Update on HCV Epidemiology 5/6/2016. What Clinicians Should Know About Hepatitis C Virus: Didactic Presentation

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1 What Clinicians Should Know About Hepatitis C Virus: Didactic Presentation David L. Wyles, MD Associate Professor of Medicine University of California San Diego La Jolla, California FLOWED: 04/19/2016 Los Angeles, California: April 26, 2016 Learning Objectives After attending this presentation, participants will be able to: List the genotypes of hepatitis C virus (HCV) and how they relate to treatment effects Recognize how to stage HCV infection and indicate why it is important to accurately stage Describe emerging treatments of HCV and how the changing landscape will impact treatment decisions in the near future Slide 2 of 36 Update on HCV Epidemiology Slide 3 of 35 1

2 HCV Worldwide 170 million infected Highest Asia & Africa Egypt > 15% USA 1.3% 3-4 million infected Slide 4 of 35 Hepatitis C in the US NHANES million (1.3%) with HCV infection (+Ab) 2.7 million (1.0%) with chronic infection Age 40-49: 1.09 million Age 50-59: 1.03 million Risks for HCV RNA + (OR) Non-Hispanic black: 1.6 ( ) Income <2x poverty level: 3.7 ( ) May be as high as 5-7 million Slide 5 of 35 Denniston MM. Annals Chak E. Liver Internat Mahajan R. CID HCV genotypes: global distribution and diversity Slide 6 of 35 46% 30% Messina JP. Hepatol S. Ray. 2

3 The rise (and underestimation) of HCV related mortality 7 Rate per 100,000 Persons Hepatitis B Hepatitis C HIV Year 19,368 deaths in 2013 CHeCS cohort: HCV-related deaths likely 5-fold higher Mean age of death: 59 X Slide 7 of 35 Ly K. Annals Intern Med CDC Viral Hepatitis Surveillance Report Mahajan R. CID Ly K CID Increase in new HCV infections 3,500 Number of acute HCV cases 3,000 2,500 2,000 1,500 1, Year Slide 8 of 35 Peaked in the 1980s at ~300,000 cases/year 45% increase in reported cases from 2010 to 2011 and CDC Surveillance for Viral Hepatitis Acute HCV (and HIV) in the Midwest 135 HIV cases Average age 35 55% male 80% reported IDU; 17% not interviewed 114/135 (84%) with HCV coinfection Slide 9 of 35 3

4 New HCV infections are increasing on a national level Change in HCV incidence age 30yrs: 2006 vs Year Incidence Non-urban (cases/100,000) Urban Slide 10 of 35 Suryaprasad AG. CID Natural History of HCV Infection Time (yrs) Resolved Exposure (Acute Phase) ~25% ~75% ~80% Stable 5-year survival in patients with HCC is <5%* Chronic ~75% Slowly Progressive ~ 30-year progression rate may be accelerated with HIV, HBV, alcohol, and steatosis 1,2 ~20% Cirrhosis ~5%/yr ESLD ESLD: end-stage liver disease ~3%-4%/yr HCC Transplant/Death ~1-4%/yr Slide 11 of 35 *NIH Consens Statement. June 10-12, 2002;19(3):1-46. NIH Consens Statement. March 24-26, 1997;15(3): Di Bisceglie AM. Hepatology. 2000;31(4): Bialek SR, Terrault NA. Clin Liver Dis. 2006;10(4): Progression of HCV Paired biopsy studies: 11% of subjects progressed 2 stages on biopsies months apart. About 1/3 showed some evidence of progression HALT-C Study: all subjects with baseline cirrhosis or bridging fibrosis 3 biopsies over a mean of 6 years of follow-up Cirrhosis: ~4%/yr decompensation Bridging Fibrosis: 10%/yr transition to cirrhosis Slide 12 of 35 Ghany et al. Gastroenterology 2003; 124: Ryder et al. Gut 2004; 53: Dienstag JL. Hepatology

5 Future burden of HCV morbidity and mortality Markov model of health outcomes Of 2.7 M HCV infected persons in primary care 1.47 M will develop cirrhosis 350,000 will develop liver cancer 897,000 will die from HCV-related complications Number Slide 13 of 35 Rein D, et al. Dig Liver Dis The HCV continuum of care in the U.S. 100% 100% 75% 50% 25% 0% 50% 38% 23% 11% 6% Slide 14 of 35 Adapted from Holmberg et al. NEJM 2013 Identifying Patients With Chronic Hepatitis C An estimated 40 to 85% of persons infected with HCV are unaware of their HCV infection status One study reported that amongst HCV-infected injection drug users who were 15 to 30 years old, 72% were unaware of their HCV infection status NHANES study conducted from 2001 through 2008 found that 50.3% of persons infected with HCV were unaware of their status In a study involving persons with access to medical care in four private health care organizations during the years 2006 to 2008, an estimated 43% were unaware of their HCV infection Slide 15 of 35 Armstrong et al. Ann Intern Med. 2006;144: Denniston MM et al. Hepatology 2012;55: Denniston MM et al. Ann Intern Med. 2014;160:

6 5/6/2016 Hepatitis C Testing in the U.S. Patients with at least 1 encounter and no previous HCV testing 865,659 Percent tested for HCV 13% 5.1% Percent of patients who were positive for HCV Percent of patients with 2 elevated ALT results tested for HCV 43.9% Percent of patients positive for HCV after 2 elevated ALT results 8.2% 2012 Kaiser study including HI, OR, MI, PA sites Spradling PR et al. CID 2012;55(8): Slide 16 of 35 Who Should be Tested for HCV: USPSTF Grade B Recommendations Slide 17 of 35 Everyone born from (one-time) Past or present injection drug use Sex with an IDU; other high risk sex Blood transfusion prior to 1992 HIV+ Persons with hemophilia Long-term hemodialysis Born to an HCV-infected mother Incarceration Intranasal drug use Unregulated tattoo Occupational percutaneous exposure Surgery prior to universal precautions Smith et al. Ann Intern Med 2012;157: Moyer et al. Ann Intern Med epub 25 June HCV screening in the birth cohort Slide 18 of 35 6

7 HCV diagnostic testing HCV ab testing- rapid POC, ELISA 3 rd generation ELISA (NS4, Core, NS3; NS5B) >98% sensitive and specific Positive Ab only confirms exposure to HCV HCV VL and genotype HVC RNA+ Defines active infection (chronic in most cases) Some role in determining treatment duration Genotyping: LiPA 2.0 vs. Abbott real-time vs. direct sequencing Critical to determining the need for additional testing (e.g. RAV testing in GT1a) Selecting appropriate therapy How long will this matter going forward? Slide 19 of 35 Screening for Acute HCV in those with HIV Delayed antibody response in those with HIV Mean time to seroconversion 7 months 5% with seroconversion at >1 year 88% with elevated ALT NEAT Consensus Statement Screening Recommendations Slide 20 of 35 Natouli E. J Clin Virol Thomson EC. AIDS NEAT AIDS Histologic Staging of HCV Slide 21 of 35 Grade: Necroinflammatory activity Stage: Degree of fibrosis Grading Systems: Multiple exist- the more common include the HAI (Knodell), mhai and METAVIR Stage mhai HAI MET Grade HAI 0-18 mhai 0-18 MET A0-A3 7

8 Approaches to fibrosis staging Modality Pro Con Comment Liver Biopsy Reference standard, Additional information Invasive Cost/availability Understaging* *adequate sample: 11 portal tracts, >2.0 cm Routine Indices Widely available, Low cost Limited accuracy (AUROC: ) APRI FIB-4 Slide 22 of 35 Proprietary Indices Transient Elastography Availability Improved accuracy (AUROC: 0.90) Non-invasive FDA approved AUROC:0.94 (F3-4) Increased cost Confounders (atazanavir) Specialized equipment (acquisition cost) FibroSure Poor for adjacent stages Transient elastography Limitations of non-invasive test 5-marker index Slide 23 of 35 Imbert-Bismut F. Lancet Ziol M. Hepatol Transient Elastography: HCV 2.5 kpa Slide 24 of 35 Affected by weight, access of probe (2 cm), steatosis 8

9 Extrahepatic manifestations of HCV Mixed cryoglobulinemia (type II and III) Prevalence of HCV 80-90%; reverse 30-50% Glomerulonephritis- MPGN Porphyria cutanea tarda Lymphoma (B cell) HCV present in 9-32% Type II DM OR 3.77 ( ) Lichen Planus Vitiligo CNS Slide 25 of 35 Subhash C. Ann Intern Med, Zuckerman E. Ann Intern Med, Mehta SH. Ann Intern Med, Harris N. NEJM, HCV identified HCV Therapeutics Timeline You are here BILN-2061 Boceprevir Telaprevir Phase 1b SOF/LDV Consensus IFN In vitro PrO-D GZP/EBR Peg-IFNa-2b HCV replication Slide 26 of IFN a-2b Sofosbuvir IFN a-2a HCV replicons Peg-IFNa-2a Simeprevir Daclatasvir (US) IFN a-2b + RBV Peg-IFNa-2a in HCV/HIV Daclatasvir (EU) SVR (%) Relative misery HCV life-cycle and antiviral targets NS5A Inhib NS3 Inhib NS5B Inhib SOF/ LDV SOF DCV IFN-free Treatment Options in 2016 SOF SMV EBR/ GZP OBV/ RBV PTV/r DSV SOF RBV Slide 27 of 35 Georgel et al. Trends in Molecular Medicine 16(2010) Moradpour D. Nat Rev

10 Advances in HCV Therapy (DAAs) = IFN-Free HCV Therapy for ALL What are the key considerations: 1. Genotype and subtype 2. Fibrosis stage 3. Treatment history 4. Drug interactions 5. What insurance do they have? Slide 28 of 35 HIV/HCV co-infection is no longer a consideration from an efficacy standpoint. Overview of HCV treatment approaches Genotype weeks for non-cirrhotic patients RBV for GT1a with some regimens Baseline resistance testing with EBR/GZP in GT1a weeks for cirrhotic patients (+/- RBV) Genotype 2: weeks SOF/RBV Genotype 3: weeks SOF + DCV (+/- RBV) Potential limited role for IFN Cure rates >95% (exception GT3 cirrhotics) Slide 29 of 35 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 Slide 30 of 35 JAMA. 2012;308(4): doi: /jama

11 SVR decreases mortality to that of the general population Slide 31 of 35 van der Meer AJ. JAMA High cost and limited access Price of Sofosbuvir at $1000/pill captured headlines IFN-free DAA regimen are cost-effective for GT1 This does not mean they are affordable The arrival of new regimens may did decrease costs PrOD 12 weeks: $83,319 EBR/GZP 12 weeks: $54,600 Slide 32 of 35 Table courtesy Camilla Graham MD, MPH. Chanal HS. JAMA hcvguidelines.org * High cost and limited access F2 07/2015 Slide 33 of 35 CA: Restrictions requiring urine drug screening, AUDIT and PHQ scoring removed as well. Barua S. Annals Intern Med

12 How big of an issue is re-infection? 2/63 subjects in Turquoise 25 I by SVR12 Both SVR4 20 No resistance mutations on relapse 5-year re-infection rate (%) patients 1203 patients 5.0 years 1285 patients 3.3 years 21.8% Slide 34 of 35 0 Low risk IVDU/prisoner HIV co-infected Hill A. CROI Sulkowski M. JAMA Sofosbuvir/velpatasvir for 12 weeks Wk 0 Wk 12 Wk 24 Wk 0 Wk 24 Wk 12 GT1, 2-6 SOF/VEL Placebo SOF/VEL SVR12 GT3 SOF/VEL SOF + RBV SVR12 (%) Total 1a 1b Genotype Slide 35 of 35 Feld JJ. NEJM Mangia A. NEJM

