Transcript hep b revised

COMPARISON OF
NUCLEOSIDE/NUCLEOTIDE ANALOGS FOR
PREVENTING REACTIVATION OF
HEPATITIS B VIRUS (HBV) IN
IMMUNOCOMPROMISED/HSCT PATIENTS.
Presented by
Francesca Bennett
City of Hope Medicine Rotation
2011 Pharm D Candidate, Western University of
Health Sciences
Overview
Meet the patient
 HBV overview
 Background/Introduction
 Pharmacologic agents for HBV
 The Guidelines
 Clinical question
 The evidence
 Clinical applications
 Conclusion
 Reference

Meet the patient
EK is a 35 y/o M with acute lymphoblastic leukemia, who recently
underwent conditioning with Etoposide and FTBI, in preparation for an
Allogeneic stem cell transplant (DAY+1 on 6/17) from his brother.
PMH:
 Diagnosed with hepatitis B in November 2008 and has been on Entecavir
since his allergic reaction to Lamivudine.
 HTN, DM2, pancreatitis, HSV infection and chlecystectomy 3 years ago.
FH
 HLA matched brother (HBsAg-, HBsAb+, HBcAb-) and no family history
of leukemia.
SH
 Heavy alcohol use in the past.
 Quit smoking.
 No radiation or industrial chemical exposure
Allergies:
Lamivudine (hives)
Meet the patient
Current medications
 Entecavir 0.5mg daily, Tacrolimus 1.1mg IV daily, Sirolimus 4mg
PO daily, Fortaz 2g IV Q8H, Ancef 2g IV Q8H, Micafungin 50mg IV
dialy, Morphine PCA Img/hr, on TPN with 25units insulin,
Escitalopram 10mg PO daily, Gabapentin 300mg PO 3x daily
Pertinent labs (indicating chronic HBV infection)
 HBsAg +
 HBcAb +
 HBsAb <10IU/L
 HBeAg –
 DNA PCR 1.5-8log IU/ml (not detectable)
 ALT/AST: 21/34 from 4/21/10, 15/26 on 6/21
 Total bilirubin 0.2mg/dl
Serologic events
Serologic events5
 HBsAg signifies HBV infection.
 HBVAb develop when HBsAg serum concentrations
decrease.
 HBcAb does not develop in vaccinated pts, only in
infected pts.
 HBeAg develop early in the infection and can persist in
chronic/active HBV infections. High levels correlates
with active viral replication or HBV-DNA
>200copies/ml.
 HBeAb is indicative of a resolution of the infection or
undectable HBV-DNA.
 HBV DNA is a good marker for HBV active infection.
Let’s get familiar with Hepatitis B




DS DNA (Hepadnavirus family)
HBV can cause chronic hepatitis
Replicates in the liver
Oncogenic (hepatocellular carcinoma)
Transmission
 Blood
 Bodily secretions (saliva, vaginal fluid, semen)
 Sexual
 Perinatal
 Mucous Membrane
HBV- antigens/antibodies
Antigens
 HBsAg (surface)
 HBcAg (core)
 HBeAg (envelope)
Antibodies
 HBsAb
 HBcAb
 HbeAb
Viral markers
 HBV DNA
HBV – Serologic events
Serologic events5
 HBsAg signifies HBV infection.
 HBVAb develop when HBsAg serum
concentrations decrease.
 HBcAb does not develop in vaccinated pts,
only in infected pts.
 HBeAg develop early in the infection and can
persist in chronic/active HBV infections. High
levels correlates with active viral replication or
HBV-DNA >200copies/ml.
 HBeAb is indicative of a resolution of the
infection or undectable HBV-DNA.
 HBV DNA is a good marker for HBV active
infection.
Background






Chronic HBV: positive HBsAg for >6months1.
HBV carriers are at increased risk of developing cirrhosis,
hepatic decompensation, and hepatocellular carcinoma1.
Reactivation of HBV replication with increase levels of
serum HBV DNA and ALT have been reported in 20-50% of
hepatitis B carriers undergoing immunosuppressive or
cancer chemotherapy2.
Generally, controlling viral replication and severity of liver
injury depend on the strength of the host immune response
to the virus2.
Disease activity profoundly altered by factors that impair
the immune response2.
Lack of immune surveillance allow viral replication to occur
resulting in hepatitis flares that are asymptomatic.
However, hepatic decompensation and death have been
observed, especially in HBsAg+ pts2.
Back to our patient
EK is therefore at high risk of HBV reactivation;
 Positive HBsAg
 Loss of immunity (WBC 0.2)
 Male
 Young adult.
Back to our patient

EK’s HLA matched brother is HBsAb+, HBsAg-,
HBcAb-).

