Transcript End point in treatment of HBV

HBV Guidelines and Cases Presentation
Prof. Gamal Esmat
Prof. Hepatology &Vice President of Cairo University, Egypt
Member of WHO Strategic Committee for Viral Hepatitis
www.gamalesmat.com
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A case study:
“You are a carrier: be
happy!!”
21 year male has a history of
dental extraction since 2 years. He
was told that he has HBsAg +ve
before traveling to work aboard.
He is Asymptomatic.
What is the next step?
1. Assurance: A Benign disease.
Needs no treatment. Be happy!
2. Fruther investigations
His liver function were completely
within normal range (ALT=37/40)
His Abdominal Ultrasound was also
normal
What is next step?
1. Assurance : you are OK.
No treatment. Be Happy.
2. Further investigations.
HBeAg is negative
Next Step
1. Assurance:

No Active Disease. BE
Happy !!
2. Further investigations
HBeAg-negative CHB
Egypt
156 HBsAg+ve CAH
NLI, Unpublished, 2004
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
HBV-DNA-ve,
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28%
26 %
HBV-DNA+ve,
103
72%
66%
HBeAg+ve
n=12
8%
HBeAg-ve
n=144
92%
Further Investigations
 Anti HBe
Positive
 Anti Delta IgG Negative
 HB DNA
3000 IU/(15000 Copies)
Next Step
1. Assurance:
you have a
mild disease just follow –
up. Need No Treatment.
2. Further investigations.
Ministry Of Health Regulations For
Management of HBV in Adults
Inclusion criteria for assessment
Age > 18 years
HBsAg: (+ve)
HBV DNA (+ve)
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Indication of Treatment
• Treat
if
HBV >2000 IU + elevation of liver enzymes.
• Follow up if HBV <2000 IU + normal liver enzymes.
• Grey zone
do liver biopsy
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Liver Biopsy: showed
 HAI-8 and F-2
 HBsAg
+ve
 HBcAg
+ve
Liver biopsy : METAVIR scoring system
F1
From Z. Goodman
F2
F3
F4
Liver biopsy(Indications)
• HBV DNA > 2000 IU/ML with persistently normal
enzymes .
• HBV DNA < 2000 IU/ML with persistently elevated
enzymes .
• Patients < 2000 IU/ML with normal enzymes who show
clinical evidence of liver disease or have a family history
of HCC
Treatment is recommended for those with >A1
and / or >F1 on the Metavir score
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What is the next step?
1. Lamivudine
2. New oral antiviral therapy
3. Pegylated interferon
4. Combination
Treatment Landscape
• Treatment has advanced dramatically due to the
introduction of new agents with different safety, efficacy,
and resistance profiles
Cytokines
Interferon
(1992)
Peg Interferon a-2a (2005)
Nucleoside Analogue
Nucleotide Analogue
Lamivudine (1999)
Entecavir
(2005)
Telbuvidine (2006)
Adefovir dipivoxil (2003)
Tenofovir
(2008)
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Medications
All Naïve patients are candidates for the
most potent drugs Entecavir 0.5 or
Tenofovir 300 mg as a first line therapy.
Entecavir 0.5 mg O.D
or
Tenofovir 300mg O.D.
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Tenofovir is preferred in:
 patients who received lamivudine previously
 young women who plan to start a family in next few
years
 patients who want more flexibility with regard to the
time of day at which they take their medicine
Entecavir is preferred in:
 older patients
 patients with medical conditions that increase risk
of renal failure
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Pegylated Interferon
Effect of Genotype
• A large multicenter study
of 52 weeks of pegylated
interferon alfa-2b, alone
or in combination with
LAM, according to
genotype:
• HBeAg-positive patients
with genotype A
responded significantly
more frequently than
those with genotypes B,
C, or D in descending
order.
Percent HBeAg response irrespective of
treatment assignment (pegylated
interferon/placebo vs pegylated
interferon/LAM).
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Pegylated Interfon
• Poor response in Egyptian patients with
predominant Genotype D.
• HbeAg positive patients with high liver enzymes
could be offered a chance of treatment with peg
Inf alfa for 24 weeks.
• Seroconversion to HBeAb →continue for 48 wks
• No seroconversion →stop ttt and shift to oral
antiviral therapy according to previous
guidelines
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For Patients already on treatment
• Chronic patients responding on regular
Lamivudine treatment (undetectable HBV
DNA) →continue treatment and HBV PCR
every 3 to 6 months.
• Patients on combined LAM & Adefovir →
continue treatment or shift to Tenofovir
300 mg
• Newly developed resistance → Shift to
Tenofovir 300 mg O.D.
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Immuntolerant cases
• Young patients under 40 years of age who are
HBeAg positive ,with high viral load and
persistently normal enzymes are not candidates
for immediate liver biopsy or treatment.
• Follow up is mandatory every 3- 6 months by
liver profile and every 6-12 months HBeAg .
