Slides for today’s webinar are available on the CIHS website at: - PowerPoint Presentation

Slides for today’s webinar are available on the CIHS website at: http://www.integration.samhsa.gov/mai-coc-grantees-online-community/webinars

How to ask a question during the webinar If you are listening to this webinar from your computer speakers, please type your questions into the question box and we will address your questions. THIS WEBINAR IS BEING RECORDED

Hepatitis C (HCV) Treatment Guidelines and Integrated Care in MAI- CoC Jay Kostman , M.D.Medical Director, John Bell Health CenterPhiladelphia FIGHTPhiladelphia, PA

Disclaimer and Disclosure Disclaimer: The views, opinions and content expressed in this presentation do not necessarily reflect the views, opinions or policies of the Center for Mental Health Services (CMHS), the Substance Abuse and Mental Health Services Administration (SAMHSA) or the U.S. Department of Health and Human Services (HHS). Disclosure: The presenter, Jay Kostman, M.D., has no financial conflicts of interest to disclose.

Learning Objectives Discuss the treatment guidelines recommended by the American Association for the Study of Liver Diseases (AASLD) and The Infectious Diseases Society of America (IDSA) Describe the main treatment options for HCV infection among HIV infected patients List host and viral factors that influence the duration and/or type of antiviral treatment Address HCV health education and risk reduction for consumers with and at high risk for mental and substance use disorders

This Guidance should be considered a "living document" and will be updated frequently FDA-approved regimens May also recommend off-label use of certain drugs or tests

The Role of AASLD/IDSA HCV Guidelines Purpose Provide evidence-based source of unbiased guidance on “best practice” for HCV managementTarget audienceVaries by guideline: HCPs, individuals with HCV, policy makersSubpopulations of pts or regions of the worldPayers: increasingly important in many regions FormatJournal publicationOnline navigable reference Slide credit: clinicaloptions.com AASLD/IDSA: American Association for the Study of Liver Disease/Infectious Disease Society of America

Evidence Used for Guidelines Clinical trial data Traditionally only published papers of high quality Additional analysesSmaller trials and abstracts“Real-world data” have increasing role Expert opinion has increasing roleFills in for subgroups with limited dataSlide credit: clinicaloptions.com

Acute HCV Chronic HCV HepaticInflammationHepaticFibrosisCirrhosisHepatocellularCarcinoma 75-85% Alcohol, HIV , and hepatitis B may accelerate fibrosis Spontaneous Resolution 15-25% 2 – 4% per yr 20% in 20 yrs Hepatic Decompensation

Prevalence of HIV/HCV Coinfection is High Shared routes of transmission 30% of HIV+ are coinfected ~400,000 HIV/HCV + in U.S. Prevalence of HCV in individuals who are HIV+ varies based on likely mode of acquisition~ 90% in IVDU60-85% in hemophiliacs4-8% in MSM

Antiretroviral Therapy Longer Lifespan Decrease in AIDS related complications Increased morbidity and mortality related to HCV Liver disease is the second leading cause of death in HIVLiver disease is primarily caused by chronic HCV Sherman K.E., et al. Clin Infect Dis 2002;34:831-7 D:A:D Study. Arch Intern Med 2006;166:1632-41

 clearance of HCV  HCV RNA levels risk of cirrhosis  risk of end-stage liver disease and hepatic decompensation risk of hepatocellular carcinoma30-50% of coinfected individuals have alcohol use disordersEffects of HIV/HCV Co-Infection

Chronic ESLD HCC HCV Exposure CirrhosisRecovery HIV ETOH Benhamou Y et al. Hepatology 1999;30:1054-1058. Graham CS et al. Clin Infect Dis 2001;33:562-569.

