Optimizing HCV Treatment Continuity and Outcomes

Optimizing HCV Treatment Continuity and Outcomes Empowering Pharmacists to Take Action Faculty Michelle T. Martin, PharmD, BCPS, BCACP Clinical Pharmacist University of Illinois Hospital and Health Sciences System Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois Disclosures Dr. Martin: Minor Shareholder Abbvie, Gilead, Merck & Co, Inc; Advisory Committee Gilead

Learning Objectives Develop a plan to implement system-wide screening practices to aid in the identification of individuals with hepatitis C virus (HCV) Describe the limitations of traditional HCV treatments and the impact of suboptimal treatment on clinical and virologic outcomes Evaluate the safety and efficacy of currently available direct-acting antiviral agents Discuss and take actions to address factors that affect patient non-adherence to HCV therapy such as access, medication burden, and adverse events Abbreviations Abbreviation Definition Brand (if applicable) ADR CI DAA Adverse drug event Confidence interval Direct-acting antiviral DCV Daclatasvir Daklinza DDI Drug-drug interaction EBR/GZR Elbasvir/grazoprevir Zepatier ESLD FDA GT HCC HCV HIV End-stage liver disease US Food and Drug Administration Genotype Hepatocellular carcinoma Hepatitis C virus Human immunodeficiency virus LDV/SOF Ledipasvir/sofosbuvir Harvoni PegIFN Pegylated interferon Pegasys, PegIntron PrOD Paritaprevir/ritonavir/ombitasvir + dasabuvir Viekira XR RBV RNA Ribavirin Ribonucleic acid SMV Simeprevir Olysio SOF Sofosbuvir Sovaldi SOF/VEL Sofosbuvir/velpatasvir Epclusa SVR Sustained virologic response HCV Basics Single-stranded RNA virus without proofreading polymerase 6 HCV genotypes with treatment recommendations 67 subtypes (denoted a, b, etc) Genotype 1 (1a>>1b) is the most common in the United States: ~75% Genotypes 2 and 3: ~20% to 25% Most common blood-borne infection in the United States 2.5 to 4.7+ million patients RNA = ribonucleic acid. McHutchison JG, et al. Am J Manag Care. 2005;11(10 Suppl): S286-S295. Smith DB, et al. Hepatology. 2014;59:318-327. http:// www.who.int/vaccine_research/diseases/viralcancer15.jpg. Global Distribution of HCV Genotypes Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6

