3/25/2014. HCV: A New Era Objectives. Implementing HCV Therapy in a Primary Care Practice. Hepatitis C: A Global Health Problem.

Transcription

1 Implementing HCV Therapy in a Primary Care Practice Anthony Martinez, MD Associate Professor of Medicine Medical Director, Hepatology University at Buffalo HCV: A New Era Objectives Update HCV related epidemiology Review of new HCV screening guidelines Review new agents for HCV Discuss HCV treatment among special populations Disclosures Speaker s Bureaus: Genentech, Kadmon, Salix, Gilead, Bayer Consultant: Genentech, Kadmon Research Support: Gilead, BMS, Abbott, Vertex Hepatitis C: A Global Health Problem 17-2 Million Carriers Worldwide (2% of the World s population) United States* 5.3 M Americas M Western Europe 5 M Africa 3-4 M Eastern Europe 1 M Far East Asia 6 M Southeast Asia 3-35 M Australia.2 M * Chak, Liver International, 211 1

2 7 Most Patients with Chronic Hepatitis C in the US Are Not Aware That They Are Infected ~5,3, individuals are infected with the hepatitis C virus in the United States 1,325, (~25%) AWARE 3,975, (~75%) UNAWARE Number of HCV Cases NYS (prevalence.6%)* Erie County (prevalence 1.2%) * Excludes NYC ** Based on CDC estimates HCV Cases Erie County (prevalence 2.9%)** Annual age adjusted rates of mortality for HBV, HCV, HIV Acute HCV Cases by age in the United States ~73% of HCV related deaths were in persons age years Klevens, CID, 212 2

3 Past Month and Past Year Heroin Use among Persons Aged 12 or Older: HCV Infected Persons In The US and Estimated Rates of Detection, Referral to Care and Treatment 11 Samhsa.gov Holmberg NEJM, 213 Worldwide Heroin Routes 1 Institute of Medicine Hepatitis and Hepatocellular Carcinoma Survey 12 Lack of knowledge and awareness providers, public Need for better integration of viral hepatitis treatment services Barriers to prevention and control efforts Inadequate screening for viral hepatitis Inadequate immunization 3

4 IOM: Comprehensive viral hepatitis services should have five core components- Institute of Medicine Recommendations to the CDC Identification of infected people Social and peer support Outreach and awareness All states mandate the HBV vaccine series be completed or in progress as a requirement for school attendance. That federally-funded health insurance programs incorporate guidelines for riskfactor screening for HBV and HCV as a required core component of preventive care. Medical Management of chronically infected people Prevention of new infections 13 Institute of Medicine Recommendations to the CDC Comprehensive evaluation of the national HBV and HCV public health surveillance system; to support core surveillance at the state level. Work with stakeholders to develop HBV and HCV educational programs for health care and social service providers. 4

5 U.S. Preventative Services Task Force Endorsement Courtesy of CDC, J. Ward CDC HCV Screening Guidelines 212 New York State HCV Screening Law January 1, 214 Screening test be offered to all individuals born between receiving services in the inpt or primary care outpt settings by an MD, PA or NP. If the screening test is reactive the provider must offer follow up care or referral to a specialist who can provide care such as diagnostic testing (ie. HCV RNA testing) 5

6 HCV Screening Algorithm HCV Antibody Screen HCV Antibody Positive Check HCV RNA Quant and Genotype Evolution of HCV Therapy Peginterferon + Ribavirin 21 Standard 1998 Interferon % + PIs % HCV RNA Negative HCV RNA Positive CBC with diff, Comp. Metabolic Panel AFP, RhF PT/INR Platelets <12 Albumin <3.5 INR > 1.3 Bilirubin >2 34% 42% 39% Stop Patient is a spontaneous resolver (antibody positive, negative viral load) Do US with PV diameter and Spleen size Consider CT or MRI with and without contrast to confirm cirrhosis and screen for HCC 6% 16% Refer to Liver Clinic SVR=Sustained Virologic Response; PIs= Protease Inhibitors HCV Lifecycle HCV Treatment 6

