A Message to Presenters

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1 A Message to Presenters As a healthcare professional speaking on behalf of Bristol-Myers Squibb (BMS), any presentation you make on our behalf must be consistent with the current FDA-approved product labeling for BARACLUDE (entecavir). The slides in this set are for use only when you are speaking on behalf of BMS and only when they are the content of your presentation on this topic. In accordance with FDA guidelines on scientific exchange of information, you may respond to unsolicited questions from your audience. When responding to such questions, you should (1) only use slides that have been approved by BMS and not use slides that you have prepared or taken from another slide set; (2) identify to the audience any information that is not consistent with approved product labeling; (3) limit your response to the question asked; and (4) return to the approved slide presentation topics as soon as you have provided the answer. BMS does not recommend the use of BARACLUDE or any other product in any manner inconsistent with that described in the Full Prescribing Information for each product. 0 Chronic Hepatitis B Hypothetical Case Studies: A Discussion of Long-term Management Strategies Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides 3-7. BARACLUDE is a registered trademark of Bristol-Myers Squibb Company Bristol-Myers Squibb Company, Princeton, NJ USA 686US08PF /

2 Learning Objectives Utilize case-based learning to generate discussion regarding: Chronic hepatitis B (CHB) screening guidelines Identification of appropriate candidates for treatment First-line treatment strategies for achieving and maintaining a long-term response Resistance considerations Important information about BARACLUDE (entecavir) 2 BARACLUDE (entecavir) INDICATION BARACLUDE is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-naïve and lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease. Limited data are available in adult patients with HIV/HBV co-infection who have received prior lamivudine therapy. BARACLUDE has not been evaluated in patients with decompensated liver disease. Please see speaker or representative for Full Prescribing Information, including boxed WARNINGS

3 IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) 0.5 mg and 1 mg Tablets Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including BARACLUDE. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted. Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. (continued) Please see speaker or representative for Full Prescribing Information, including boxed WARNINGS. 4 IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) 0.5 mg and 1 mg Tablets (cont d) There are no adequate and well-controlled studies of BARACLUDE in pregnant women. BARACLUDE should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits. There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV. Risks and benefits should be considered when deciding whether to discontinue breastfeeding or discontinue BARACLUDE in nursing women. Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have not been established. Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance <50 ml/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). (continued) Please see speaker or representative for Full Prescribing Information, including boxed WARNINGS

4 IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) 0.5 mg and 1 mg Tablets (cont d) The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus. Since entecavir is primarily eliminated by the kidneys, coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. (continued) Please see speaker or representative for Full Prescribing Information, including boxed WARNINGS. 6 IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) 0.5 mg and 1 mg Tablets (cont d) The most common adverse events of moderate to severe intensity among patients treated with BARACLUDE in clinical trials included: headache (4%), fatigue (3%), diarrhea (1%), and dyspepsia (1%). The recommended dose of BARACLUDE is 0.5 mg once daily in nucleoside-naïve adults, and 1 mg once daily in lamivudinerefractory adults. BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and at least 2 hours before the next meal). The optimal duration of treatment with BARACLUDE for patients with chronic HBV infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown. Please see speaker or representative for Full Prescribing Information, including boxed WARNINGS

5 Hypothetical Case Study I: Treatment-naïve HBeAg(+) Asian Male Co-managed by Community Primary Care Physician and Specialist Research Chemist 8 Patient Profile Family History His father, who resides in China, was recently diagnosed with liver disease Profile Gender/ Age Ethnicity Height/ Weight BMI (kg/m 2 ) Note: May be associated with high daily alcohol consumption Male 35 years Chinese Immigrated to US 6 years ago lbs

6 Discussion Questions In your opinion, should this Primary Care Physician (PCP) screen this patient for CHB? Why or why not? 10 Recommended Screening Practices Screen for CHB if patient meets any of these criteria: Country of Origin/Social Contacts Lifestyle Factors Individuals from areas of high HBV endemicity, including immigrants, adopted children, and travelers Household, sexual contacts, family members of HBsAg(+) persons Multiple sexual partners Men who have sex with men Intravenous (IV) drug use Inmates of correctional facilities Clinical Factors Hemodialysis HIV and/or HCV infection Chronically elevated AST or ALT History of sexually transmitted disease All pregnant women Developmentally disabled persons in long-term care facilities 1. Lok ASF and McMahon BJ. Hepatology. 2007;45: Centers for Disease Control and Prevention. MMWR Recomm Rep. 2005;54(RR16): Centers for Disease Control and Prevention. MMWR Recomm Rep. 2006;55(RR16): Centers for Disease Control and Prevention. Viral Hepatitis B: Frequently Asked Questions (FAQs). Available at: Accessed July 17,

7 Initial Patient Diagnosis: Primary Care Physician Diagnostic Tests HBsAg HBsAb + - Profile Gender/ Age Male 35 years Ethnicity Chinese Immigrated to US 6 years ago Height/ Weight lbs BMI (kg/m 2 ) 22.8 HBeAg HCV HAV Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides Discussion Questions In your opinion, should this PCP initiate CHB treatment, or refer the patient to a specialist? Why or why not? Is there a need to recommend hepatic viral disease screening for this patient s household family members/close contacts? Why or why not? What other lab values, if any, would you consider testing for? Why?