HCV Screening Recommendations 1. All patients with risk factors for HCV infection 2. Everyone born between 1945 and 1965 should get tested for HCV once regardless of risk factors 3. Annual testing of patients with ongoing risk factors Persons who inject drugs HIV+ men who have sex with men patients who have unprotected sex HIV = human immunodeficiency virus. www.cdc.gov/hepatitis/hcv/guidelinesc.htm. www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm. www.hcvguidelines.org/. www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?ncaid=272. HCV Transmission High Risk Intravenous drug use Blood transfusions or solid organ transplantations Prior to 1992 Clotting factors Prior to 1987 Lower Risk Hemodialysis Intranasal drug use Occupational exposure Tattoos, acupuncture, or body piercing with unsterilized instruments Perinatal transmission Sexual transmission McHutchison JG, et al. Am J Manag Care. 2005;11(10 Suppl):S286-S295. HCV Bloodwork HCV Antibody If positive, check RNA HCV RNA Level If detectable, check genotype HCV Genotype Determine treatment options Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Point-of-Care Testing FDA approved an HCV rapid antibody test in 2011 (OraQuick HCV ) 1-µL blood sample Results in 20 minutes 98% accurate in detecting HCV antibody Requires confirmatory testing FDA = US Food and Drug Administration. Orasure Technologies, Inc [Web site]. http://www.orasure.com/products-infectious/productsinfectious-oraquick-hcv.asp. Last updated January 21, 2013. Accessed February 17, 2017. Opportunities for Interdisciplinary Age-Cohort HCV Screening Community pharmacies Must ensure linkage to care General medicine/primary care Infectious diseases clinics Colonoscopy suites Emergency department Opt-out screening Inpatient services HCV Treatment Cascade in US (2014) 3,500,000 Prevalence Estimates, 95% CI (%) 100 90 80 70 60 50 40 30 20 10 0 100 Chronic HCV- Infected* 50 43 27 17 16 9 Diagnosed and Aware Access to HCV Outpatient RNA Care Confirmed Underwent Liver Biopsy Prescribed HCV Treatment Achieved SVR** *Chronic HCV-infected; N=3,500,000. Calculated as estimated number chronic HCV-infected (3,500,000) x estimated percentage diagnosed and aware of their infection (49.8%); n=1,743,000. Calculated as estimated number diagnosed and aware (1,743,000) x estimated percentage with access to outpatient care (86.9%); n=1,514,667. Calculated as estimated number with access to outpatient care (1,514,667) x estimated percentage HCV RNA confirmed (62.9%); n=952,726. Calculated as estimated number with access to outpatient care (1,514,667) x estimated percentage who underwent liver biopsy (38.4%); n=581,632. Calculated as estimated number with access to outpatient care (1,514,667) x estimated percentage prescribed HCV treatment (36.7%); n=555,883. **Calculated as estimated number prescribed HCV treatment (555,883) x estimated percentage who achieved SVR (58.8%); n=326,859. Note: Only non-va studies are included in the above HCV treatment cascade. http://www.plosone.org/article/info%3adoi%2f10.1371%2fjournal.pone.0101554.

Progression of HCV Resolution 15% Acute Infection 85% Chronic Infection Chronic Hepatitis Mild, Moderate, Severe 20% Cirrhosis 3%-6%/yr ESLD, transplant Decompensation 1%-4%/yr HCC 0 0.5 10 20 30 Approximate Time (Years) ESLD = end-stage liver disease; HCC = hepatocellular carcinoma. McHutchison JG, et al. Am J Manag Care. 2005. 40 Goal of HCV Treatment Eradication of infection: SVR = CURE SVR = undetectable viral load 12 weeks after treatment completion Prevention of complications and death Cirrhosis ESLD and need for liver transplantation HCC Why screen if we do not or cannot treat? Knowledge = Power lifestyle changes and HCC surveillance (if F3 or F4) SVR = sustained virologic response. Edlin BR, et al. Hepatology. 2015;62(5):1353-1363. http://www.hcvguidelines.org/. Picture: www.webmd.com/hepatitis/ss/slideshow-hepatitis-overview. HCV Treatment Evolution SVR Rate (%) 100 90 80 70 60 50 40 30 Barriers to success: Adverse events! Stage of disease Viral load IL-28B / Race Age Gender 25 45 70 92 97 97 97 98 20 10 10 0 1990 1998 2001 2011 2013 2014 2015 2016 2016 Interferon IFN + Pegylated Telaprevir Simeprevir Paritaprevir/ Daclatasvir Elbasvir/ Velpatasvir (IFN) Ribavirin Interferon (TVR), (SMV) + Ritonavir/ (DCV) Grazoprevir (SOF/VEL) (RBV) (PegIFN) Boceprevir Sofosbuvir Ombitasvir (DCV + SOF) (EBR/GZR) + RBV (BOC) (SOF) + Dasabuvir (PrOD), Ledipasvir/Sofosbuvir (LDV/SOF) Ahn J, et al. Gastroenterol Hepatol. 2014;10(2):90-100. Webster DP, et al. Lancet. 2015;385(9973):1124-1135. Wyles, et al. N Engl J Med. 2015;373:714-725. Zeuzem A, et al. Ann Intern Med. 2015;163:1-13. Feld JJ, et al. N Engl J Med. 2015;373(27):2599-2607.