13 Hepatology for the Nonhepatologist (by a Nonhepatologist): Didactic Presentation Kara W. Chew, MD, MS Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California FINAL: 04/19/2016 Los Angeles, California: April 26, 2016 Learning Objectives After attending this presentation, participants will be able to: Assess liver disease stage Describe clinical and laboratory findings of advanced liver disease Describe approaches to liver fibrosis assessment and their strengths and limitations Provide basic management of chronic liver disease Slide 2 of 35 Hepatic fibrosis and definitions Hepatic stellate cell activation extracellular matrix production and deposition GRADE of disease = degree of hepatic necroinflammation STAGE of disease = degree of fibrosis Different staging systems: Ishak (modified Knodell) (0-6), METAVIR (0-4), Scheuer (0-4), Batts and Ludwig (0-4) Typically categorized in trials by METAVIR stages 0-4 (F0, 1, F2, F3, F4) F0 = no fibrosis F4 = cirrhosis Slide 3 of 35 1

14 Stages of fibrosis Healthy portal/periportal fibrosis portal with mild bridging (portalportal septa) (F2) numerous septae without cirrhosis (F3) cirrhosis (F4) Slide 4 of 35 Image borrowed from Kenneth Sherman Fibrosis stage and HCV outcome Slide 5 of 35 Hepatic decompensation or HCC Xu et al, CHeCS cohort, CID HCV-infected 4 U.S. integrated health systems Liver biopsies Mean age at biopsy 50.7 years Mean observation: 5 years Estimated risk of progression to HCC or decompensation at 5 years: F4-37.2% F3 19.6% F2 4.7% F0-F1 2.3% Cox regression of F2-F4: predictors of decompensation or HCC = F3 or F4, platelets<normal, elevated bilirubin Case 52 y.o. man with HIV/HCV seeing you for HCV management HIV and HCV diagnosed in 1994 Well-controlled HIV on ART Former IDU, last 15 years ago. Has generalized fatigue, some joint aches, no joint swelling Low mood chronically No jaundice, GI bleeding, edema, abdominal distension What do you look for on physical examination to assess his liver disease stage? Slide 6 of 35 2

15 Physical examination for liver disease stage Jaundice (sclera, mucous membranes below tongue) Spider nevi (SVC region chest, shoulders, upper arms), facial telangiectasia Palmar erythema (thenar and hypothenar eminences) Gynecomastia Liver and spleen palpation Ascites Edema Asterixis Mentation Slide 7 of 35 Spider nevi Slide 8 of 35 JAMA 2012;307(8): ) Laboratory and other signs of hepatic impairment and portal HTN Thrombocytopenia Hypoalbuminemia Elevated bilirubin Elevated PT/INR Elevated creatinine Abdominal ultrasound: splenomegaly (may see with HIV alone) Slide 9 of 35 3

16 Assessing fibrosis stage Serum biomarkers Elastography Liver biopsy Slide 10 of 35 Non-invasive measures of fibrosis Indirect serum biomarkers FIB-4: age, plt, ALT, AST APRI: AST, plt FibroSURE TM : age, gender, alpha-2-macroglobulin, alpha-2-globulin, gamma globulin, apolipoprotein A1, GGT, ALT, total bilirubin APRI >2.0 or FIB-4 > high specificity for advanced fibrosis/cirrhosis (<0.7 and <1.45 high-ish negative predictive value for advanced fibrosis) Direct serum markers (extracellular matrix) Fibrosis serum panel: hyaluronic acid (HA), TIMP-1, alpha-2-macroglobulin ELF: TIMP-1, procollagen III amino-terminal peptide, HA Slide 11 of 35 Chou, Ann Intern Med 2013; Sterling, Hepatology 2006; Lin, Hepatology 2011; Thompson, Hepatology 2012 Serum biomarkers for fibrosis Non-invasive, high acceptance Easy to calculate Not specific for the liver Confounded in certain settings (e.g. bilirubin elevation with atazanavir or Gilbert s) Not sufficiently sensitive used alone for detection of advanced fibrosis Perform best at extremes of scores, poor discrimination in intermediate range Slide 12 of 35 Chou, Ann Intern Med 2013; Sterling, Hepatology 2006; Lin, Hepatology 2011; Thompson, Hepatology

17 Transient Elastography (TE) Noninvasively measures liver stiffness FDA-approved Reproducible and validated >12.5 kpa with F4 correlates well with advanced fibrosis Overlap in kpa ranges between stages Results affected by hepatic inflammation, obesity, ascites, central venous pressure, food/fasting status XL probe for higher BMI Operator dependent requires experience Look at IQR if <30% of median value, more reliable Slide 13 of 35 Castera et al, Gastroenterology 2005, Lucidarme et al, Hepatology 2009 Transient Elastography Slide 14 of 35 Summary of performance of serum biomarkers Test AUROC Sensitivity Specificity PPV NPV APRI < % APRI >1.0 76% 72% 55% 0.83 APRI >2.0 46% 91% 82% FIB-4 < FIB-4 > % 97-98% 65-82% FibroTest % 72-91% Transient elastography % 82-91% 90-95% Advanced fibrosis Cirrhosis Advanced fibrosis Slide 15 of 35 Lin et al, Hepatology 2011, Vallet-Pichard et al, Hepatology 2007, Sterling et al, Hepatology 2006, D Nunes BMC 5

18 Misclassification by noninvasive markers Boursier et al, Liver Int 2009 Slide 16 of 35 Magnetic Resonance Elastography (MRE) Similar to transient elastography Detects propagating shear waves within the liver Liver stiffness calculated from wave displacement patterns (colorencoded images) Looks at the whole liver High accuracy for cirrhosis (>90% sensitivity and specificity) Slide 17 of 35 Liver stiffness across fibrosis stages by MRE Slide 18 of 35 Venkatesh et al, JMRI

19 Magnetic Resonance Elastography Potentially greater accuracy for intermediate stages (80-85% sensitivity and specificity) Not affected by obesity Reproducible Stiffness calculations impacted by severe inflammation, cholestasis, hepatic congestion (as with TE) Cost? Takes more time to perform than TE Slide 19 of 35 Nguyen and Talwalkar, Hepatology 2011 Slide 20 of 35 Liver biopsy Liver biopsy gold standard, but Subject to sampling error, heterogeneity in distribution of fibrosis Understaging if tissue samples too small Best minimum of 2-2.5cm length, 11 portal triads Up to one-third of bilobar biopsies with difference of at least 1 stage between the lobes Invasive Can evaluate for other causes of liver disease Can evaluate simultaneously for necroinflammation Bedossa, Hepatology 2003, Rockey, AASLD Liver Biopsy Guidelines, Hepatology 2009 Pathologic Staging of Fibrosis Size vs Accuracy 161 Patients Bx Length Cirrhosis No Cirrhosis PPV NPV Accuracy >3 cm 11.2% 88.8% % 1.5 cm 7.4% 92.6% % 1.0 cm 4.9% 95.1% % Bx Length Signif Fibr No Signif Fibr PPV NPV Accuracy >3 cm 41.0% 59.0% % 1.5 cm 31.6% 68.4% % 1.0 cm 19.8% 80.2% % Slide 21 of 35 Colloredo et al, J Hepatol

20 A suggested approach: Combine measures Clinical assessment (exam, labs) Serum biomarkers: FIB-4, APRI + Fibrosure or fibrosis serum panel If discordant, elastography- preferably transient elastography If not available, consider US or MR elastography If discordant or advanced fibrosis/cirrhosis still of concern, consider liver biopsy May have to tailor to availability of the different measures/cost Slide 22 of 35 Two noninvasive tests simultaneously is most efficient and reduces need for liver biopsy Low Boursier rate of large paper discrepancies in stage ( 2) Accuracy 86.7% Transient elastography and Fibrotest Slide 23 of 35 Boursier et al, Hepatology 2012 Lifelong assessment of hepatic disease Monitor hepatic function and for complications Decompensated disease: Ascites, hepato-renal syndrome, hepatic hydrothorax, spontaneous bacterial peritonitis Encephalopathy Variceal bleeding Hepatocellular carcinoma For cirrhotics, calculate MELD and Child-Turcotte-Pugh Score Slide 24 of 35 8

21 Score Child-Turcotte-Pugh Score: Cirrhosis staging Bilirubin (mg/dl) Albumin (g/dl) PT (INR) Hepatic Encephalo pathy Ascites (grade) 1 <2 >3.5 <1.7 None None Mild 3 >3 <2.8 > Severe Child Class A 5 6 B 7 9 C >9 Predicts survival (including mortality with surgery) and risk of complications (1-year survival 100% 80% 45%) Slide 25 of 35 Pugh et al, Brit J Surg 1973 Slide 26 of 35 MELD Score: Prediction of mortality Uses serum bilirubin, INR, creatinine Predicts mortality Used to prioritize orthotopic liver transplantation (OLT) candidates MELD Score <9 1.9% % % % % 3-month mortality Kamath et al, Hepatology 2007;45: Hepatocellular carcinoma screening Risk for HCC with F3-F4 Q6 month HCC screening with abdominal ultrasound AFP? Not recommended by AASLD AASLD Guidelines, Management of Hepatocellular Carcinoma, 2011 Slide 27 of 35 9

22 Screening and prophylaxis for variceal bleeding Varices present in ~50% cirrhotic patients 40% CTP Class A, 85% CTP class C Rate of hemorrhage with varices present = 12-15%/year 15-20% mortality with acute hemorrhage Refer for EGD to evaluate and treat varices Follow-up EGD interval to be determined by findings/gi May need prophylaxis with non-selective beta blocker (e.g. propranolol) for prophylaxis or endoscopic variceal ligation Slide 28 of 35 Garcia-Tsao et al, Am J Gastro 2009 AASLD Guidelines 2007 Initial management of ascites Compensated cirrhosis: 30% 5-year cumulative risk of ascites Diagnostic paracentesis: cell count with differential, albumin, total protein Calculate serum-ascites albumin gradient (SAAG): SAAG 1.1 g/dl c/w portal HTN Sodium restriction 2g/day Diuretics: Spironolactone 50mg po daily, furosemide 20mg po daily. Titrate to max spironolactone 400 mg daily + furosemide 160 mg daily as tolerated. Tense ascites: Paracentesis Be cautious/avoid ACE inhibitors and ARBs monitor BP and renal function Slide 29 of 35 Gines et al, Hepatology 1987 Runyon, AASLD Management of Ascites Guidelines 2012 When to refer for liver transplant evaluation Refer if: Hepatic decompensation (clinical or CTP B or C) MELD > 10 (may depend on your center) Hepatocellular carcinoma Slide 30 of 35 10

23 Counseling to minimize risk of liver disease progression and complications Abstain from alcohol Abstain from cigarettes Avoid nonsteroidal antiinflammatory agents (NSAIDs) Limit acetaminophen use to max 2 grams/day Avoid raw shellfish Evaluation for comorbid NASH/NAFLD- counseling on weight loss, diet, exercise Slide 31 of 35 Evaluation for advanced fibrosis is recommended for all Necessary to determine the appropriate HCV treatment strategy Impacts treatment options Depending on the genotype and regimen Treatment duration may need to be extended Addition of ribavirin may need to be considered Additional management necessary for advanced fibrosis/cirrhosis Screening for hepatocellular carcinoma Screening for esophageal varices Monitoring of hepatic function Counseling to avoid NSAIDs, limit acetaminophen use, avoid raw shellfish Referral to hepatology/liver transplantation evaluation Slide 32 of 35 Summary Assess liver disease stage by combining multiple modalities (exam, serum biomarkers, elastography, imaging) Don t rely on one indirect measure alone not adequate Don t forget chronic liver disease management with HCV Refer to Hepatology if decompensated or HCC Slide 33 of 35 11

24 Recommended resources AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Calculators (FIB-4, APRI, MELD, CTP): hepatitisc.uw.edu AASLD Practice Guidelines for management of cirrhosis Management of Hepatocellular Carcinoma (HCC screening recommendations) Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis Management of Adult Patients with Ascites Due to Cirrhosis Slide 34 of 35 Thank you! Acknowledgments: Kenneth Sherman, MD (University of Cincinnati) Arthur Kim, MD (Harvard Medical School/MGH) Slide 35 of 35 12

