CPE Session 4 Recent Advances in the Journey to Cure Hepatitis C Friday, April 24, 2015 ACPE UAN 0128-0000-15-024-L01-P 1.0 CPE Hour Jennifer Hickman, PharmD, BCACP Dr. Jennifer Hickman is an ambulatory care pharmacist in Internal Medicine at Nebraska Medicine and a clinical assistant professor at the University of Nebraska College of Pharmacy. She is a 2001 graduate of the UNMC College of Pharmacy. Jennifer has worked at the UNMC Physician s Internal Medicine clinic since 2002 with a primary focus on anticoagulation and hepatitis C. She also serves as a preceptor for fourth-year pharmacy students and PGY-1 residents in ambulatory care. She received ACCP board certifi cation in ambulatory care pharmacy (BCACP) in 2012. Jennifer lives in Omaha with her husband, Hubert, several dogs, and six children at home and scattered about at various colleges across the country. Dr. Hickman has no fi nancial interests or arrangements that would be considered a confl ict of interest for the presentation of this program. NPA 2015 Annual Convention
Recent Advances in the Journey to Cure Hepatitis C Jennifer Hickman, PharmD, BCACP Disclosure: I have no relevant financial relationships that would be considered a conflict of interest for the purposes of this program. This CPE program will not include discussion of non FDA approved medication use. Abbreviations HCV: Facts and Stats HCV= hepatitis C virus HCC= hepatocellular carcinoma PEG IFN= pegylated interferon RBV= ribavirin PI= protease inhibitors SVR= sustained virologic response RNA virus spread through contact with blood/body fluids Leading reason for liver transplantation in the US Initially non A, non B hepatitis until identified in late 1980 s Reliable screening test developed in 1992 Picture of human body and liver Hepatitis C in the US Screening Recommendations Reported New Cases Incidence of acute hepatitis C by year graph Estimated New and Chronic Cases New 24,700 in 2012 Chronic 2.7 3.9 million High risk behavior IV or intranasal drug use Risk exposures Long term hemodialysis Needlestick or mucosal exposure to HCV infected blood Children born to HCV infected mothers Persons who have been incarcerated recipients of organ transplants or blood products Other HIV, unexplained liver disease, organ donors All persons born between 1945 1965 CDC.gov: Division of Viral Hepatitis and National Center for HIV/AIDS, Viral Hepatitis,STD and TB Prevention 1
Distribution of HCV Genotypes in the US Picture of the United States Genotypes 1a and 1b account for 79% Genotype 2 accounts for 15% 2 15% 3 4 5% 1% Natural Course of Hepatitis C Acute infection Chronic infection 80% 20% ( risk if male, dx after 40 55yrs, alcohol use) 1b 21% 1a 58% Hepatocellular carcinoma 3% annual risk (1/3 of HCC is related to HCV, mostly pts with cirrhosis/advanced fibrosis) CDC.gov: Division of Viral Hepatitis and National Center for HIV/AIDS, Viral Hepatitis,STD and TB Prevention Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hurter D, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology. 1998;28:1687 95. Prevalence of HCV and Complications Prevalence of HCV graph Hepatitis C Progression Progression to fibrosis graph natap.org Fibrosis & Disease Progression in Hepatitis C. Marcellin, et al. Hepatology, 2002 HCV/HIV Co Infection Economic Burden of HCV in the US* 25% of people with HIV are co infected with hepatitis C Common risk factors 80% of patients with HIV who injected drugs are co infected Liver disease is the leading cause of non AIDS related death in HIV patients More rapid progression of liver disease *Per year, per person in $2010 Liver transplant $201,000 Hepatocellular carcinoma $23 44,000 Variceal hemorrhage $25,500 Refractory ascites $24,700 Hepatic encephalopathy $16,430 Sensitive ascites $2450 Compensated cirrhosis $585 1110 Moderate chronic hepatitis C $155 Mild chronic hepatitis C $145 Picture of dollar sign http://www.cdc.gov/hepatitis/populations/pdfs/hivandhep FactSheet.pdf El Khoury AC, Klimack WK, Wallace C, and Razavi H. Economic burden of hepatitis C associated diseases in the United States. Journal of Viral Hepatitis, 2012; 19(3): 153 60. 2
