UPDATE ON HEPATITIS C

UPDATE ON HEPATITIS C May 5, 2017 Dan Virnig, MD Park Nicollet / HealthPartners Thanks to everyone who shared slides and information Adnan Said, MD, MS Terry Box, MD with CCO Christine Strahl,, HP Clinical Pharmacy Program Manager Dr. Virnig indicated no potential conflict of interest to this presentation. He does not intend to discuss any unapproved/investigative use of a commercial product/device. HCV prevalence U.S. Population More than 3.9 million Americans chronically infected 15,000 deaths annually -increase to 35,000 by 2030 Worldwide 150 million infected 500,000 deaths annually

Primary Care Clinicians Have a Critical Role in Hepatitis C Care US prevalence of hepatitis C infection [1] 2% Average pt load for primary care clinician [2] x 2000 pts Average primary care clinician has 40 pts with hepatitis C infection in his/her practice [2] 1. Chak E, et al. Liver Int. 2011;31:1090-1101. 2. Ferrante JM, et al. Fam Med. 2008;40:345-351. Who should we screen for HCV?

Sources of Infection for Persons with Hepatitis C Injection drug use 60% Sexual 15% Transfusion 10% (before screening) Other* 5% Unknown 10% *Perinatal, Nosocomial, & Healthcare work Source: Centers for Disease Control and Prevention HCV Screening Based on increased risk for infection Ever injected or snorted illegal drugs Received clotting factors made before 1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease (elevated ALT ) Based on need for exposure management Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood Children born to HCV-positive women

Risk Factor Based Screening for HCV Only 25 to 50% aware they have the virus Most common situation leading to HCV testing is a routine physical (not risk factor based testing) Risk-based screening alone is ineffective Patient Factors Many of these individuals are poor and have limited access to care Some patients may not be able to recall risky behaviors in the distant past Many patients are uncomfortable discussing risk behaviors with their physicians Provider Factors Some practitioners may not be aware of risk behaviors or are reluctant to ask about them A primary care physician has numerous tasks and lacks the time to ask about these risky behaviors

56-Yr-Old Woman Presenting to Primary Care A 56-yr-old woman visits your office She has recently moved to the area following a promotion and is looking for a primary care clinician No history of IV drug use, blood transfusions etc She is not aware of having been tested for hepatitis C infection previously Should you screen her? CDC, USPSTF, and AASLD/IDSA HCV Screening Recommendations Population Recommendation Age One-time screening is recommended for persons born between 1945 and 1965, without ascertainment of HCV risk [1-3] Raisk One-time screening is recommended for persons with these risk factors [1,3] : History of illicit injection drug use (IDU) or intranasal illicit drug use History of long-term hemodialysis Receiving a tattoo in an unregulated facility/setting Healthcare workers upon accidental exposure Children born to anti-hcv positive mothers History of transfusion with blood or organ transplantation Were ever in prison HIV infection Chronic liver disease/hepatitis with unknown cause, including elevated liver enzymes Annual screening is recommended for current IDUs and HIV-infected MSM [3] 1. Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32. 2. US Preventive Services Task Force.

VA Baby Boomer Population prevalence of HCV is 10% HCV and baby boomers Most deaths from HCV in US are in persons ages 45 to 64 (in 2007) CDC now also recommends a one time HCV test for those born between 1945 and 1965

Currently, Very Few HCV Patients Are identified and Treated 41-Yr-Old Man Presenting to Primary Care A 41-yr-old man visits your office because his wife made him Numerous tattoos No history of IV drug use, blood transfusions etc He is not aware of having been tested for hepatitis C infection previously Should you screen him? Maybe

Tattoos Receiving a tattoo in an unregulated facility/setting is a risk factor for hepatitis C I frequently ask to see someone s first tattoo 5 Patients - Who needs screening? History of IV drug use, last used 15 years ago. No infection when tested 10 years ago Mother died from hepatitis C cirrhosis Served two tours in military with combat No history of drug use etc. Was in prison for tax evasion Two runs of dialysis while in the hospital. Recovered and doing well