Sulkowski M. 2011. HRSA http://hab.hrsa.gov Elevated ALT primary prevention/ risk reduction

Additional Laboratory T esting The following laboratory tests are recommended within 12 weeks prior to starting antiviral therapy: Complete blood count (CBC); international normalized ratio (INR) Hepatic function panel (albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels) Calculated glomerular filtration rate (GFR) The following laboratory testing is recommended at any time prior to starting antiviral therapy: HCV genotype and subtype Quantitative HCV RNA (HCV viral load)

Additional Laboratory T esting All patients initiating HCV DAA therapy should be assessed for HBV coinfection with HBsAg, anti-HBs, and anti-HBc. Testing for the presence of resistance-associated substitutions (RASs) prior to starting treatment should be performed See recommendations in the Initial Treatment and the Retreatment Sections of the Guidance.Patients scheduled to receive an HCV NS3 protease inhibitor should be assessed for a history of decompensated liver disease and for severity of liver disease using Childs-Turcotte-Pugh (CTP) score. CTP score of 7 or > should NOT receive treatment with NS3 protease inhibitors CTP score of 5 or 6, who cannot be closely monitored for laboratory or clinical symptoms during treatment, should not receive treatment with a regimen that contains paritaprevir /ritonavir.

Staging HCV Liver Fibrosis Important part of chronic HCV work-up Identify cirrhosis:  hepatocellular ca risk: need to screenMonitor for hepatic decompensationConsider liver transplant evaluation Determine cirrhosis by: Liver biopsy Non-invasive tests

The Patient with Cirrhosis Evaluate for encephalopathy & ascites If ascites refer to hepatologist Diagnostic paracentesis Evaluation for liver transplant Endoscopy to evaluate for the presence of esophageal varices need for prophylaxis with a non-selective beta blocker

Advanced fibrosis and cirrhosis Hepatic ultrasound +/- AFP every 6 months Suspicious mass lesion requires more specific testing with a multi-phase contrast CT or MRI AFP alone is inadequate screening test for HCC Routine screening for HCC without advanced fibrosis is not recommendedMonitoring for Hepatocellular Carcinoma ( HCC)

Current All-Oral Therapies Highly Effective, Simple, Well Tolerated Sustained HCV Virologic Response (%) IFN 6 Mos [5] PegIFN/ RBV 12 Mos [7-9] IFN 12 Mos [5,6] IFN/RBV 12 Mos [5-8] 2001 [3] 1998 [2] 2011 [4] Standard Interferon Ribavirin Peginterferon 1991 [1] PegIFN/ RBV + DAA [9-10] IFN/RBV 6 Mos [5-7] < 10 15 35 40 50 70+ 0 20 40 60 80 100 DAA + RBV ± PegIFN [11] 90+ 2013 [4] All–Oral DAA± RBV [12-16] Current 95+ All-Oral Therapy DAA Therapy Slide credit: clinicaloptions.com

DAA: Direct Acting Antiviral

Mnemonic to Remember DAAs Look at end of the drug’s name PRE vir = PR ot E ase inhibitor Tela pre vir, boce pre vir, sime pre vir , grazo pre vir , gleca pre vir , voxila pre vir U vir = n U cleotide or non- n U cleotide polymerase inhibitor Sofosb uvir , dasab uvir A svir = NS5 A inhibitor Ledip asvir , ombit asvir , daclat asvir, velpat asvir , elb asvir, pibrent asvir

HCV Genotype 1, 2, 3, 4, 5, 6 Subtype: 1a, 1b Stage of liver fibrosis Cirrhosis versus no cirrhosis Metavir score F0-F4 HCV treatment status Naïve versus treatment experienced Special populations Transplant, chronic kidney dis, children Factors Associate with Treatment and Cure

AASLD/IDSA Recommendations for First-line HCV Treatment AASLD/IDSA. HCV guidelines. September 2017. Slide credit: clinicaloptions.comHCV GT Regimen Duration, Wks No Cirrhosis Compensated Cirrhosis 1 GLE/PIB GZR/EBR* SOF/LDV SOF/VEL 8 12 8 or 12 † 12 12 12 12 12 2 or 3 GLE/PIB SOF/VEL 8 12 12 12 ‡ 4 GLE/PIB SOF/VEL GZR/EBR SOF/LDV 8 12 12 12 12 12 12 12 5 or 6 GLE/PIB SOF/LDV SOF/VEL 8 12 12 12 12 12 *If GT1a, use only if no baseline NS5A elbasvir RASs detected. † If nonblack, no HIV, and HCV RNA < 6 million IU/mL, 8-wk duration recommended. ‡ For GT3, if Y93H RAS detected, add RBV or consider SOF/VEL/ VOX .