25 Management of HCV Genotype 2 and 3 Infected Patients Kara W. Chew, MD, MS Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California Los Angeles, California: April 25, 2016 Financial Relationships With Commercial Entities Dr Chew has received a research grant awarded to the University of California Los Angeles from Merck & Co, Inc. (Updated 04/26/16) Slide 2 of 46 Learning Objectives After attending this presentation, participants will be able to: Select treatment for genotype 2 infected noncirrhotic patients Select treatment for genotype 3 infected noncirrhotic patients Identify where uncertainty remains in treatment of genotype 2 and 3 cirrhotic patients Slide 3 of 46 1

26 Case 51 y.o. man with HIV/HCV co-infection HCV diagnosed 2008 HCV treatment naïve HIV well-controlled on raltegravir + abacavir/lamivudine Feels generally well except for mild fatigue No history of liver decompensation no ascites, GI bleeding, encephalopathy No current EtOH, rarely in past, no tobacco. Remote methamphetamine use Slide 4 of 46 Case PMH HIV HCV Hypertension Anal dysplasia with ASCUS H/o secondary syphilis Medications Raltegravir + abacavir/lamivudine Hydrochlorothiazide Multivitamin NKDA Slide 5 of 46 Case Physical Exam Vital signs normal, BMI 28 Well-appearing Anicteric Abdomen with normal liver edge, no hepatosplenomegaly No lower extremity edema No spider nevi, palmar erythema, rash Labs Wbc 7.8, hgb 14.9, plt 285 Creatinine 0.9 T.bili 0.4, AST 57, ALT 51, Alk phos 73, albumin 4.8 INR 1.0 CD (43%), HIV RNA <20 HBsAg negative, HBsAb positive, HBcAb total positive Hepatitis A Ab total positive Slide 6 of 46 2

27 Case HCV RNA 485,000 IU/mL HCV genotype 2a/2c Fibrosure: fibrosis score of 0.42 = F1-F2 FIB-4: 1.43 APRI: Liver biopsy in 2013: Grade 2, stage 1 disease Multiple cores of hepatic parenchyma with overall intact architecture. Approximately 15 portal areas. Some of the portal areas have a mild predominantly lymphocytic infiltrate. There is minimal interface activity. The lobules show mild, scattered lymphocytic infiltrates and rare small clusters of lymphocytes, associated with minimal hepatocyte injury. The trichrome stain demonstrates fibrous portal expansion. Iron stain is negative. Reticulin stain demonstrates conserved hepatic architecture Abdominal ultrasound is normal Slide 7 of 46 What is your recommendation for HCV treatment? 1. Sofosbuvir 400 mg plus RBV 800 mg daily x 12 weeks 2. Sofosbuvir 400 mg daily plus weight-based RBV x 12 weeks 3. Sofosbuvir 400 mg daily plus weight-based RBV x 24 weeks 4. Sofosbuvir 400 mg plus daclatasvir 30 mg daily x 12 weeks 5. Sofosbuvir 400 mg plus daclatasvir 60 mg daily x 12 weeks 6. Sofosbuvir 400 mg plus daclatasvir 60 mg daily plus weight-based RBV x 12 weeks Slide 8 of 46 Treatment recommendations - HCV genotype 2 Non-cirrhotic patients Treatment naïve or PEG-IFN/RBV experienced Sofosbuvir/RBV experienced Daily sofosbuvir (400 mg) + WBR x 12 weeks (IA) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) x 12 weeks if not eligible for RBV (IIaB) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IIaC) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) +/- WBR x 24 weeks if PEG-IFN and/or RBV ineligible (IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 9 of 46 AASLD/IDSA HCV Guidance 3

28 Sofosbuvir plus weight-based ribavirin x 12 weeks for genotype 2 HCV, treatment-naïve patients Sofosbuvir + RBV PEG + RBV Patients (%) with SVR 12 94% SVR ACROSS 3 CLINICAL TRIALS of SOF/RBV in GT 2 (FISSION, POSITRON, VALENCE) Slide 10 of GT 2 and 3 (n=496) GT 2 (n=137) Lawitz, FISSION trial, NEJM 2013 (FIGURE),, Jacobson, NEJM 2013, Zeuzem, NEJM 2014 Figure from University of Washington Hepatitis Web Study GT 3 (n=359) Daclatasvir plus sofosbuvir x 24 weeks for genotype 2 HCV, treatment-naïve patients: A Patients with SVR12 (%) 100 Slide 11 of GT2 = /16 11/11 14/14 5/6 12/14 2/2 SOF x 7d DCV + SOF x 23 wk DCV = daclatasvir; SOF = sofosbuvir GT2 = 8 GT2 = 9 Sulkowski et al, NEJM 2014 Figure adapted from University of Washington Hepatitis Web Study 86 DCV + SOF DCV + SOF + RBV 24 wk Treatment-Naïve: GT 2 or 3 24 wk Daclatasvir plus sofosbuvir x 12 weeks for genotype 2 HCV, treatment-naïve patients: ALLY-2 (HIV/HCV) Patients with SVR12 (%) /11 5/6 2/2 Treatment Naïve Treatment Naïve Treatment Experienced *Daclatasvir (DCV)/sofosbuvir (SOF) not FDA-approved for genotype 2 HCV treatment Slide 12 of 46 Wyles et al, NEJM Figure from University of Washington Hepatitis Web Study 4

29 Does your management change if your patient is cirrhotic? 51 y.o. man with HIV/HCV co-infection, HCV treatment-naïve CD4 400, HIV <20 on raltegravir + abacavir/lamivudine Exam with +spider nevi, palmar erythema. Abdomen non-distended, no ascites WBC 2.59, Platelets 52K, Cr 1.2, INR 1.1, t.bili 1.3, AST 145, ALT 175, albumin 4.1 HCV 5,365,349 IU/mL, genotype 2a/2c FIB-4 = 13.3 APRI = 8.6 Fibrosis serum panel: score = 99 (upper limit 100, c/w F2-F4) Abdominal ultrasound with splenomegaly, liver appears normal, no mass What are your recommendations for management of his liver disease? What is his Child-Pugh score? Slide 13 of 46 Score Child-Turcotte-Pugh Score: Cirrhosis staging Bilirubin (mg/dl) Albumin (g/dl) PT (INR) Hepatic Encephalo pathy Ascites (grade) 1 <2 >3.5 <1.7 None None Mild 3 >3 <2.8 > Severe Child Class A 5 6 B 7 9 C >9 Predicts survival (including mortality with surgery) and risk of complications (1-year survival 100% 80% 45%) Slide 14 of 46 Pugh et al, Brit J Surg 1973 Child-Pugh score = 5 = Class A, compensated cirrhosis Reduce abacavir dose to 200 mg po BID with Child-Pugh Class A liver disease Do not use abacavir with Child-Pugh Class B or C liver disease EGD for screening for varices Case Slide 15 of 46 5

30 What would you recommend for HCV treatment? 1. Daily sofosbuvir plus weight-based RBV x 12 weeks 2. Daily sofosbuvir plus weight-based RBV x 16 weeks 3. Daily sofosbuvir plus weight-based RBV x 24 weeks 4. Daily sofosbuvir plus daclatasvir plus weight-based RBV x 12 weeks 5. Daily sofosbuvir plus daclatasvir plus weight-based RBV x 16 weeks 6. Daily sofosbuvir plus daclatasvir plus weight-based RBV x 24 weeks Slide 16 of 46 Treatment recommendations - HCV genotype 2 patients with compensated cirrhosis Treatment naïve and PEG-IFN/RBV experienced Sofosbuvir/RBV experienced Daily sofosbuvir (400 mg) + WBR x weeks (IIaC, IIaB) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IIaC) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) x weeks if not eligible for RBV (IIaB) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) +/- WBR x 24 weeks if PEG- IFN and/or RBV ineligible (IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 17 of 46 AASLD/IDSA HCV Guidance Optimal duration of treatment with sofosbuvir/ribavirin (SOF/RBV) for genotype 2 cirrhotic patients is unknown Overall few cirrhotics included in registration trials of SOF/RBV for genotype 2 HCV infection TRIAL SVR rates with 12 weeks of SOF/RBV Cirrhotics (n/n) Non-cirrhotics (n/n) FISSION (TN) 83% (10/12) 97% (59/61) POSITRON (TN/TE) 94% (16/17) 92% (85/92) FUSION (TE) 60% (6/10) 90% (7/9) VALENCE (TN/TE) 90% (9/10) 94% (59/63) TN=treatment-naïve; TE=treatment-experienced Slide 18 of 46 Lawitz, NEJM 2013,, Jacobson, NEJM 2013, Zeuzem, NEJM

31 Extending therapy improves response rates to SOF/RBV in genotype 2 cirrhotic patients: FUSION trial, 12 vs 16 wks SOF + RBV (12 wks) 100 SOF + RBV (16 wks) No Cirrhosis Cirrhosis SOF = sofosbuvir; RBV = ribavirin Jacobson, NEJM 2013 Slide 19 of 46 Figure adapted from University of Washington Hepatitis Web Study Extending therapy improves response rates to SOF/RBV in genotype 2 cirrhotic patients: BOSON trial, 16 vs 24 wks Patients with SVR 12 (%) SOF + RBV x 16 wks SOF + RBV x 24 wks SOF + PEG + RBV x 12 wks / 15 17/ 17 15/ 16 Overall Genotype 2 Genotype 3 71 All genotype 2 patients treatment-experienced with cirrhosis Foster, Gastroenterology 2015 Slide 20 of 46 Figure adapted from University of Washington Hepatitis Web Study Few cirrhotic patients treated in daclatasvir plus sofosbuvir treatment-naïve trials: ALLY-2 (HIV/HCV) Patients with SVR12 (%) /11 5/6 2/2 Treatment Naïve Treatment Naïve Treatment Experienced *Daclatasvir (DCV)/sofosbuvir (SOF) not FDA-approved for genotype 2 HCV treatment Slide 21 of 46 Wyles et al, NEJM Figure from University of Washington Hepatitis Web Study 7

32 Few cirrhotic patients treated in daclatasvir plus sofosbuvir treatment-naïve trials: A Patients with SVR12 (%) 100 Slide 22 of GT2 = /16 11/11 14/14 5/6 12/14 2/2 SOF x 7d DCV + SOF x 23 wk DCV = daclatasvir; SOF = sofosbuvir GT2 = 8 GT2 = 9 Sulkowski et al, NEJM 2014 Figure adapted from University of Washington Hepatitis Web Study 86 DCV + SOF DCV + SOF + RBV 24 wk Treatment-Naïve: GT 2 or 3 24 wk TREATMENT OF HCV GENOTYPE 3 INFECTION in NON-CIRRHOTIC PATIENTS TREATMENT-NAÏVE TREATMENT-EXPERIENCED (PEG- IFN/RBV OR SOF/RBV) Slide 23 of 46 Case 51 y.o. man with HIV/HCV co-infection HCV diagnosed 2008 HCV treatment naïve HIV well-controlled on efavirenz + TDF/FTC Feels generally well except for mild fatigue Slide 24 of 46 8

