1. Challenges of Treatment of Hepatitis C in the Incarcerated US Population USPHS Scientific and Training Symposium June 23, 2011 Dr William Resto-Rivera MD, USPHS Kiesha Resto Pharm D, USPHS

2. Objectives # 1) Compare Hepatitis C Virus (HCV) infections in prison population versus the regular population. #2) Analyze the challenges of identifying and treating prison population. #3) Review common & rare side effects that are related to Hepatitis C therapy. #4) Discuss challenges in treating patients with co-morbid conditions. #5) Review recent FDA approved medications for HCV.

3. US Hepatitis Statistics 1.3% US population infected Hepatitis C Virus (HCV) 29-43% People infected with HCV will pass through US prison system every year 16-40% US Prison population infected with HCV Reference #4

4. Population Baby boomers account for 2 out of 3 cases of HCV patients. Peak prevalence men born in early 1950’s HCV is over-represented in African Americans. Reference #5

5. Every 100 people infected with HCV 75-85 develop chronic infection 60-70 develop chronic liver disease 5-20 develop cirrhosis 1-5 die from cirrhosis or liver cancer

6. Center of Disease Control & National Institutes of Health Convention January 2003 identified 5 optimal approaches to Screening & treating HCV in US prisons #1 Testing of HCV in Prisons would identify many Infected Americans #2 Prison Substance Abuse programs would decrease HCV infections & future prisons cost #3 Patients can be Selected using Published Guidelines #4 Prisons Treatment Reflects Community Standards and Require Sufficient Medical Workforce #5 Collaboration Between Correctional & Public Health Systems is Needed Reference #14

7. Factors for Treatment Screening Screening and Diagnosis of Hepatitis C individuals. Screening for candidates for treatment Safety, Efficacy & Cost Monitoring Laboratories and ADR Patient Tolerate treatment Viral Response to treatment EVR/SVR Source of funding

8. Hepatitis C Not a Routine Universal Screening Routine screening based on 4 criteria: Amenable to treatment Interfere with activities of daily living Progress without treatment during time of incarceration Risk of transmission Reference # 14

9. To Screen or to Not Screen Rhode Island State Corrections Screened all incoming inmate 4263 Males – 23% + HCV 499 Females – 40% HCV Out of inmates who tested + HCV 66% did not report high risk behaviors Wisconsin State Corrections 91% HCV infected inmates identified through testing 27% of population with risk factor IVDA Indiana State Corrections Universal testing found 13% of population HCV (+) Reference #16Reference #14

10. USA and territories Incarcerated population 2008 Total 2,424,279 Federal & State Prisons1,518,559 Territorial Prisons13,576 Local Jails 785,556 ICE Facilities9,957 Military Facilities1,651 Jails in Indian Country2,135 Juvenile Facilities92,845 Reference #3

11. Break down of 2,424,279 US prison population infected with HCV 387,884 -- 969,711 16-40% Progress to end stage liver disease 3,878 -- 29,091 1 to 3 %

12. Medicare Disease StatesCommercialAge<65Age >65 Chronic HCV Infection (without Cirrhosis) $174 more than avg $525 more than avg$460 more then avg Compensated Cirrhosis without Complication $370 more than avg$772 more then avg$611 more than avg Decompensated Cirrhosis 0- 6 months$13,900$7,100 Decompensated Cirrhosis + 6 months$12,700$4,200 Hepatocellular Carcinoma 0-6 months $5,500$2,400 Hepatocellular Carcinoma + 6 months $4,900$2,100 Liver Transplant 0- 6 months $38,900$24,700 Liver Transplant 6- 18 months $5,600$3,800 Liver Transplant + 18 months $3,900$2,200 Summary of Assumptions of Paid Cost per Patient Per Month (PPPM) as of 2008 Reference #22

13. Missed Opportunity Lower cost in long run for HCV treatment Stable living environment Accessible medical care High Risk Population Direct Observed Medication Abstinence from Substance abuse Coordination between Rehabilitation programs and treatment Benefits for treatment during Incarceration

14. Hepatitis C Multiple Genotypes 1 Most common (US) Approx. 80% 2/3 US Approx 20% 4 Egypt RNA Virus Family Flavovirus ( Denque, yellow fever)

15. US Hepatitis C Statistics Genotype 1 40-50% Successful SVR at 12 months Genotype 2/3 70-80% Successful SVR at 12 months

16. Contraindications to Ribavirin 1. Thalassemias (sickle cell anemia) or other hemoglobinopathy. 2. Significant cardiac disease ( arrhythmias, angina, CABG, MI) in the past 12 months. 3. Renal dialysis or creatinine clearance < 50 mL/min. 4. Hypersensitivity to ribavirin 5. Pregnancy Reference # 1

