Program Disclosure. A maximum of 1.5 contact hours may be earned for successful completion of this activity.

Transcription

1

2 Program Disclosure This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation (CLDF). The Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. The Annenberg Center for Health Sciences at Eisenhower designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. The Annenberg Center for Health Sciences is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. A maximum of 1.5 contact hours may be earned for successful completion of this activity. The Annenberg Center for Health Sciences at Eisenhower is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program has been assigned ACPE Universal Program # L01-P. This program is designated for up to 1.5 contact hours (1.5 CEUs) of continuing pharmacy education credit. This program is supported by an educational grant from AbbVie, Bristol-Myers Squibb and Salix.

3 Educational Objectives Describe the epidemiology and natural history of chronic hepatitis C Summarize the CDC and AASLD/IDSA/IAS-USA recommendations relating to HCV screening and diagnosis Describe current treatment options for chronic hepatitis C and analyze real-world data on these treatments

4 State of HCV Care National Survey Survey assessed the landscape of HCV care practices and capacity 418 respondents from 41 states (93% were physicians) The survey found: Providers anticipate increased HCV caseloads in the coming years; they will need to scale up HCV care and treatment within the next 3 years One reported barrier to providing HCV care to patients is limited provider clinical knowledge about screening and/or treatment Insurance restrictions provide significant limitations to treating HCV patients Report on the State of Hepatitis C Care National Survey. Available at: Accessed May 4, 2016.

5 Survey Findings Indicate Providers Need Education and Resources Increased resources and education to support the provider Recruitment of specialists into HCV care and strengthening referral networks between PCPs and specialists Engagement of allied health professionals to support patients and address co-morbidities and other social determinants experienced by HCV patients Provider training on current practice guidelines and treatment of coinfections and co-morbidities Report on the State of Hepatitis C Care National Survey. Available at: Accessed May 4, 2016.

6 Chronic Hepatitis C Infection Is a Major Concern in the US

7 Total No. Infected (millions) HCV Is Nearly 4 Times as Prevalent as HIV and HBV 4 Prevalence of Chronic Viral Infections 2.7 to 3.9 Million 1 75% Unaware of Infection Million 1 21% Unaware of Infection ~800,000 to 1.4 Million 1 65% Unaware of Infection Undiagnosed Diagnosed 0 HIV HBV HCV A 2011 study estimated that as many as 5 million persons are living with HCV in the United States 2, 3 Based on a 2015 literature search that takes into account populations excluded from NHANEs, the number of US residents who have been infected with HCV is ~4.6 million (range 3.4 million-6.0 million) 4 HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus. 1. Institute of Medicine. Washington, DC: The National Academies Press. 2010; 2. Chak E, et al. Liver Int. 2011;31(8): ; 3. Gish R, et al. Hepatology. 2016: DOI /hep.28026; 4. Edlin BR, et al. Hepatology. 2015;62(5):

8 Rate per 100,000 People Deaths from HCV Surpassed Those from HIV Change in Mortality Rates from 1999 to HIV Hepatitis C Hepatitis B Year 15,106 12,734 The number of HCV-related deaths has since continued to increase; HCV-related deaths rose to 19,659 in , Ly KN, et al. Ann Intern Med. 2012;156(4): ; 2. Available at: Accessed May 10, 2016.

9 Chronic HCV Infection May Lead to Chronic Liver Disease and Liver Cancer ~75% of patients infected with HCV will develop a chronic infection ~65% of these patients are expected to develop progressive chronic liver disease 40% risk of cirrhosis and HCC may occur in the setting of F3 fibrosis Fibrosis Cirrhosis Hepatocellular Carcinoma (with cirrhosis)

10 Cases, N Complications Due to HCV-Related Cirrhosis Expected to Rise Over the Next 10 Years Projected Number of Cases of Hepatocellular Carcinoma and Decompensated Cirrhosis Due to HCV 160, , , ,000 80,000 60,000 40,000 20,000 0 Decompensated cirrhosis Hepatocellular carcinoma Year Davis GL. Gastroenterology. 2010;138:

11 HCV Can Now Be Cured in Most Patients Unlike HIV and HBV infection, HCV infection is a curable disease HCV does not archive its genome in the nucleus and does not integrate in the host DNA What does cure mean? Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection SVR12 is almost invariably durable Ghany MG, et al. Hepatology. 2009;49(4):

12 10-Year Cumulative Occurrence Rate (%) SVR and All-Cause Mortality in CHC Patients with Advanced Fibrosis Baseline factors significantly associated with all-cause mortality: Older age GT 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use 530 patients followed for a median of 8.4 years SVR patients 26.0 All-cause mortality Liver-related mortality or liver transplant Non-SVR patients HCC Liver failure Van der Meer A, et al. JAMA. 2012; 308:

13 Cumulative Mortality (%) SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study 0.3 Genotype 1 (n=12,166) SVR rate: 35% 0.3 Genotype 2 (n=2904) SVR rate: 72% 0.3 Genotype 3 (n=1794) SVR rate: 62% Non-SVR 0.15 Non-SVR 0.15 Non-SVR P< P< P< SVR 0.05 SVR 0.05 SVR Years Years Years Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility ( ). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:

14 Which Patients Should We Screen?

15 Individuals, N Majority of Persons Chronically Infected with HCV Are Baby Boomers (Those Born Between ) Estimated Prevalence by Age Group 1,600,000 1,400,000 1,200,000 1,000, , , , ,000 0 < Birth Year Group Centers for Disease Control and Prevention. MMWR. 2012;61(RR-4):1-32.

16 AASLD/IDSA HCV Guidance Document Recommendations for Screening One-time HCV testing recommended for persons born between 1945 and 1965 (regardless of birth country) without prior ascertainment of risk Other persons should be screened for risk factors for HCV infection One-time testing should be performed for all persons with behaviors, exposures, and conditions associated with an increased risk of HCV infection Available at: Accessed May 17, 2017.

17 AASLD/IDSA HCV Guidance Document Recommendations for Screening (cont d) Risk Behaviors Injection-drug use (current or ever, including those who injected once) Intranasal illicit drug use Other HIV infection Sexually active persons about to start preexposure prophylaxis for HIV Unexplained chronic liver disease and/or chronic hepatitis including elevated alanine aminotransferase levels Solid organ donors (deceased and living) Available at: Accessed May 17, Risk Exposures Long-term hemodialysis (ever) Percutaneous/parenteral exposures in an unregulated setting Healthcare, emergency medical, and public safety workers after needlesticks, sharps, or mucosal exposures to HCV-infected blood Children born to HCV-infected women Prior recipients of transfusions or organ transplants, including persons who: Were notified that they received blood from a donor who later tested positive for HCV Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992 Received clotting factor concentrates produced before 1987 Persons who were ever incarcerated

18 AASLD/IDSA HCV Guidance Document Recommendations for Screening (cont d) For patients with ongoing risk factors: Annual HCV testing is recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV Available at: Accessed May 17, 2017.

19 The AASLD/IDSA Recommendations for Patients with Active HCV Abstinence from alcohol Evaluation for other conditions that may lead to fibrosis (e.g. HIV, HBV, NASH) Evaluation for advanced fibrosis APRI, Fib4, imaging Vaccination against HAV, HBV and pneumococcal infection (in patients with cirrhosis) Education on avoidance of transmission Available at: Accessed May 17, 2017.

20 CDC Recommended Testing Sequence for Identifying Current HCV Infection HCV antibody Nonreactive Reactive HCV RNA Not detected Detected No HCV antibody detected Current HCV infection No current HCV infection Stop * Link to care Additional testing as appropriate Available at: Accessed April 28, Adapted from Centers for Disease Control and Prevention (CDC), 2013.

