2/26/2015. Hepatitis C Are We Winning the War? HCV Infection Worldwide 170 million persons with HCV 3-4 million newly infected each year

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1 Hepatitis C Are We Winning the War? Ann Moore, FNP HCV Infection Worldwide 17 million persons with HCV 3-4 million newly infected each year * * Prevalence of infection > 1% 2.5% to 1% 1% to 2.5% NA * World Health Organization 28. Available at: Accessed October 8, 21. 1

2 HCV Prevalence in High-Risk US Populations Incarcerated ~31, (15%) IDUs ~3, (8%-9%) HIV Infected ~3, (3%) Alcoholics ~25, (11%-36%) Homeless ~175, (22%) Veterans ~28, (8%) Weinbaum C, et al. MMWR Recomm Rep. 23;52(RR-1):1-36. Edlin BR. Hepatology. 22;36(5 suppl 1): National Survey on Drug Use & Health (NSDUH). NSDUH Report. 23. Khalili MA, et al. Clin Inf Dis. 2;31: LaBreque DR, et al. In: Hepatitic C Choices. 22. Alter MJ, et al. N Engl J Med. 1999;341(8): Nyamathi AM, et al. J Gen Intern Med. 22;17(2): Bräu N, et al. Am J Gastroenterol. 22;97(8): Jonas MM. Hepatology. 22;36(5 suppl 1):S173-S178. Over 5.2 Million People Living With Chronic HCV in the US Number of HCV Cases (millions) Conservative estimate Upper limit of estimate NHANES Estimate HCV Cases Not Included in NHANES* Estimated Total HCV Cases *Homeless (n=142, ,61); incarcerated (n=372, ,826); veterans (n=1,237,461-2,452,6); active military (n=685); healthcare workers (n=64,89-259,234); nursing home residents (n=63,69); chronic hemodialysis (n=2,578); hemophiliacs (n=12,971-17,). Chak E, et al. Liver Int. 211; 31: Global Burden of Disease Study 21: Causes of Death From Chronic Liver Disease 5 45% Global 21 5 USA % 4% 39% Patients (%) % 2% 3% 28% 27% 14% Patients (%) % 29% 14% 13% 1 9% 1 8% HBV HCV ETOH Other Liver Cancer HBV HCV ETOH Other HBV HCV ETOH Other Liver Cancer HBV HCV ETOH Other Increase in liver-cancer deaths (past 2 years): Globally (from 1.25 to 1.75 million/year); USA (45, to 7,/year). Cowie BC, et al. Hepatology. 213;58(suppl 1):218A-219A. Abstract

3 Clinical Considerations on the Progression of HCV Infection Of every 1 persons infected with HCV, approximately 75% to 85% will develop chronic infection 6% to 7% will develop chronic liver disease 5% to 2% will develop cirrhosis in 2 to 3 years 1% to 5% will die from the consequences of chronic infection (liver cancer or cirrhosis) 7 Extrahepatic Manifestations of Chronic HCV Infection Arthralgia Arthritis Bechet s disease Canities Cerebral vasculitis Cryoglobulinemia Diabetes Fatigue Fibromyalgia Hypertrophic cardiomyopathy Immune thrombocytopenic purpura Insulin resistance Lichen planus Lung abnormalities Membranoproliferative glomerulonephritis Membrane nephropathy Mooren corneal ulceration Multiple myeloma Neutropenia Non-Hodgkin s lymphoma Paresthesia Porphyria cutanea tarda Pruritus Raynaud s syndrome Sialadenitis Sjogren s syndrome Spider nevi Systemic lupus erythematosis Thrombocytopenia Thyroid disease Vasculitis Vitiligo Waldenstrom macroglobulinemia 8 Chronic HCV in the US: Underdiagnosed and Untreated Number (in s) M Unaware of Infection 38% Diagnosed 1.6 M 5.5% Treated Prevalence Diagnosed Treated 89 Estimated treatment rate is based on Q2 and Q4 211 chart audits. Hepatitis C Monitor. Ipsos Healthcare. 3