7 The Evolution Continues: The Era of Specifically Targeted Antiviral Therapy for HCV 214 The beginning of the end? Or, the end of the beginning? High potency Low barrier to resistance Limited genotype coverage NS3/4A Inhibitors NS5B Nucleoside inhibitors (NI) Intermediate potency Pan genotype coverage High barrier to resistance Boceprevir / Telaprevir Sofosbuvir Simeprevir NS5A Inhibitors NS5B Non Nucleosides (NNI) G1 = G2, 3 SVR = 75% SVR >9% High Potency Multi geno coverage Intermediate barrier to resistance Intermediate potency Limited geno coverage Low barrier to resistance HCV Treatment 214 Use in special populations: cirrhotics, HIV coinfection, renal patients, transplant Ease of dosing, QD, reduced # pills Higher SVR rates across all genotypes Limited Resistance Development All oral regimens Sofosbuvir (Sovaldi) HCV-specific uridine analog chain terminating polymerase inhibitor Potent pan-genotypic antiviral activity against HCV GT1 6 High barrier to resistance Once-daily, oral, 4-mg tablet Favorable clinical pharmacology profile No food effect Few drug interactions Generally safe and well-tolerated in clinical studies to date (> 2, patients) No safety signal in preclinical/clinical studies 7

8 Sovaldi (Sofosbuvir) Recommended Regimens and Treatment Duration for SOVALDI Combination Therapy in HCV Mono-infected and HCV/HIV-1 Co-infected Patients VALENCE: GT 2 and 3, naïve and experienced GT2 SOVALDI 4 mg once daily + RBV 1 12 mg/day* 12 weeks N=73 31 Primary endpoint: SVR12 Treatment Duration Patients with genotype 1 or 4 CHC SOVALDI + peginterferon alfa + ribavirin 12 weeks Patients with genotype 2 CHC SOVALDI + ribavirin 12 weeks GT3 SOVALDI 4 mg once daily + RBV 1 12 mg/day* 24 weeks N=25 b Patients with genotype 3 CHC SOVALDI + ribavirin 24 weeks Indicated for: All HCV genotypes (NOT as monotherapy) HCV / HIV co-infection HCV related HCC awaiting transplant NO response guided therapy Genotype 2 Genotype 3 SOVALDI + RBV 12weeks N=73 SOVALDI + RBV 24 weeks N=25 Overall SVR 93% (68/73) 84% (21/25) Non-cirrhotic 97% (29/3) 93% (86/92) Cirrhotic 1% (2/2) 92% (12/13) Treatment-experienced 9% (37/41) 77% (112/145) Non-cirrhotic 91% (3/33) 85% (85/1) SOVALDI full Prescribing Information. Gilead Sciences, Inc. December 213. Cirrhotic 88% (7/8) 6% (27/45) 3 NEUTRINO: Treatment-Naïve GT1,4,5,6 HCV GT 1, 4, 5, 6 Treatment-naïve N=327 SOVALDI 4 mg once daily + Peg-IFN alfa 2a 18 mcg/week + RBV 1 12 mg/day* 12 weeks of treatment SOVALDI full Prescribing Information. Gilead Sciences, Inc. December 213. Primary endpoint: SVR12 SOVALDI + Peg-IFN alfa + RBV 12 weeks N=327 a Overall SVR 9% (295/327) Genotype 1 89% (261/292) Genotype 1a 92% (26/225) Genotype 1b 82% (54/66) Genotype 4 96% (27/28) Cirrhosis No 92% (252/273) Yes 8% (43/54) Oral HCV NS3/4A protease inhibitor One-pill, once-daily Genotype 1 Simeprevir: (Olysio) 8

9 33 Simeprevir Overall SVR rates: Tx naïve and prior relapsers 1 SMV + PEG/RBV PEG/RBV Indicated in combination with peginterferon alfa and ribavirin in HCV genotype 1 infected subjects with compensated liver disease (including cirrhosis). NO monotherapy. Screening patients with HCV genotype 1a infection for the presence of the NS3 Q8K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q8K polymorphism Patients Achieving SVR12 (%) % 21/ 264 5% 65/ 13 81% 29/ 257 5% 67/ % 26/ 26 37% 49/ 133 QUEST-1 QUEST-2 PROMISE QUEST-1, QUEST-2 and PROMISE Study Designs Response Guided Treatment SMV 15mg/ PEG/RBV* Placebo/ PEG/RBV PEG/RBV PEG/RBV Post-Therapy Follow-Up Post-Therapy Follow-Up PEG/RBV PEG/RBV Post-Therapy Follow-Up Weeks Response Guided Therapy: if HCV RNA <25 International Units/mL at Week 4 and undetectable at Week 12, complete treatment at Week % of patients met the criteria and qualified for total treatment duration of 24 weeks. Patients Achieving SVR12 (%) SVR Stratified by Stages of Fibrosis/Cirrhosis (QUEST-2) / 195 SMV + PEG/RBV PEG/RBV / 12 24/ 36 F-F2 F3 F4 (Cirrhosis) Similar results seen in QUEST-1 and PROMISE studies 9/ 17 11/ / 15 *PEG/RBV=Peginterferon/Ribavirin 9