33 Case PMH HIV HCV Hypertension Anal dysplasia with ASCUS H/o secondary syphilis Medications Efavirenz + TDF/FTC Hydrochlorothiazide Multivitamin NKDA Slide 25 of 46 Case Physical Exam Vital signs normal, BMI 28 Well-appearing Anicteric Abdomen with normal liver edge, no hepatosplenomegaly No lower extremity edema No spider nevi, palmar erythema, rash Labs Wbc 7.8, hgb 14.9, plt 285 Creatinine 0.9 T.bili 0.4, AST 57, ALT 51, Alk phos 73, albumin 4.8 INR 1.0 CD (43%), HIV RNA <20 HBsAg negative, HBsAb positive, HBcAb total positive Hepatitis A Ab total positive Slide 26 of 46 What is your recommendation for HCV treatment? GT2, treatment-naïve, non-cirrhotic, on efavirenz + TDF/FTC 1. Sofosbuvir plus daclatasvir 30 mg x 12 weeks 2. Sofosbuvir plus daclatasvir 30 mg plus weight-based RBV x 12 weeks 3. Sofosbuvir plus daclatasvir 60 mg x 12 weeks 4. Sofosbuvir plus daclatasvir 60 mg plus weight-based RBV x 12 weeks 5. Sofosbuvir plus daclatasvir 90 mg x 12 weeks 6. Sofosbuvir plus weight-based RBV plus PEG-IFN x 12 weeks 7. Sofosbuvir plus ledipasvir daily x 12 weeks Slide 27 of 46 9

34 Genotype 3 infection has emerged as harder to treat FISSION Trial: Treatment-naïve, 20% cirrhotic 12 weeks 24 weeks 100 Sofosbuvir + RBV PEG + RBV Patients (%) with SVR GT 2 and 3 (n=496) GT 2 (n=137) GT 3 (n=359) Slide 28 of 46 Lawitz, NEJM 2013; Figure from University of Washington Hepatitis Web Study Treatment recommendations - HCV genotype 3 Non-cirrhotic patients Treatment naïve and PEG-IFN/RBV experienced Sofosbuvir/RBV experienced Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) x 12 weeks (IA) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IIaC) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IA) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) + WBR x 24 weeks (IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 29 of 46 AASLD/IDSA HCV Guidance High response rates with sofosbuvir/daclatasvir in noncirrhotic HCV genotype 3 infection: ALLY-3 Study Open-label, 12 week treatment course Slide 30 of 46 Nelson et al, Hepatology

35 Daclatasvir dose-adjustment with ART Daclatasvir (DCV) -Standard DCV dose is 60 mg No restrictions Dose adjustment with select ART DCV dose to 30 mg with r/atv, IDV, NFV, SQV, cobicontaining ART (except DRV-cobi) DCV dose to 90 mg with efavirenz, etravirine, nevirapine Slide 31 of 46 TREATMENT OF HCV GENOTYPE 3 INFECTION in CIRRHOTIC PATIENTS TREATMENT-NAÏVE TREATMENT-EXPERIENCED (PEG- IFN/RBV OR SOF/RBV) Slide 32 of 46 Does your management change if your patient is cirrhotic? 51 y.o. man with HIV/HCV co-infection, HCV treatment-naïve CD4 400, HIV <20 on raltegravir + abacavir/lamivudine Exam with +spider nevi, palmar erythema. Abdomen non-distended, no ascites WBC 2.59, Platelets 52K, Cr 0.9, INR 1.1, t.bili 1.3, AST 145, ALT 175, albumin 4.1 HCV 5,365,349 IU/mL, genotype 2a/2c FIB-4 = 13.3 APRI = 8.6 Fibrosis serum panel: score = 99 (upper limit 100, c/w F2-F4) Abdominal ultrasound with splenomegaly, liver appears normal, no mass Slide 33 of 46 11

36 What is your recommendation for HCV treatment? GT2, treatment-naïve, cirrhotic, on efavirenz + TDF/FTC 1. Sofosbuvir plus daclatasvir 90 mg x 12 weeks 2. Sofosbuvir plus daclatasvir 90 mg +/- weight-based RBV x 12 weeks 3. Sofosbuvir plus daclatasvir 90 mg x 24 weeks 4. Sofosbuvir plus daclatasvir 90 mg +/- weight-based RBV x 24 weeks 5. Sofosbuvir plus weight-based RBV plus PEG-IFN x 12 weeks 6. Sofosbuvir plus weight-based RBV plus PEG-IFN x 24 weeks Slide 34 of 46 Treatment recommendations - HCV genotype 3 Patients with compensated cirrhosis Treatment naïve PEG-IFN/RBV and sofosbuvir/rbv treatment experienced Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IA) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IA, IIaC) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) +/- WBR x 24 weeks (IIaB) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) + WBR x 24 weeks (IIaB, IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 35 of 46 AASLD/IDSA HCV Guidance Low response rates with sofosbuvir/daclatasvir in cirrhotic HCV genotype 3 infection: ALLY-3 Study Open-label, 12 week treatment course Slide 36 of 46 Nelson et al, Hepatology

37 Optimal duration of treatment for genotype 3 HCV with compensated cirrhosis is not known: ALLY-3+ (%) with SVR Slide 37 of 46 Advanced Fibrosis Cirrhosis Treatment-Experienced Cirrhosis /14 31/36 26/30 6/6 15/18 14/16 8/8 16/18 12/14 0 Overall 12 weeks 16 weeks No difference between 12 vs 16 weeks of daclatasvir+sofosbuvir+ribavirin for GT3 and advanced fibrosis Leroy, Hepatology 2016; Figure from University of Washington Hepatitis Web Study Daclatasvir + sofosbuvir +/- RBV for 24 weeks HCV genotype 3 European real-world compassionate use cohort Daclatasvir + sofosbuvir x 24 weeks recommended to providers Addition of RBV or shorter course at provider s discretion Slide 38 of 46 7 deaths, 44 (9.4%) serious AEs, 2 (0.4%) treatmentrelated, 3 (0.6%) discontinuations for AEs Hezode, AASLD November 13-17, 2015, Abstract 206 SOF/RBV x 24 weeks is an alternative regimen for treatmentnaïve HCV GT 3-infected patients if daclatasvir or IFN ineligible Patients (%) with SVR /92 12/13 85/98 29/47 0 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Treatment-Naive Treatment-Experienced Slide 39 of 46 Zeuzem, VALENCE Study, NEJM 2014; Figure from University of Washington Hepatitis Web Study 13

38 TREATMENT OF HCV GENOTYPE 2 AND 3 INFECTION PROMISING NEW PANGENOTYPIC REGIMENS Slide 40 of 46 Sofosbuvir/velpatasvir for Genotype 3 HCV: ASTRAL-3 12 wks 24 wks Baseline NS5A resistance profile RAVs present (including A30K, L31M, Y93H), n=43 (16%) SVR12 88% Y93H, n=25 84% No RAVs 97% Genotype 2 HCV (ASTRAL-2): 29% cirrhotic, 99% SVR12 vs 94% with SOF/RBV x 12 wks Slide 41 of 46 Foster, NEJM 2015 ABT-493 plus ABT-530 +/- RBV for Genotype 3 HCV: SURVEYOR-II Treatment naïve, compensated cirrhotics (Child-Pugh A) No discontinuations due to adverse events Few serious AEs ABT-530 with activity against common NS3 and NS5A RAVs RAV = Resistance-associated variant Slide 42 of participants with baseline NS3 or NS5A RAVs Kwo, EASL, April 13-17,

39 Summary Good treatment options are currently available for non-cirrhotic genotype 2 and 3 HCV infection Optimal treatment duration for genotype 2 and 3 cirrhotic patients is unknown Role of ribavirin in treatment of genotype 3 is cirrhotics unclear, but would include Slide 43 of 46 Slide 44 of 46 Summary Presence of baseline NS5A RAVs has been associated with lower SVR rates with treatment of genotype 3 infection using SOF + an NS5A inhibitor Coming DAA therapies may provide better alternatives to the currently available therapies for genotype 2 and 3 infection No ribavirin Shorter durations Greater efficacy in cirrhotic patients Activity against common resistance-associated variants Recommended resources AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. University of Liverpool hepatitis drug interactions database: Hepatitis C Online and Hepatitis Web Study, University of Washington: Slide 45 of 46 15

40 Thank you! Slide 46 of 46 16

41 Treatment of HIV/Hepatitis C Virus Coinfection and the Management of Drug-Drug Interactions Jennifer J. Kiser, PharmD Associate Professor University of Colorado School of Pharmacy Aurora, Colorado FORMATTED: 04/18/16 Los Angeles, California: April 26, 2016 Case #1 55 yo Caucasian male Diagnosed HIV ~25 years ago Acute retroviral syndrome MSM CD4 nadir = 12 cells/mm 3, currently 378 cells/mm 3 Has taken didanosine, TDF, stavudine, zidovudine, lamivudine, efavirenz, indinavir, lopinavir/ritonavir, and T20 Current regimen (since 2008): TDF/FTC, ATV/r, maraviroc, raltegravir Believes infected with HCV ~10 years ago genotype 1a HCV treatment naïve HCV RNA 3,760,000 IU/mL Transient elastography = 11.8 kpa (IQR 0.1, IQR/med 1%) h/o depression (stable on citalopram 40mg QD) Slide 2 of 35 Laboratory and Test Results ALT 78 U/L (7-52) WBC /L (4-11.1) AST 63 U/L (12-39) ANC /L ( ) Alk Phos 97 U/L (39-117) RBC /L ( ) Tbili 2.9 mg/dl ( ) Hgb 18.7 g/dl ( ) Albumin 4.3 g/dl ( ) Hct 52.1% (39.2 to 50.2) SCr 0.93 mg/dl ( ) Platelet /L ( ) Wt 63 kg, 5 4 Ht CrCl ~92 ml/min FIB-4 = 2.8 APRI = Slide 3 of 35 1

42 Which DAA treatment does NOT require a change to ARV or increased monitoring? 46% 1. SOF/DCV 4% 2. SOF/LDV 17% 3. PrOD 33% 4. GZR/EBR Slide 4 of 35 Drug Interaction Potential Ritonavir-boosted Atazanavir SOF/DCV SOF/LDV PrOD GZR/EBR Reduce the dose to 30mg Avoid or monitor if cannot be Drop the ritonavir boost TDF avoided X Maraviroc?? Raltegravir Citalopram Slide 5 of 35 Daclatasvir Primarily hepatically metabolized (88%), minimal renal elimination (7%) Dose depends on concomitant medications Enzymes Transporters Victim Substrate CYP3A4 Substrate P-gp Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3 Slide 6 of 35 2

43 Slide 7 of 35 Daclatasvir Dosing with Concomitant Medications Strong CYP3A Inhibitors Decrease DCV dose to 30mg Ritonavir-boosted atazanavir Moderate CYP3A Inhibitors Standard DCV dose 60mg Ritonavir-boosted darunavir Strong CYP3A Inducers DCV Contraindicated Rifamycins Moderate CYP3A Inducers Increase DCV dose to 90mg Bosentan Clarithromycin Ritonavir-boosted St Johns Wort Dexamethasone lopinavir Itraconazole Ciprofloxacin Antiepileptics Efavirenz Ketoconazole Diltiazem Etravirine Nefazodone Erythromycin Modafinil Nelfinavir Fluconazole Nafcillin Posaconazole Fosamprenavir Rifapentine Telithromycin Verapamil Voriconazole Use Full Dose DCV with DRV/r and LPV/r 9/12 patients that relapsed in ALLY-2 were taking DRV/r with a reduced dose of DCV (30mg) 1 Healthy volunteer PK study indicated DCV Cmax and AUC were 62% and 30%, respectively when used at a reduced dose with DRV/r 2 Slide 8 of 35 1 Garimella T, et al. AASLD, 11/13-11/17, Boston, MA, #728, 2 Gandhi, et al. International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, 5/26-5/28, 2015, poster #80 Ledipasvir Minimal metabolism, 70% eliminated unchanged, 1% renally eliminated Enzymes Transporters Victim Unknown pathway, CYP3A4? Substrate P-gp Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3 Slide 9 of 35 3