4 HCV and HIV Mortality in the US ( ) US multiple-cause mortality data (NCHS, 5 states plus DC) Death certificate data Approximately 21.8 million decedents Change in age-adjusted mortality rates (per 1, person-years) HCV: increased.18 (P=.2) HIV: decreased.21 (P=.1) New policy initiatives are needed to detect and link HCV patients to care and treatment Death Rate (per 1, Persons) Annual Age-Adjusted Mortality Rates* 7 6 HIV 5 4 HCV NCHS: National Center for Health Statistics. *A record listing >1 type of infection was counted for each type of infection. Ly KN, et al. Ann Intern Med. 212;156: Year 1 HCV Screening and Testing Recommendations (CDC and AASLD/IDSA) HCV testing is recommended at least once for persons born between 1945 and 1965 Other persons should be screened for risk factors for HCV infection 1-time testing should be performed for all persons with behaviors, exposures, and conditions associated with an increased risk of HCV infection Annual HCV testing is recommended Persons who inject drugs HIV-positive MSMs who have unprotected sex Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV Centers for Disease Control and Prevention. MMWR. 212;61(RR-4): HCV Screening: Behaviors, Exposures, and Conditions Associated With Increased Risk of HCV Infection Adults born between 1945 and 1965 Risk behaviors Past or current injection drug use Intranasal illicit drug use Other medical conditions HIV infection Unexplained chronic liver disease and chronic hepatitis including persistently abnormal ALT Risk exposures Chronic hemodialysis Getting tattoo in an unregulated setting Persons with recognized exposures (needlesticks, mucosal exposures) Birth to an infected mother Recipients of transfusions or organ transplants Recipients of clotting factors (prior 1987) Ever incarcerated Centers for Disease Control and Prevention. MMWR. 212;61(RR-4):

5 Prevalence of Antibody to HCV: NHANES ( ) General Risk Factors Number of Sex Partners % ( ) Prevalence (%) % ( ) General Population 5.8% (3.7-9.) IDU Blood Transfusion (<1992) 13.8% ( ) HIV 7.8% Dialysis Prevalence (%) % (.2-1.4) 1.1% (.5-2.1) 2.6% ( ) 7.5% ( ) 12.% ( ) Number of Sex Partners Armstrong GL, et al. Ann Intern Med. 26;144: Finelli L, et al. Semin Dial. 25;18: Recommended Laboratory Tests for Chronic HCV Infection Hepatitis C antibody by enzyme immunoassay (EIA) Test Application Screening for past or present HCV infection Sensitive and inexpensive PCR for HCV RNA Confirmation of positive EIA Medical evaluation and management 14 Markers for Acute HCV Infection HCV RNA Symptoms +/- ALT Total Ant-HCV Antibodies Titer ULN Weeks After Infection Chevaliez S, et al. Liver Int. 29;29:9-16. Pawlotsky JM, et al. Hepatology. 22;36:S65-S

6 Markers for Chronic HCV Infection HCV RNA Symptoms +/- ALT Total Ant-HCV Antibodies Titer ULN Weeks After Infection Chevaliez S, et al. Liver Int. 29;29: ELISA Screening Tests for HCV Serologic assays to detect circulating HCV antibodies Sensitivity (97% to 1%) Positive predictive value 95% with risk factors and elevated ALT 5% without risk factors and normal ALT False positives More likely in patients with low risk of HCV infection False negatives More likely in severely immunocompromised patients, transplant recipients, patients with chronic renal failure on dialysis, HIV-positive patients 17 When to Test for HCV RNA (AASLD Recommendation) Positive anti-hcv antibody test Considering antiviral treatment Use sensitive quantitative assay Unexplained liver disease and negative anti-hcv antibody test and who are Immunocompromised Suspected of having acute HCV infection 18 6