17. Ribavirin Side Effects Black Box Warnings: Hemolytic Anemia Warning (primarily in the first two weeks of therapy) Pregnancy Warning. Negative pregnancy test is required pre-therapy & at every evaluation Respiratory Warning for patients requiring assisted ventilation Reference #1

18. Contraindication Peg-Interferon Serious concurrent medical diseases; severe hypertension, heart failure, coronary heart disease, COPD, autoimmune disorders, uncontrolled endocrine disorder Decompensate cirrhosis, History of solid organ transplant Platelet count <75,000/mm3 or ANC <1,500 cells/mm3 Ongoing injection drug use or alcohol use Severe uncontrolled psychiatric disease Reference #1

19. Adverse Event Carswell 2007- 2010 Statistical Data: Annals Internal Medicine 2004 (6) Statistical Data: Hematology 2002 (7) Headache 26%55%64% Pruritis 63%25% Decrease Appetitie 63%21%32% Nausea / vomiting 42%35%43% Fatigue 63%48%64% Mood Changes 42%26%35% Gastro-intestinal 21%20% Anemia 42% 22% Neutropenia 21% 20% Thrombocyto 21% 4% Reference # 6 & #7

20. Management of Side Effects Headaches/ Body aches Tylenol FLUIDS, FLUIDS, FLUIDS NSAIDS!!!??? Nausea & Vomiting Promethazine

21. Hemoglobin adjustment 10-11 g/dl If no or minimal symptoms, then no dose modification If symptomatic, decrease ribavirin by 200 mg/day 8.5-10 g/dl Peginterferon alfa 2b ( Peg-Intron) Reduce 25-50% Ribavirin ↓ to 600 mg daily (200 mg AM & 400mg PM) <8.5 g/dl Peginterferon alfa 2b (Peg-Intron) Discontinue until resolved. Ribavirin Discontinue until resolved. If hemoglobin is <12g/dL for over 4 weeks at the reduced/adjusted dose then discontinue ribavirin Reference #1

22. Absolute Neutrophil Count (ANC) Adjustment <750 Peginterferon alfa 2b (Peg-Intron) Reduce to a 25% -50% dose <500 Peginterferon & Ribavirin Discontinue both until resolved Granulocyte Colony Stimulating Factor (G-CSF): If the patient is responding to treatment and neutropenia persists despite reduced peginterferon dose, consider G-CSFDosage: Filgrastim 300 microgram subcu. daily. Goal: ANC >1500 Reference #1

23. Platelet Adjustment <50,000 Peginterferon alfa 2b (Peg-Intron) Discontinue until resolved. Ribavirin If on Peg-Intron, then discontinue ribavirin. <30,000 Peginterferon Discontinue until resolved. Ribavirin Discontinue until resolved. Reference #1

24. Serious Adverse Reaction Auto immune Arrhythmias Depression / Psychosis CHF Permanent thyroid dysfunction

25. Patients with Co- morbid conditions Pre-exiting Cardiac Condition Renal Disease Autoimmune Disease Depression

26. Tx 23 pre-existing heart disease patients with INF & Ribavirin 52% reached SVR, 39% relapse, 9% non responders EKG & Echo show no signs of progression of pre- exiting heart disease Digest of Liver Disease 2011 Tx 7 patients with vasculititis and GN successfully with INF & Ribavirin Nephrology, Dialysis, Transplant 2003 19 patient referred from PCP for polyarthritis, polyarthralgia, or positive rheumatoid factors where found to have hepatitis Journal of Rheumatology 1996 Case Studies Reference # 8-#10

27. New Treatment Options Boceprevir ( Victrelis) FDA approved May 13, 2011 Hepatitis C Genotype 1 Naïve & Relapse patients 800 mg tablets x 44 weeks after 4 week lead in Telaprevir (Incivek) FDA approved May 23, 2011 Hepatitis Genotype 1 Naïve and Relapse patient 750 mg tablets TID for first 12 weeks of therapy

28. Telaprevir (Incivek) Naive & Relapser (1088) Treatment 75% SVR Control 45% SVR ADVANCE Naïve ( 704) Treatment 80% SVR Control 50% SVR No benefit extending tx 92% SVR @ 24wks 88% SVR @ 48wks ILLUMINATE Relapsers (650) Treatment 56% SVR Control 22% SVR REALIZE Reference #20

29. Boceprevir (Victrelis) Treatment Naïve (1,097) Treatment Group 69% SVR Control Group 40% SVR African American Treatment 69%SVR Control 40% SVR SPRINT-2 Non-Responders and Relapsers (403) Treatment Group 66% SVR Control Group 21% SVR RESPOND- 2 Reference #21

30. Boceprevir (Victrelis) Fatigue, Headache, Nausea, Dysgeusia Anemia (3% require discontinuation of therapy) Telaprevir (Incivek) Fatigue, Headache, Nausea, Pruritis Anemia & Rash ( 0.6-1.1% require discontinuation of therapy) Adverse Effects

31. Summary Prison are an ideal setting to treat a large population of HCV (+) people. Screening for HCV need to be examined cost/benefit per institution. Treating patient while incarcerated can be a cost saving to society HCV treatment is associated with multiple side effects that need an educated multidiscipline approach to manage

32. Summary Guidelines are established for screening and to help guide management of adverse events. Patient with co-morbidies are an increase challenge to treat but can be treated safely and effectively with proper monitoring. New Antiviral medications just approved will improve overall outcomes in the future.

