Hepatitis C in 2015 Dr. Michael Bays D.O.
HCV Virology Member of the Flavivirus family (Yellow Fever, Dengue) Hepacivirus genus Enveloped, positive, singlestranded RNA virus 9.6 Kb genome encodes a single ~3000 amino acid polyprotein (single reading frame) Infects only man and chimpanzee Viral half life only a few hours 10 12 virions/day Moradpour et. al., Nature Reviews, Vol 5. June 2007
Global Prevalence of Chronic HCV Infection About 2% of world population estimated to have chronic HCV In the U.S. 3.2 million people, with estimates as high as 7 million, have chronic HCV, and ~12,000 die each year E.U. 5.5-6.5M U.S. 3.2 M Egypt ~18M* China 43-45M Pakistan >8M * Miller et al. estimate about 18 million overall prevalence; In another study, Guerra et al estimated ~ 12.1 million 15-59 year olds are infected. 1. Averhoff FM, et al. Clin Infect Dis. 2012;55(suppl 1):S10-S15. 2. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm; 3. Chak E, et al. Liver Int. 2011;31(8):1090-1101.
The US Prevalence of Hepatitis C Is Likely Underestimated The CDC estimates US prevalence to be 2.7-3.9 million (1%-1.5%) 1,2 Based on NHANES data, which excludes homeless and incarcerated populations 2 HCV infection prevalence may be as high as ~7 million with inclusion of populations omitted or underrepresented * by NHANES 3 Estimates of US HCV Infection Prevalence 1,3 2.7 million Conservative estimate NHANES 3.9 million Upper limit estimate NHANES Conservative estimate Chak et al 5.2 million 7.1 million Upper limit estimate Chak et al *Homeless, incarcerated, Veterans, active military duty, healthcare workers, nursing home residents, and patients on chronic hemodialysis or with hemophilia who received transfusions before 1992. CDC=Centers for Disease Control and Prevention; NHANES=National Health and Nutrition Examination Survey; HCV=hepatitis C virus. 1. Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32. 2. Armstrong GL, et al. Ann Intern Med. 2006;144(10):705-714. 3. Chak E, et al. Liver Int. 2011;31(8):1090-1101.
Projected Incidence of HCV-Related Liver Cancer and Death Also Expected to Peak in Coming Decades DCC=decompensated cirrhosis; HCC=hepatocellular carcinoma 1. Rein DB, et al. Dig Liver Dis. 2011;43(1):66-72.
HCV Is Leading Cause of Liver Transplants in the US 17,500 Number of Candidates All on HCV Wai2ng List HCC at Year End 1 15,000 12,500 10,000 7,500 5,000 Registrants 2,500 0 2002 2003 2004 2005 2006 2007 2008 Between 1995 and 2010, 41% of the 126,862 new primary registrants for liver transplants carried a diagnosis of HCV 1. Available at: www.ustransplant.org/annual_reports/current/chapter_iv_forprint.pdf 2. Biggins SW, et al. Liver Transpl. 2012;18(12):1471-1478.
HCV is a Progressive Disease and HCV-Related Healthcare Costs are Directly Related to Disease Severity Numbers in parentheses are +SD. *P<.001 vs non-cirrhotic liver disease. Gordon SC, et al. Hepatology. 2012;56:1651-1660.
Acute vs. Chronic HCV 6 months 15%-25% Virus Cleared 6 months Acute HCV Detectable HCV RNA < 6 months 15%-25% clear without treatment 75%-85% develop chronic HCV Chronic HCV 75%-85% Chronic HCV Detectable HCV RNA 6 months 5%-20% develop cirrhosis 20-30 years 5%-20% Cirrhosis Chen SL and Morgan TR. Int. J. Med. Sci. 2006. 3:47-52.
Extrahepatic Manifestations of HCV Strongly associated (% of cases) Mixed cryoglobulinemia ( 50%) Sjögren (sicca) syndrome (10%) Lymphoproliferative disorders ( 6%) Porphyria cutanea tarda (<5%) Neuropathy Membranoproliferative glomerulonephritis (10%-20%) Cryoglobulinemic vasculitis (<10% of cryoglobulinemia cases) Possibly associated Corneal ulcers (Mooren ulcers) Thyroid disease Lichen planus Pulmonary fibrosis Type 2 diabetes Systemic vasculi>s (polyarteri>s nodosa, microscopic polyangii>s) Arthralgias, myalgias, inflammatory polyarthri>s Autoimmune thrombocytopenia Adapted from Ali A, Zein NN. Cleve Clin J Med. 2005;72:1005-1008.
Active HCV Infection is Associated With Higher All-Cause Mortality REVEAL study: a prospective community-based cohort study in Taiwan designed to study the natural history and long-term disease burden of chronic hepatitis C Risk of all causes mortality, hepatic diseases and extrahepatic diseases, significantly higher in anti-hcv seropositives with detectable HCV RNA vs. anti-hcv seropositives with undetectable HCV RNA and anti-hcv seronegatives (P<0.001) REVEAL., Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer) Lee MH, et al. J Infect Dis. 2012;206(4):469-477.
