Download بنام خداوند مهربان Management of chronic hepatitis B virus infection

‫بنام خداوند مهربان‬
‫دکتر نرگس نجفی‬
‫دانشیار دانشگاه‬
Case presentation:
 A 33-year-old man was diagnosed with hepatitis B
virus (HBV) infection 4 months ago when his entire
family was tested because an uncle living in Gorgan
was found to have hepatocellular carcinoma (HCC).
The patient had no remarkable medical problems and
no symptoms of liver disease
Initial laboratory results :
 Platelet count: 180,000 cells/mm3
 White blood cell count: 4600 cells/mm3
 Hematocrit: 41%
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Alkaline phosphatase: 85 U/L
Total bilirubin: 0.4 mg/dL
Albumin: 4.6 g/L
Globulin: 2.4 units
 International normalized ratio: 0.9
 Alpha-fetoprotein: 4.0 ng/mL
 Thyroid-stimulating hormone: 4.0 IU/mL
laboratory results :
 HBV DNA: 3.7 x 108 IU/mL
 ALT: 55 IU/L
 AST: 45 IU/L
 HBV genotype C
 Hepatitis B e antigen (HBeAg) positive
physical examination
 the patient’s physical exam is normal and he
undergoes imaging, which reveals a normal sized liver
and no enlargement of the spleen.
QUESTION: Based on these laboratory results, how
would you manage this patient?
 A. Begin treatment with an oral agent
 B. Monitor every 3-6 months to determine ALT rises
 C. Begin 48-week course of treatment with
peginterferon alfa-2a
 D. liver biopsy
liver biopsy
 which reveals moderate chronic hepatitis,
 with an Ishak necroinflammatory score of 10 (out of 18)
and a fibrosis score of 3 (out of 6).
QUESTION: Based on these laboratory and liver biopsy
results, how would you manage this patient?
 A. Begin treatment with an oral agent
 B. Monitor every 3-6 months to determine ALT rises
 C. Begin 48-week course of treatment with
peginterferon alfa-2a
Indications for treatment
 The indications for treatment are generally the same
for both HBeAg-positive and HBeAg-negative CHB.
This is based mainly on the combination of three
criteria:
 Serum HBV DNA levels.
 Serum ALT levels.
 Severity of liver disease.
Indications for treatment
 Immunotolerant patients: HBeAg-positive patients
under 30 years of age with persistently normal ALT
levels and a high HBV DNA level, without any
evidence of liver disease and without a family history
of HCC or cirrhosis, do not require immediate liver
biopsy or therapy. Follow-up at least every 3–6 months
is mandatory.
 Consider liver biopsy or even therapy in such patients
over 30 years of age and/or with a family history of
HCC or cirrhosis.
Selection of drug
treatment with
 (PEG-)IFN
or
 NA
Pre-treatment factors for IFN/PEG-IFN based
treatment
In HBeAg-positive CHB, predictors of anti-HBe
seroconversion
 low viral load (HBVDNAbelow 2 108 IU/ml),
 high serum ALT levels (above 2–5 times ULN),
 HBV genotype A and B
 high activity scores on liver biopsy (at least A2)
laboratory results :
 HBV DNA: 3.7 x 108 IU/mL
 ALT: 55 IU/L
 AST: 45 IU/L
 HBV genotype C
 Hepatitis B e antigen (HBeAg) positive
Duration of treatment?
Case presentation:
 A 45-year-old woman with chronic hepatitis B is
referred to you.
 Her hepatitis B virus (HBV) infection was diagnosed
during her first pregnancy.
laboratory evaluations

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Hepatitis B surface antigen (HBsAg): positive
Hepatitis B e antigen (HBeAg): negative
HBV DNA: 1,650,000 IU/mL
Alanine aminotransferase (ALT): 50 IU/L
HBV genotype: D
liver biopsy and the results indicate moderate
(Metavir stage 2-3) fibrosis.
QUESTION: What type/duration of regimen
would you recommend for initial therapy?