May confer some immunity against HBV for EK.

But only after he has completely engrafted and is off
immunosuppressive therapy will this happen.

Until he can build this immunity, there is a need to
prevent reactivation of the virus.
Pharmacologic agents
 Fortunately,
it can be prevented by
administering prophylactic therapy
with anti-HBV
nucleoside/nucleotide analogs.
Pharmacologic agents for HBV
Lamivudine (Epivir)
One of the first agents approved for HBV treatment.
Most studies done with lamivudine in HSCT.

Adefovir (Hepsera)
FDA approval in Sept. 2002 for treatment of chronic HBV.

Telbivudine (Tyzeka )
Approved in Oct. 2006 for treatment of chronic HBV.

Entecavir (Baraclude)
FDA approved in Mar. 2005 for treatment of chronic HBV.

Tenofovir(Viread)
FDA approval in Aug. 2008 for first-line treatment of HBV.

Lamivudine (Epivir)
First nucleoside analog approved in the US
for treatment of HBV.
 Pyrimidine analog that incorporates into
HBV polymerase, resulting in viral DNA
chain termination.
 Efficacy proven in HSCT for prevention of
reactivation*.

AASLD Guidelines
To prevent reactivation of HBV in HSCT patients;
 Lamivudine is preferred for prophylaxis <12months
(I), OR telbivudine (III)
 Adefovir, tenofovir and entecavir are alternatives in
patients anticipatied to require >12months of
therapy in whom the risk of resistance is higher with
lamivudine (III).
 Entecavir or tenofovir is preferred because of rapid
onset of aciton and lack of nephrotoxicity (III).
ASBMT Guidelines


Lamivudine is the first choice for antiviral
therapy (AI).
Entecavir is only recommended for donor
with detectable HBV-DNA (CIII).
At COH….

Entecavir: DOC for HBeAg+/HBeAg-patients who are
to receive HSCT.

Tenofovir: indicated in all chronic HBV patients
(HBeAg+/HBeAg-).

Lamivudine: indicated in HBeAg+ patients only but
resistance is high after 12months of therapy.

Indication for lamivudine is not strong
Guideline summary



AASLD recommends lamivudine (I) or
telbivudine (III) if duration of treatment is
<12months.
ASBMT recommends lamivudine.
COH SOP recommends entecavir (DOC) or
tenofovir.
So, the Clinical question is…..

In adult patients with chronic hepatitis B
undergoing HSCT, is adefovir, entecavir,
telbivudine or tenofovir better in preventing
HBV reactivation than Lamivudine?
Lamivudine, the Evidence…
Extensive Lamivudine therapy against HBV in HSCT
receipients (Liang-Tsai, H et al; ASBMT 2005):
 71 patients with HBsAg+ including a subgroup of 16
patients who received pretreatment lamivudine
which was continued into posttransplantation.
 Median duration of study 73weeks
 63% of pts has mutations detected during
lamivudine therapy at a median of 28weeks.
 54% of HBsAg+ pts developed posttransplant
hepatitis after 39months of follow-up.
Limitations of Lamivudine
1.
2.
3.
4.
Prolonged therapy has been associated with
increased likelihood of treatment–resistant HBV
variants from 24% at 1yr to 38% at 2yrs and 67% at
4yrs10.
The emergence of lamivudine-resistant strains is
usually associated with breakthrough increase in
HBV-DNA and ALT levels10.
In patients with decompensated cirrhosis
lamivudine therapy can be associated with flares
that result in liver failure and death10.
Occurrence of withdrawal hepatitic flare upon
cessation of lamivudine.
The evidence..
Although the evidence is most extensive for
lamivudine for short duration of therapy,
 There is a concern that resistant strains may
emerge especially in HSCT patients since
there is a good chance of prolonged
immunosuppressive therapy for >12months,
And
 EK is allergic to lamivudine (hives).
EK is allergic to lamivudine…

Up to date, no studies have been conducted
to evaluate the effectiveness of the other NA
in HSCT/immunocompromised patients…

How do the other nucleoside analogs
compare to each other?