21 Linkage to Care

22 The AASLD/IDSA Recommendation for Linkage to Care All persons with current active HCV infection should be linked to a practitioner who is prepared to provide comprehensive management Available at: Accessed May 17, 2016.

23 Current Status of HCV in the US: Screening and Linkage to Care Rates Remain Low US population with chronic HCV infection 3.2 million* HCV detected 1.6 million (50%) Referred to care million (32%-38%) HCV RNA test 630, ,000 (20-23%) Liver biopsy 380, ,000 (12%-18%) Treated 220, ,000 (7-11%) Successfully treated 170, ,000 (5-6%) *Recent analysis estimates 5 million Holmberg SD, et al, New Engl J Med. 2013; ; Gish R, et al. Hepatology. 2016: DOI /hep

24 Can We Predict Who Is at Higher Risk for Disease Progression?

25 Factors Associated with Accelerated Fibrosis Progression Modifiable Alcohol consumption Nonalcoholic fatty liver disease Obesity Insulin resistance Non-modifiable Fibrosis stage Inflammation grade Older age at time of infection Male sex Organ transplant Viral Genotype 3 Coinfection with HBV or HIV Available at: Accessed April 28, 2016.

26 What Treatments Are Available and How Effective Are They?

27 Cure Rate* Rising Cure Rates for Chronic HCV 100% 80% Telaprevir or Boceprevir + PegIFN/RBV 2 nd Gen DAAs IFN-Free Regimens >90% 3 rd Gen DAAs IFN-Free Regimens >95% 60% PegIFN/RBV 70% 40% 20% 0% IFN IFN/RBV 35% 44% 16% Year *Cure rates based on data from clinical trials

28 Messina JP, et al. Hepatology, 2015; 61: Global Distribution and Prevalence of HCV Genotypes

29 p7 4A Approved DAAs from Multiple Classes: Combination All-oral Regimens for HCV 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 (NNI) Simeprevir Paritaprevir/r Grazoprevir Voxilaprevir Glecaprevir Daclatasvir Ledipasvir Ombitasvir Elbasvir Velpatasvir Pibrentasvir Sofosbuvir Dasabuvir Note the common root name for each drug class Current as of August 9, 2017

30 Principles of All Oral Regimens for HCV Combine drugs from different classes Target multiple targets to increase efficacy Decrease risk of viral resistance If done properly Near universal efficacy Shortened duration of therapy Adverse events have minimal impact on patient s quality of life

31 General Concepts About Selecting HCV Regimens Choice of regimen, treatment duration, and use of ribavirin may depend on: Presence of cirrhosis Prior treatment experience Treatment-naive Prior NS5A failure Prior sofosbuvir failure Genotype Presence of advanced kidney disease

32 Important Information Needed at Diagnosis: Consultation with a Liver Specialist Making sure the patient is not cirrhotic: Accurate staging of liver disease is important History, physical exam Laboratory data: Focus on platelets Subtle clues: Decreased albumin Hepatic imaging may be suggestive of cirrhosis PV diameter >12mm; spleen >12 cm, liver contour, large left lobe or caudate lobe Non-invasive testing: FIB4 or APRI Fibrosure or equivalent serum tests Elastography Use clinical judgment to reconcile conflicting results

33 Excluding Cirrhosis Is Important Presence of cirrhosis Triggers routine cirrhosis care Evaluation for varices Surveillance for hepatocellular carcinoma May impact SVR May affect treatment duration

34 Reviewing Potential Drug: Drug Interactions Is Important Is the patient taking any drugs that could have a potential drug: drug interaction with a DAA? Antiarrhythmics e.g. digoxin, amiodarone PPIs/acid reducing agents Herbal supplements HIV antivirals e.g. tenofovir, lopinavir/ritonavir Drugs that are renally cleared Is a co-medication contraindicated or is a dose adjustment required? Can plasma levels of co-medications be easily monitored to ensure they remain within the established therapeutic range? PPI = proton pump inhibitor

35 Real-World Data on Approved Therapies

36 Combination Therapies for HCV: Sofosbuvir/Velpatasvir

37 Combination Therapies for HCV: Elbasvir/Grazoprevir

38 Combination Therapies for HCV: Ombitasvir/Paritaprevir/rRtonavir ± Dasabuvir ± Ribavirin Hinrichsen H, et al. Presented at the 51st Annual Meeting of the European Association for the Study of the Liver; Barcelona, Spain, April 2016.