HCV Medication Class Suffixes DAAs: 2011-Present -previr = NS3/4A Protease Inhibitors (PIs) -asvir = NS5A Replication Complex Inhibitors -buvir = NS5B Inhibitors simeprevir paritaprevir grazoprevir (1 st generation: telaprevir and boceprevir not used in US) ledipasvir ombitasvir daclatasvir elbasvir sofosbuvir dasabuvir DAA Adverse Events Drug SMV SOF LDV/SOF PrOD DCV EBR/GZR SOF/VEL Adverse Event Rash, photosensitivity, pruritus, nausea Fatigue, headache Fatigue, headache Nausea, pruritis, insomnia Fatigue, headache Fatigue, headache, nausea Fatigue, headache Olysio [package insert]. Titusville, NJ: Janssen Therapeutics; 2016. Sovaldi [package insert]. Foster City, CA: Gilead Sciences; 2017. Harvoni [package insert]. Foster City, CA: Gilead Sciences; 2017. Viekira XR [package insert]. North Chicago, IL: AbbVie; 2017. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017. Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co; 2017. Epclusa [package insert]. Foster City, CA: Gilead Sciences; 2017. SMV + SOF Pearls GT 1 (CrCl 30 ml/min) Use *SMV recommended only in GT 1a patients without Q80K polymorphism 1 capsule (SMV 150 mg) with food + 1 tablet (SOF 400 mg) once daily Dosing x 12-24 weeks 2 copays +/- RBV (up to 8 pills daily) Monitor HCV RNA at week 4; CrCl, CBC if on RBV Cost $$$$ - 2 DAA copays SMV: CYP 3A4 inhibitor, inducer, mild inhibitor of CYP 1A2, DDIs inhibitor P-gp, and OATP1B1/3 SOF: P-gp substrate Risk SMV: NS3 resistance Role Used less commonly after newer DAAs were approved in 2014-2015 SVR GT 1 = ~88%-97% (OPTIMIST-1/2) DDI = drug-drug interaction. Olysio [package insert]. Titusville, NJ: Janssen Therapeutics; 2016. Sovaldi [package insert]. Foster City, CA: Gilead Sciences; 2017. Kwo P, et al. Hepatology. 2016;64(2):370-380. Lawitz E, et al. Hepatology. 2015;61(3):769-775.

Ledipasvir/Sofosbuvir (LDV/SOF) Pearls Use GT 1, 4, 5, 6 (CrCl 30 ml/min) 1 combination tablet (LDV 90 mg/sof 400 mg) once daily x 8, Dosing 12, or 24 weeks +/- RBV (up to 7 pills daily) Monitor HCV RNA at week 4; CrCl, CBC if on RBV Cost $$ - 1 DAA copay LDV: Requires acidic environment for absorption; DDIs discuss antacid/h2ra/ppi use SOF: P-gp substrate Risk NS5A resistance Role Highest used DAA combination in 2015 SVR GT 1 = ~94%-99% (ION-1/2/3) Harvoni [package insert]. Foster City, CA: Gilead Sciences; 2017. Afdhal N, et al. N Engl J Med. 2014; 370(20):1889-1898. Kowdley KV, et al. N Engl J Med. 2014;370(20):1879-1888. PrOD (PTV/r/OBV + DSV) Pearls Use GT 1 (CrCl 15 ml/min) 2 tablets once daily (OBV 12.5 mg, PTV 75 mg, ritonavir 50 mg) with Dosing food + 1 tablet twice daily (DSV 250 mg) with food x 12 or 24 weeks +/- RBV (up to 10 pills daily) Monitor HCV RNA at week 4; CrCl, CBC if on RBV Cost $$ - 1 DAA copay DDIs Risk Role SVR All: P-gp substrates; PTV: CYP 3A4 inhibitor, inducer; ritonavir: CYP 3A4, 2D6 substrate; DSV: CYP 2C8, 3A substrates; OBV: Hydrolysis, oxidative metabolism Contraindicated in decompensated cirrhosis NS3 and NS5A resistance Lower use than other DAAs due to DDIs, complex regimen GT 1 = ~95%-100% (SAPPHIRE-I/II, PEARL-II/III/IV) Viekira XR [package insert]. North Chicago, IL: AbbVie; 2017. Feld JJ, et al. N Engl J Med. 2014;370 (17):1594-1603. Zeuzem S, et al. N Engl J Med. 2014;370(21):1993-2001. Ferenci P, et al. N Engl J Med. 2014;370(21):1983-1992. Andreone P, et al. Gastroenterology. 2014;147(2):359-365. SOF + Daclatasvir (DCV) Pearls Use GT 1-3 (SOF: CrCl >30 ml/min; no renal limit for DCV) Dosing 2 tablets once daily (DCV 60 mg* + SOF 400 mg) x 12, 24 weeks +/- RBV (up to 9 pills daily) *DCV 30 mg or 90 mg if DDIs Monitor HCV RNA at week 4; CrCl, CBC if on RBV Cost $$$$ 2 DAA copays DDIs Risk Role SVR DCV: P-gp substrate and inhibitor; CYP 3A4 substrate (*Decrease dose to 30 mg daily with strong inhibitors, increase dose to 90 mg daily with moderate inducers) SOF: P-gp substrate NS5A resistance Less use due to cost Decreased SVR in cirrhotic, treatment experienced GT 3 pts GT 1-4 with HIV = ~96%-98%; GT 3 = ~63%-94% (ALLY-2/3) Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017. Wyles DL, et al. N Engl J Med. 2015;373(8):714-725. Nelson DR, et al. Hepatology. 2015;61(4):1127-1135.