Which alternative is best for EK and/or
patients undergoing HSCT?
The evidence
 What
evidence is available to guide
the selection of a
nucleotide/nucleoside analogue?
Two studies have compared adefovir with
tenofovir and entecavir.
 One study comparing entecavir with
telbivudine.

Study 1
 Tenofovir
Dsoproxil fumarate (TD)
versus Adfovir Dipivoxil (AD) for Chronic
Hepatitis B
 Citation
Marcellin, P,NeJM 359; December 4, 2008
Tenofovir Disoproxil versus Adefovir Dipivoxil
for HBV
Design
Two (S102 and S103) randomized, multi-centered, double blinded
phase 3 trial assigned to either Tenofovir (TD) 300mg daily or
Adefovir (AD) 10mg daily in a ratio of 2:1 for 48weeks.
 Study groups

S102 HBeAg-, n=375 (TD=250, AD=125) and S103 HBAg+, n=266 (TD=176,
AD=90).
 Inclusion criteria
-HBeAg-/+
-Compensated liver disease
Tenofovir Disoproxil versus Adefovir Dipivoxil
for HBV
Results
 Baseline characteristics were balanced between groups except
for ALT levels in HBeAg- group: more patients in the AD group
had higher mean ALT elevations.
 Primary endpoint
Tenofovir Disoproxil versus Adefovir Dipivoxil
for HBV
Secondary endpoints
S103; Significantly more patients in the TD group achieved
ALT normalization (68 vs. 54%),
-HBsAg loss (3 vs. 0%)
-proportion of patients achieving HBeAg titer
improvements was similar (21 vs. 18%).
S102; The proportion of patients achieving ALT
normalization was similar (77 vs. 78%).
Safety and tolerability
-Similar in both groups.
-Nauseaconsistently occurred more frequently in the
tenofovir arm. Headache and nasopharyngitis was
similar in both groups.

Tenofovir Disoproxil versus Adefovir Dipivoxil
for HBV
Conclusion
-Tenofovir 300mg daily is superior to Adefovir
10mg daily in suppressing HBV DNA.
 Study limitations
-The manufacturers of Tenofovir, Gilead,
sponsored the study.
-Study could not justify the similarity in HBeAg
titer rates, although decrease in HBV-DNA has
a positive correlation with HBeAg titer.

Study 2
 Early
Hepatitis B virus DNA reduction in
HBeAg-positive patients with chronic
Hepatitis B: A Randomized International
Study of Entecavir versus Adefovir
 Citation
Leung et al, Hematology vol 49, 2009.
Entecavir versus Adefovir in HBeAg+
patients
Design
prospective, randomized, open labeled phase IIIb trial.
 Study groups
Entecavir 0.5mg daily (n=35) or adefovir 10mg daily (n=34)
for 52 weeks.
 Inclusion criteria
-HBeAg+
-Compensated liver disease; ALT 1.3-10x UNL
-Nucleotide/nucleoside naïve
-HBV DNA level of 10^8copies/ml

Entecavir versus Adefovir in HBeAg+
patients
Results
 Baseline characteristics between groups
were similar except mean ALT level
(entecavir 110.6 vs. adefovir 172.3U/L).
 Primary endpoint
mean reduction in serum HBV DNA level from
baseline to week 48 was significantly greater
in the entecavir group compared to adefovir;
-6.23 versus -4.42log copies/ml (p <0.0001).
Entecavir versus Adefovir in HBeAg+
patients
Secondary endpoint
-HBV DNA of <300copies/ml was significantly
higher in the entecavir group between weeks
2 and 48.
-3% of patients who received entecavir had
HBV DNA of ≥105copies/ml at weeks 24 and
48 compared with 47% adefovir treated
patients.
-HBeAg seroconversion rates were not
statistically significantly different between
both arms.

Entecavir versus Adefovir in HBeAg+
patients
Safety and tolerability
Most common adverse effect was headache, URTI and
nasopharyngitis. Occurrence of ADE’s were similar in
both groups.
 Conclusion
-Entecavir produced more rapid and significantly
greater suppression of HBV DNA than adefovir in
nucleoside-naïve HBeAg+ patients.
-Less variability in the HBV DNA reduction in the
entecavir group than the adefovir group with HBV
DNA <300copies/ml at week 48.

