Hepatitis Update. HCV Cure As A Paradigm for Convergence of Interests. Evidence Based Nuts and Bolts For the Family Doc 11/5/2014

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1 Evidence Based Nuts and Bolts For the Family Doc Hepatitis Update William Carey MD MACG, FAASLD Oct 25, 2014 HCV Cure As A Paradigm for Convergence of Interests Hepatitis C Cure 1

2 Get Ready Get SET Go SET = Screen, Evaluate, Treat Why Hepatitis C Matters 4/180 million in US/world infected Lifelong infection for 50% 80% Consequences for those infected Decreased QOL 10% > Cirrhosis and/or liver cancer 2

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5 Impact of HCV Cure Effects of Sustained Virological Response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and re infection: meta analysis of 129 studies in 23,309 patients with Hepatitis C infection Compared to those who did not achieve SVR Hepatocellular cancer Death: Liver Transplant: 68 79% reduction 60 84% reduction 90% reduction The annual absolute risk reductions in mortality were 1% in mono infected patients. there was a significant risk of subsequent re infection after SVR in some studies. Hill et al. Hepatology 2014; 60:219A Health and Economic Impact of HCV on US Medicare System Over 1 million Americans with HCV will age into Medicare by 2024 Disease related deaths Increased QALYs No Treatment Interferon + oral All Oral 661, , ,000 Base case +1.6 million +7.7 million Rein et al. Hepatology 2014; 60: 233A 5

6 APatient s Perspective October 1, 2014 Dear Dr. Carey, In January of this year I came to see you about the new hepatitis C drugs the FDA had just approved. I am happy to say my insurance finally approved the payment for the medication. The side effects have been mild, nothing like the side effects of the interferon treatment of 2007/08. After only 2 weeks the viral count went from 1.4 million to undetectable. After treatment was over the viral count remained undetectable. Needless to say, I am thrilled with the results and that, at my age, I have been given a second chance at living a healthy life. This is the best present I could ever receive. I no longer am living with the Sword of Damocles poised over your head. Most of the people I ve talked to who have undergone the treatment feel this way Thank you from the bottom of my heart. MEF New York Patient Well Being Before During and After All Oral Therapy Systematic review of 73 publications shows HCV associated with decreased Health related quality of life measures, and worsened with interferonbased therapy HCV modified chronic liver disease questionnaire given before, during and after therapy (sofosbuvir ledipasvir +/ ribavirin) vitality, fatigue, work productivity, etc. Ribavirin free sofosbuvir ledipasvir is associated with high efficacy and significant improvement in patient reported outcomes as early as two weeks after beginning treatment Younossi et al. Hepatology 2014;60:235A Younossi et al ACG Abstract P

7 Management of HCV by the Non Specialist ALL must be engaged in screening for this highly treatable disease Many should be encouraged and trained to treat HCV infected Screening 7

8 Birth Cohort Screening for HCV HCV is a major cause of morbidity and mortality in the US 70% of infected individuals are unaware 70% of infections are in those born between CDC and USPTF recommend birth cohort screening as well as for those with risk factors BCS alone will miss younger patients!!! Treatment of HCV by Non Specialist There are not enough HCV treating health care providers Treatment is easy Monitoring not time consuming Treatment is effective Side effects infrequent Ideal candidate for treatment by the non specialist A young mono infected individual without evidence of advanced liver disease HCV genotype 1 normal platelet count and liver tests except AST/ALT normal liver US normal renal function takes no medications 8

9 Treatment of HCV by Non Specialist Continue to leave to the specialist Cirrhosis certain or possible Pre and post transplant HCV HIV Co infected Previously treated If ribavirin needed Treatment of HCV by Non Specialist Definitions: VR = virologic response ETR = absence of virus on last day of treatment SVR12= absence of virus 12 weeks after treatment end Pre Treatment Testing: HCV genotype HCV viral load CBC and platelets Standard liver tests BUN, creatinine Absence of HIV Liver US if disease > 10 years During Treatment CBC if ribavirin used End of Treatment HCV viral load Liver tests 6months after treatment: viral load 9

10 Case Study 28 Year old woman with a one year old son is referred for HCV evaluation and treatment. She has persistently mildly elevated AST and ALT typical for HCV She denies IVDU for 1.5 year She may have had HCV for as long as 5years She has depression requiring RX and is much better on RX Exam normal Lab AST 44 ALT 67 Otherwise normal CMP and CBC Liver imaging with elastography: normal HCV genotype 1b HCV viral load 835,000 Should I treat? How long should I treat? Should I wait for better treatment? Ideal Treatment Single dose Oral administration Inexpensive Highly effective Infection cured Freedom from side effects 10

11 Choices in Late 2014 How Robust is G1 Hepatitis C Response to All Oral Therapy?? Product Naïve Re treated G1a +Cirrhosis ABT 450/r/ABT mg/100 mg/ 25+ ABT mg twice a day 24 weeks 93% 93% 100% ABT 450/r/ABT mg/100 mg/ 25+ ABT mg twice a day 24 weeks Sofosbuvir + ledipasvir combined in one pill 8,12 or 24 weeks G1 b + Cirrhosis 100% 100% G1 overall + cirrhosis 95% 94% Bourliere et al. Hepatology 2014; 60:239A Everson et al. Hepatology 2014; 60: 239A 11