Who needs screening History of IV drug use, last used 15 years ago. No infection when tested 10 years ago Mother died from hepatitis C cirrhosis Served two tours in military with combat No history of drug use etc. Was in prison for tax evasion Two runs of dialysis while in the hospital. Recovered and doing well HCV not just in baby boomers Mini epidemic in youth 2012 - largest increase in new cases of HCV in ages 20 to 29 (incidence increased from 0.75 to 1.18 cases per 100,000) Acute HCV cases doubled in those<19 30 states reported increase in HCV infection rates between 2006 and 2012

Additional Testing when HCV Ab+ CBC, creat, liver panel, HAV, HBV, abdominal US Consider HIV Why test for HAV and HBV antibodies? How does an abdominal ultrasound help with management? 50 Year-old-male Presents because he was noted to have elevated liver tests and cholesterol on life insurance testing He is 150kg, BP 170/90 Plt 145, AST 55, ALT 35, Bili 1.1, INR 1.0 Should you check HCV, order an abdominal US or both?

Everyone Wants Prevention Recommendations Blood and body fluid exposures Items of personal hygiene including toothbrushes, fingernail clippers and razors What should you tell them about sexual transmission Risk of sexual transmission is low, except for people with HIV, multiple partners, or STIs Should Everyone with Hepatitis C Receive Treatment?

Rate per 100,000 PY* Hepatitis C killing more Americans than HIV HIV Hepatitis C Hepatitis B *Mortality rates = HBV, HCV, HIV listed as cause of death Because decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection Ly KN, et al. Ann Intern Med. 2012;156:271-278. Average Annual All-Cause Healthcare Costs rise with liver disease Patient Population Mean Annual All-Cause Healthcare Cost per Person, $ HCV uninfected [1] 9979 HCV positive, noncirrhotic [2] 17,277 HCV positive, compensated cirrhosis [2] 22,752 HCV positive, ESLD [2] 59,995 1. McAdam-Marx C, et al. J Manag Care Pharm. 2011;17:531-546. 2. Gordon SC, et al. Hepatology. 2012;56:1651-1660.

34yo with HCV 34yo male with known HCV History of IV drug use, has been sober for 10 years Normal labs and ultrasound He is a new dad and requests treatment Appropriate treatment requested and his insurance company denied the PA What should you tell him? Appeal letter? Natural History of HCV Infection 100 Time Resolve 15-30% Chronic 70-85 20% 80% Stable 68 Stable 13 Cirrhosis 17 25% 75% Seeff, LB and Alter, MJ. And Deuffic, S. Poynard T. Hepatology 1999;29:1596 Mortality 4-8

Our 34yo Male What do I tell them? Don t worry about the denial. This used to be very common, still happens a lot This is a disease of decades, not months or years Should I write a letter? Only if there s a very compelling reason. Insurance companies have fairly strict criteria and I haven t found sympathy points to help Our 34yo Male Should we send a new request for a different medication? Probably not. If they ve been approved and the insurance wants a different medication they will let us know I usually send a request once per year for non-cirrhotics without other indications. Most get approved within 3 years

Our 34yo Male Is there anything else that can be done if he really wants treatment now? He can call himself. I have had a handful of times where a phone call from the patient directly to their insurance company resulted in approval 1-2 days later HCV therapy reduces mortality Successful HCV eradication (SVR) in those with cirrhosis and advanced fibrosis had a 74% reduction in all-cause mortality over 10 years Van De Meer et al

HCC Incidence (%) HCC Incidence in Cirrhosis: Therapy reduces HCC risk 50 40 No SVR SVR 30 15.6% 20 10 7.7% P =.0009 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Yrs) Median follow-up: 10 yrs Purevsambuu T, et al. EASL 2014. Abstract O125. Manns MP, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. Ferenci P, et al. N Engl J Med. 2014;370:1983-1992. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Kwo P, et al. EASL 2015. Abstract LB14. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13. Feld JJ, et al. N Engl J Med. 2015;373:2599-2607. Foster GR, et al. N Engl J Med. 2015;373:2608-2617.