Patients Should be Screened for HCV According to Birth Cohort and Risk Factors 1,2 PATIENT SCREENING FOR HCV Birth Cohort Screening Persons Born Between 1945 and 1965 1,2 The 1945-1965 birth cohort was selected on the basis of HCV prevalence and disease burden One-time screening for HCV infection in the birth cohort may identify infected patients at earlier stages of disease Risk Factor Based Screening Important Risk Factors 1,2 Past or current injection drug use Receiving a blood transfusion before 1992 Long-term hemodialysis Being born to an HCV-infected mother Incarceration Intranasal drug use Getting an unregulated tattoo Other percutaneous exposures 1. Smith BD, et al. MMWR Recomm Rep. 2012;61:1-32. 2. Moyer VA; US Preventive Services Task Force. Ann Intern Med. 2013;159:349-357.
AASLD Guidelines for Hepatitis C 1) A one time HCV-Ab should be ordered in patients with birth date 1945-1965 2) First test is HCV- antibody if positive then order PCR 3) Annual HCV testing for IVDA,homosexuals and HIV + patients. 4) HCV positive patients should be educated about how to prevent further liver damage. 5) HCV positive patient should seen by a practitioner that is prepared to discuss and possibly treat the HCV 6) Antiviral treatment is recommended for all HCV positive patients, except those with limited life expectancy due to non-hepatic causes
AASLD Guidelines for Hepatitis C 7) If resources limit the ability to treat all patients then it is most appropriate to treat only those at greatest risk of complications of the disease. 8) Use of noninvasive or Liver biopsy to assess the degree of fibrosis. 9-23) Relate to Regimens for therapy 24) Patients who fail to achieve SVR should be monitored for progression with CBC and INR and LFT s every 6-12 months. If cirrhotic then an EGD to evaluate for varices and an US every 6 months. 25) Patients with SVR do not need further follow up unless they have cirrhosis. 26) Patients with decompensated cirrhosis should be referred for consideration for liver transplant.
AASLD Guidelines for Hepatitis C 27-33) Guidelines for treatment in decompensated cirrhosis, post liver transplant treatment, and renal failure patients. 34-37) Guidelines for treating HIV co-infected patients. 38 and 39) Guideline for treatment or observation of Acute Hepatitis C. Treatment is the same as that for chronic disease.
AASLD Treatment Genotype 1 1) Ledipasvir90mg/Sofosbuvir400mg (Harvoni) once daily for 12 weeks 2)Partaprevir 150mg/ Ritonavir 100mg/ Ombitasvir 25mg/Dasabuvir 250mg (Vieirka Pac)plus Ribovirin for 12 weeks in non-cirrhotic and 24 weeks in cirrhotic.
AASLD Treatment for Genotype 1 3) Sofosbuvir 400mg (Sovaldi) plus Simeprevir (Olysio) 150mg for 12 weeks in noncirrhotic and 24 weeks in cirrhotic.
HARVONI: Indicated for the Treatment of chronic Hepatitis C (CHC) GT 1 Infection in Adults1 A complete once-daily single-tablet regimen1 Interferon (IFN)- and ribavirin (RBV)-free2 HARVONI1 ledipasvir (90 mg) An HCV NS5A inhibitor 1. 2. + sofosbuvir (400 mg) A nucleotide analog inhibitor of HCV NS5B polymerase HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. October 2014. Gilead Sciences, Inc. U.S. Food and Drug Administration approves Gilead s Harvoni (ledipasvir/sofosbuvir), the first once-daily single tablet regimen for the treatment of genotype 1 chronic hepatitis C [press release]; October 10, 2014.
The role of ledipasvir and sofosbuvir in the hcv lifecycle HARVONI is a single-tablet regimen of ledipasvir and sofosbuvir which are direct-acting antiviral agents against the hepatitis C virus. Sofosbuvir An inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication Ledipasvir An inhibitor of the HCV NS5A protein, which is required for viral replication HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. October 2014.
HARVONI is available as a once- Daily single-tablet regimen RECOMMENDED TREATMENT DURATION IN ADULT CHC GT 1 PATIENTS 1 Treatment-naïve HARVONI TABLET DAILY TAKEN WITHOUT REGARD TO FOOD 8 weeks Can be considered for treatment-naïve patients without cirrhosis and with pre-treatment HCV RNA <6 million IU/mL 12 weeks 12 weeks patients with or without cirrhosis Treatment-experienced patients a without cirrhosis 24 weeks Treatment-experienced patients a with cirrhosis No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [egfr] <30 ml/min/1.73m 2 ) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite a Treatment-experienced patients who have failed treatment with either peginterferon (Peg-IFN) alfa + RBV or an HCV protease inhibitor (PI) + Peg-IFN alfa + RBV. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. October 2014.