12 HCV Drugs You Need To Know About All Oral Therapy October 2014 Agent Dosing HCV Genotype Special Concerns sofosbuvir + ledipasvir 8, 12, or 24 weeks Sofosbuvir ABT 450+ritonavir+ombitasvir* One pill a day G 1 Drug drug interactions Pregnancy: B Breast Feeding:? Two pills in AM; one in PM 3 pills in AM; 2 in PM 2 pills in AM; 1 pill in PM G 2(+ribavirin) G 3(+ribavirin) G1a(+ribavirin) G1b( ribavirin) Same (see Ribavirin) Ribavirin (never used alone) Twice a day Anemia Teratogenicity *FDA approval soon dacalatasvir (approved in EU) requires sofosbuvir (or interferon/ribavirin): may not be economically viable. HCV Treatment Summary Q Genotype 1 3 months of all oral therapy for most 2months if no prior treatment, no cirrhosis and viral load < 6 million IU/ml 6 months if cirrhosis and prior treatment failure Genotype 2 3 months of sofosbuvir + ribavirin Genotype 3 6 months sofosbuvir + ribavirin Expect > 90% SVR12 except in G3 with cirrhosis, failing prior treatment (60%) 12

13 Agent Side Effects Common/ important side effects* sofosbuvir + ledipasvir Fatigue 16% 18% Headache 11% 17% Diarrhea 4% 7% Insomnia 3% 6% Uncommon: bilirubin, lipase, CK Ribavirin BIRTH DEFECTS Anemia Renal excretion use with caution ABT 450+ritonavir+ombitasvir* * See complete prescribing information for all drugs Fatigue 21% Headache 23% Nausea 5% Pruritus 6% Asthenia 6% Insomnia 4% Uncommon: bilirubin (mainly indirect) Agent sofosbuvir + ledipasvir Drug Drug Interactions Common/ important Solution Drug Drug Interactions interactions* Acid reducing agents reduces ledipisvir concentration Avoid or minimize acid suppression Digoxin level increase Rosuvastatin levels increase Anticonvulsants (carbamazepine, phenytoin, phenobarbital, oxcarbazepine St Johns Wort Antibacterials rifampin, rifapentine, rifabutin Antiretorviral Monitor digoxin level Avoid Avoid Avoid Avoid See prescribing information * See complete prescribing information for all drugs before prescribing 13

14 Insurance Approval for Sofosbuvir Based HCV Treatment Sofosbuvir/Ribavirin +/ interferon Sofosbuvir/Simeprevir Approved 78% 68% Prior Authorization Required 46% 52% Disapproved 13% 26% Free Drug/Support Path 5% 13% Pending 9% 6% George et al ACG Abstract P Who To Treat? 14

15 Projected Effect of Birth Cohort Screening and All Oral Therapy Markov Model was constructed to explore relative value of 4 strategies A. Screen for HCV based on risk and treat only if significant fibrosis on biopsy B. Screen for HCV based on risk and treat regardless of fibrosis score C. Birth cohort screening and treat only if significant fibrosis on biopsy D. Birth cohort screening and treat all regardless of fibrosis score Younossi et al. Hepatology 2014; 60: 256A Projected Effect of Birth Cohort Screening and All Oral Therapy A B C D To Cirrhosis 56% 55% 6% <1% Decompensation 17% 17% 3% 1.5% Cancer 15% 15% 5% 3% Transplant 7% 7% 2% 1% Life expectancy years Cost per unknown HCV x 1000 $66 $69 $71 $75 Compared to strategy A, strategy D cost an extra $123 billion but produced and additional 22.9 million QALYs ($5371/QALYs) Conclusion: Availability of highly efficacious and well tolerated oral agents makes birth cohort screening of baby boomers highly cost effective with great health and economic benefit at the population level Younossi et al. Hepatology 2014; 60: 256A 15

16 Wait for Better RX? Cost Effectiveness of Novel Hepatitis C Drug Regimens Among Treatment Experienced U.S. Veterans Markov model with one year cycle length for a cohort of 50 year old Veterans with genotype 1, 2, or 3 HCV Conclusion: For treatment experienced U.S. Veterans, using current SOF based regimens cost less and was more effective than waiting to treat with future all oral therapies, regardless of genotype or METAVIR fibrosis score. Alexis P. Chidi 11 School of Medicine, University of Pittsburgh, Ideal Treatment Single dose (decreased from 52 > 8 weeks for some) Oral administration Inexpensive Highly effective Infection cured Freedom from side effects 16

17 Treatment of HCV by Non Specialist There are not enough HCV treating health care providers Treatment is easy Monitoring not time consuming Treatment is effective Side effects infrequent Ideal candidate for treatment by the non specialist A young mono infected individual without evidence of advanced liver disease HCV genotype 1 normal platelet count and liver tests except AST/ALT normal liver US normal renal function takes no medications Thank You 17