Interferon: 48 weeks of Adverse Effects (if you can make it through) Expected Flu-Like Symptoms - Fever, headache, fatigue, arthralgias, myalgias, anorexia, vomiting, & diarrhea Dose limiting Cytopenias, neuropsychiatric, autoimmune Severe-Life threatening Thyroid, visual, auditory, renal and cardiac impairment, and pulmonary fibrosis Direct Acting Antivirals (DAA) HCV Genome capsid envelope protein protease/helicase RNA-dependent RNA polymerase c22 33c c-100 5 3 cor e E1 E2 NS 2 NS 3 NS 4 NS 5 hypervariable region Source: CDC

Even More Adverse Events with 1st generation direct acting antivirals Boceprevir-anemia- Hb<10 in 49% vs 29% of PegIFN/RBV Telaprevir- Drug Rash -(Any) 56% vs 32% of PegIFN/RBV. Severe in 1%.

p7 1st generation direct acting agents - not great Low barrier to resistance and only GT1 High pill burden Long durations of therapy 32 to 48 weeks Poor Adherence Multiple Drug-Drug Interactions Telaprevir not marketed anymore Multiple Classes of second generation Direct-Acting Antiviral Agents 5 UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3 UTR Protease Polymerase Ribavirin NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors Telaprevir Boceprevir Simeprevir Asunaprevir Paritaprevir MK-5172 Faldaprevir Sovaprevir ACH-2684 *Representative list; may not be fully inclusive. Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5885 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir Sofosbuvir VX-135 IDX21437 ACH-3422 Nucs Dasabuvir BMS-791325 PPI-383 GS-9669 TMC647055

Interferon Free 2013: Sofosbuvir + Simeprevir Sofosbuvir (SOF) Single-tablet, once-daily, HCV nucleotide analogue NS5B polymerase inhibitor FDA Approved Safe and well tolerated Simeprevir (SIM) Single-capsule, once-daily, HCV NS3/4A protease inhibitor FDA Approved Safe and well tolerated Active only against GT 1 Studied together in a Phase 2, randomized, open-label study: COSMOS Combination FDA approved 11/5/14 Ledipasvir-Sofosbuvir (Harvoni) One tablet orally once daily for 12 weeks Approval Status: FDA approved October 10, 2014 Indications and Usage - Indicated for the treatment of chronic HCV genotype 1 in adults Class & Mechanism - Ledipasvir: NS5A inhibitor - Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor Dosing: Ledipasvir-Sofosbuvir (fixed dose 90 mg/400 mg) Adverse Effects (AE): Fatigue, headache

Phase III Studies of SOF/LDV FDC ± RBV for 12 or 24 Wks in GT1 Patients ION-1 [1,2] Treatment-naive HCV GT1; cirrhosis in 15% to 17% per arm (N = 865) SOF/LDV (n = 214) SOF/LDV + RBV (n = 217) SOF/LDV (n = 217) SOF/LDV + RBV (n = 217) Wk 12 Wk 12 Wk 24 Wk 24 SVR12, % 99 97 98 99 ION-2 [3] Treatmentexperienced HCV GT1; 20% cirrhotics (N = 440) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) 94 96 99 99 ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure 1. Mangia A, et al. EASL 2014. Abstract O164. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1983. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. ION-3: Phase III Study of SOF/LDV FDC ± RBV for 8-12 Wks in Tx-Naive Wk 8 Wk 12 SVR12, % Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV (n = 215) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) 94 93 95 Kowdley KV, et al. N Engl J Med. 2014;3701879-1888.

Patients (%) with SVR24 Viekira Pak Approved December 19, 2014 ABT-450/r + ABT-267 + ABT-333 + Ribavirin for 12 weeks 100 96 95 98 80 60 40 20 0 455/473 307/322 148/151 Overall Genotype 1a Genotype 1b SAPPHIRE I & II: Phase III Studies of Paritepravir (PI) + Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV SAPPHIRE-I Treatment-naive noncirrhotic pts with HCV GT1 [1,2] (N = 631) Wk 12 SVR12, % ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 473) 96 Placebo (n = 158)* SAPPHIRE-II Treatment-experienced noncirrhotic pts with HCV GT1 [3,4] (N = 394) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 297) Placebo (n = 97) 96 SAPPHIRE: no difference in outcomes according to 1a/1b subtype, type of treatment failure *Placebo recipients crossed over to active treatment regimen at Wk 12. 1. Feld JJ, et al. EASL 2014. Abstract O60. Reproduced with permission. 2. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. 3. Zeuzem S, et al. EASL 2014. Abstract O1. 4. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

