing stem cell transplantation)
  •                   • Anti-viral is recommended
  •                   • Continue anti-viral for 18 months after stopping immunosuppressive
  •                   • Prophylaxis with LAM, ETV recommended

HBsAg -ve, Anti HBc +ve Patients with moderate/low risk HBV reactivation

  • – Preemptive therapy but no prophylaxis is recommended
  • – Preemptive therapy
  •               • Start with ETV/TDF/TAF if HBV DNA is detectable or HBsAg seroreversion
  •               • Monitor HBsAg/HBV DNA every 1-3 months during and after immune-suppression

HBV  Vaccination

  • – Antibody titre>100 mIU/ml is 100% protective
  • – Antibody titre <10 mIU/ml is sero-protective in most instances
  • – Antibody titre drops steadily over the first 2 years after vaccination, sometimes <10 mIU/ml
  • – Anti HBs titre decrease to non-protective levels in at least 25-50% recipients over a period of 5-10 years
  • – 5-8% HBV vaccine recipoients do not achieve detectable anti HBsAb (non-responder)

Causes of inadequate response after vaccination

  • – Smoking
  • – Obesity
  • – Injection into buttock
  • – CLD
  • – Extreme of age
  • – Immunocompromised state (transplant recipient, chemotherapy, end stage liver disease)

HBV Treatment in Dialysis and Kidney Transplant Patients

  • – All dialysis and transplant patient should be screened for HBV markers.
  • – HBV sero negative patients should be vaccinated preferably by reinforced vaccine
  • – All HBsAg +ve renal transplant recipient should receive ETV/TAF as prophylaxis or treatment
  • – HBsAg +ve patients who require treatment should receive ETV/TAF
  • – HBsAg –ve , Anti Hbc +ve patients should be monitored for HBV infection after transplantation

 

                                           For Dialysis Patients:

  • – Chronic HBV infection (not chronic hepatitis) should be monitored
  • – HBsAg +ve/-ve chronic hepatitis B should receive NA as preferred treatment
  • – ETV is recommended for NA naïve patients
  • – All doses of NA should be adjusted if eGFR is <50 mi/min
  •                • Only TAF does not require dose adjustment until eGFR<15mi/min
  • – IFN can be used in selected patients

                       

                                               For transplant recipients:

  • – All HBsAg +ve patients should receive anti HBV prophylaxis or treatment with NA
  • – ETV is the preferred option for NA naïve patient
  • – TDF should be avoided
  • – NA prophylaxis and treatment should be continued long-term
  • – Peg-IFN alpha is contraindicated because of the risk of rejection
  • – Unexpected deterioration of renal function during NA therapy may necessitate a change of treatment or dose adjustment
  • HBsAg-ve, anti HBc +ve renal transplant recipient patient do not need prophylaxis/treatment

 


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