44 With SOF/LDV, TFV exposures are high in those on PIs NNRTIs Without With LDV/SOF 1 LDV/SOF 2 RTV-Boosted PIs Without With LDV/SOF 3-8 LDV/SOF 9 Range of TFV exposures with available safety data Slide 10 of 35 EFV RPV ATR CPA N = FPV SQV LPV/r ATV DRV ATV DRV * 24 17* TFV exposures are higher when TDF is coadministered with LDV/SOF compared to without LDV/SOF, but Compared to the range of TFV exposures with available safety data For EFV or RPV: TFV exposures fall within the range 1 For RTV-boosted PIs: TFV exposures partially exceed the range 2 * HIV-infected subjects in CASTLE study 1. Hoetelmans RMW, et al. 6 th IWCPHT Quebec City, Canada. 5. Zhu. 9th IWCPHT #023 (ATV+RTV & LPV/r ) Poster # Kearney B, et al. JAIDS. 2006;43(3): (LPV/r) 2. German P, et al. ICPHHT #O6 7. Agarwala S, et al. 6th IWCPHT #16. (ATV+RTV) 3. Luber AD, et al. HIV Medicine. 2010;11:193-9 (FPV+RTV) 8. Hoetelmans RMW, et al. BJCP. 2007;64(5): (DRV+RTV) 4. Chittick GE, et al. AAC. 2006; 50(4): (SQV+RTV) 9. German P, et al. CROI 2015 Guidelines Recommendation on SOF/LDV with TDF SOF/LDV and tenofovir should be avoided in those with CrCl below 60 ml/min The combination of SOF/LDV with TDF and ritonavir-boosted PI should be avoided (pending further data) unless antiretroviral regimen cannot be changed and the urgency of treatment is high Slide 11 of 35 If you can t avoid TDF + boosted regimen, monitor Baseline parameters should include estimated renal function, electrolytes (including phosphorus), and urinary protein and glucose levels Monitor every 2-4 weeks on therapy Estimated renal function CKD in HIV guidelines suggest using CKD-EPI equation Urinary protein and glucose Slide 12 of 35 Lucas GM, et al. CID 2014;59(9):e96-138, 4

45 PrOD Primarily hepatically metabolized, minimal renal elimination Ritonavir-boosted Paritaprevir (Protease Inhibitor) Ombitasvir (NS5A Inhibitor) Dasabuvir Enzymes Transporters Victim Substrate CYP3A4 Substrate P-gp, OATP1B1, BCRP Perpetrator Inhibits CYP2C8, UGT1A1 Inhibits P-gp, OATP1B1/3, BCRP (ritonavir inhibits CYP3A) Victim Substrate CYP3A4 Substrate P-gp Perpetrator Inhibits CYP2C8, UGT1A1 Victim Substrate CYP2C8>3A4>2D6 Substrate P-gp (Non-nucleoside NS5B inhibitor) Perpetrator Inhibits UGT1A1 Inhibits BCRP PrO plus ribavirin is approved for genotype 4. Many interactions are similar to PrOD but not all. Slide 13 of 35 PrOD with RPV and RAL DDI Study of PrOD Regimen with Effect of HIV-1 ARV Drugs on C max and AUC of PrOD Regimen Effect of PrOD regimen on C max, AUC and C trough HIV-1 ARV Drugs Comments ok ok Not recommended theoretical concern for QTC prolongation Slide 14 of 35 Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC PrOD and HIV PI Interactions DDI Study of PrOD Regimen with Effect of PrOD regimen on Effect of HIV PI on C max C and AUC of PrOD Regimen max, AUC and C trough of HIV PI Comments Drop the ritonavir booster while on PrOD Median DRV trough is 3300 ng/ml without PrOD*, troughs are with PrOD Not recommended too much RTV Slide 15 of 35 Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC, *DRV package insert 5

46 DRV PK with PrOD in HIV/HCV coinfected patients Slide 16 of 35 DRV reductions less than in healthy volunteers 100% achieved SVR 2 patients had HIV between copies/ml on study, but did not appear to be related to DRV exposures Reassuring, but use with caution until results are available from the parent study, n=230 Wyles D, et al. CROI, 2/22-2/25, 2016, Boston, MA #574 Grazoprevir/Elbasvir Hepatically metabolized, less than 1% renally eliminated Grazoprevir (Protease Inhibitor) Elbasvir (NS5A Inhibitor) Enzymes Transporters Victim Substrate CYP3A4 Substrate OATP1B1 and P- gp Perpetrator Inhibitor of CYP3A4, UGT1A1 Inhibitor of BCRP Victim Substrate CYP3A4 Substrate P-gp Perpetrator Inhibitor of BCRP and P-gp Slide 17 of 35 GZR/EBR Interaction Potential with ARV PK Changes and Recommendation Ritonavir-boosted atazanavir Ritonavir- boosted darunavir Ritonavir-boosted lopinavir Ritonavir-boosted tipranavir Efavirenz Rilpivirine Etravirine Raltegravir GZR, EBR, ATV GZR, EBR, DRV GZR, EBR, LPV No data GZR, EBR, EFV GZR, EBR, RPV No data GZR, EBR, RAL Cobicistat-boosted elvitegravir No data Dolutegravir Maraviroc Tenofovir disoproxil fumarate GZR, EBR, DTG No data GZR, EBR, TFV Slide 18 of 35 Kiser JJ, 6

47 Renal Safety of Boosted TDF in HIV/HCV-patients on SOF/LDV Average egfr appeared to decline slightly with the initiation of SOF/LDV, but No difference in egfr in those on TDF plus boosted PI vs. without boosted PI At end of treatment, no difference in those with egfr < 70 ml/min between groups Slide 19 of 35 Vivancos Gallego MJ, et al. CROI, 2/22-2/25, 2016, Boston, MA, #452 Monitoring egfr (CKD-EPI, ml/min/1.73 m 2 ) Baseline Week 4 Week 8 Week Urinary glucose Negative Negative Negative UPCR (normal <0.2) HCV RNA (IU/mL) *in vitro nucleic acid amplification test ,760,000 0* 0* Slide 20 of 35 Tenofovir Alafenamide (TAF) lower TFV plasma levels Tenofovir (TFV) Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) Gut TFV TDF TAF Plasma TFV TDF TAF TFV Lymphoid Cells TFV TDF TFV-MP TAF TFV-DP Intact TAF transits directly into target cells where it is intracellularly activated to tenofovir diphosphate (TFV-DP) 1-3 TAF has 90% lower circulating plasma TFV levels compared to TDF 300mg 4-6 Basolateral transporters (OAT1, OAT3) effectively transfer TFV, but not intact TAF, into renal proximal tubular cells 7 Lower systemic level of TFV, improved renal safety profile Lee W et. Antimicr Agents Chemo 2005;49(5): Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63: Bam R, et al. Antiviral ther Apr 4 [Epub] 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2): Sax P, et al. JAIDS Sep 1;67(1): Ruane P, et al. JAIDS 2013;63: Babusis D, et al. Mol Pharm 2013;10(2): Sax P, et al. CROI Seattle, WA. #143LB 9. Sax P, et al. JAIDS Sep 1;67(1): Mills A, et al. ICAAC Washington D.C. Abstract# H-647c. Slide 21 of 35 7

48 TAF Possible TDF Alternative in Patients on Cobicistat and Ritonavir TFV was increased by SOF/LDV in those on F/TAF/ELV/cobi by 27%, but TFV AUC with TAF only ~20% of AUC typically seen with TDF (~400 vs ng*hr/ml) Slide 22 of 35 Garrison KL, et al. 16 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Alexandria, VA, May 26-28, 2015, abstract 71. Velpatasvir ph dependent absorption More reliant on hepatic metabolism than LDV <1% of the dose is excreted in urine Enzymes Transporters Victim CYP3A4, CYP2C8, CYP2B6 Substrate P-gp, BCRP Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3 Slide 23 of 35 Mogalian E, et al. Clin Pharmacokin Epub Oct 30, 2015 Velpatasvir Interactions with ARV Cannot be used with EFV Tenofovir Levels Increased Slide 24 of 35 Mogalian E, et al. AASLD 11/13-11/17, 2015, Boston, MA #2265 8

49 VEL + Boosted ARV Regimens on TFV PK TFV increased when administered as TDF story looks similar to LDV Limitation: raw concentrations not reported, only GMRs, so can t evaluate against the range of TFV exposures with available safety data Slide 25 of 35 Mogalian E, et al. CROI, 2/22-2/25, 2016, Boston, MA #100 SOF/VEL in Co-infection (ASTRAL - 5) Week N=106 SOF/VEL SVR12 95% SVR12 (2 relapse, 2 LTFU, 1 withdrew consent) ½ on TDF plus protease inhibitor Wyles D, EASL 2016 Slide 26 of 35 Results: Renal Function ASTRAL-5 HIV/HCV Coinfection Study FU-4/12, follow-up Week 4/12; Creatinine Clearance calculated using the Cockroft-Gault method; errors bars represent Q1, Q Non-boosted TDF Boosted TDF Non-TDF containing regimen Median Creatinine Clearance (ml/min) Median CL cr, ml/min Weeks BL FU-4 FU Wyles D, EASL 2016 Slide 27 of

50 Summary of Interactions ARV and DAAs Available at: Slide 28 of 35 Therapeutic Classes to Consider Class SOF/DCV GZR/EBR SOF/LDV PrOD Methadone Analgesics? Anxiolytics/Sedative hypnotics/benzos a /X SSRIs? Oral contraceptives X b Immunosuppressants NOT CSA, TAC OK Antiepileptics (old) X X X X Statins /X? c /X Calcium channel blockers /X? a midazolam given orally AUC increased 34%, b progestin-containing only, LFT elevations with ethinyl estradiol, c rosuvastatin not recommended, others not studied Slide 29 of 35 Selected based on interaction potential and Lauffenburger JC, et al. Eur J Gastro & Hepatol 2014;26(10): Transporters in the Liver Systemic Circulation Systemic Circulation NTCP OATP1B1 OATP1B3 OATP2B1 OAT2 MRP2 BCRP Bile ABCG5/G8 BSEP MRP3 MRP4 OCT1 P-gp MDR3 Sinusoidal Membrane Canalicular Membrane Like enzymes, transporters can also be inhibited or induced. Adapted from Oswald S. et al. Xenobiotica 2007;37(10-11):

51 Statin Interactions SOF/LDV PrOD SOF/DCV GZR/EBR Rosuvastatin Max dose 10mg* Max dose 5mg Reduce dose by 1/2 Max dose 10mg Atorvastatin Monitor, X No data Max dose 20mg consider dose reduction Pravastatin No data Reduce dose by 1/2 No data * My recommendation differs from labeling Slide 31 of 35 LDV dosing with gastric acid modifiers Separate antacids by 4 hours. PPI doses comparable to omeprazole 20mg can be administered simultaneously with SOF/LDV under fasted conditions. H2 blocker doses should not exceed the equivalent of famotidine 40mg BID. Avoid if possible. Equivalent PPI Doses Esomeprazole 40mg Pantoprazole 40mg Lansoprazole 30mg Rabeprazole 20mg Omeprazole 20mg Slide 32 of 35 PPI use may compromise SVR with SOF/LDV HCV-Target is a multicenter, prospective, observational cohort Odds of SVR in individuals not receiving a PPI were 2.47-times those of individuals taking a PPI Slide 33 of 35 HCV Target. Terrault N, et al. AASLD

52 VEL absorption is ph-dependent Unlike the current guidance with ledipasvir, recommended to take the 20mg OME equivalent in the fed state VEL exposures in the healthy volunteers receiving 20mg OME in the fed state similar to VEL exposures in Phase 3 trials Slide 34 of 35 Mogalian E, et al. ASCPT, 3/8-3/12, 2016, San Diego, CA, #PI-050 Resources for Drug Interactions University of Liverpool Toronto General Hospital Specific to antiretroviral interactions DHHS Guidelines Drug Interaction Tables Slide 35 of 35 12