AASLD/IDSA: Treatment Recommendations for GT1 HCV Infection HCV GT SOF + SIM SOF/LDV SOF + DCV OMB/PTV/ RTV + DSV GRZ/ELB SOF/VEL Without cirrhosis 1a 1b With compensated cirrhosis 1a 1b AASLD/IDSA HCV Guidance. 2016. Slide credit: clinicaloptions.com Alternative Recommended

Eligibility Criteria for 8-Wk HCV Treatment by Regimen GLE/PIB [1] Eligible pts must beNoncirrhotic Treatment-naive with GT1-6SOF/LDV[2-4]Eligible pts must beNoncirrhoticTreatment naive with GT1HCV RNA < 6 million IU/mLNonblackNo HIV coinfectionEASL: caution if F3 fibrosis1. GLE/PIB [package insert]. 2. SOF/LDV [package insert]. 3. AASLD/IDSA. HCV guidelines. September 2017. 4. EASL. HCV guidelines. September 2016. Slide credit : clinicaloptions.com

HCV Regimen Dosing and Administration Slide credit : clinicaloptions.com All regimens given QD PO, except as noted.RegimenTotal DosePills/Day Administration Notes Recommended regimens GLE/PIB 300/120 mg 3 With food GZR/EBR 50/100 mg 1 SOF/LDV 90/400 mg 1 SOF/VEL 400/100 mg 1 Additional regimens OBV/PTV/RTV ± DSV 25/150/100 mg + 500 mg 4 With food; DSV BID PO OBV/PTV/RTV/DSV XR 25/150/100/600 mg 3 With food SOF + DCV 400 mg + 60 mg 2 SOF + SMV 400 mg + 150 mg 2 With food SOF/VEL/VOX 400/100/100 mg 1 With food

AASLD/IDSA HCV Treatment Guidelines: People Who Inject Drugs “Recent and active IDU should not be seen as an absolute contraindication to HCV therapy” “Scale up of HCV treatment in PWID is necessary to positively impact the HCV epidemic in the United States and globally” AASLD/IDSA HCV Guidelines. Slide credit: clinicaloptions.com

Benefits of Achieving Sustained V irologic Response ↓ Cirrhosis↓ Decompensation↓ HCC↓ Transplantation↓ All-cause mortalityImproved QoLMalignancyDiabetesCVDRenalNeurocognitiveCureImproved clinical outcomes[1,2] Slide credit: clinicaloptions.com 1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. 2. Negro F, et al. Gastroenterology. 2015;149:1345-1360. 3. George SL, et al. Hepatology. 2009;49:729-738. Hepatic Extrahepatic Decreased transmission [1]

HCV Cure Associated With Improved 15-Yr Survival in Pts With F0/F1 Disease Single-center cohort of consecutive pts since 1992 (N = 1381) Progression to F3/F4 was observed in 15.3% of F0/F1 pts with available liver biopsy (n = 157) Slide credit: clinicaloptions.com Jézéquel C, et al. EASL 2015. Abstract P0709. 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 Yrs From Biopsy to Death F0/F1 Fibrosis P = .003 Treated pts without SVR Untreated pts Treated pts with SVR Survival

Liver-Related Mortality Increases With Age Mortality observed in community cohort (N = 2913) in inner-city Vancouver, Canada, 2003-2009 Deans GD, et al. CMAJ Open. 2013;1:E68-E76. Slide credit: clinicaloptions.com Rate per 10,000 Persons-Yrs 80 60 40 20 0 < 35 35-39 40-44 45-49 ≥ 50 Age Group (Yrs) Drug related Liver related HIV related Cause of Death

Note: Daclatasvir requires dose adjustment with the following: ritonavir-boosted atazanavir (a decrease to 30 mg daily) efavirenz or etravirine (an increase to 90 mg daily)

AASLD and IDSA. http://www.hcvguidelines.org/full-report-view . Version July 15 2017. *