Entecavir versus Adefovir in HBeAg+
patients
Limitations
-Open label trial (no blinding)
-Sponsor of study are the manufacturers of entecavir
-More patients randomized to the adefovir group
had decompensated liver failure (as measured by
serum ALT) than the entecavir group (172U/ L
versus 111).
-Seroconversion to HBeAb was similar in both groups
although more pts in entecavir group than
adefovir had higher decrease in HBV-DNA.

Study 3
A
24-Week, Parallel-Group, Open-Label,
Randomized Clinical Trial Comparing the
Early Antiviral Efficacy of Telbivudine and
Entecavir in the Treatment of Hepatitis B e
Antigen-Positive Chronic Hepatitis B Virus
Infection in Adult Chinese Patients
 Citation:
Ming-Hua Z. et al; Clinical
Therapeutics/Volume 32, Number 4, 2010
Efficacy of Telbivudine versus Entecavir in the
HBeAg+ patients
Design
Randomized, open-labeled trial
 Study groups
Random assignment to either telbivudine 600mg daily
(n=65) or entecavir 0.5mg daily (n=66) for 24 weeks.
 Inclusion criteria
 Age 18-65 years
 HBeAg-positive chronic HBV infection
 Compensated liver disease with a serum ALT value ≥2x
ULN
 Nucleosides/nucleotides naive
 Serum HBV-DNA concentration ≥6 log10 copies/mL.

Efficacy of Telbivudine versus Entecavir in the
HBeAg+ patients
Results
 Baseline characteristics were similar
between groups
Efficacy of Telbivudine versus Entecavir in the
HBeAg+ patients
Primary endpoint
mean reduction in serum HBV-DNA concentration at week 24 was
not significant between groups; 6000 copies/ml for telbivudine
vs. 5800 copies/ml for entecavir arm.
 Secondary endpoints

Endpoint
Telbivudine
%(n=65)
Entecavir %
(n=66)
p value
Undetectable HBV DNA
67.7 (44)
57.6 (38)
0.232
ALT normalization
78.5 (51)
74.2 (49)
0.570
HBeAg absence
36.9 (24)
28.8 (19)
0.321
HBeAg seroconversion
24.6 (16)
13.6 (9)
0.110
Efficacy of Telbivudine versus Entecavir in the
HBeAg+ patients
Safety profile
most ADE’s reported were URTI, fatigue,
diarrhea and coughing all of mild to
moderate intensity.
Increase in CPK level was statistically more
significant (p=0.003). Eight patients (12.3%)
in the telbivudine arm had elevated CPK
levels vs. none in the entecavir group.

Efficacy of Telbivudine versus Entecavir in the
HBeAg+ patients
Conclusion
No statistical significant difference exist in effectiveness
or tolerability between telbivudine 600mg and
entecavir 0.5mg except elevated CPK
(telbivudine>entecavir) at the end of 24weeks of
treatment.
 Limitations
-Open label study
-Small sample size
-Follow-up was for 24 weeks only.
-Study did not evaluate resistance profile associated with
telbivudine
-Results applicable to adult Han Chinese patients.

Adefovir
Both studies comparing adefovir proved
adefovir is not as affective as tenofovir and
entecavir.
Also as demonstrated by combined evidence;
 Less potent in reducing HBV-DNA relative to
entecavir and tenofovir1.
 Higher risk of developing resistant strains1.
 Low rates of histologic improvement1.
 Low durability of response1.