53 Management of HCV Genotype 2 and 3 Infected Patients Kara W. Chew, MD, MS Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California Los Angeles, California: April 25, 2016 Financial Relationships With Commercial Entities Dr Chew has received a research grant awarded to the University of California Los Angeles from Merck & Co, Inc. (Updated 04/26/16) Slide 2 of 46 Learning Objectives After attending this presentation, participants will be able to: Select treatment for genotype 2 infected noncirrhotic patients Select treatment for genotype 3 infected noncirrhotic patients Identify where uncertainty remains in treatment of genotype 2 and 3 cirrhotic patients Slide 3 of 46 1

54 Case 51 y.o. man with HIV/HCV co-infection HCV diagnosed 2008 HCV treatment naïve HIV well-controlled on raltegravir + abacavir/lamivudine Feels generally well except for mild fatigue No history of liver decompensation no ascites, GI bleeding, encephalopathy No current EtOH, rarely in past, no tobacco. Remote methamphetamine use Slide 4 of 46 Case PMH HIV HCV Hypertension Anal dysplasia with ASCUS H/o secondary syphilis Medications Raltegravir + abacavir/lamivudine Hydrochlorothiazide Multivitamin NKDA Slide 5 of 46 Case Physical Exam Vital signs normal, BMI 28 Well-appearing Anicteric Abdomen with normal liver edge, no hepatosplenomegaly No lower extremity edema No spider nevi, palmar erythema, rash Labs Wbc 7.8, hgb 14.9, plt 285 Creatinine 0.9 T.bili 0.4, AST 57, ALT 51, Alk phos 73, albumin 4.8 INR 1.0 CD (43%), HIV RNA <20 HBsAg negative, HBsAb positive, HBcAb total positive Hepatitis A Ab total positive Slide 6 of 46 2

55 Case HCV RNA 485,000 IU/mL HCV genotype 2a/2c Fibrosure: fibrosis score of 0.42 = F1-F2 FIB-4: 1.43 APRI: Liver biopsy in 2013: Grade 2, stage 1 disease Multiple cores of hepatic parenchyma with overall intact architecture. Approximately 15 portal areas. Some of the portal areas have a mild predominantly lymphocytic infiltrate. There is minimal interface activity. The lobules show mild, scattered lymphocytic infiltrates and rare small clusters of lymphocytes, associated with minimal hepatocyte injury. The trichrome stain demonstrates fibrous portal expansion. Iron stain is negative. Reticulin stain demonstrates conserved hepatic architecture Abdominal ultrasound is normal Slide 7 of 46 What is your recommendation for HCV treatment? 1. Sofosbuvir 400 mg plus RBV 800 mg daily x 12 weeks 2. Sofosbuvir 400 mg daily plus weight-based RBV x 12 weeks 3. Sofosbuvir 400 mg daily plus weight-based RBV x 24 weeks 4. Sofosbuvir 400 mg plus daclatasvir 30 mg daily x 12 weeks 5. Sofosbuvir 400 mg plus daclatasvir 60 mg daily x 12 weeks 6. Sofosbuvir 400 mg plus daclatasvir 60 mg daily plus weight-based RBV x 12 weeks Slide 8 of 46 Treatment recommendations - HCV genotype 2 Non-cirrhotic patients Treatment naïve or PEG-IFN/RBV experienced Sofosbuvir/RBV experienced Daily sofosbuvir (400 mg) + WBR x 12 weeks (IA) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) x 12 weeks if not eligible for RBV (IIaB) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IIaC) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) +/- WBR x 24 weeks if PEG-IFN and/or RBV ineligible (IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 9 of 46 AASLD/IDSA HCV Guidance 3

56 Sofosbuvir plus weight-based ribavirin x 12 weeks for genotype 2 HCV, treatment-naïve patients Sofosbuvir + RBV PEG + RBV Patients (%) with SVR 12 94% SVR ACROSS 3 CLINICAL TRIALS of SOF/RBV in GT 2 (FISSION, POSITRON, VALENCE) Slide 10 of GT 2 and 3 (n=496) GT 2 (n=137) Lawitz, FISSION trial, NEJM 2013 (FIGURE),, Jacobson, NEJM 2013, Zeuzem, NEJM 2014 Figure from University of Washington Hepatitis Web Study GT 3 (n=359) Daclatasvir plus sofosbuvir x 24 weeks for genotype 2 HCV, treatment-naïve patients: A Patients with SVR12 (%) 100 Slide 11 of GT2 = /16 11/11 14/14 5/6 12/14 2/2 SOF x 7d DCV + SOF x 23 wk DCV = daclatasvir; SOF = sofosbuvir GT2 = 8 GT2 = 9 Sulkowski et al, NEJM 2014 Figure adapted from University of Washington Hepatitis Web Study 86 DCV + SOF DCV + SOF + RBV 24 wk Treatment-Naïve: GT 2 or 3 24 wk Daclatasvir plus sofosbuvir x 12 weeks for genotype 2 HCV, treatment-naïve patients: ALLY-2 (HIV/HCV) Patients with SVR12 (%) /11 5/6 2/2 Treatment Naïve Treatment Naïve Treatment Experienced *Daclatasvir (DCV)/sofosbuvir (SOF) not FDA-approved for genotype 2 HCV treatment Slide 12 of 46 Wyles et al, NEJM Figure from University of Washington Hepatitis Web Study 4

57 Does your management change if your patient is cirrhotic? 51 y.o. man with HIV/HCV co-infection, HCV treatment-naïve CD4 400, HIV <20 on raltegravir + abacavir/lamivudine Exam with +spider nevi, palmar erythema. Abdomen non-distended, no ascites WBC 2.59, Platelets 52K, Cr 1.2, INR 1.1, t.bili 1.3, AST 145, ALT 175, albumin 4.1 HCV 5,365,349 IU/mL, genotype 2a/2c FIB-4 = 13.3 APRI = 8.6 Fibrosis serum panel: score = 99 (upper limit 100, c/w F2-F4) Abdominal ultrasound with splenomegaly, liver appears normal, no mass What are your recommendations for management of his liver disease? What is his Child-Pugh score? Slide 13 of 46 Score Child-Turcotte-Pugh Score: Cirrhosis staging Bilirubin (mg/dl) Albumin (g/dl) PT (INR) Hepatic Encephalo pathy Ascites (grade) 1 <2 >3.5 <1.7 None None Mild 3 >3 <2.8 > Severe Child Class A 5 6 B 7 9 C >9 Predicts survival (including mortality with surgery) and risk of complications (1-year survival 100% 80% 45%) Slide 14 of 46 Pugh et al, Brit J Surg 1973 Child-Pugh score = 5 = Class A, compensated cirrhosis Reduce abacavir dose to 200 mg po BID with Child-Pugh Class A liver disease Do not use abacavir with Child-Pugh Class B or C liver disease EGD for screening for varices Case Slide 15 of 46 5

58 What would you recommend for HCV treatment? 1. Daily sofosbuvir plus weight-based RBV x 12 weeks 2. Daily sofosbuvir plus weight-based RBV x 16 weeks 3. Daily sofosbuvir plus weight-based RBV x 24 weeks 4. Daily sofosbuvir plus daclatasvir plus weight-based RBV x 12 weeks 5. Daily sofosbuvir plus daclatasvir plus weight-based RBV x 16 weeks 6. Daily sofosbuvir plus daclatasvir plus weight-based RBV x 24 weeks Slide 16 of 46 Treatment recommendations - HCV genotype 2 patients with compensated cirrhosis Treatment naïve and PEG-IFN/RBV experienced Sofosbuvir/RBV experienced Daily sofosbuvir (400 mg) + WBR x weeks (IIaC, IIaB) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IIaC) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) x weeks if not eligible for RBV (IIaB) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) +/- WBR x 24 weeks if PEG- IFN and/or RBV ineligible (IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 17 of 46 AASLD/IDSA HCV Guidance Optimal duration of treatment with sofosbuvir/ribavirin (SOF/RBV) for genotype 2 cirrhotic patients is unknown Overall few cirrhotics included in registration trials of SOF/RBV for genotype 2 HCV infection TRIAL SVR rates with 12 weeks of SOF/RBV Cirrhotics (n/n) Non-cirrhotics (n/n) FISSION (TN) 83% (10/12) 97% (59/61) POSITRON (TN/TE) 94% (16/17) 92% (85/92) FUSION (TE) 60% (6/10) 90% (7/9) VALENCE (TN/TE) 90% (9/10) 94% (59/63) TN=treatment-naïve; TE=treatment-experienced Slide 18 of 46 Lawitz, NEJM 2013,, Jacobson, NEJM 2013, Zeuzem, NEJM

59 Extending therapy improves response rates to SOF/RBV in genotype 2 cirrhotic patients: FUSION trial, 12 vs 16 wks SOF + RBV (12 wks) 100 SOF + RBV (16 wks) No Cirrhosis Cirrhosis SOF = sofosbuvir; RBV = ribavirin Jacobson, NEJM 2013 Slide 19 of 46 Figure adapted from University of Washington Hepatitis Web Study Extending therapy improves response rates to SOF/RBV in genotype 2 cirrhotic patients: BOSON trial, 16 vs 24 wks Patients with SVR 12 (%) SOF + RBV x 16 wks SOF + RBV x 24 wks SOF + PEG + RBV x 12 wks / 15 17/ 17 15/ 16 Overall Genotype 2 Genotype 3 71 All genotype 2 patients treatment-experienced with cirrhosis Foster, Gastroenterology 2015 Slide 20 of 46 Figure adapted from University of Washington Hepatitis Web Study Few cirrhotic patients treated in daclatasvir plus sofosbuvir treatment-naïve trials: ALLY-2 (HIV/HCV) Patients with SVR12 (%) /11 5/6 2/2 Treatment Naïve Treatment Naïve Treatment Experienced *Daclatasvir (DCV)/sofosbuvir (SOF) not FDA-approved for genotype 2 HCV treatment Slide 21 of 46 Wyles et al, NEJM Figure from University of Washington Hepatitis Web Study 7

60 Few cirrhotic patients treated in daclatasvir plus sofosbuvir treatment-naïve trials: A Patients with SVR12 (%) 100 Slide 22 of GT2 = /16 11/11 14/14 5/6 12/14 2/2 SOF x 7d DCV + SOF x 23 wk DCV = daclatasvir; SOF = sofosbuvir GT2 = 8 GT2 = 9 Sulkowski et al, NEJM 2014 Figure adapted from University of Washington Hepatitis Web Study 86 DCV + SOF DCV + SOF + RBV 24 wk Treatment-Naïve: GT 2 or 3 24 wk TREATMENT OF HCV GENOTYPE 3 INFECTION in NON-CIRRHOTIC PATIENTS TREATMENT-NAÏVE TREATMENT-EXPERIENCED (PEG- IFN/RBV OR SOF/RBV) Slide 23 of 46 Case 51 y.o. man with HIV/HCV co-infection HCV diagnosed 2008 HCV treatment naïve HIV well-controlled on efavirenz + TDF/FTC Feels generally well except for mild fatigue Slide 24 of 46 8

61 Case PMH HIV HCV Hypertension Anal dysplasia with ASCUS H/o secondary syphilis Medications Efavirenz + TDF/FTC Hydrochlorothiazide Multivitamin NKDA Slide 25 of 46 Case Physical Exam Vital signs normal, BMI 28 Well-appearing Anicteric Abdomen with normal liver edge, no hepatosplenomegaly No lower extremity edema No spider nevi, palmar erythema, rash Labs Wbc 7.8, hgb 14.9, plt 285 Creatinine 0.9 T.bili 0.4, AST 57, ALT 51, Alk phos 73, albumin 4.8 INR 1.0 CD (43%), HIV RNA <20 HBsAg negative, HBsAb positive, HBcAb total positive Hepatitis A Ab total positive Slide 26 of 46 What is your recommendation for HCV treatment? GT2, treatment-naïve, non-cirrhotic, on efavirenz + TDF/FTC 1. Sofosbuvir plus daclatasvir 30 mg x 12 weeks 2. Sofosbuvir plus daclatasvir 30 mg plus weight-based RBV x 12 weeks 3. Sofosbuvir plus daclatasvir 60 mg x 12 weeks 4. Sofosbuvir plus daclatasvir 60 mg plus weight-based RBV x 12 weeks 5. Sofosbuvir plus daclatasvir 90 mg x 12 weeks 6. Sofosbuvir plus weight-based RBV plus PEG-IFN x 12 weeks 7. Sofosbuvir plus ledipasvir daily x 12 weeks Slide 27 of 46 9