Do not use zidovudine with ribavirin Greater  in hemoglobin Higher risk of anemia Do not use didanosine with ribavirin Risk of mitochondrial toxicity Do not use stavudine with ribavirin Abacavir May compete intracellularly with ribavirin No  in SVR with weight-based ribavirin Ribavirin Drug Interactions Alvarez D, et al. J Viral Hepat 2006;13:683-9 Amorosa VK, et al. Antivir Ther 2010;15:91-9

Abacavir Emtricitabine Enfuvirtide Lamivudine Raltegravir Dolutegravir Rilpivirine Tenofovir (TDF) Elb /Graz Sof / Vel Sof /Led PrOD ** Simeprevir † * Can be used with most antiretrovirals Can be used with most antiretrovirals *probably ok **atazanavir ok † maraviroc ok Vel and Led increase tenofovir levels when given as TDF. Avoid in those with CrCl below 60 mL/min. Renal monitoring is recommended during the dosing period Avoid Led+ TDF + ritonovir or cobi

Clinic visits or telephone contact as clinically indicated CBC, Cr level, GFR, hepatic function panel after 4 weeks and as clinically indicated Patients receiving elbasvir /grazoprevir should be monitored with hepatic function panel at 8 weeks (and again at 12 if receiving 16 weeks treatment)10 fold increase in ALT at week 4 <10 fold increase with symptoms should prompt discontinuationIf <10 fold and no symptoms, repeat ALT at week 6 and 8Monitoring Guidance

Quantitative HCV testing at 4 weeks of therapy and 12 weeks following completion of therapy Antiviral therapy should NOT be interrupted or discontinued if viral load testing is not able to be done Viral load testing can be considered at the end of treatment and 24 weeks or longer following completion Patients with compensated cirrhosis on paritaprevir/ritonavir based regimen should be monitored per guidelinesFor HBsAg+ patients who are not already on HBV suppressive therapy, monitor HBV DNA levels during and immediately after treatment and antiviral treatment should be given if criteria are metMonitoring Recommendations

If HCV RNA is detectable at week 4 of treatment, repeat quantitative HCV RNA viral load testing is recommended treatment week 6 If quantitative HCV viral load has increased by greater than 10-fold (>1 log 10 IU/mL) on repeat testing at week 6 (or thereafter), then discontinuation of HCV treatment is recommended Testing Recommendations

Use of DAA Therapy in PWID AASLD/IDSA: recent or active IDU should not be seen as an absolute contraindication to HCV therapy; treating PWID necessary to positively impact the HCV epidemic[1]Selected reports of use of recommended regimens in PWID Slide credit: clinicaloptions.com References in slidenotes. Regimen Study Findings GLE/PIB ENDURANCE-3 [2] Noncirrhotic pts with GT3 HCV; 63% to 66% had history of IDU SVR12: 95% to 97% (entire population) GZR/EBR C-EDGE CO-STAR [3] Treatment-naive PWID with GT1/4/6 HCV on OST (N = 301) SVR12: 92% (immediate treatment) Drug use at BL and during treatment had no impact on SVR12 or regimen adherence SOF/LDV (± RBV) ION subanalysis [4] Pts with GT1 HCV on OST (n = 70) or not (n = 1882) SVR12: on OST, 94%; not on OST, 97% SOF/VEL SIMPLIFY [5] Single-arm phase IV trial of pts with GT1-6 HCV and recent IDU (N = 103) SVR12: 94%

Use Your Collective Genius to Maximize Delivery of Comprehensive HCV Care Slide credit: clinicaloptions.com Multidisciplinary careProviderNurse Hepatologist/ transplant team Case manager Addictions specialist Mental health treatment provider Community outreach specialist Administrative coordinator FibroScan technician Pharmacist

Hepatitis C Primary Care Process Flow Patient ready for Hep C Treatment PCP consults with or refers to Lead Clinician Lead Clinician reviews chart and E-Consults with Hep C Pharmacist as needed Lead Clinician or PCP finalizes treatment plan & writes prescription Treatment Access Support Person obtains authorization for meds Adherence & Monitoring Person dispenses meds, orders labs, follows patient through treatment Lead clinician or PCP sees patient as needed and manages complications Patient completes treatment, monitored for reinfection by PCP Liver Clinic Referral f or patient ineligible for community based treatment