10 Genotype 1A, Q8K Mutation Cohort 1: SVR12 in Null Responders (F- 2) 24 week treatment 12 week treatment Patients Achieving SVR12 (%) /15 19/24 SMV/SOF SMV/SOF/RBV Patients Achieving SVR12 (%) /14 26/27 SMV/SOF SMV/SOF/RBV Jacobson IM, et al. Abstract #LB-3, AASLD 213 COSMOS: Phase IIa, randomized, open-label study investigating simeprevir + sofosbuvir +/- ribavirin Cohort 2: Naive and prior null responders (F3-4); Interim Analysis, SVR4 Patients Achieving SVR12 (%) 12 week treatment /14 26/27 Total Naïves Nulls 93 7/7 12/12 7/7 14/15 SVR4 (SMV/SOF) SVR4 (SMV/SOF/RBV) Jacobson IM, et al. Abstract #LB-3, AASLD 213 1

11 ESLD Emerges as a Leading Cause of Non-AIDS Death in HCV/HIV Co-Infected Patients in the ART Era 43 Special Populations AIDS 21, 24: Special populations: HIV/HCV Co- Infection HIV/HCV Co-infection Low SVR with PegIFN/RBV in HCV/HIV Coinfected patients Genotype 1 Genotype 2, 2/3 3 HIV/HC V 25% HIV 75% Co-infection rates among people who inject drugs ~1% SVR (%) 29% 14% 36% 19% 22% SVR (%) 62% 73% 44% 72% 66% Kim 213; Soriano 213; Sulkowski 28 APRICOT (n=176) ACTG A571 (n=51) PRESCO (n=191) RBV 8 RBV 1-12 PARADIGM (n=135/275) APRICOT (n=95) ACTG A571 (n=15) RIBAVIC (n=8) PR: pegifn + RBV. Torriani FJ, et al. N Engl J Med. 24;351:438-45; Chung R, et al. N Engl J Med. 24;351: ; Carrat R, et al. JAMA. 24;292: ; Nunez M, et al. AIDS Res Human Retrovir. 27;23: ; Rodriguez-Torres M, et al. HIV Clin Trials. 212;13: ; Laguno M, et al. Hepatology. 29;49: PRESCO (n=46) Laguno (n=65) 11

12 47 HIV accelerates natural history of HCV HIV accelerates rate of liver fibrosis progression 2.9 times higher in HIV/HCV co-infection 1 PHOTON-1: Sofosbuvir + RBV in Individuals Coinfected with HCV and HIV-1 Time to progression to cirrhosis 6 to 1 years in HIV/HCV co-infected individuals. 2 2 to 3 years in HCV mono-infected patients Limited access to liver transplantation 48 centers out of 242 in 211 up from 25 centers in HIV-positive people received organ transplants in 211, an increase from ~58 in 25 Effective HCV Tx is associated with 66% reduction in liver mortality/esld/hcc HCV GT 1 Treatment-naïve HCV GT 2, 3 Treatment-naïve or -experienced N=223 GT1 GT2 a GT3 a SOVALDI 4 mg once daily + RBV 1 12 mg/day* 24 weeks N=114 (Treatment-naïve) SOVALDI 4 mg once daily + RBV 1 12 mg/day* 12 weeks N=26 (Treatment-naïve) SOVALDI 4 mg once daily + RBV 1 12 mg/day* 24 weeks N=13 (Treatment-experienced) Primary endpoint: SVR12 1. CDC. MMWR. 24;53(RR-15): Chun S, Clin Liver Dis. 25;9: *Weight-based. SOVALDI full Prescribing Information. Gilead Sciences, Inc. December Challenges Drug interactions are likely and difficult to predict CYP3A4 inhibition (ritonavir); induction (Efavirenz) DAAs are promising DDI studies are essential for HCV and ARV regimens FDA mandates on-label status (3 patient study) SOF + RBV in HIV Co-infected Patients 7% Cirrhotic SVR 12 (%) % 88% 92% Genotype 1 Genotype 2 Genotype 3 87/114 23/26 12/13 12