7 HCV Assays: What the Results Mean Anti- HCV HCV RNA Interpretation + + Acute or chronic HCV depending on the clinical context + False positive HCV antibody Resolved infection Low-level intermittent viremia + Early acute HCV infection Chronic HCV in setting of immunosuppressed state False positive HCV RNA test Absence of HCV infection 19 Counseling HCV-Infected Patients: Avoiding Transmitting HCV to Others Items to avoid Sharing toothbrushes and dental or shaving equipment Using illicit drugs Those who continue to inject drugs, avoid reusing or sharing syringes, needles, water, cotton or other paraphernalia. Clean the injection site with a new alcohol swab and dispose of syringes and needles after one use in a safe, puncture-proof container Bandage bleeding wounds to prevent contact with others Do not donate blood, body organs, other tissue or semen Safe, sexual practices Encourage barrier protection for HIV-positive MSMs and those with multiple sexual partners or STIs For others with HCV infection, the risk of sexual transmission of HCV is low 2 Counseling HCV-Infected Patients: Minimizing Disease Progression Avoid alcohol HCV-related fibrosis progression is increased with alcohol consumption >5 g/day Lower levels of alcohol consumption is associated with increases in HCV RNA levels Administer HAV and HBV vaccines as needed Consider treatment for chronic HCV infection 21 7

8 Vitamin D and Coffee: Role in Chronic HCV Infection Vitamin D levels (HCV genotype 1 [n=197] versus age- and sex-matched healthy controls [n=49]) 25(OH) D levels significantly lower in HCV versus controls (25 versus 43 µg/l; P<.1) Low levels significantly associated with female sex, increased liver inflammation, increased liver fibrosis, and decreased SVR (n=167) Coffee consumption >3 cups/day (HALT-C trial, serial liver biopsies every 2 years) Lower rates of disease progression (relative risk.47 [P=.3]) Lower insulin and HOMA-2 score Independent predictor of improved virologic response to PR (adjusted* odds ratio 1.8 [P=.34]) *Adjusted for age, race/ethnicity, sex, alcohol, cirrhosis, AST/ALT ratio, IL28B polymorphism rs , and dose reduction in peginterferon. PR: pegifn + RBV. Petta S, et al. Hepatology. 21;51: Freedman ND, et al. Hepatology. 29;5: Freedman ND, et al. Gastroenterology. 211;14: Tobacco and HCC Risk The relationship between cigarette smoking and HCC has been examined in >6 studies (both areas of high and low incidence of HCC) Both positive associations and no associations have been reported Studies with positive associations Effects limited to subgroups defined by HCV or HBV status Meta-analysis of 16 publications HBV and cigarette smoking: more than additive interaction HCV and cigarette smoking: more than multiplicative interaction El-Serag HB. Gastroenterology. 212;142: Chuang SC, et al. Cancer Epidemiol Biomarkers Prev. 21;19: HCV Linkage-to-Care: Missed Opportunities in a Large Primary Care Setting (25-21) Number of Patients HCV RNA Positive 38% Received Care From Specialist 117 Seen by Specialist 6.8% Treated 21 Treated 2.6% Achieved SVR 8 Achieved SVR Patients with a positive anti-hcv antibody test and visit to primary care from (n=566). Of these patients, 458 underwent HCV RNA testing. Brown KA, et al. Hepatology. 213;58(suppl 1):1291A. Abstract