Elbasvir/Grazoprevir (EBR/GZR) Pearls Use GT 1, 4 (OK in hemodialysis) 1 tablet once daily (EBR 50 mg/grz 100 mg) x 12-16 weeks Dosing +/- RBV (up to 7 pills daily) Monitor Cost DDIs Risk Role SVR If GT1a must check baseline NS5A resistance. HCV RNA, LFTs at week 8 (and week 12 if on 16-week); CrCl, CBC if on RBV $ 1 DAA copay EBR: CYP 3A4 and P-gp substrate GRZ: Weak CYP 3A4 inhibitor, CYP 3A4, and P-gp substrate NS5A resistance. NS3? Contraindicated in decompensated cirrhosis, and pts on strong CYP3A inducers 1 st FDA-approved DAA combination for use in hemodialysis; lowest cost HCV regimen, but GT 1a requires resistance test GT 1 = ~95%-99% (C-EDGE, C-SURFER) Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co; 2017. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13. Roth D, et al. Lancet. 2015;386(10003):1537-1545. Sofosbuvir/Velpatasvir (SOF/VEL) Pearls Use GT 1-6 (CrCl 30 ml/min) 1 combination tablet (SOF 400 mg /VEL 100 mg) once daily x 12 or Dosing 24 weeks +/- RBV (up to 7 pills daily) Monitor HCV RNA at week 4; CrCl, CBC if on RBV Cost $$ - 1 DAA copay VEL: Requires acidic environment for absorption; DDIs discuss antacid/h2ra/ppi use SOF: P-gp substrate Risk NS5A resistance Role High use in GT 2, 3 SVR GT 1 = ~98%-99%; GT 2 = ~99%-100%, GT 3 = ~89%-98% (ASTRAL-1/2/3) Epclusa [package insert]. Foster City, CA: Gilead Sciences; 2017. Feld JJ, et al. N Engl J Med. 2015; 373(27):2599-2607. Foster GR, et al. N Engl J Med. 2015;373(27):2608-2617. Recommended HCV Regimens for Treatment-Naïve, Non-Cirrhotics (2/23/2017) Regimen 1a 1b 2 3 4 5 6 DCV + SOF 12 wks 12 wks 12 wks* 12 wks -- -- -- EBR/GZR 12 wks, or 16 wks + wt-based RBV^ 12 wks -- -- 12 wks -- -- LDV/SOF 12 wks 12 wks -- -- 12 wks 12 wks 12 wks PrOD 12 wks + wt-based 12 wks -- -- -- -- -- RBV SMV + SOF 12 wks 12 wks -- -- -- -- -- SOF/VEL 12 wks 12 wks 12 wks 12 wks 12 wks 12 wks 12 wks PrO -- -- -- -- 12 wks + wt-based RBV -- -- *Alternative regimen. ^If NS5A RASs present. http://www.hcvguidelines.org/.