39 What is Real-World Experience? RCTs RCTs are considered the gold standard for evidence on clinical efficacy and safety RWE RWE = real-world experience; RCTs = randomized controlled trials.

40 What is Real-World Experience? RCTs However, RCTs cannot answer all clinical questions Key clinical data can be obtained in the real world RWE

41 SVR12 (%) HCV TARGET: Interim Analysis of GT1b-Infected Patients Receiving DAAs in the Real World SVR Rates Across Treatment Regimens SVR12 rates are uniformly high across most regimens as reported in phase 3 clinical trials n N SOF + RBV SMV + SOF ± RBV DCV + SOF ± RBV LDV/SOF ± RBV OBV/PTV/r + DSV ± RBV Manns M, et al. Hepatol Int. 2016; (suppl) #O-005.

42 SVR, % Real-World Effectiveness in 9,604 HCV patients treated with DAAs in the VA Cohort SVR ,679 3,068 5,148 5,524 2,669/ 3, ,012 0 SOF+SMV LDV/SOF OBV/PTV/RTV +DSV Data collected prior to September 2015 *SOF+SMV data were collected primarily in 2014 before other DAA approvals McCombs, EASL. 2016, Poster LBP510.

43 Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in GT1 HCV: Real-World Experience from the TRIO Network The purpose of this study was to understand the real-world utilization of LDV/SOF and SOF/VEL in patients with GT1 chronic HCV Data were collected from providers and specialty pharmacies through TRIO s Health Innovation Platform, a cloud-based disease management program LDV = ledipasivr; SOF = sofosbuvir; VEL = velpatasvir Tsai N, et al. Journal of Hepatology. 2017;66:S726.

44 Patient Disposition Patients with GT1 who initiated 8 or 12 week treatment between July and October 2016 were included in the analyses Disc. (n=4) Death (n=1) LTFU (n=12) 8 week LDV/SOF (n=378) Completed Therapy n=361 Disc. (n=41) Death (n=1) LTFU (n=11) 12 week LDV/SOF (n=949) Completed Therapy n=893 Disc. (n=4) Death (n=0) LTFU (n=1) 12 week SOF/VEL (n=89) Completed Therapy n=84 SVR12 pending n=166 SVR12 not achieved n=6 SVR12 achieved n=189 SVR12 pending n=504 SVR12 not achieved n=7 SVR12 achieved n=382 SVR12 pending n=54 SVR12 not achieved n=1 SVR12 achieved n=29 SVR12 (PP): 97% (189/195) SVR12 (PP): 98% (382/389) SVR12 (PP): 97% (29/30) Tsai N, et al. Journal of Hepatology. 2017;66:S726.

45 Outcomes 8 weeks LDV-SOF 12 weeks LDV-SOF 12 weeks SOF-VEL 100% 97% 98% 96% 95% 99% 100% 98% 100% 100% 97% 98% 90% 97% 98% 100% 100% 98% 91% 80% 60% 40% 20% 0% 147/ /288 23/24 23/41 91/92 5/5 177/ /259 20/20 12/12 120/122 9/10 183/ /327 19/19 6/6 61/62 10/11 GT1A GT1B F0-3 F4 TN TE *FO-3=non-cirrhotic, F4=cirrhotic, TN=treatment naïve, TE=treatment experienced. Tsai N, et al. Journal of Hepatology. 2017;66:S726.