Goal of Treatment SVR (%) by Therapy SUSTAINED VIROLOGIC RESPONSE (SVR)!! Test for presence of virus 12 weeks after completion of therapy If negative, then considered CURED 99.7% will never recur/relapse Patients achieving SVR (%) 100 90 80 70 60 50 40 30 20 10 0 IFN IFN+RBV PEG+RBV PEG+RBV+PI IFN Free Clinical trials data Cost of Medication Therapy* Economic Burden of Antiviral Therapy Acquisition Cost ($) 160000 140000 120000 100000 80000 60000 40000 20000 0 PEG+RBV PEG+RBV+PI Harvoni Viekira+RBV Olysio+Sovaldi Cost projections estimate that treating HCV will cost the US health system $136 billion over the next 5 years!! Will account for 1 in 10 dollars spent on prescriptions Government will bear a large burden of the cost 12 35% of prison inmates have chronic HCV Treating all of the HCV patients in the VA Health System would cost nearly $12 billion even with discounted pricing!! *Genotype 1, treatment naive, non cirrhotic http://www.militarytimes.com/story/military/pentagon/2015/01/07/hepatitis c sovaldi cost/21334481/ Chhatwal J, Kanwal F, Roberts M, Dunn M. Cost Effectiveness and Budget Impact of Hepatitis C Virus Treatment with Sofosbuvir and Ledipasvir in the United States. Annals of Internal Medicine, 2015; 162 (6): 397 428. Hepatitis C Antivirals Picture of hepatitis C viral replication NS5A protein inhibitor Ledipasvir (Harvoni ) Ombitasvir (Viekira ) NS5B polymerase inhibitor Sofosbuvir (Sovaldi, Harvoni ) Dasabuvir (Viekira ) Ribavirin Unknown MOA Ritonavir (Viekira ) No activity against HCV, only used to boost paritaprevir NS3/4A protease inhibitor Paritaprevir (Viekira ) Simeprevir (Olysio ) [http://www.nature.com/nature/journal/v465/n7294/images/465042a f1.2.jpg] 3
Choice and Duration of Therapy Genotype and baseline HCV RNA quantitation Harvoni and Viekira approved for genotype 1 Previous treatment experience PEG/RBV PEG/RBV/PI Presence or absence of cirrhosis Other disease states/medications Harvoni x 12 wk Viekira+RBV x 24wk Sovaldi+Olysio+ RBV x24wk 24wk Genotype 1a Harvoni x 24wk Harvoni+RBV x 12wk Viekira +RBV x 24wk Sovaldi+Olysio+ RBV x24wk No Harvoni x 12wk Viekira +RBV x 12 wk Sovaldi+Olysio +RBV x12wk Harvoni x 12wk Viekira+RBV x 12wk Sovaldi+Olysio +RBV x12wk Genotype 1b Genotype 2 No No 24wk Harvoni x 12 wk Viekira+RBV x 12wk Sovaldi+Olysiox24wk Harvoni x 24wk Harvoni+RBV x 12wk Viekira +RBV x 12wk Sovaldi+Olysio+ RBV x24wk Harvoni x 12wk Viekira x 12 wk Sovaldi+Olysiox12wk Harvoni x 12wk Viekira x 12wk Sovaldi+Olysio +RBV x12wk Sovaldi + RBV x 16wk Sovaldi +RBV x 16wk Sovaldi + RBV + PEG IFN x 12 wk Sovaldi + RBV x 12wk Sovaldi +RBV x12wk Sovaldi + RBV + PEG IFN x 12wk + Genotype 3 Genotype 1, No cirrhosis, previous PEG/RBV/PI failure Treatment Sovaldi + RBV x 24wk Sovaldi + RBV + PEG IFN x 12wk PEG/RBV Failure Daily fixed dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is recommended for retreatment of patients without cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior PEG IFN, RBV, and HCV protease inhibitor regimen has failed. 4