9 Stepwise Barriers to Hepatitis C Treatment HCV Infection Barriers Asymptomatic disease Poor awareness/education Lack of medical coverage MD failure to screen/test Diagnosis Barriers Non-adherence MD failure to identify need for referral Logistical concerns Limited specialists availability Treatment Initiation Barriers Patient fears/misunderstandings Stigmatization Substance abuse Psychiatric comorbidity Financial concern Transportation/logistical concern Communication difficulties Referral to Specialist McGowan CE, et al. Liver Int. 212;32(suppl 1): Achieving a Sustained Virologic Response is Associated With Improved Outcomes Sustained viral response Durable 99% stay HCV negative for >1 years Leads to improved histology Leads to clinical benefits Decreased decompensation Prevents de novo esophageal varices Decreased hepatocellular carcinoma Decreased mortality Bruno S, et al. Hepatology. 21;51: Veldt BJ, et al. Ann Intern Med. 27;147: Maylin S, et al. Gastroenterology. 28;135: SVR is Significantly Associated With Reduction in All-Cause Mortality Genotype 1 (n=12,166) Genotype 2 (n=294) Genotype 3 (n=1794).3.25 SVR rate: 35%.3.25 SVR rate: 72%.3.25 SVR rate: 62% Non- SVR Cumulative Mortality (%) P<.1 Non- SVR Cumulative Mortality (%) P<.1 Non- SVR Cumulative Mortality (%) P<.1.5 SVR.5 SVR.5 SVR Years Years Years Retrospective analysis of veterans who received pegifn + RBV at any VA medical facility (21-28). Backus LI, et al. Clin Gastroenterol Hepatol. 211;9:

10 Advanced Liver Disease: Basic Principles Hepatic fibrosis Not reliably diagnosed by ultrasound or other imaging modalities Liver fibrosis rates Not predictable or linear Progression from compensated cirrhosis to decompensated liver disease Occurs in 5% of patients per year Hepatocellular carcinoma Develops in 1% to 2% of patients with hepatitis-related cirrhosis each year Liver Biopsy no longer routinely recommended for Hepatitis C therapy decisions Sherman KE. Top HIV Med. 211;19: Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir) No Fibrosis Stage 1 Stage 2 Fibrous expansion of some portal areas Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 3 Stage 4 Fibrous expansion of portal areas with marked bridging (portal-to-portal and portal-to-central) Cirrhotic Liver Faria SC, et al. Radiographics. 29;29: Adapted from Everson GT. 29 Payers and Guidelines are currently restricting access to F3 and F4 patients Normal (F) (F4) Nodules Irregular surface Nodules surrounded by fibrous tissue 1

11 Transient Elastography (Fibroscan ) Fibroscan 52 Touch Non invasive liver stiffness measurement Received 51(k) clearance from FDA on April 5, 213 Manufactured by Echosens (Paris) Distributed in the United States by Sandhill Scientific, Inc. Courtesy of Echosens. Available at Accessed January 214. Transient Elastography (Fibroscan ) Works by measuring deformation of tissue caused by mechanical compression Non-invasive High concordance with biopsy Fibroscan eliminates the need for biopsy in some patients Afdhal NH. Gastroenterol Hepatol (N Y) 212;8: Transient Elastography (Fibroscan ) Technical limitations of transient elastography Testing cannot be performed in all patients Either the test cannot be performed or the results are unreliable in patients who: Have ascites Are morbidly obese Have large amounts of chest wall fat Afdhal NH. Gastroenterol Hepatol (N Y) 212;8:

12 FibroScan Elastography The probe induces an elastic wave through the liver The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface Diagnostic accuracy: Significant fibrosis:.79 Advanced fibrosis:.91 :.97 FibroScan (kpa) F-F1 F2 F3 F4 Liver Fibrosis (METAVIR) Ziol M, et al. Hepatology. 25;41: SuperSonic Aixplorer Ultrasound 35 Confidential MultiWave Technology Two waves to better characterize tissue : One Ultrasound Wave : Impeccable image quality in B-mode One Shear Wave : Measures and displays, in real time, local tissue elasticity in kilopascals 36 Confidential 12