 A. Nucleos(t)ide analogue monotherapy for an
indefinite duration
 B. Combination nucleos(t)ide analogue therapy for
an indefinite duration
 C. Peginterferon alfa-2a for 48 weeks
Decision making for treatment
 Patients with obviously active CHB: HBeAg-positive and
HBeAg-negative patients with ALT above 2 times ULN and
serum HBV DNA above 20,000 IU/ml may start treatment
even without a liver biopsy (B1).
 In such patients, liver biopsy may provide additional useful
information, but it does not usually change the decision for
treatment.
 A non-invasive method for the estimation of the extent of
fibrosis and most importantly to confirm or rule out
cirrhosis is extremely useful in patients who start
treatment without liver biopsy (B1).
Selection of drug
 Peginterferon alfa-2a vs
 Nucleos(t)ides as First-line Therapy
Selection of drug
 efficacy (and durability of response),
 tolerability,
 risk of resistance,
 duration of treatment,
 mode of administration
Selection of drug
 Other factors that may influence the choice among the
5 available oral nucleos(t)ide analogues include
 pregnancy (or potential pregnancy),
 presence of coinfections
 comorbidities,
 schedule/food restrictions,
 and cost
Selection of drug
 peginterferon alfa-2a therapy is restricted to a limited
duration (typically 48 weeks)
 whereas nucleos(t)ide analogue therapy can be, and
often is, prolonged over long or indefinite time periods
in HBeAg-negative patients
Drugs
Drugs available for the treatment of CHB include
 IFN, PEG-IFN and six NAs.
 NAs for HBV therapy can be classified into
nucleosides (lamivudine, telbivudine, emtricitabine,
entecavir) and
nucleotides (adefovir and tenofovir).
NAs
 Lamivudine is an inexpensive agent, but engenders
very high rates of resistance with long-term
monotherapy
 Adefovir is less efficacious and more expensive than
tenofovir, engendering higher rates of resistance
NAs
 Telbivudine is a potent inhibitor of HBV replication,
but,
 lower barrier to resistance,
 high incidence of resistance has been observed in
patients with high baseline HBV DNA levels
NAs
 Entecavir and tenofovir are potent HBV inhibitors
with a high barrier to resistance
Thus, they can be confidently used
as first-line monotherapies
Selection of drug
 HBV genotype has been found to strongly correlate
with sustained virologic response to interferon in both
HBeAg-positive and HBeAg-negative hepatitis
Selection of drug
 The lowest rates of sustained virologic response
with interferon alfa-2b have been shown to occur in
HBeAg-negative patients infected with genotype D
and high baseline viral loads.
Factors in Selecting an Oral Nucleos(t)ide
Analogue–Based Regimen for Initial Therapy
 Among the 5 nucleos(t)ide analogues approved for the
treatment of chronic HBV infection, only entecavir
and tenofovir are the recommended agents for
initial therapy in HBeAg-negative patients
Selection of
 Low baseline HBV DNA level (< 2 x 104 IU/mL) has
been identified as a more consistent predictor of
virologic response for agents such as lamivudine,
adefovir, and telbivudine.
Selection of drug
 It has been suggested that for the more potent
nucleos(t)ide analogues, baseline HBV DNA does
not effectively predict the likelihood of achieving and
maintaining undetectable HBV DNA
Selection of drug
 HBV genotype does not appear to influence the
response to any nucleos(t)ide analogues
Selection of drug
 most clinical studies to date have not demonstrated
improved outcomes with combination therapy vs
monotherapy for the initial treatment of patients
with compensated chronic HBV infection
Goal of therapy
 The goal of therapy for chronic HBV infection in both
HBeAg-positive and HBeAg-negative patients is longterm virologic suppression without drug resistance to
prevent or reduce the risk of progressive liver disease.
Goal of therapy
 Secondary goals of therapy in HBeAg-negative patients
include
 sustained biochemical response (ALT normalization)
 and HBsAg loss or seroconversion
 the latter representing the ultimate indication of
therapeutic success and possibly disease cure.
References:
 AASLD Guidelines for Treatment of Chronic
Hepatitis B 2015
 EASL Recommendations on Treatment of
Hepatitis B 2012
 Principles and practice of infectious diseases.
Mandell 2015