COMPARISON OF NUCLEOSIDE/NUCLEOTIDE ANALOGS FOR PREVENTING REACTIVATION OF HEPATITIS B VIRUS (HBV) IN IMMUNOCOMPROMISED/HSCT PATIENTS.

1
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 Rotation2011 Pharm D Candidate, Western
  University of Health Sciences

2
Overview

• Meet the patient
• HBV overview
• Background/Introduction
• Pharmacologic agents for HBV
• The Guidelines
• Clinical question
• The evidence
• Clinical applications
• Conclusion
• Reference

3
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 (DAY1 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)

4
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 lt10IU/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

5
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 gt200copies/ml.
• HBeAb is indicative of a resolution of the
  infection or undectable HBV-DNA.
• HBV DNA is a good marker for HBV active
  infection.

6
Lets 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

7
HBV- antigens/antibodies

• Antigens
• HBsAg (surface)
• HBcAg (core)
• HBeAg (envelope)
• Antibodies
• HBsAb
• HBcAb
• HbeAb
•  
• Viral markers
• HBV DNA

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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 gt200copies/ml.
• HBeAb is indicative of a resolution of the
  infection or undectable HBV-DNA.
• HBV DNA is a good marker for HBV active infection.

9
Background

• Chronic HBV positive HBsAg for gt6months1.
• 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.

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Back to our patient

• EK is therefore at high risk of HBV reactivation
• Positive HBsAg
• Loss of immunity (WBC 0.2)
• Male
• Young adult.

11
Back to our patient

• EKs 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.

12
Pharmacologic agents

• Fortunately, it can be prevented by administering
  prophylactic therapy with anti-HBV
  nucleoside/nucleotide analogs.

13
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.

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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.

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AASLD Guidelines

• To prevent reactivation of HBV in HSCT patients
• Lamivudine is preferred for prophylaxis lt12months
  (I), OR telbivudine (III)
• Adefovir, tenofovir and entecavir are
  alternatives in patients anticipatied to require
  gt12months 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).

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ASBMT Guidelines

• Lamivudine is the first choice for antiviral
  therapy (AI).
• Entecavir is only recommended for donor with
  detectable HBV-DNA (CIII).

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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

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Guideline summary

• AASLD recommends lamivudine (I) or telbivudine
  (III) if duration of treatment is lt12months.
• ASBMT recommends lamivudine.
• COH SOP recommends entecavir (DOC) or tenofovir.

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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?

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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.

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Limitations of Lamivudine

1. Prolonged therapy has been associated with
   increased likelihood of treatmentresistant HBV
   variants from 24 at 1yr to 38 at 2yrs and 67
   at 4yrs10.
2. The emergence of lamivudine-resistant strains is
   usually associated with breakthrough increase in
   HBV-DNA and ALT levels10.
3. In patients with decompensated cirrhosis
   lamivudine therapy can be associated with flares
   that result in liver failure and death10.
4. Occurrence of withdrawal hepatitic flare upon
   cessation of lamivudine.

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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 gt12months,
• And
• EK is allergic to lamivudine (hives).

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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?

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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.

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Study 1

• Tenofovir Dsoproxil fumarate (TD) versus Adfovir
  Dipivoxil (AD) for Chronic Hepatitis B
• Citation
• Marcellin, P,NeJM 359 December 4, 2008

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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 21 for 48weeks.
• Study groups
• S102 HBeAg-, n375 (TD250, AD125) and S103
  HBAg, n266 (TD176, AD90).
• Inclusion criteria
• -HBeAg-/
• -Compensated liver disease

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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

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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.

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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.

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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.

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Entecavir versus Adefovir in HBeAg patients

• Design
• prospective, randomized, open labeled phase IIIb
  trial.
• Study groups
• Entecavir 0.5mg daily (n35) or adefovir 10mg
  daily (n34) for 52 weeks.
• Inclusion criteria
• -HBeAg
• -Compensated liver disease ALT 1.3-10x UNL
• -Nucleotide/nucleoside naïve
• -HBV DNA level of 108copies/ml

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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 lt0.0001).

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Entecavir versus Adefovir in HBeAg patients

• Secondary endpoint
• -HBV DNA of lt300copies/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.

34
Entecavir versus Adefovir in HBeAg patients

• Safety and tolerability
• Most common adverse effect was headache, URTI and
  nasopharyngitis. Occurrence of ADEs 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 lt300copies/ml at week 48.

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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.

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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

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Efficacy of Telbivudine versus Entecavir in the
HBeAg patients

• Design
• Randomized, open-labeled trial
• Study groups
• Random assignment to either telbivudine 600mg
  daily (n65) or entecavir 0.5mg daily (n66) 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.

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Efficacy of Telbivudine versus Entecavir in the
HBeAg patients

• Results
• Baseline characteristics were similar between
  groups

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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 (n65) Entecavir (n66) 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
40
Efficacy of Telbivudine versus Entecavir in the
HBeAg patients

• Safety profile
• most ADEs reported were URTI, fatigue, diarrhea
  and coughing all of mild to moderate intensity.
• Increase in CPK level was statistically more
  significant (p0.003). Eight patients (12.3) in
  the telbivudine arm had elevated CPK levels vs.
  none in the entecavir group.

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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
  (telbivudinegtentecavir) 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.

42
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.

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Entecavir, Telbivudine or Tenofovir?? Lets
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 (lt50ml/min) Renal (lt50ml/min) Renal (lt50ml/in)
Resistant strains Rare Rare Possible
Cost (30 day supply) 5mg 811.16 1mg 800.70 723.55 751.58
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Can we apply the evidence to EK?

• EKs 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

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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 HBsAg- patients.
• 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.

46
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 telbivudines place in HBV therapy
• -correlation between HBeAg seroconversion to the
  HBeAb form
• -to evaluate efficacy of the newer nucleoside
  ananlogs.

47
Treatment Duration

• Recommendation is for gt1 year after
  discontinuation of immunosuppressive therapy.

48
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.

49
Back to EK

• EK is allergic to Lamivudine would u have
  continued on lamivudine if he wasnt?
• EK has been on entecavir since 2008..
• EK is negative for HBeAg which indicates that his
  hepatitis is under control with entecavir. 

50
Back to EK

• EKs HLA matched brother is HBsAb.
• Since he received stem cells from him, EK is
  likely to acquire the surface antibody after
  engraftment.

51
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.

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References

• 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.
• Extensive Lamivudine therapy against HBV in HSCT
  receipients (Liang-Tsai, H et al ASBMT 2005)
• Diagnosis, prevention and management of HBV
  during anticancer therapy A Concise Review in
  Meachanism of Disease 2006.

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Thank you!