46 Conclusions Overall, per protocol SVR12 results were not significantly different between 8 week LDV/SOF, 12 week LDV/SOF and 12 week SOF/VEL Similarly, per protocol SVR 12 rates were not significantly different between regimens by genotype subtype, fibrosis or prior treatment status Tsai N, et al. Journal of Hepatology. 2017;66:S726.

47 SOF/VEL in GT2 6 HCV: Real-World Experience from the TRIO Network The purpose of this study was to examine real-world treatment utilization and compare outcomes between SOF/VEL +/- RBV and existing standards of care in patients with GT2-6 chronic HCV Data were collected from providers and specialty pharmacies through TRIO s Health Innovation Platform Curry M, et al. Journal of Hepatology. 2017;66:S58.

48 Study Data Inclusion criteria: 18 year or older patients Not enrolled in a clinical trial Initiated anti-hcv therapy in 2016 GT2-6 HCV Data collection as of Mar Representation from 40 US states and DC Majority of care in community practice Metric Academic Community Total Patients Physicians Curry M, et al. Journal of Hepatology. 2017;66:S58.

49 Patient Disposition: GT2 In therapy n=0 SOF + RBV n=337 SOF-VEL +/- RBV n=394 In therapy n=20 Discontinued n=10 LTFU n=29 Death n=2 Completed Therapy n=296 Discontinued n=15 LTFU n=1 Death n=0 Completed Therapy n=358 SVR Pending n=44 SVR Not Achieved n=14 SVR Achieved n=238 SVR Pending n=264 SVR Not Achieved n=3 SVR Achieved n=91 SVR (PP): 94% (238/252) SVR (PP): 97% (91/94) Curry M, et al. Journal of Hepatology. 2017;66:S58.

50 Patient Disposition: GT3 DCV + SOF +/- RBV n=392 In therapy n=3 SOF-VEL +/- RBV n=244 In therapy n=20 Discontinued n=16 LTFU n=20 Death n=5 Completed Therapy n=348 Discontinued n=9 LTFU n=2 Death n=2 Completed Therapy n=211 SVR Pending n=72 SVR Not Achieved n=10 SVR Achieved n=266 SVR Pending n=143 SVR Not Achieved n=2 SVR Achieved n=66 SVR (PP): 96% (266/276) SVR (PP): 97% (66/68) Curry M, et al. Journal of Hepatology. 2017;66:S58.

51 Patient Disposition: GT4, GT5, GT6 LDV-SOF +/- RBV n=204 (113 GT4, 1 GT5, 90 GT6) In therapy n=2 SOF-VEL +/- RBV n=38 (13 GT4, 25 GT6) In therapy n=1 Discontinued n=1 LTFU n=11 Death n=2 Completed Therapy n=188 Discontinued n=2 LTFU n=0 Death n=0 Completed Therapy n=35 SVR Pending n=53 SVR Not Achieved n=8 SVR Achieved n=127 SVR Pending n=24 SVR Not Achieved n=1 SVR Achieved n=10 SVR (PP): 94% (127/135) SVR (PP): 91% (10/11) Curry M, et al. Journal of Hepatology. 2017;66:S58.

52 Conclusions The pan-genotypic 12-week treatment of SOF/VEL +/- RBV is now the standard of care for GT2 and GT3 The duration of therapy is reduced to 12 weeks for most patients; RBV is rarely necessary SVR rates in this study are similar to those reported from clinical trials Curry M, et al. Journal of Hepatology. 2017;66:S58.

53 Recently Approved Pangenotypic DAA Regimens Sofosbuvir/velpatasvir (SOF/VEL) Approved in 2016 Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) Approved in July 2017 Pibrentasvir/glecaprevir (PIB/GLE) Approved in August 2017 All are pangenotypic, oral, once-daily regimens Treatment can be as short as 8 weeks for many patients

54 IDSA/AASLD Guidance Document Remains Current and Best Resource (