13 Patients (%) Preliminary SVR rates in HIV/HCV coinfected patients treated with Simprevir+PR SVR4 SVR12 1 Overall Naïve* Relapse* /35 1/13 21/25 6/8 9/1 4/5 Data presented for patients with SVR data available at the time of the interim analysis RGT-eligible patients: non-cirrhotic treatment-naïve and non-cirrhotic relapse patients PR, pegifn-α2a + ribavirin; SMV, simeprevir *Including only non-cirrhotic patients Barriers to Treatment Uptake -Lack of HCV-related knowledge that treatment cures -Fear of side effects, stigmatization -Mistrust of health care system -Low perceived need for treatment -Concern regarding adherence, reinfection -Coexisting mental health diagnoses or active drug use -Many PWID uninsured -Less than 1/3 of those referred to specialty clinics appear for appointment - Lack of provision of services Special Populations: People Who Inject Drugs (PWID) PWID: Treatment Uptake Injection drug use accounts for 8% of new cases, 6% of chronic HCV in the developed world -Heroin users age 12 and over -Injectors age Non-Hispanic white population, particularly suburban Unwilling 2% Willing to be treated 8% 1-2% treated annually -Hispanic - African American Strathdee, CID, 25; Grebely, Drug and Alcohol Dependence 28; Alavi, CID,

14 HCV Treatment is Effective Among PWID (Dual Therapy Era P/R) 55.5% SVR (95% CI, 5.6% - 6.3%) HCV Evaluation Maximization Discipline Modality Setting 55 IM/FP CHC/FHC Substance Abuse Clinics/MMTPs Addiction Specialist Rural GI HCV Specialist Co- Localization Telemedicine Traditional Referral Setting GI/Hepatology Correctional Institutions ID HIV Clinics VA Dimova, CID, PWID Linkage to Care and Treatment Export TEST ASSESS Education and Screening - Patient and Provider -POC tests Guideline Development - Collaboration between academia, industry, government and professional societies ENGAGE 54 Novel Treatment Modalities -Multidisciplinary -Engagement of substance abuse treatment facilities, correctional and psychiatric institutions - Telemedicine, co-localization or referral Prevention, Evaluation and Treatment of HCV (PET-C) Telemedicine offers opportunity to remotely link patients with physicians geographically separated. HCV management via tele-care Prior limited attempts in prisons 1,2 and at rural clinics 2 Never attempted in drug treatment facility. Study objectives To assess staff and patient knowledge and perception changes towards HCV treatment after educational intervention To demonstrate feasibility of HCV management via tele-care in opiate treatment program 1 Sterling et al, Amer J Gastro, 24;99:866; 2 Arora, Hepatology 21; 52:

15 Education and Treatment Acceptance HCV Outcomes Tested for HCV (antibody) (93.44) Do you have hepatitis C? 32 Yes 148 (46.25) No 155 (48.44) Don t know 17 (5.31) If ever diagnosed, would you be willing to be treated? 318 Yes 248 (77.99) No 53 (16.67) Not sure 17 (5.35) Would you be willing to attend an HCV educational activity? 318 Yes 249 (78.3) No 69 (21.7) If not willing, would you be willing if compensated? 68 Yes 26 (38.24) No 42 (61.76) If willing, what type of compensation? 26 Metrocard 9 (34.62) Money 17 (65.38) Treatment Uptake Adherence SVR Cirrhosis HCC Need for X-plant Mortality 59 Most are Aware of Basic HCV Facts Basic facts mostly correctly identified: - 9% identified HCV spread via injection drug use - 87% knew that medication exists to treat HCV - 78% knew reinfection possible after clearance Topics for educational intervention: - 57% knew majority of HCV infected are asymptomatic - 51% knew that everyone with positive antibody test has chronic infection is a false statement - 67% incorrectly thought that vaccine is available. Beginning of the end? Or the End of the beginning? Even more new agents on the way SVR quickly approaching 1% Regimens safer, shorter, easier IFN almost gone Can we engage the epidemic s base? Infrastructure? Cost? 15