62 Genotype 3 infection has emerged as harder to treat FISSION Trial: Treatment-naïve, 20% cirrhotic 12 weeks 24 weeks 100 Sofosbuvir + RBV PEG + RBV Patients (%) with SVR GT 2 and 3 (n=496) GT 2 (n=137) GT 3 (n=359) Slide 28 of 46 Lawitz, NEJM 2013; Figure from University of Washington Hepatitis Web Study Treatment recommendations - HCV genotype 3 Non-cirrhotic patients Treatment naïve and PEG-IFN/RBV experienced Sofosbuvir/RBV experienced Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) x 12 weeks (IA) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IIaC) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IA) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) + WBR x 24 weeks (IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 29 of 46 AASLD/IDSA HCV Guidance High response rates with sofosbuvir/daclatasvir in noncirrhotic HCV genotype 3 infection: ALLY-3 Study Open-label, 12 week treatment course Slide 30 of 46 Nelson et al, Hepatology

63 Daclatasvir dose-adjustment with ART Daclatasvir (DCV) -Standard DCV dose is 60 mg No restrictions Dose adjustment with select ART DCV dose to 30 mg with r/atv, IDV, NFV, SQV, cobicontaining ART (except DRV-cobi) DCV dose to 90 mg with efavirenz, etravirine, nevirapine Slide 31 of 46 TREATMENT OF HCV GENOTYPE 3 INFECTION in CIRRHOTIC PATIENTS TREATMENT-NAÏVE TREATMENT-EXPERIENCED (PEG- IFN/RBV OR SOF/RBV) Slide 32 of 46 Does your management change if your patient is cirrhotic? 51 y.o. man with HIV/HCV co-infection, HCV treatment-naïve CD4 400, HIV <20 on raltegravir + abacavir/lamivudine Exam with +spider nevi, palmar erythema. Abdomen non-distended, no ascites WBC 2.59, Platelets 52K, Cr 0.9, INR 1.1, t.bili 1.3, AST 145, ALT 175, albumin 4.1 HCV 5,365,349 IU/mL, genotype 2a/2c FIB-4 = 13.3 APRI = 8.6 Fibrosis serum panel: score = 99 (upper limit 100, c/w F2-F4) Abdominal ultrasound with splenomegaly, liver appears normal, no mass Slide 33 of 46 11

64 What is your recommendation for HCV treatment? GT2, treatment-naïve, cirrhotic, on efavirenz + TDF/FTC 1. Sofosbuvir plus daclatasvir 90 mg x 12 weeks 2. Sofosbuvir plus daclatasvir 90 mg +/- weight-based RBV x 12 weeks 3. Sofosbuvir plus daclatasvir 90 mg x 24 weeks 4. Sofosbuvir plus daclatasvir 90 mg +/- weight-based RBV x 24 weeks 5. Sofosbuvir plus weight-based RBV plus PEG-IFN x 12 weeks 6. Sofosbuvir plus weight-based RBV plus PEG-IFN x 24 weeks Slide 34 of 46 Treatment recommendations - HCV genotype 3 Patients with compensated cirrhosis Treatment naïve PEG-IFN/RBV and sofosbuvir/rbv treatment experienced Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IA) Daily sofosbuvir (400 mg) + WBR + PEG- IFN x 12 weeks (IA, IIaC) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) +/- WBR x 24 weeks (IIaB) Daily daclatasvir (60 mg*) + sofosbuvir (400 mg) + WBR x 24 weeks (IIaB, IIaC) *Daclatasvir dose may need to be increased or decreased when used with cytochrome P450 3A/4 inducers and inhibitors, respectively WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 35 of 46 AASLD/IDSA HCV Guidance Low response rates with sofosbuvir/daclatasvir in cirrhotic HCV genotype 3 infection: ALLY-3 Study Open-label, 12 week treatment course Slide 36 of 46 Nelson et al, Hepatology

65 Optimal duration of treatment for genotype 3 HCV with compensated cirrhosis is not known: ALLY-3+ (%) with SVR Slide 37 of 46 Advanced Fibrosis Cirrhosis Treatment-Experienced Cirrhosis /14 31/36 26/30 6/6 15/18 14/16 8/8 16/18 12/14 0 Overall 12 weeks 16 weeks No difference between 12 vs 16 weeks of daclatasvir+sofosbuvir+ribavirin for GT3 and advanced fibrosis Leroy, Hepatology 2016; Figure from University of Washington Hepatitis Web Study Daclatasvir + sofosbuvir +/- RBV for 24 weeks HCV genotype 3 European real-world compassionate use cohort Daclatasvir + sofosbuvir x 24 weeks recommended to providers Addition of RBV or shorter course at provider s discretion Slide 38 of 46 7 deaths, 44 (9.4%) serious AEs, 2 (0.4%) treatmentrelated, 3 (0.6%) discontinuations for AEs Hezode, AASLD November 13-17, 2015, Abstract 206 SOF/RBV x 24 weeks is an alternative regimen for treatmentnaïve HCV GT 3-infected patients if daclatasvir or IFN ineligible Patients (%) with SVR /92 12/13 85/98 29/47 0 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Treatment-Naive Treatment-Experienced Slide 39 of 46 Zeuzem, VALENCE Study, NEJM 2014; Figure from University of Washington Hepatitis Web Study 13

66 TREATMENT OF HCV GENOTYPE 2 AND 3 INFECTION PROMISING NEW PANGENOTYPIC REGIMENS Slide 40 of 46 Sofosbuvir/velpatasvir for Genotype 3 HCV: ASTRAL-3 12 wks 24 wks Baseline NS5A resistance profile RAVs present (including A30K, L31M, Y93H), n=43 (16%) SVR12 88% Y93H, n=25 84% No RAVs 97% Genotype 2 HCV (ASTRAL-2): 29% cirrhotic, 99% SVR12 vs 94% with SOF/RBV x 12 wks Slide 41 of 46 Foster, NEJM 2015 ABT-493 plus ABT-530 +/- RBV for Genotype 3 HCV: SURVEYOR-II Treatment naïve, compensated cirrhotics (Child-Pugh A) No discontinuations due to adverse events Few serious AEs ABT-530 with activity against common NS3 and NS5A RAVs RAV = Resistance-associated variant Slide 42 of participants with baseline NS3 or NS5A RAVs Kwo, EASL, April 13-17,

67 Summary Good treatment options are currently available for non-cirrhotic genotype 2 and 3 HCV infection Optimal treatment duration for genotype 2 and 3 cirrhotic patients is unknown Role of ribavirin in treatment of genotype 3 is cirrhotics unclear, but would include Slide 43 of 46 Slide 44 of 46 Summary Presence of baseline NS5A RAVs has been associated with lower SVR rates with treatment of genotype 3 infection using SOF + an NS5A inhibitor Coming DAA therapies may provide better alternatives to the currently available therapies for genotype 2 and 3 infection No ribavirin Shorter durations Greater efficacy in cirrhotic patients Activity against common resistance-associated variants Recommended resources AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. University of Liverpool hepatitis drug interactions database: Hepatitis C Online and Hepatitis Web Study, University of Washington: Slide 45 of 46 15

68 Thank you! Slide 46 of 46 16

69 Treatment of Hepatitis C Infection in Special Populations Kara W. Chew, MD, MS Assistant Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California FORMATTED: XX/XX/2016 Los Angeles, California: April 26, 2016 Financial Relationships With Commercial Entities Dr Chew has received a research grant awarded to the University of California Los Angeles from Merck & Co, Inc. (Updated 04/26/16) Slide 2 of 39 Slide 3 of 39 Learning Objectives After attending this presentation, participants will be able to: Select hepatitis C treatment in patients with renal insufficiency Select hepatitis C treatment and identify contraindicated regimens in decompensated cirrhosis Be familiar with recommendations for retreatment of patients who failed hepatitis C antiviral regimens that included 2 or more direct-acting antivirals 1

70 50 y.o. man with hepatitis C HCV first diagnosed 1993 Case HCV treatment naive. S/p prior deceased donor renal transplant 2006, failed (chronic allograft nephropathy) Back on intermittent HD since 2011, 5 days/week at home via RUE fistula. Listed for renal transplant for past 1.5 years, difficult match Feels well with good energy, no signs/symptoms of decompensation Rare EtOH, NSAIDs, acetaminophen Liver biopsy: stage 3, grade 2 Slide 4 of 39 Case PMH ESRD secondary to hypertensive nephropathy Chronic hepatitis C infection H/o subdural hematoma H/o gastric ulcer with GI bleeding secondary to NSAIDs IDU in remission since 2001 HTN Anemia, baseline hemoglobin 10 Hyperparathyroidism Depression Obstructive sleep apnea Medications Allergies: cephalexin Acyclovir Diltiazem Omeprazole Labetalol Lisinopril Sevelamer Cinacalcet Fluticasone nasal spray Epoetin alfa Slide 5 of 39 Case Physical Exam BP 166/90, BMI 24.5 Exam unremarkable Labs/Studies Wbc 5.3, hgb 11.5, plt 160 Creatinine 9.5, BUN 40 T.bili 0.6, AST 70, ALT 37, Alk phos 251, albumin 4.5 INR 1.1 CD4 536 (36%), HIV RNA <20 HBsAg neg, HBsAb+, HBcAb neg HCV RNA 1,570,000 IU/mL HCV genotype 1a Slide 6 of 39 2

71 Would you treat for hepatitis C now or wait until after renal transplant? 85% 1. Treat now 15% 2. Wait until after transplant Slide 7 of 39 HCV infection adversely impacts renal transplant outcomes Reduced allograft survival De novo or recurrent glomerulonephritis Possible association with transplant glomerulopathy (TG) Worse allograft survival with TG in HCV Reduced patient survival Liver-related Extrahepatic complications Increased risk of new onset diabetes after transplantation Slide 8 of 39 Bald-Aggrawal, Am J Transplantation 2014 To treat pre- or post-renal transplant? Chronic HCV infection is not a contraindication to renal transplantation Interferon-alfa increased risk of renal allograft rejection and failure Pre-DAAs, preference to treat prior to transplantation DAAs provide good options for treatment posttransplant Treat pre-transplant if urgency is high and immediate kidney transplantation is not an option Consider risk for need for concomitant liver transplant Slide 9 of 39 Bald-Aggrawal, Am J Transplantation 2014; AASLD/IDSA HCV Guidance 3

72 What do you choose for HCV treatment for this patient with end-stage renal disease on dialysis? 17% 1. Sofosbuvir plus ledipasvir x 12 weeks 50% 0% 0% 17% 17% 2. Elbasvir/grazoprevir x 12 weeks if no NS5A resistance 3. Elbasvir/grazoprevir x 16 weeks with ribavirin if NS5A resistance 4. Elbasvir/grazoprevir x 12 weeks without resistance testing 5. Paritaprevir/ritonavir/ombitasvir + dasabuvir x 12 weeks 6. PEG-IFN + RBV 200 mg daily Slide 10 of 39 Recommended regimens in end-stage renal disease Genotype GT 1a or 4 GT 1b GT 2, 3, 5, 6 Recommendation Usual dose Elbasvir (50 mg)/grazoprevir (100mg) x 12 weeks* Usual dose Elbasvir/grazoprevir x 12 weeks Paritaprevir/ritonavir/ombitasvir + dasabuvir x 12 weeks PEG-IFN + dose-adjusted RBV (200 mg daily) *Note no recommendation made for or against genotype 1a NS5A resistance testing Slide 11 of 39 AASLD/IDSA HCV Guidance Elbasvir/grazoprevir x 12 weeks in advanced kidney disease: C-SURFER CKD stages 4/5 Genotype 1 Treatment-naïve and experienced N=122 75% on dialysis 52% GT1a 6% cirrhotic Low rates of AEs 1 relapse- GT1b No impact of baseline NS5A RAVs on SVR Slide 12 of 39 Roth, Lancet 2015; Figure from University of Washington Hepatitis Web Study 4