Genotype 1, with, Previous PEG/RBV/PI failure Daily fixed dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks Daily fixed dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks Monitoring Therapy Pre Treatment During Treatment Post Treatment HCV genotype HCV quantitation Renal function Liver enzymes Presence/absence of cirrhosis Pregnancy (ribavirin) Drug Interactions CBC, pregnancy test monthly if using RBV SCr if concern for unstable renal function Liver enzymes??? Check for sustained virologic response, 12 weeks post treatment Continued surveillance for hepatocellular carcinoma Sofosbuvir (Sovaldi ) Dosed 400mg daily with or without food Do not use if ClCr <30ml/min Most common adverse effects: fatigue, headache, nausea, and insomnia Drug interactions metabolized by P gp Avoid with inducers: phenytoin, rifampin, St. John s Wort, carbamazepine Serious (and fatal) bradycardia has occurred when using sofosbuvir/ledipasvir with amiodarone Sofosbuvir/Ledipasvir (Harvoni ) Genotype 1 ONLY!! 400mg/90mg tablet qday with/without food Adverse effects: fatigue, headache, nausea, diarrhea, insomnia Important drug interactions same as sofosbuvir AND: No amiodarone unless admitted under telemetry x 48 hrs., even if amiodarone recently stopped Digoxin increased levels No rosuvastatin Antacids 4 hrs apart If on PPI/H2RA, take @ same time and no more than 20mg omeprazole or 40mg bid famotidine equivalent Prescribing Information: Sovaldi Prescribing Information: Harvoni Simeprevir (Olysio ) Genotype 1 only!! 150mg daily with food Only guideline recommended regimen is simeprevir, sofosbuvir + ribavirin Adverse effects: nausea, headache, fatigue, rash, photosensitivity, may cross react with sulfa allergy Interactions through CYP3A and P gp NUMEROUS including: statins, cyclosporine, macrolides, azole antifungals, antiarrhythmics, calcium channel blockers, rifampin, phenytoin, carbamazepine, digoxin Ombitasvir/Paritaprevir/Ritonavir/ Dasabuvir (Viekira ) Genotype 1 only!! Comes in daily dosing pack with instructions Adverse effects: fatigue, nausea, insomnia, rash, pruritis Drug interactions through numerous mechanisms: CYP3A and 2C8, P gp, OAT and BRCP Many drugs contraindicated including: ethinyl estradiol, gemfibrozil, simvastatin, daily sildenafil, rifampin, phenytoin, St. John s Wort, salmeterol Careful with antiarrhythmics, fluticasone, furosemide, amlodipine, cyclosporine, tacrolimus, azole antifungals, alprazolam, rosuvastatin, pravastatin Prescribing Information: Olysio Prescribing Information: Viekira 5
Ribavirin Used in combination therapy only 1000mg if < 75kg, 1200mg if > 75kg, in 2 divided doses Primary adverse effect is hemolytic anemia dose to 600mg if Hgb <10g/dL, stop if < 8.5 If stable CAD, to 600mg if >2g drop in Hgb and stop if Hgb < 12g/dL Do not use if ClCr < 50ml/min TERATOGENIC! Pregnancy test before treatment and monthly if childbearing potential Use 2 forms of birth control if treating male OR female during treatment and for 6 months after treatment HCV/HIV Co infection MANY potentially serious drug drug interactions between HCV and HIV medications Should be managed by or in conjunction with HIV practitioner Do NOT interrupt anti retroviral therapy to treat HCV!! After recognizing and addressing interactions, treatment options and duration should be the same as non HIV infected individuals Lexicomp Addressing Adherence 80% rule has historically been considered the standard for optimal outcomes with HCV therapy Predictors of adherence Personal connection with pharmacist/pharmacy Affordability Perceived effectiveness Simplicity of regimen Adverse effects Connectedness with a health facility Take Home Message Finally, a cure for the MAJORITY of patients with hepatitis C Opportunity to change the long term prognosis and future healthcare costs associated with chronic hepatitis C Can we afford to treat everyone? Pharmacists are well positioned to make a real impact on outcomes Medication Adherence in America, from http://www.ncpanet.org/pdf/reportcard/adherencereportcard_full.pdf JJ Weis, N Brau, A. Stivala, T. Swain, D. Fishbein. (2009). Adherence to medication for chronic hepatitis C building on the model of human immunodeficiency virus antiretroviral adherence research. Aliment Pharmacol Ther 30(1): 14 27. Case #1 TO is a 60yowm with chronic hepatitis C, genotype 2b with cirrhosis. He previously attempted therapy with PEG/RBV but discontinued due to intolerable adverse effects. He re presents for treatment and is prescribed a 12 week course of sofosbuvir, PEG IFN, and ribavirin. Case #1: Is the prescribed therapy appropriate? a. Yes, therapy choices and duration are appropriate b. Therapy choice is appropriate, but not duration c. Duration is appropriate, but therapy is inappropriate d. Both therapy choice and duration are inappropriate What monitoring needs to be done prior to and during treatment? 6