8 Initial Patient Diagnosis: Specialist Diagnostic Tests and Laboratory Values HBV genotype C ALT: 60 U/L (1.5 x ULN) Profile HBV DNA level by PCR assay: 5.5 x 10 7 IU/mL (8.5 log 10 copies/ml) a Gender/ Age Male 35 years Ethnicity Chinese Immigrated to US 6 years ago Height/ Weight lbs BMI (kg/m 2 ) 22.8 Serum creatinine: 0.7 mg/dl Creatinine clearance: 142 ml/min Knodell necroinflammatory score: 8 Ishak fibrosis score: 2 a Based on IU/mL conversion factor associated with the COBAS Taqman HBV assay (Roche Molecular Systems); 1 IU/mL = 5.8 copies/ml 14 AASLD CHB Treatment Guidelines for HBeAg(+) Patients HBsAg(+) HBeAg(+) HBV DNA >20,000 IU/mL ALT <1 x ULN HBV DNA >20,000 IU/mL ALT 1-2 x ULN HBV DNA >20,000 IU/mL ALT >2 x ULN Q 3-6 mo ALT Q 6-12 mo HBeAg Q 3 mo ALT Q 6 mo HBeAg Consider biopsy if persistent or age >40 Treat as needed Q 1-3 mo ALT, HBeAg Treat if persistent Liver biopsy optional Adapted from: Lok ASF and McMahon BJ. Hepatology. 2007;45:

9 Discussion Questions Should this specialist initiate treatment in this patient? Why or why not? How, if at all, would ethnicity, age, and/or suspected time of infection affect the decision to initiate treatment? Why? 16 Discussion Questions If this specialist chooses to initiate treatment in this patient, which agent should he or she select? Why? How, if at all, should considerations regarding the potential for resistance development long-term impact initial agent selection? Why? Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides

10 Hypothetical Case Study I: Treatment Timeline Gastroenterologist prescribes 0.5 mg BARACLUDE (entecavir) once daily HBV DNA (copies/ml) 10 log 10 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 1 log 10 How should this patient be counseled regarding the dosing and possibility of adverse events while on therapy? Why? <300 copies/ml During this office visit the patient requests comanagement with his local community PCP How should this specialist work with the community PCP to successfully manage this patient? How frequently should this patient be monitored during the first year of therapy? Why? ALT (U/L) Time on Treatment (months) Patient Counseling Information for BARACLUDE (entecavir) Information About Treatment Inform patients of the following points when initiating BARACLUDE treatment: Remain under a physician s care while taking BARACLUDE and discuss any new symptoms or concurrent medications Treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination Take BARACLUDE on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal) For the oral solution, the dosing spoon should be held vertically and filled gradually to the mark corresponding to the prescribed dose. Rinsing of the dosing spoon with water is recommended after each daily dose BARACLUDE (entecavir) Full Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ

11 Patient Counseling Information for BARACLUDE (entecavir) (continued) Post-treatment Exacerbation of Hepatitis: Deterioration of liver disease may occur in some cases if treatment is discontinued. Any change in regimen should be discussed with their physician. HIV/HBV Co-infection: Offer HIV antibody testing before starting BARACLUDE. If the patient has HIV infection and is not receiving effective HIV treatment, BARACLUDE may increase the chance of HIV resistance to HIV medication. Important Safety Information (slides 4-7) BARACLUDE (entecavir) Full Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. 20 Hypothetical Case Study I: Treatment Timeline Gastroenterologist prescribes 0.5 mg BARACLUDE (entecavir) once daily HBV DNA (copies/ml) 10 log 10 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml How long would you expect to treat this patient? Why? What factors inform your decision to continue/discontinue CHB therapy? Why? ALT (U/L) 1 log Time on Treatment (months)

12 AASLD Recommended Treatment Endpoint Guidelines for Oral Nucleos(t)ide Agents HBeAg(+): Seroconversion from HBeAg(+) to HBeAb(+) Duration of therapy: Minimum 1 year, continue until at least 6 months after HBeAg seroconversion HBeAg(-): Undefined endpoint Duration of therapy: >1 year Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely for at least several months after discontinuation. Initiation of anti-hepatitis B therapy may be warranted. The optimal duration of therapy with BARACLUDE is unknown. 1. Lok ASF and McMahon BJ. Hepatology. 2007;45: BARACLUDE (entecavir) Full Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides Hypothetical Case Study II: Treatment-naïve HBeAg(+) Caucasian Male with Adult-acquired CHB Professional Musician