33. References 1. Federal Bureau of Prisons Clinical Guideline Prevention of Hepatitis C and Cirrhosis June 2009 Federal Bureau of Prisons Clinical Guideline Prevention of Hepatitis C and Cirrhosis June 2009 2. Raison. Depression During Pegylated Interferon-Alpha Plus Ribavirin Therapy: Prevalence and Prediction. J Clin Psychiatry. 2005 January ; 66(1): 41–48. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615913/pdf/nihms3152.pdf ( Accessed 4/11)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615913/pdf/nihms3152.pdf 3. http://en.wikipedia.org/wiki/Incarceration_in_the_United_States (Accessed 9/24/10) http://en.wikipedia.org/wiki/Incarceration_in_the_United_States 4. Jennifer A. Tan, Tom A. Joseph, Sammy Saab, Treating hepatitis C in the prison population is cost-saving,Hematology. 2008; 48: 1387-1395 5. Suzanne M. Kirchhoff, Economic Impacts of Prison Growth, Congressional Research Service, April 13, 2010. http://assets.opencrs.com/rpts/R41177_20100413.pdf (Accessed 9/24/10 ) http://assets.opencrs.com/rpts/R41177_20100413.pdf 6. Hadziyannis, S. Peginterferon-2a and Ribaviriin Combination Therapy in Chronic Hepaitits C. Annals of Internal Medicine. 2004 ;140: 346-357 7. Fried, M. Side Effects of Therapy of Hepaptitis C and Their Management. Hepatology. 2002: 36.

34. References 8. Bruchfeld, A. Lindahl, K. Interferon and Ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrology Dialysis Transplantation, 2002;18, 1573-1580. http://ndt.oxfordjournals.org/content/18/8/1573.short ( Accessed 4/2011) http://ndt.oxfordjournals.org/content/18/8/1573.short 9. EL-Atrebi, K. El-Bassyouni, H. Management of rare side effects of peginterferon and ribavirin therapy during hepatitis C treatment: a case report. Case Journal 2009:2 : 7429 10. Lovy M.R, Starkemaum G. Hepatitis C Infection Presenting with Rheumatic Manifestations: Mimic of Rheumatoid. Journal of Rheumatology 1996; 23;979-983 11. Center of Disease Control Morbidity and Mortality Weekly Report. Prevention and Control of Infections with Hepatitis Viruses in Correctional Settings. January 24, 2003 / Vol. 52 / No. RR-1 12. Durante-Mangoni E, Iossa D. Safey and efficacy of peginterferon alpha plus ribavirin in patients with chronic hepatitis C and coexisting heart disease. Dig Liver Dis 2011 [ pub ahead of print]. 13. Ghany M, Strader B. Diagnosis, Management, and Treatment of Hepatitis C: An Update. HEPATOLOGY 2009; 49: 1335-74

35. References 14. Spaulding A, Weinbaum C. A Framework for Management of Hepatitis C in Prisons. Annals of Internal Medicine 2006; 144: 762-769 15. 15. Kim R. The Burden of Hepatitis C in the United States. Hepatology 2002;36:S30-S34 16. Macalino G. A Missed Opportunity: Hepatitis C Screening of Prisoners. AM J Public Health. 2005;95: 1739-1740 17. Sutton A, Edmund J. Estamating the cost-effectiveness of detecting cases of chronic hepatitis C infection on reception into prison. BMC Public Health 2006;6;170 18. Mc Hutchinson J, Brunce B. Chronic Hepatitis C: An Age Wave of Disease Burden. Am J Manag Care 2005;11:S286-S295 19. Wong J, McQuillan G. Estimating Future Hepatitis C Morbidity Mortality, and Cost in the United States. Am J Public Health. 2000;90:1562-1569 20. http://www.hivandhepatitis.com/hep_c/news/2011/0524_2011_a.html ( Accessed 6/2/11)http://www.hivandhepatitis.com/hep_c/news/2011/0524_2011_a.html 21. http://www.hivandhepatitis.com/hep_c/news/2011/0517_2011_a.html ( Accessed 6/2/11)http://www.hivandhepatitis.com/hep_c/news/2011/0517_2011_a.html

36. References 22. B. Pyenson. Consequences of Hepatitis C virus (HCV): Cost of a Baby Boomer Epidemic of Liver Disease. Vertex Pharmaceuticals Incorporations. Miliman, Inc. May 2009.

37. QUESTIONS ??