Recommended HCV Regimens for Treatment- Naïve, Compensated Cirrhotics (2/23/2017) Regimen 1a 1b 2 3 4 5 6 24 wks+/- 24 wks +/- 24 wks +/- 16-24 DCV + SOF wt-based wt-based wt-based -- -- -- wks* RBV* RBV* RBV* EBR/GZR 12 wks or 16 wks + wt-based RBV*^ 12 wks -- -- 12 wks -- -- LDV/SOF 12 wks 12 wks -- -- 12 wks 12 wks 12 wks PrOD ǂ + RBV 24 wks 12 wks -- -- -- -- -- SMV + SOF 24 wks +/- wt-based RBV (no Q80K)* 24 wks +/- wt-based RBV* -- -- -- -- -- SOF/VEL 12 wks 12 wks 12 wks 12 wks 12 wks 12 wks 12 wks PrO ǂ -- -- -- -- 12 wks+ wt-based RBV -- -- *Alternative regimen. ^If NS5A RASs present. ǂ Contraindicated in decompensated cirrhotics. http://www.hcvguidelines.org/. Pharmacists Roles Ambulatory Care Community/Specialty Inpatient Screening and referrals Medication selection DDI screening + management Education Liaison with pharmacy and assistance programs Screening + linkage to care Verify medication selection and length of treatment DDI screening + management Education adherence, administration, ADRs Liaison with clinic and assistance programs Screening + linkage to care Prevent interruption of treatment DDI screening + management Education adherence, administration, ADRs Liaison with clinic Labs and follow-up Refill management Labs ADR = adverse drug event. Sebhatu P, et al. Am J Health Syst Pharm. 2016 Jun 1;73(11):764-774. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C www.hcvguidelines.org First published on January 29, 2014 Updated several times since http://www.hcvguidelines. org/full-report-view.

Drug-Drug Interaction Evaluation www.hep-druginteractions.org. Promoting Adherence Alarms/cell phone alarms Pill boxes Medication charts Phone calls from Specialty pharmacies Clinic Manufacturer support programs Patient support groups Promoting Access Alerting prescribers about insurance requirements Letters of Medical Necessity/Appeals Patient Assistance Programs Manufacturer Foundations HealthWell Foundation PAN Foundation HealthWell Foundation [Web site]. https://www.healthwellfoundation.org/. Accessed February 24, 2017. PAN Foundation [Web site]. https://www.panfoundation.org/index.php/en/. Accessed February 24, 2017.