73 Drug interactions of his other meds with HCV DAAs GZR/EBR PrOD LDV/SOF SOF/DCV Diltiazem Monitor dose dilt Monitor Monitor Omeprazole? OME dose Max 20mg QD Cinacelcet dose cinacelcet Sevelamer Separate dosing (DAA 1 hr before, 3 hrs after) Separate dosing (DAA 1 hr before, 3 hrs after) Separate dosing (DAA 1 hr before, 3 hrs after) Separate dosing (DAA 1 hr before, 3 hrs after) Lisinopril Labetolol Monitor Fluticasone X Slide 13 of 39 Pharmacokinetics in renal impairment GZR/EBR PrOD LDV/SOF SOF/DCV Diltiazem Monitor dose dilt Monitor Monitor Omeprazole? OME dose Max 20mg QD Cinacelcet dose cinacelcet Sevelamer Separate dosing (DAA 1 hr before, 3 hrs after) Separate dosing (DAA 1 hr before, 3 hrs after) Separate dosing (DAA 1 hr before, 3 hrs after) Separate dosing (DAA 1 hr before, 3 hrs after) Lisinopril Labetolol Monitor Fluticasone X Slide 14 of 39 Treatment in mild-moderate renal impairment (CrCl ml/min) Select regimen based on genotype No dose adjustment needed for Daclatasvir Ledipasvir/sofosbuvir Paritaprevir/ritonavir/ombitasvir, dasabuvir Simeprevir Sofosbuvir Elbasvir/grazoprevir In HIV co-infected patients on tenofovir be cautious and monitor closely with ledipasvir Avoid coadmin if CrCL <60 ml/min Avoid ledipasvir + TDF with ritonavir- or cobicistat-boosted ART Tenofovir alafenamide (TAF) instead of TDF may be an option Slide 15 of 39 AASLD/IDSA HCV Guidance 5

74 Renal monitoring on ledipasvir/sofosbuvir + tenofovir disoproxil fumarate (TDF) Renal assessment: creatinine level, electrolytes (including phosphorus), and urinary protein and glucose levels Assess at baseline and every 2-4 weeks in high risk patients Adjust TDF dose for creatinine clearance on treatment Slide 16 of 39 AASLD/IDSA HCV Guidance TREATMENT OF PATIENTS WITH DECOMPENSATED CIRRHOSIS (Child- Turcotte-Pugh Class B and C) TOXICITY LIVER DISEASE MANAGEMENT TREATMENT RECOMMENDATIONS Slide 17 of 39 Important considerations for treatment of CTP B and C cirrhotic patients Should be done with Hepatology involvement Refer all Child-Pugh B and C cirrhotics to Hepatology Preferably linked to a transplant center NS3 protease inhibitors should be avoided due to risk of hepatic decompensation and liver failure NS3 protease inhibitors: paritaprevir, simeprevir, grazoprevir Seen with paritaprevir and simeprevir Safety data lacking for grazoprevir Slide 18 of 39 6

75 Case 60 y.o. woman with HIV/HCV co-infection, HCV treatment-naïve CD4 500, HIV <20 on darunavir/ritonavir + TDF/FTC Exam with +spider nevi, palmar erythema. Abdomen non-distended, no ascites. No peripheral edema. WBC 3.4, Platelets 60K, Cr 1.0, INR 1.3, t.bili 2.0, AST 145, ALT 175, albumin 3.2 CrCl = 68 HCV 7,365,349 IU/mL, genotype 1a FIB-4 = APRI = 6.04 Fibrosure: F4 Abdominal ultrasound with splenomegaly, liver appears normal, no mass What is her Child-Pugh score? Slide 19 of 39 Score Bilirubin (mg/dl) What is her Child-Pugh score? Albumin (g/dl) PT (INR) Hepatic Encephalo pathy Ascites (grade) 1 <2 >3.5 <1.7 None None Mild 3 >3 <2.8 > Severe Child Class A 5 6 B 7 9 C >9 Slide 20 of 39 Pugh et al, Brit J Surg 1973 What would you do with her ART? 44% 1. Keep it the same 56% 2. Switch the regimen She is on DRV/r + TDF/FTC Slide 21 of 39 7

76 What do you recommend for HCV treatment? 23% 1. Sofosbuvir plus ledipasvir x 12 weeks 31% 2. Sofosbuvir plus ledipasvir with RBV x 12 weeks 23% 3. Sofosbuvir plus ledipasvir x 24 weeks 8% 4. Sofosbuvir plus daclatasvir x 12 weeks 8% 5. Sofosbuvir plus daclatasvir with RBV x 12 weeks 8% 0% 6. Paritaprevir/ritonavir/ombitasvir + dasabuvir with RBV x 24 weeks 7. Elbasvir/grazoprevir x 12 weeks if no NS5A resistance Slide 22 of 39 Lower rates of SVR Treatment outcomes with CTP B and C % SVR12 (CTP C does worse than CTP B) Higher rates of adverse events Decompensation and deaths during treatment likely due to underlying liver disease and not treatment-related Low rates of toxicities secondary to DAAs, increased toxicity from ribavirin Some have improvement in MELD and CTP scores with treatment Slide 23 of 39 Charlton, Gastroenterology 2015; Poordad, Hepatology 2016; Welzel, AASLD, November 13-17, 2015 Recommended regimens for CTP Class B and C cirrhosis GENOTYPE RECOMMENDED Ribavirin-ineligible Genotype 1 and 4 Daily ledipasvir (90 mg)/sofosbuvir (400 mg) with initial low dose RBV (600 mg, titrate up as tolerated) x 12 weeks (IA) Genotype 1 and 4, prior SOF-based failure Genotype 2 and 3 Daily daclatasvir (60 mg*) plus sofosbuvir (500 mg) with initial low dose RBV (600mg, titrated up) x 12 weeks (IB) Daily ledipasvir (90 mg)/sofosbuvir (400 mg) with initial low dose RBV (600 mg, titrate up as tolerated) x 24 weeks (IIC) Daily daclatasvir (60 mg*) plus sofosbuvir (500 mg) with initial low dose RBV (600mg, titrated up) x 12 weeks (IIB) Daily ledipasvir (90 mg)/sofosbuvir (400 mg) x 24 weeks (IIC) Daily daclatasvir (60 mg*) plus sofosbuvir (500 mg) x 24 weeks (IIC) Consider extension to 24 weeks *Daclatasvir dose adjusted when used with CYP3A4 inhibitors or inducers; RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon Slide 24 of 39 AASLD/IDSA HCV Guidance 8

77 RETREATMENT OF PATIENTS WHO FAILED DIRECT-ACTING ANTIVIRAL REGIMENS HCV DRUG RESISTANCE AND IMPLICATIONS FOR RETREATMENT Slide 25 of 39 Review of HCV DAA classes and select clinically significant resistance-associated variants NS3/4A protease inhibitor Slide 26 of 39 NS5A inhibitor NS5B nucleotide inhibitor NS5B nonnucleoside inhibitors Grazoprevir Elbasvir Sofosbuvir Dasabuvir Simeprevir Paritaprevir Q80K, R155K, D168E, A156T/V Ledipasvir Daclatasvir Ombitasvir M28A/G/T, Q30D/E/H/G/K/L/R, L31F/M/V, Y93C/H/N/S S282T Not an exhaustive list of RAVs that may be clinically significant Treatment-emergent resistance associated variants HCV NS3 protease inhibitor and NS5A resistanceassociated variants (RAVs) commonly arise or are enriched with treatment failure Potential for cross-resistance Significant treatment-emergent NS5B nucleotide inhibitor RAVs (i.e. S282T) are rare but seen with re-treatment failures (sofosbuvir in both initial and retreatment regimen) RAVs may persist for a long time (>2 years) NS5A RAVs longer than NS3 - less of a fitness cost Genotype 1a more than 1b Slide 27 of 39 Sarrazin, J Hepatology

78 HCV resistance with daclatasvir/sofosbuvir failure in a real world cohort Slide 28 of 39 Fourati et al, CROI 2016, Abstract 577 Optimal re-treatment strategy not yet known Defer retreatment unless urgent (cirrhosis and other indications) Test for presence of NS3 and NS5A inhibitor RAVs that confer decreased susceptibility Selection of retreatment regimen guided by presence or absence of RAVs Slide 29 of 39 AASLD/IDSA HCV Guidance Strategies for retreatment with currently available therapies Retreatment regimens should include an NS5B nucleotide inhibitor (e.g. sofosbuvir) Retreatment regimens should include ribavirin, unless contraindicated If the retreatment regimen uses TWO DAAs only, treat for 24 weeks Consider triple or quadruple DAA regimens Pegylated interferon may have a role Consider a clinical trial Slide 30 of 39 AASLD/IDSA HCV Guidance 10

79 Potential regimens for genotype 1 DAA failures Resistance testing No NS5A RAVs NS5A RAVs PRESENT No NS3 RAVs NS5A RAVs PRESENT NS3 RAVs PRESENT POTENTIAL RETREATMENT REGIMENS for which limited data exist Ledipasvir/sofosbuvir with weight-based ribavirin x 24 weeks Simeprevir plus sofosbuvir with weight-based ribavirin x 24 weeks Sofosbuvir plus elbasvir/grazoprevir with weight-based ribavirin x 12 weeks Sofosbuvir plus paritaprevir/ritonavir/ombitasvir plus dasabuvir with weight-based ribavirin x 24 weeks (GT1a) or 12 weeks (GT1b) Slide 31 of 39 AASLD/IDSA HCV Guidance Next generation DAAs in clinical trials are promising for retreatment of DAA-experienced patients Retained activity against common NS3/4A protease inhibitor and NS5A inhibitor RAVs Higher barrier to resistance Slide 32 of 39 ABT-530 (pangenotypic NS5A inhibitor) is active against common GT1a NS5A variants Slide 33 of 39 Poordad, EASL April 13-17,

80 ABT ABT-530 +/- RBV x 12 weeks for Genotype 1 Retreatment (MAGELLAN-I) ABT-493 = NS3/4A protease inhibitor ABT-530 = NS5A inhibitor 200mg/ 300mg/ 300mg/ 80mg 120mg 120mg + RBV 200mg/ 300mg/ 300mg/ 80mg 120mg 120mg + RBV 50 DAA-experienced, including -8 LDV/SOF -8 SMV + SOF +/-RBV -4 OBV/PTV/r + DSV +/-RBV All GT1 Non-cirrhotic 2 virologic failures 92% (23/25) SVR12 with 2 RAVs Slide 34 of 39 Poordad, EASL April 13-17, 2016 Sofosbuvir/velpatasvir + GS-9857 x 12 weeks for genotype 1-6 retreatment Velpatasvir = NS5A inhibitor GS-9857 = NS3/4A protease inhibitor N=128 48% cirrhotic 63 (49%) GT 1 Prior treatment: 27 (21%) no DAAs 36 (28%) 1 DAA class 65 (51%) 2 DAA classes Slide 35 of 39 Lawitz, EASL, April 13-17, 2016 Sofosbuvir/velpatasvir + GS-9857 x 12 weeks for genotype 1-6 retreatment 60% RAVs at baseline 20% NS5A RAVs only 15% NS3 RAVs only 23% Multiple class RAVs Slide 36 of 39 Lawitz, EASL, April 13-17,