Overview

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 (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)

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 <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

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 >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.

6. 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

7. HBV- antigens/antibodies Antigens HBsAg (surface) HBcAg (core) HBeAg (envelope) Antibodies HBsAb HBcAb HbeAb Viral markers HBV DNA

8. 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.

9. Background Chronic HBV: positiveHBsAg for >6months1. HBV carriers areat 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.

10. 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 • 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.

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.

14. 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*.

15. 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).

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

17. 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

18. 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.

19. 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?

20. 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.

21. Limitations of Lamivudine • 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.

22. 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).

23. 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?

24. 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.

25. Study 1 Tenofovir Dsoproxil fumarate (TD) versus Adfovir Dipivoxil (AD) for Chronic Hepatitis B Citation Marcellin, P,NeJM 359; December 4, 2008

26. 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

27. 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

28. 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.

29. 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.

30. 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.

31. 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

32. 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).

33. 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.

34. 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.

35. 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.

36. 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

37. 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.

38. Efficacy of Telbivudine versus Entecavir in the HBeAg+ patients Results Baseline characteristics were similar between groups

39. 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

40. 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.

41. 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.

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.

43. Entecavir, Telbivudine or Tenofovir?? Let’s compare!

44. 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 15/26on 6/21/10

45. 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 telbivudine’s 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 >1 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 wasn’t? 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 • EK’s HLA matched brother is HBsAb+. • Since he received stem cells from him, EK is likely to acquire the surface antibody after engraftment.