Case 2: HCV Drug Drug Interactions TL is currently being treated with sofosbuvir/ledipasvir x 12 weeks for HCV genotype 1a (treatment naïve, no cirrhosis). During the course of treatment, he is diagnosed with H. Pylori. The physician prescribes Pylera *plus omeprazole 20mg bid to treat his H.Pylori and he presents these prescriptions to fill at your pharmacy. *Pylera = bismuth subcitrate potassium, metronidazole, tetracycline Case 2: HCV Drug Drug Interactions Are there any concerns with treating this patient s H.Pylori while on HCV treatment? a. No concerns, fill as prescribed b. Counsel patient to take omeprazole 4 hours apart from sofosbuvir/ledipasvir c. Omeprazole should be reduced to once daily d. Pylera should be changed to another regimen due to antibiotic interaction Case 3: The co infected patient MK is a 44 year old male who is co infected with HIV and chronic hepatitis C, genotype 1a. His current HIV regimen consists of Atripla (efavirenz/emtricitabine/tenofovir). He presents to clinic for treatment of hepatitis C. He has never been treated before and has no cirrhosis. Case 3 Which of the following is TRUE when it comes to treating MK? a. His HIV regimen will likely require adjustment b. His case should be co managed by an HIV specialist c. Treatment duration for a co infected patient is the same as for any other patient d. All of the above For more information: Questions??? hcvguidelines.org cdc.gov References: Center for Disease Control Division of Viral Hepatitis and National Center for HIV/AIDS, Viral Hepatitis,STD and TB Prevention. Hepatitis C Information for Health Professionals. Retrieved from http://www.cdc.gov/hepatitis/hcv/index.htm Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hurter D, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology, 1998;28:1687 95. Marcellin P, Asselah T, Boyer N. Fibrosis & Disease Progression in Hepatitis C. Hepatology, 2002;36(5 Suppl 1):S47 56. American Association for the Study of Liver Diseases/Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C, updated January 28, 2015. Retrieved from: http://www.hcvguidelines.org El Khoury AC, Klimack WK, Wallace C, and Razavi H. Economic burden of hepatitis C associated diseases in the United States. Journal of Viral Hepatitis, 2012; 19(3): 153 60. Chhatwal J, Kanwal F, Roberts M, Dunn M. Cost Effectiveness and Budget Impact of Hepatitis C Virus Treatment with Sofosbuvir and Ledipasvir in the United States. Annals of Internal Medicine, 2015; 162 (6): 397 428. Sovaldi [package insert]. Foster City, CA: Gilead Sciences; 2015. Harvoni [package insert]. Foster City, CA: Gilead Sciences; 2015. Olysio [package insert]. Titusville, NJ: Janssen Therapeutics; 2013. Viekira [package insert]. North Chicago, IL: AbbVie Inc; 2015. Lexi Comp, Inc. (Lexi Drugs); Updated 3/10/15. Medication Adherence in America: A National Report 2013. Retrieved from http://www.ncpanet.org/pdf/reportcard/adherencereportcard_full.pdf Weis JJ, Brau N, Stivala A, Swain T, Fishbein D. Adherence to medication for chronic hepatitis C building on the model of human immunodeficiency virus antiretroviral adherence research. Aliment Pharmacol Ther, 2009 30(1): 14 27. Kime, Patricia. (2015, January 28). Hepatitis C drug costing VA, DoD millions. Retrieved from http://www.militarytimes.com/story/military/pentagon/2015/01/07/hepatitis c sovaldi cost/21334481 7