Sample Insurance Plan Requirements for HCV Medication Coverage Documentation of Documentation of METAVIR HCV RNA Additional Sobriety Treatment Adherence and Fibrosis Score Required in the Lab Testing (EtOH and Illicits) Counseling Covered Last: 12 months Yes in MD note + Etoh/Tox letter must be F3/F4 3 months NS5A if GT 1a screen signed by pt 12 months Yes in MD note + Tox Screen letter must be F4 only 3 months NS5A if GT 1a w/in 15 days of PA signed by pt Yes HIV Ab-last 6 mos, 6 months must be documented F3/F4 6 months Hep B serologies, Tox Screen in MD note by MD in clinic note NS5A if GT 1a Yes HIV Ab-last 6 mos, 6 months must be documented F3/F4 6 months Hep B serologies, Tox Screen in MD note by MD in clinic note NS5A if GT 1a Hep B serologies; Yes + Yes If HIV infected - must EtOH/Tox screen letter must be F4 only 3 months be stable w/ out OI in w/in 15 days of PA signed by pt past 6 months; NS5A if GT 1a Patient's signed Negative pregnancy EtOH/Tox screen commitment to F4 only 3 months test, w/in 15 days of PA treatment plan NS5A if GT 1a 12 months - in MD note NS5A if GT 1a Patient Assistance Programs Patient Assistance Foundation (Janssen) My Support Path (Gilead) ProCeed (AbbVie) Patient Assistance Foundation (Bristol-Myers Squibb) Merck Helps (Merck) Drug SMV SOF; LDV/SOF; SOF/VEL PrO, PrOD, RBV(?) DCV EBR/GZR Web site http://www. jjpaf.org/ http://www. mysupportpath. com/ https://www. viekira.com/ proceedsupport http://www. bms.com/ products/page s/programs. aspx http://www. merckhelps. com/contact. aspx Phone 1-800- 652-6227 1-855- 7-MYPATH (855-769-7284) 1-844- 2 PROCEED (844-277-6233) 1-844- 44-CONNECT (844-442-6663) 1-800- 727-5400 Cost of HCV Medications Treatment Cost per 12-Week Regimen Cost per 24-Week Regimen SMV ($66,360) + SOF ($84,800) $151,160 $302,320 LDV/SOF $94,500 $189,000 PrOD $83,319 $166,638 DCV ($63,000) + SOF ($84,800) $147,800 $295,600 EBR/GZR $54,600 N/A SOF/VEL $74,760 $149,520 Add on: RBV $5880) $11,760 RED BOOK Online http://wwww.micromedexsolutions.com. Accessed August 12, 2016.

Weighing the Costs Cost of GT 1 HCV Treatment (~$55,000 $95,000) Cost of a Liver Transplantation (~$577,000) http://www.transplantliving.org/before-the-transplant/financing-a-transplant/the-costs/. Future HCV Treatment Ideal Regimen Easy regimen (once daily) Short length of treatment High barrier to resistance Pan-genotypic No/few drug interactions Affordable Widely available Remaining Challenges Cost/access to treatment Screening/diagnosis Genotype 3 Viral resistance/previous DAA failures Vaccine Select HCV Pipeline Agents Manufacturer Treatment Regimen SVR Potential Approval Year AbbVie Gilead Merck Glecaprevir / Pibrentasvir (PI + NS5A) Sofosbuvir / Velpatasvir / Voxilaprevir (NS5B + NS5A + PI) Ruzasvir / Grazoprevir / MK-3682 (NS5A + PI + NS5B) ~99% 2017 ~96%-98% 2017 ~96%-98% 2018? Zeuzem S, et al. ENDURANCE-1. 67th AASLD; Boston, MA; November 11-15, 2016. Abstract 253. Bourlière M, et al. POLARIS-1. 67th AASLD. Abstract 194. Zeuzem S, et al. POLARIS-4. 67th AASLD. Abstract 109. Lawitz E, et al. C-CREST-1 & 2. 67th AASLD. Abstract 110.

HCV Resources for Patients and Providers HCV Guidelines Drug-Drug Interactions HCV Clinical Information Online Courses / Certificate Programs Free Online Hepatitis Textbook Patient Support Groups American Association for the Study of Liver Diseases, Infectious Disease Society of America, and International Antiviral Society-USA: www.hcvguidelines.org University of Liverpool: www.hep-druginteractions.org Clinical Care Options: www.clinicaloptions.com/hepatitis.aspx National AIDS Treatment Advocacy Project: www.natap.org ViralEd: www.viraled.com National Association of Specialty Pharmacy: http://education.nasprx.org/products/1204/hepatitis-c-certificate-program University of Washington: http://hepatitisc.uw.edu inpractice Hepatology: www.inpractice.com/textbooks/hepatology.aspx American Liver Foundation: www.liverfoundation.org/support HCV Advocate: http://hcvadvocate.org/resources/support-groups HCV Support: www.hcvsupport.org Questions?