13 Patient Profile Patient History Past IV-drug use and high-risk sexual behavior Both stopped 10 years ago Profile Gender/ Age Male 36 years Ethnicity Caucasian US-born Height/ Weight lbs BMI (kg/m 2 ) 31.9 obese A statin is currently prescribed for high serum cholesterol 24 Routine Evaluation: PCP Laboratory Values ALT: 41 U/L (1 x ULN) Total Serum Cholesterol: 193 mg/dl Profile Gender/ Age Male 36 years Ethnicity Caucasian US-born Height/ Weight lbs BMI (kg/m 2 ) 31.9 obese HDL: 38 mg/dl LDL: 132 mg/dl Serum Triglycerides: 115 mg/dl Serum creatinine: 0.8 mg/dl Creatinine clearance: 128 ml/min

14 Discussion Questions Should this patient be tested for CHB? Why? What, if any, additional diseases/conditions should this physician test for in this patient? Why? 26 Initial Patient Diagnosis Diagnostics Test HBsAg (at baseline and 6 months later) HBsAb + - Profile Gender/ Age Male 36 years Ethnicity Caucasian US-born Height/ Weight lbs BMI (kg/m 2 ) 31.9 obese HBeAg HCV/HAV/HDV HIV Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides

15 Hypothetical Case Study II: Patient Management Timeline PCP decides to monitor patient HBV DNA (copies/ml) 10 log 10 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml Should this PCP initiate treatment in this patient? Why or why not? How, if at all, should ethnicity, age, and/or suspected time of infection affect the decision to initiate treatment? Why? If this PCP chooses to initiate treatment in this patient, which agent should be selected? Why? How, if at all, should considerations regarding the potential for longterm resistance development impact agent selection? Why? ALT (U/L) 1 log Time After Diagnosis (months) 28 Hypothetical Case Study II: Treatment Timeline PCP prescribes an oral nucleos(t)ide analogue HBV DNA (copies/ml) 10 log 10 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml In your opinion, what would be your approach to counseling this patient for long-term compliance? How frequently do you think this patient should be monitored? Why? ALT (U/L) 1 log Time After Diagnosis (months)

16 AASLD CHB Practice Guidelines: Potential for Resistance and Long-term Treatment Considerations Choose an Agent that Achieves Effective Viral Load Suppression and Has Low Genotypic Resistance Monitor Viral Load and ALT Closely a Reinforce the Importance of Patient Compliance a Monitor every 3-6 months Lok ASF and McMahon BJ. Hepatology. 2007;45: Hypothetical Case Study III: Treatment-naïve HBeAg(-) Vietnamese Female Stay-at-home Mother

17 Patient Profile Patient History Stay-at-home mother Married with 3 children Profile Gender/ Age Female 45 years Ethnicity Vietnamese Immigrated to US 15 years ago Height/ Weight lbs BMI (kg/m 2 ) 22.1 HBsAg(+) 1 year ago, confirmed 6 months later by PCP Viral load and ALT values not tested Recent liver disease in family prompted patient to visit gastroenterologist for a second opinion Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides Initial Patient Diagnosis: Gastroenterologist Diagnostic Tests and Laboratory Values HBsAg HBsAb + -- Profile HBeAg Gender/ Age Female 45 years Ethnicity Vietnamese Immigrated to US 15 years ago Height/ Weight lbs BMI (kg/m 2 ) 22.1 Serum Creatinine: 1.1 mg/dl Creatinine Clearance: 53 ml/min ALT: 22 U/L (0.73 x ULN) Serum HBV DNA by PCR Assay: 2.73 x 10 6 IU/mL a (7.2 log 10 copies/ml) a Based on IU/mL conversion factor associated with the COBAS Taqman HBV assay (Roche Molecular Systems); 1 IU/mL = 5.8 copies/ml

18 AASLD CHB Treatment Guidelines for HBeAg(-) Patients HBsAg(+) HBeAg(-) HBV DNA <2,000 IU/mL ALT <1 x ULN HBV DNA 2,000-20,000 IU/mL ALT 1-2 x ULN HBV DNA >20,000 IU/mL ALT >2 x ULN Q 3 mo ALT x3 then Q 6-12 mo if ALT still <1 x ULN Q 3 mo ALT & HBV DNA Consider biopsy if persistent Treat as needed Treat if persistent Liver biopsy optional Adapted from: Lok ASF and McMahon BJ. Hepatology. 2007;45: Discussion Questions Should a liver biopsy be conducted? Why or why not? Should a genotype test be conducted? Why or why not?