13 Abdomen - Liver 37 Confidential Liver Fibrosis F2 38 Confidential Liver Fibrosis F4 39 Confidential 13

14 Chronic HCV Infection: Natural History Exposure (Acute phase) 15%-45% 55%-85% Resolved 75%-95% Chronic 5%-25% Over 2-3 Years Stable Liver Decompensation (5%/year) HCC (2%-8%/year) Poynard T, et al. Lancet. 1997;349: Risk Factors for Progressive Fibrosis and Persistently elevated ALT levels Longer duration of infection Alcohol excess (>5 g/day) Age >4 years at time of infection HIV or HBV coinfection High BMI Male gender Poynard T, et al. Lancet. 1997;349: Kim WR, et al. Gastroenterology. 24;127: Health Maintenance of the Cirrhotic Patient Vaccinations Bone disease screening, surveillance, and management HCC screening and surveillance Varices screening and surveillance Nutritional support Vitamin assessment for vitamin A and D deficiency Mineral assessment: zinc and magnesium (Mg++) Review medication list 42 14

15 Estimated 3-Month Survival as a Function of MELD 1 3-Month Survival (%) MELD Score MELD = 3.8[Ln serum bilirubin (mg/dl)] [Ln INR] + 9.6[Ln serum creatinine (mg/dl)] Wiesner R, et al. Gastroenterology. 23;124: When to Refer to Hepatologist Any hepatic decompensation Ascites Jaundice Encephalopathy Variceal bleeding MELD >1 Hepatocellular carcinoma 44 Chronic HCV Therapy: Advances in Raising Cure Rates SVR (%) IFN 1998 IFN/RBV 35% 21 PegIFN/RBV 44% 211 Telaprevir or Boceprevir + PegIFN/RBV ~7% >213 2 nd Generation DAAs PegIFN-Free Regimens >9% 2 16% Schaefer EA, et al. Gastroenterology. 212;142:

16 DAAs in Late-Stage Clinical Development for Chronic HCV Infection Approved Phase 3 Phase 2 NS3/4A Protease Inhibitors Simeprevir Boceprevir Telaprevir Paritaprevir/r Asunaprevir* Grazoprevir GS-9256 GS-9451 ABT-493 Sovaprevir GS-9857 Nucleotide NS5B Polymerase Inhibitors Non-Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors Sofosbuvir Dasabuvir Ledipasvir Ombitasvir ACH-3422 MK-3682 Beclabuvir Daclatasvir* Elbasvir GS-5816 ABT-72 GS-9669 TMC64755 ABT-53 ACH-312 MK-848 GSK PPI-668 Cyclophilin Inhibitors SCY-635 *Approved in Japan. Approved in Europe. Not all inclusive

17 The Ideal HCV Antiviral High Antiviral Activity Activity against all genotypes High barrier to resistance Simple application (few pills, QD dosing) Highly favorable safety profile No Drug-Drug interactions Short and finite duration of therapy Efficacious in all patient populations Cure (very high SVR rates) High value Sofosbuvir HCV-specific nucleotide polymerase inhibitor (chain terminator) H Antiviral activity and clinical 3 C O O CH 3 efficacy in HCV GT 1 6 H O 3 C NH O HN P O High barrier to resistance O O N O Once-daily, oral, 4-mg tablet CH 3 HO Approved for use in combination with other agents for the treatment of chronic HCV F Safety established in >3 patients including patients with compensated cirrhosis 5 17

18 Viekira Pak AASLD and IDSA: Recommended HCV Regimens for Treatment-Naïve Patients (Genotype 1) Genotype 1a No Duration of Therapy (weeks) With Genotype 1b No With Ledipasvir/sofosbuvir (9/4 mg qd) 12* 12 12* 12 Sofosbuvir 4 mg + simeprevir 15 mg qd RBV Ombitasvir/paritaprevir/r (25/15/1 mg qd) + dasabuvir 25 mg bid + RBV 12 (with RBV) 24 (with RBV) 12 (no RBV) 12 (with RBV) Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). *8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-therapy HCV RNA <6 million IU/mL. Shortening treatment to less than 12 weeks should be done with caution and performed at the discretion of the practitioner. Role of RBV is unclear, awaiting results from larger phase 3 studies for clarification 12 weeks may be considered for some patients based on prior treatment history