• Consider liver biopsy with fluctuating ALT levels
or a positive family history of HCC .
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Special Groups
I) Compensated Cirrhosis:
Naive Cirrhotic patients with any detectable level of HBV
DNA should receive Entecavir 0.5 mg or Tenofovir
300mg.
II)Decompensated Cirrhosis:
Entecavir 1 mg may be appropriate. The dose of all NA,s
needs to be adjusted in patients with low creatinine
clearance (< 50ml/min)
lll)Renal Insufficiency:
Entecavir preferred with dose adjustments according to
creatinine clearance.
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Pregnancy
For mothers:
- All pregnant females should be screened for
HBsAg
- Newly diagnosed pregnant women in the last
trimester showing an HBV DNA level > 100.000
IU/ML are candidates for Lamivudine 100 mg or
Tenofovir 300 mg starting last trimester and for 3
months after delivery to decrease chance of newborn infection . Re-evaluate the condition after 3
months of delivery and consider treatment
according to the previous guidelines
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Pregnancy
• For newborns:
•
HB Ig and HBV vaccine first (birth) dose for
the baby in the first 6-12 hours after delivery.
• Birth dose vaccination is recommended for
all newborns.
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Females who become pregnant while on
treatment
– On Lamivudine monotherapy: Continue on
treatment
– On Other lines of treatment : shift to class B drug
(Tenofovir 300 mg O.D.)
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HBV/HDV Coinfection
• Peg –INF is the only effective drug against HDV.
• Efficacy of Peg –INF is assessed during
treatment after 3-6 months by measuring HDV
RNA levels.
• Optimal duration of therapy is not well defined
but therapy for at least 72 wks .
• NAs have no impact on HDV replication and
related disease.
• Refer the patient to a specialized HBV center.
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Acute HBV
• Spontaneous recovery in more than 95% of
cases and seroconversion to anti HBs without
antiviral therapy. Supportive management and
close monitoring for early identification of
fulminant hepatitis or liver cell failure
• Fulminant or impending liver cell failure:
Entecavir 0.5 mg during the condition and for at
least 6 months after seroconversion to anti HBs
or for at least 12 months after seroconversion to
anti HBe without HBs Ag loss
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Dialysis and Renal patients
• All renal patients should be screened for HBV .
• Seronegative patients should be vaccinated.
• Entecavir is preferred for treatment.
• All drugs should be dose adjusted according to
creatinine clearance.
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HBV/HCV Co infection
-Treat predominant virus according to PCR level.
-Patients fulfilling the inclusion criteria for HBV
treatment and have co-infection with active HCV
(HCV RNA +ve by quantitative PCR)
Peg IFN + Ribavirin
Monitoring for HBV is performed every 3-6
months.
Reassessment of the condition after termination
of the course and starting oral HBV treatment if
needed.
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Vaccination
-Mass vaccination is recommended.
-Vaccination is highly recommended for:
Health care workers
Close contacts of viremic patients
Chronic renal failure patients before they start renal
dialysis.
Chronic hepatitis C patients.
Immunosupressed patients.
Multitransfused individuals
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Follow up
Follow up visits (every 2-3 months)for receiving
medications & follow up for side effects and relapsing
symptoms.
Checking liver enzymes every 3 months.
Serum creatinine is done every 3 months in those
receiving Adefovir. For Tenofovir in addition monitor
creat.clearance and serum phosphate for risk of renal
impairement and osteomalacia.
Liver function tests, complete blood count, A.F.P.,
Abdominal U/S & HBV/DNA by PCR quantitative is
done every 6 months
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Immunosupressed Patients
• All candidates for chemotherapy and
immunosuppressive therapy should be screened
for HBsAg and anti HBcAb prior to initiation of
treatment
• Vaccination is mandatory for seronegative
cases
• HBsAg positive patients with any detectable
level of viremia should receive NA during
therapy and for 6 months after cessation of
therapy
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Immunosupressed Patients
• Patients with high HBV DNA level should receive
NA with high viral potency according to
guidelines.
• HBsAg neg patients with positive anti- HBc
antibodies should be tested for HBV DNA.
Patients with detectable viremia should be
treated as HBsAg positive cases.
• Follow up of cases with undetectable viremia
every 1-2 months during treatment by liver
enzymes and HBV DNA.
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Case 2
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 A 30 years old female patient presented
with easy fatigability and right
hypochondrial pain.
CBC : Normal .
• ALT: 80/40
 HBsAg : +ve
 HBeAg: -ve
 Anti HCV: - ve
 HBV- DNA: 2500 IU/ml
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• Fibroscan F2
• Does this patient needs treatment?
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• Patient received mono therapy in the form
of lamivudine. After 6 months of therapy
her ALT normalized and her HBV-DNA
decreased to 200 IU/ml.
• What are the goals for treatment of HBV?
• What is the end point in treatment of HBV?