Treatment Readiness Checklist Patient wants hepatitis C treatment Patient generally keeps scheduled medical appointmentsCan contact patient by phone or have another reliable way to reach themIf substance use and/or mental health issues, stabilized or engaged in treatment to the degree that patient can complete 12 weeks of hepatitis C therapyOther active medical issues (HIV, diabetes, etc.) stable with adherence to other prescribed medicationsPatient can articulate a plan to avoid hepatitis C reinfection after treatment

HCV Treatment Opportunities Specialty Clinic Primary Care Hospital SNFInpatient RehabOutpatient rehabPrisonCorrectionsMethadone ClinicMental Health ClinicSyringe Exchange Program Homeless Shelter TB Clinic Street medicine

Adherence with All Oral DAAs for HCV

Adherence to DAA therapy over 12 week treatment course

Potential Strategies to Optimize Adherence to DAA Therapy

Questions & Answers

References and Citations Alvarez D, Dieterich DT, Brau N, et al. Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. Journal of Viral Hepatitis. 2006;13:683–9.  American Association for the Study of Liver Diseases. HCV Guidance: Recommendation for Testing, Managing, and Treating Hepatitis C. Accessed November 2017: https://www.hcvguidelines.org/ Amorosa VK, Slim J, Mounzer K et al. The influence of abacavir and other antiretroviral agents on virological response to HCV therapy among antiretroviral-treated HIV-infected patients. Antiviral Therapy. 2010; 15: 91–9 Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999;30:1054-1058. Deans GD, Raffa JD, Lai C, et al. Mortality in a large community-based cohort of inner-city residents in Vancouver, Canada. CMAJ Open. 2013;1(2):E68–E76.Dore GJ, Altice F, Litwin AH, Dalgard O, Gane EJ, Shibolet O, et al. Elbasvir-grazoprevir to treat hepatitis C virus infections in persons receiving opioid agonist therapy: a randomized trial. Annals of Internal Medicine. 2016;165:625-634. George SL, Bacon BR, Brunt EM, et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009; 49:729–738

References and Citations Graham CS, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis.  Clin Infect Dis. 2001;33:562–569. Grebely J, Mauss S, Brown A, et al. Efficacy and safety of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic HCV genotype 1 infection receiving opioid substitution therapy: analysis of phase 3 ION trials. Clinical Infectious Diseases. 2016;63:1405-1411 Foster GR, et al. ENDURANCE-3: Safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3-infected patients without cirrhosis. 52nd EASL; Amsterdam, Netherlands; April 19-23, 2017. Abstract GS-007 Jezequel C, Bardou-Jacquet E, Desille E. Survival of patients infected by chronic hepatitis C and F0F1 fibrosis at baseline after a 15 year follow-up. Poster presented at: 50th Annual Meeting of the European Association for the Study of the Liver (EASL); April 22-26, 2015; Vienna, Austria. [Abstract P0709] Negro F., Forton D., Craxì A. et al, Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology 2015;149:1345–1360. Sherman KE, Rouster SD, Chung RT, and Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS clinical trials group. Clinical Infectious Diseases 2002; 34: 831-837

References and Citations Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits. BMC Infectious Diseases 2015; 15:19  Sulkowski MS, Cheever LW, Spach DH. A guide for evaluation and treatment of hepatitis C in adults coinfected with HIV. US Department of Health and Human Services, Health Resources and Services Administration (HRSA) (January 14, 2011). http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf  Weber R, Sabin CA, Friis-Møller N., et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Archives of Internal Medicine 2006; 166: 1632-41 

NEXT WEBINAR: Financing and Sustainability Tuesday, December 19, 2017 12:00 – 1:00 PM ET https://register.gotowebinar.com/register/4804600117656846593

For More Information & Resources Visit www.integration.samhsa.gov or e-mail integration@thenationalcouncil.org

Thank you for joining us today. Please take a moment to provide your feedback by completing the survey at the end of today’s webinar.