19 AASLD and IDSA: Recommended HCV Regimens for Treatment-Naïve Patients (Genotype 2, 3, 4, 5, 6) Genotype 2 Sofosbuvir + RBV for 12 weeks (16 weeks is recommended for cirrhotics) Genotype 3 Sofosbuvir + RBV for 24 weeks Genotype 4 Genotype 5 Ledipasvir/sofosbuvir (9/4 mg qd) for 12 weeks Sofosbuvir + RBV for 24 weeks Ombitasvir/paritaprevir/r (25/15/1 mg qd) + dasabuvir 25 mg bid + RBV for 12 weeks Sofosbuvir + PR for 12 weeks Genotype 6 Ledipasvir/sofosbuvir (9/4 mg qd) for 12 weeks Sofosbuvir 4 mg qd. Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. 55 AASLD and IDSA: Alternative HCV Regimens for Treatment-Naïve Patients Genotype 1 None Genotype 2 None Genotype 3 Sofosbuvir + PR for 12 weeks (IFN eligible) Genotype 4 Genotype 5 Sofosbuvir + PR for 12 weeks (IFN eligible) Sofosbuvir (4 mg qd) + simeprevir (15 mg qd) + RBV PR for 48 weeks (IFN eligible) Genotype 6 Sofosbuvir + PR for 12 weeks (IFN eligible) Sofosbuvir 4 mg qd. Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. 56 AASLD and IDSA: HCV Regimens Not Recommended for Treatment-Naïve Patients Genotype 1 Genotype 2 Genotype 3 Genotype 4 Sofosbuvir + RBV for 24 weeks PR + sofosbuvir, simeprevir, telaprevir or boceprevir for 12 to 48 weeks PR + direct-acting antiviral agent PR for 24 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir-, boceprevir-, or ledipasvir-containing regimens PR for 24 to 48 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir-, boceprevir-, or simeprevir-containing regimens PR + simeprevir for 24 to 48 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir- or boceprevir-based regimens Genotype 5 or 6 Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir- or boceprevir-based regimens 57 19

20 AASLD and IDSA: Recommended HCV Regimens for Prior PegIFN + RBV Failure (Genotype 1) Genotype 1a No Ledipasvir/sofosbuvir (9/4 mg qd) + RBV 12 (no RBV) Duration of Therapy (weeks) With 12 (with RBV) 24 (no RBV) Genotype 1b No 12 (no RBV) With 12 (with RBV) 24 (no RBV) Sofosbuvir 4 mg + simeprevir 15 mg qd RBV * Ombitasvir/paritaprevir/r (25/15/1 mg qd) + dasabuvir 25 mg bid + RBV 12 (with RBV) 24 (with RBV) 12 (no RBV) 12 (with RBV) Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). *Role of RBV is unclear, awaiting results from larger phase 3 studies for clarification. 58 AASLD and IDSA: Recommended HCV Regimens for Prior PegIFN + RBV Failure (Genotype 2, 3, 4, 5, 6) Genotype 2 Sofosbuvir + RBV for 12 to 16 weeks Genotype 3 Sofosbuvir + RBV for 24 weeks Genotype 4 Genotype 5 Ledipasvir/sofosbuvir (9/4 mg qd) for 12 weeks Sofosbuvir + RBV for 24 weeks Sofosbuvir + PR for 12 weeks (IFN eligible) Ombitasvir/paritaprevir/r (25/15/1 mg qd) + dasabuvir 25 mg bid + RBV for 12 weeks Sofosbuvir + PR for 12 weeks Genotype 6 Ledipasvir/sofosbuvir (9/4 mg qd) for 12 weeks Sofosbuvir 4 mg qd. Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. 59 AASLD and IDSA: Alternative HCV Regimens for Prior PegIFN + RBV Failure Genotype 1 None Genotype 2 Sofosbuvir + PR for 12 weeks (IFN eligible) Genotype 3 Sofosbuvir + PR for 12 weeks (IFN eligible) Genotype 4 None Genotype 5 PR for 48 weeks (IFN eligible) Genotype 6 Sofosbuvir + PR for 12 weeks (IFN eligible) Sofosbuvir 4 mg qd. Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. 6 2