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goals for treatment of HBV
• The goal of therapy for hepatitis B is to improve quality of
life and survival by preventing progression of the disease
to cirrhosis, decompensated cirrhosis, end-stage liver
disease, HCC and death. This goal can be achieved if
HBV replication can be suppressed in a sustained
manner, the accompanying reduction in histological
activity of chronic hepatitis lessening the risk of cirrhosis
and decreasing the risk of HCC in non-cirrhotic patients
and probably also, but to a lesser extent, in cirrhotic
patients. However, HBV infection cannot be completely
eradicated due to the persistence of covalently closed
circular DNA (cccDNA) in the nucleus of infected
hepatocytes.
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Higher viral loads
associated with long-term complications
.04
≥106c/ml
.03
105-106c/ml
.02
104-105c/ml
.01
300-104c/ml
Progression to HCC
Cumulative incidence of HCC %
Cumulative incidence of cirrhosis%
Progression to Cirrhosis
<300 c/ml
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Year of follow-up
Iloeje UH et al. Gastroenterology 2006; 130: 678–86.
>106c/ml
14
12
105-106c/ml
10
8
6
4
104-105c/ml
2
300-104cml
< 300c/ml
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Year of follow-up
Chen CJ et al. JAMA 2006; 295: 65-73
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End point in treatment of HBV
• Therapy must reduce HBV DNA to as low a
level as possible, ideally below the lower limit of
detection of real-time PCR assays (10–15
IU/ml), to ensure a degree of virological
suppression that will then lead to biochemical
remission, histological improvement and
prevention of complications.
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End point in treatment of HBV (cont.)
• Sustained HBV DNA reduction to
undetectable levels is necessary to reduce
the risk of resistance to NUCs. It also
increases
the
chance
of
HBe
seroconversion in HBeAg-positive patients
and the possibility of HBsAg loss on the
mid to long term in HBeAg-positive and
HBeAg-negative patients.
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End point in treatment of HBV (cont.)
(1) In HBeAg-positive and HBeAg-negative patients, the
ideal end-point of therapy is sustained HBsAg loss with
or without seroconversion to anti-HBs. This is
associated with a complete and definitive remission of
the activity of chronic hepatitis B and an improved longterm outcome.
(2)
In
HBeAg-positive
patients,
durable
HBe
seroconversion is a
satisfactory end-point because it
has been shown to be associated with improved
prognosis.
(3) In HBeAg-negative and in In HBeAg-positive patients
who do not achieve HBe seroconversion, and patients, a
maintained undetectable HBV DNA level on treatment
with NUCs.
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• One year after the start of treatment the
patients HBV DNA started to increase by
more than one log while her ALT levels
are still normal in spite of her compliance
to treatment.
• Shall we replace lamivudine or add
another drug?
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• Patient stopped treatment 3 years later
after having persistent normal ALT and
undetectable HBV DNA for 2 years while
her HBsAg was still + ve. The patient got
married and pregnant.
• Does she need to restart therapy?
• What precautions to be taken for the new
born?
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Guidelines for mang. of pregnant females with
HBV
• Lamivudine, adefovir and entecavir are listed by
the FDA as pregnancy category C drugs, and
telbivudine and tenofovir as category B drugs.
These classifications are based on the risk of
teratogenicity in preclinical evaluation.
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Guidelines for mang. of pregnant
females with HBV
• Recent reports suggest that lamivudine
therapy during the last trimester of
pregnancy in pregnant women with high
levels of viremia reduces the risk of intrauterine and perinatal transmission of HBV
if given in addition to passive and active
vaccination by HBIg and HBV vaccination.
• HBV-infected women should be monitored
closely after delivery as exacerbations of
chronic hepatitis B may occur
J Viral Hepat 2008;15:37–41
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–Ten years later the patient complained
of enlarged cervical lymph nodes. Biopsy
revealed Hodgkins lymphoma. She was
scheduled to receive chemotherapy.
•What to do ?
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• Reactivation of HBV replication with increase
in serum HBV DNA and ALT level has been
reported in 20% to 50% of hepatitis B carriers
undergoing immunosuppressive or cancer
chemotherapy.
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• Prophylactic antiviral therapy should be
administered to hepatitis B carriers
(regardless of baseline serum HBV DNA
level) at the onset of cancer chemotherapy
or a finite course of immunosuppressive
therapy, and maintained for 6 months
afterwards.
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A meta-analysis of LAM in HBsAg+ve
subjects receiving chemotherapy
No
prophylaxis
Lamivudine
prophylaxis
95% CI
p<
HBV
reactivation
41–100%
0–40%
86–99% 0.0001
Liver failure
24–100%
0–28%
85–95% 0.0001
Liver-related
mortality
0–50%
0%
55–91% 0.0001
Chemotherapy
withdrawal
11–20%
2–6%
60–90% 0.0001
All mortality
6–100%
0–35%
38–76% 0.0001
Katz et al. J Viral Hepat 2008; 15: 89–102.
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