Predictors of decreased response BMI>30 Decompensated Liver Disease Prior Treatment Failure APRI>2 (Fibrosis) SOF/PEG/RBV (vs Sofosbuvir+Simperivir) Cost of HCV Therapies - 2014 Therapy Estimated Cost* PEG IFN+RBV x 48 weeks $37000 PEG IFN/RBV/TVR x 24 weeks $70,000 PEG IFN/RBV/Sofosbuvir x 12 weeks $93,000 Sofosbuvir+Simperivir x 12 weeks $150,000 Sofosbuvir + Ribavirin x 24 weeks $170,000

Ledipasvir-Sofosbuvir (Harvoni) Estimated Cost of Therapy Estimated Cost of Ledipasvir-Sofosbuvir Based on Treatment Duration Duration of Treatment Estimated Cost* 8 Weeks $63,000 12 Weeks $94,500 24 Weeks $189,000 *Estimated cost based on Wholesaler Acquisition Cost in United States of $1125 per pill Cost comparison by Treatment Regimen - Recent Drug Regimen* Genotype 1 Genotype 4 Zepatier (elbasvir/grazoprevir) (12 or 16 week regimen) Harvoni (Ledipasvir/Sofosbuvir) $65,520 $87,360 $65,520 $87,360 $75,600 8 weeks $113,400 12 weeks $226,800 24 weeks $113,400 12 weeks Viekira Pak (12 or 24 week regimen) Daklinza and Sovaldi (12 or 24 week regimen) $99,984 $199,967 Not recommended $176,400 - $352,800 Not recommended Sovaldi and ribavirin $202,386 24 weeks $202,386 12 weeks Sovaldi, peginterferon, & Not recommended $113,134 ribavirin *All regimens may be used with ribavirin depending on patient characteristics. These costs are not included here.

63yo with HCV 63yo female with HCV felt to be from a blood transfusion when she was child Completed Peg Interferon / Rbv years ago. Hasn t returned to GI because the treatment was so horrible. Has been seeing commercial for HCV on the television. What treatment do you offer her?

63yo with HCV What treatment do you offer her? On your way into the exam room you ask you PA nurse what insurance she has and what they ve been approving lately. Which brings us to Zepatier (elbasvir/grazoprevir) Treats Genotype 1 and 4 Treatment length is typically 12 weeks 16 weeks in patients with: Genotype 1a and NS5A resistance polymorphism Genotype 4 who are treatment experienced Requires use of RBV in these patients, as well as in patients with genotype 1 who are treatment experienced Patients with genotype 1a require testing for NS5A resistance-associated polymorphism Polymorphism occurs in approx. 5-10% of the population

Clinical Trial Data Efficacy Sustained Virologic Response (SVR) rates: Treatment naïve Treatment Experienced (F0-F4) Genotype 1 Genotype 4 Non-cirrhotic: 94% Cirrhosis: 97% 12 weeks: 94% SVR rates range between 90-100% in the different clinical trials based on treatment length and patient characteristics (treatment and cirrhosis status) Zepatier was not studied in the other genotypes Combined SVR: 97% Indicated for patients with severe renal disease SVR in CKD Stage V = 93% Few adverse reactions well tolerated regimen Sofosbuvir/velpatasvir (Epclusa) in Genotypes 2 and 3 Foster et al., NEJM 2015

Sofosbuvir/velpatasvir (Epclusa) Velpatasvir NS5A GT 1 2 3 4 5 6 Regimen 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks Subjects SVR 328 98% 238 99% 277 95% 116 100% 35 97% 41 100% NEJM, 12/31/15 Hepatitis C Drug Treatment Direct-acting antivirals changed the paradigm of treatment by dramatically improving anticipated cure rates Newer agents are more effective, require shorter durations and eliminate the need for interferon Two additional products are likely to be approved by the FDA late Summer 2017 and will provide 8-week pan-genotypic regimen for all non-cirrhotic patients Regimens to treat DAA failures

67yo Female Failed treatment with PEG interferon / RBV Failed treatment with Ledipasvir-Sofosbuvir Comes to see you in clinic requesting another treatment because she has heard there are more available What do you recommend? Should you check for NS5A RAVs?