21 AASLD and IDSA: HCV Regimens Not Recommended for Prior PegIFN + RBV Failure Genotype 1 Genotype 2 Genotype 3 Genotype 4 Monotherapy with either pegifn, RBV, or direct-acting antiviral agent PR + sofosbuvir, simeprevir, telaprevir, or boceprevir Any IFN-free regimen containing an HCV protease inhibitor (simeprevir, paritaprevir) PR + telaprevir or boceprevir Ledipasvir/sofosbuvir Monotherapy with pegifn, RBV, or a direct-acting antiviral agent PR for 24 to 48 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir-, boceprevir-, or simeprevir-containing regimens PR + telaprevir or boceprevir Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Genotypes 5 or 6 Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir- or boceprevir-based regimens 61 AASLD and IDSA: Recommended HCV Regimens for Prior Sofosbuvir- or HCV PI-Based Regimen Failure Sofosbuvir-Based Regimen Failure Without advanced fibrosis Advanced fibrosis Defer antiviral therapy (patients without an urgent need of therapy) Ledipasvir/sofosbuvir (9/4 mg qd) + RBV for 24 weeks Emerging data suggest that approximately 1% to 15% of patients with HCV genotype 1 infection treated for 12 weeks with the combination of simeprevir plus sofosbuvir will experience treatment failure, typically owing to viral relapse after discontinuing therapy - Very limited clinical experience and trial data on the retreatment of these patients - For patients with minimal liver disease, consider deferring retreatment pending availability of data - For patients who require urgent retreatment, based on emerging data and the expected pattern of HCV drug resistance, consider ledipasvir/sofosbuvir + RBV for 24 weeks HCV PI-Based Regimen Failure* Without cirrhosis With cirrhosis Ledipasvir/sofosbuvir (9/4 mg qd) for 12 weeks Ledipasvir/sofosbuvir (9/4 mg qd) for 24 weeks Ledipasvir/sofosbuvir (9/4 mg qd) + RBV for 12 weeks Weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]). *Regardless of HCV genotype 1 subtype. 62 Summary Active HCV infections with a detectable viral load are at increased risk of death due to hepatic and extrahepatic diseases Chronic HCV patients with active infection may benefit from antiviral treatment, once diagnosed, to reduce overall mortality HCV-related mortality among baby boomers prompted US health officials and the CDC to expand HCV testing to this entire age group Stress the importance of testing and including an HCV RNA test for anti-hcv seropositives in clinical practice HCV mortality may be reduced by increased treatment as a result of expanding screening to identify patients unaware of their infection Lee M-H, et al. J Infect Dis. 212;26: Nelson KE. J Infect Dis. 212;26: Centers for Disease Control and Prevention. MMWR. 212;61(RR-4):

22 Summary Active HCV infections with a detectable viral load are at increased risk of death due to hepatic and extrahepatic diseases Chronic HCV patients with active infection may benefit from antiviral treatment, once diagnosed, to reduce overall mortality Approval of newer, direct-acting, oral agents have high HCV cure rates, fewer adverse events, and negligible resistance compared with the first generation HCV PI IFN-free regimens are options for many patients PR-based regimens are no longer recommended for treatment-naïve genotypes 1, 2, 3, 4, and 6s Further research is needed on regimens based on newer, direct-acting, oral agents, especially for patients who failed previous HCV PI-based therapy PR: pegifn + RBV. 64 HCV: SCREEN, TREAT, CURE! WE CAN WIN THE WAR! THANK YOU 65 22