Entecavir, Telbivudine or Tenofovir?? Let’s
compare!
Entecavir
Tenofovir
Telbivudine
Side effects
Nausea, dizziness, HA, lactic
acidosis, fatigue, increased
lipase, hyperglycemia
Rash, asthenia, GIT side effects,
HA, LA, hepatomegaly,
osteopenia, H ARF, immune
hypersensitive reaction
High CPK, HA, cough, LA,
abnormal LFT
BBW
Severe acute HBV exacerbation
upon d/c
Lactic acidosis and severe
hepatomegaly with steatosis
LA, severe hepatomegaly with
steatosis, severe acute HBV
exacerbation upon d/c
Pharmacokinetics
Fatty food delays absorption,
extensive tissue binding, min.
hepatic metabolism, up to 73%
excreted unchanged renally, t1/2
128-149H
Increased F with high fat meal,
serum protein 7.2% bound, min
systemic metabolism, IV 70-80%
renally excreted unchanged vs PO
32%. t1/2 IV 4-8H, PO 17H
Not affected by food, 3% protein
bound, not metabolized, 42%
renally excreted unchanged, t1/2
40-49H
Drug interactions
Cytovene/Valcyte and Ribavirin
Didanosine
Interferon 2a and peg interferon
2a/2b
Formulation
Oral tab 5mg/solution
0.05mg/ml
Oral tab 600mg
Oral tab 300mg
Dose adjustments
Renal (<50ml/min)
Renal (<50ml/min)
Renal (<50ml/in)
Resistant strains
Rare
Rare
Possible
Cost (30 day supply)
5mg $811.16
1mg $800.70
$723.55
$751.58
Can we apply the evidence to EK?
EK’s baseline characteristics match that of the
sample populations:
 Age
 Evidence of chronic hepatitis B; HBsAg+ and
DNA PCR assay of 1.5-8log IU/ml (status post
initiation of entecavir) confirming the
presence of HBV.
ALT/AST:
 21/34 on 4/21/10
 15/26 on 6/21/10
Clinical applications
Evidence exists to prove that Tenofovir and
Entecavir are superior to adefovir in
preventing HBV reactivation.
 They are more effective than adefovir in
reducing HBV DNA in both HBsAg+ and HBsAgpatients.
 Resistance to tenofovir and entecavir are rare.
 Tenofovir and entecavir have been shown to
significantly cause seroconversion to HBsAg-.
 Headache and fatigue were the most common
adverse events for both entecavir & tenofovir.

Clinical applications
One study comparing entecavir and telbivudine in Han
Chinese adults found that there was no significant
difference in effectiveness and tolerability.
 Application of this study to the whole population is
not feasible due to small sample size, limitation of
study population to Han Chinese and long term
efficacy was not studied.
 More studies need to be conducted;
-to determine telbivudine’s place in HBV therapy
-correlation between HBeAg+ seroconversion to the
HBeAb form
-to evaluate efficacy of the newer nucleoside ananlogs.

Treatment Duration

Recommendation is for >1 year after
discontinuation of immunosuppressive
therapy.
Our patient…
EK 35y/o M s/p Allo HSCT from HLA matched
brother (HBsAb+, HBsAg-, HBcAb-)
 PMH of chronic HBV, DM
 Current meds include entecavir 0.5mg.

Back to EK
EK is allergic to Lamivudine… would u have
continued on lamivudine if he wasn’t?
 EK has been on entecavir since 2008..
 EK is negative for HBeAg which indicates that
his hepatitis is under control with entecavir.

Back to EK


EK’s HLA matched brother is HBsAb+.
Since he received stem cells from him, EK is
likely to acquire the surface antibody after
engraftment.
Recommendations





Follow-up with patient post transplant and continue
close monitoring of HBV-DNA, LFT and bilirubin.
May be a candidate for HBV vaccination?
Continue entecavir due to clinical evidence
supporting long term use with little risk of
resistance for at least 1year post cessation of
immunosuppressive therapy.
Resistance to entecavir is rare but if it occurs,
addition of tenofovir is recommended
Hepatitis flare may be treated with tenofovir.
References
1.
2.
3.
4.
5.
6.
7.
8.
AASLD PRACTICE GUIDELINES: Chronic Hepatitis B: Update 2009
Hepatitis B virus reactivation following immunosuppressive therapy: guidelines
for prevention and management; Lubel J. S. et al, Royal Australian College of
physicians, 2007
Lexi-comp
Micromedex
UpToDate
ASBMT Guidelines
City of hope SOP for prevention and management of HBV in HCT donors and
recipients
Systemic Review: the effect of preventative lamivudine on HBV reactivation
during chemotherapy.
9.
Extensive Lamivudine therapy against HBV in HSCT receipients (Liang-Tsai,
H et al; ASBMT 2005)
10.
Diagnosis, prevention and management of HBV during anticancer therapy; A
Concise Review in Meachanism of Disease; 2006.
Thank you!