19 Additional Test Results Diagnostic Tests and Laboratory Values HBV genotype C Profile Gender/ Age Female 45 years Ethnicity Vietnamese Immigrated to US 15 years ago Height/ Weight lbs BMI (kg/m 2 ) 22.1 Knodell necroinflammatory score: 8 Ishak fibrosis score: 3 a Based on IU/mL conversion factor associated with the COBAS Taqman HBV assay (Roche Molecular Systems); 1 IU/mL = 5.8 copies/ml 36 Discussion Questions In your opinion, should this specialist initiate treatment for this patient? Why or why not? If this specialist chooses to initiate treatment, which agent(s) should be considered? Why? How, if at all, should considerations regarding the potential for long-term resistance development impact agent selection? Why? Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides

20 Case Study III: Treatment Timeline Gastroenterologist prescribes 0.5 mg of BARACLUDE (entecavir) once daily HBV DNA (copies/ml) 10 log 10 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml Would your approach to the assessment and treatment of this patient differ from that of the physician in this case study? If so how? If not, why? For how long do you anticipate that this patient would require treatment? Why? What, if any, concerns would you have regarding the potential for long-term development of resistance? Why? ALT (U/L) 1 log Time on Treatment (months) Case Study III: Treatment Timeline Patient continues on therapy for the next 3 years with biannual monitoring 10 log log HBV DNA (copies/ml) 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml HBsAg seroconversion is not observed, HBV DNA remains undetectable Would you consider therapy discontinuation at this time? Why or why not? ALT (U/L) 1 log Time on Treatment (months)

21 Hypothetical Case Study IV: Ghanian HBeAg(+) Male with Suboptimal Response to First-line Nucleos(t)ide Therapy Small Business Owner 40 Patient Profile Patient History Recently diagnosed with CHB and treated with nucleos(t)ide analogue therapy Profile Gender/ Age Male 37 years Ethnicity Ghanian Immigrated to US 5 years ago Height/ Weight lbs BMI (kg/m 2 ) 23.7 HBsAg HBsAb HBeAg HCV/HAV/HDV Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides

22 Initial Patient Diagnosis Laboratory Values ALT: 60 U/L (1.5 x ULN) Profile Gender/ Age Ethnicity Height/ Weight BMI (kg/m 2 ) HBV DNA by PCR assay: 6.6x10 6 IU/mL a (7.58 log 10 copies/ml) Male 37 years Ghanian Immigrated to US 5 years ago lbs 23.7 Serum creatinine: 1.4 mg/dl Creatinine clearance: 82 ml/min a Based on IU/mL conversion factor associated with the COBAS Taqman HBV assay Molecular Systems); 1 IU/mL = 5.8 copies/ml (Roche 42 Case Study IV: Treatment Timeline Physician prescribes an oral nucleos(t)ide analogue 10 log HBV DNA (copies/ml) 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml Physician assesses patient compliance Physician conducts genotypic resistance test: No nucleos(t)ide analogue resistance mutations detected In your opinion, should this physician modify therapy at this time or continue to treat with current therapy and monitor over time? Why? ALT (U/L) 1 log Time on Treatment (months)

23 Case Study IV: Treatment Timeline Physician switches the patient to a different agent 10 log HBV DNA (copies/ml) 9 log 10 8 log 10 7 log 10 6 log 10 5 log 10 4 log 10 3 log 10 2 log 10 <300 copies/ml How would your approach to the treatment of this patient be similar to or different than the physician in this case study? Why? ALT (U/L) 1 log Time on Treatment (months) 44 Summary The CDC and AASLD guidelines recommend screening of patients who are at increased risk for CHB based on: country of origin/social contacts, lifestyle factors, clinical factors The AASLD CHB treatment guidelines provide recommendations for when to initiate therapy in nucleoside-naïve HBeAg(+) and HBeAg(-) patients based on clinical markers including HBV DNA (viral load) and ALT Choosing a first-line anti-chb agent that achieves effective viral load suppression and has low genotypic resistance minimizes the potential for long-term resistance development In patients who do not respond or respond suboptimally to initial nucleos(t)ide analogue therapy and demonstrate no evidence of emergent genotypic resistance, different agents should be considered Please see Indication and Important Safety Information for BARACLUDE (entecavir), including boxed WARNINGS in bold, on slides

24 References BARACLUDE (entecavir) Full Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part I: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54 (RR16):1-23. Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR16):1-25. Centers for Disease Control and Prevention. Viral Hepatitis B: Frequently Asked Questions (FAQs). Available at: Accessed July 17, Chu C-J, Hussain M, Lok ASF. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology. 2002;122: Hepatitis B Foundation: Additional Blood Tests. Available at: Accessed July 16, Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22: Kao J-H, Chen P-J, Lai M-Y, Chen D-S. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol. 2004;72: Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1(5): Lok ASF and McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45: