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

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

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. 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.

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.

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

CitationMarcellin, P,NeJM 359; December 4, 2008

Tenofovir Disoproxil versus Adefovir Dipivoxil for HBV

DesignTwo (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 groupsS102 HBeAg-, n=375 (TD=250, AD=125) and S103 HBAg+, n=266 (TD=176,

AD=90). Inclusion criteria-HBeAg-/+-Compensated liver disease


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


Secondary endpointsS103; 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.-Nauseaconsistently occurred more frequently in the tenofovir

arm. Headache and nasopharyngitis was similar in both groups.


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

CitationLeung et al, Hematology vol 49, 2009.

Entecavir versus Adefovir in HBeAg+ patients

Designprospective, randomized, open labeled phase IIIb trial. Study groupsEntecavir 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


Results Baseline characteristics between groups were

similar except mean ALT level (entecavir 110.6 vs. adefovir 172.3U/L).

Primary endpointmean 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).


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.


Safety and tolerabilityMost 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.


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

DesignRandomized, open-labeled trial Study groupsRandom 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.


Results Baseline characteristics were similar

between groups


Primary endpointmean 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 endpointsEndpoint 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


Safety profilemost 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 ConclusionNo 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 $811.161mg $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 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.

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. AASLD PRACTICE GUIDELINES: Chronic Hepatitis B: Update 20092. Hepatitis B virus reactivation following immunosuppressive therapy: guidelines

for prevention and management; Lubel J. S. et al, Royal Australian College of physicians, 2007

3. Lexi-comp4. Micromedex5. UpToDate6. ASBMT Guidelines7. City of hope SOP for prevention and management of HBV in HCT donors and

recipients8. 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!

Documents

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