HARVONI Provided High SVR12 Rates in CHC GT 1 SUBjects Regardless of the inclusion of RBV OVERALL SVR12 RATES ACROSS ION STUDIES 1-4 SVR12, % 202 215 201 216 208 216 210 211 213 a 217 102 109 107 111 108 109 110 111 b a Excluding 1 subject with GT 4 infection. 1 b SVR rates for all treatment-naïve subjects enrolled in the 24-week treatment groups (N = 434) were not available at the time of the interim analysis. HCV RNA analyzed by COBAS TaqMan HCV Test v2.0 HPS, with lower limit of quantification (LLOQ) of 25 IU/mL. 1 1. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. October 2014. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 4. Kowdley KK, et al. N Engl J Med. 2014;370:1878-1888.
SVR12 by fibrosis score among treatment-naïve subjects in ION-3 1 ION-3 SVR12, % 20 22 16 16 60 62 55 59 40 43 51 52 28 29 28 29 Fibrosis stage a a The presence of fibrosis was determined by means of liver biopsy (METAVIR stage, on a scale from F0 to F4, with higher stages indicating a greater degree of fibrosis). No subject in this study had a fibrosis score of F4. 2 1. Kowdley KK, et al. N Engl J Med. 2014;370:1878-1888. Supplementary appendix. 2. Kowdley KK, et al. N Engl J Med. 2014;370:1878-1888.
HIGH SVR12 RATES among treatment-experienced harvoni subjects REGARDLESS OF PRIOR HCV Therapy ION-2 100 80 ION-2 SVR12 BY PRIOR TREATMENT RESPONSE 95% 92% 100% 98% 100 80 ION-2 SVR12 BY PRIOR HCV THERAPY 93% 94% 100% 98% SVR12, % 60 40 SVR12, % 60 40 20 0 57 60 45 49 HARVONI 12 Weeks 60 60 48 49 HARVONI 24 Weeks 20 0 40 43 62 66 HARVONI 12 Weeks 58 58 49 50 HARVONI 24 Weeks Prior Relapse/Breakthrough Prior Nonresponder Prior Peg-IFN + RBV Failure Prior HCV PI + Peg-IFN + RBV Failure HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. October 2014.
AASLD Treatment for Genotype 2 Sofosbuvir 400mg (Sovaldi) plus wieght based RBV for 12 weeks
AASLD Treatment for Genotype 3 1) Sofosbuvir 400mg (Sovaldi) plus wieht based RBV plus Peg IFN for 12 weeks 2)(New) Daclatasvir 60mg (Daklinza) plus Sofosbuvir 400mg (Sovaldi) for 12 weeks
ELECTRON-2 Trial (LDV/SOF+RBV) GT3 SVR12 Results with LDV/SOF±RBV for 12 Weeks SVR12 (%) 26/26 16/25 LDV/SOF + RBV LDV/SOF The regimens were safe and well tolerated Gane E, EASL, 2014, O6
AASLD Treatment for Genotype 4 1) Ledipasvir 90mg / Sofosbuvir400mg (Harvoni) for 12 weeks 2) Paritaprevir 150mg/ Ritonavir 100mg/ Ombitasvir 25mg (Technivie) plus weight based RBV for 12 weeks 3) Sofosbuvir 400mg (Solaldi) plus weight based RBV 24 weeks
LDV/SOF in GT 4 Patients Multicenter study in TN/TE GT 4 patients in France Week 0 12 24 N=44 LDV/SOF SVR12 Naïve n=22 Experienced n=22 Mean age, years (range) 52 (21 69) 50 (30 62) Male, n (%) 11 (50) 17 (77) White, n (%) 19 (86) 17 (77) Cirrhosis, n (%) 1 (5) 9 (41) IL28B non-cc, n (%) 15 (68) 21 (95) Mean HCV RNA, log 10 IU/mL (range) 6.0 (5.1 6.8) 6.3 (5.6 7.5) GT 4a, n (%) 13 (59) 12 (55) GT 4d, n (%) 5 (23) 5 (23) GT 4b, 4f, 4m, 4o, 4r, n (%) 4 (18) 5 (23) 21/22 20/22 31/34 10/10 TN TE No Yes No subjects D/C study due to AEs LDV/SOF for 12 weeks was highly effective and well tolerated, without the need for RBV Abergel, EASL, 2015, O056 32 SVR12 (%) Treatment Status Cirrhosis
AASLD Treatment for Genotype 5 & 6 1) Ledipasvir 90mg / Sofosbuvir 400mg (Harvoni) for 12 weeks 2) Sofosbuvir 400mg plus weight based RBV plus PEG-IFN for 12 weeks
LDV/SOF in GT 5 Patients Multicenter study in TN/TE GT 5 patients in France Week 0 12 24 N=41 LDV/SOF SVR12 Naïve n=21 Experienced n=20 Mean age, years (range) 61 (40 78) 64 (50 79) Male, n (%) 11 (52) 10 (50) White, n (%) 21 (100) 20 (100) Cirrhosis, n (%) 3 (14) 6 (30) IL28B non-cc, n (%) 8 (38) 14 (70) Mean HCV RNA, log 10 IU/mL (range) 6.2 (5.3 6.9) 6.6 (5.7 7.1) GT 5a, n (%) 20 (95) 20 (100) TN TE No Yes LDV/SOF for 12 weeks was highly effective and well tolerated, without the need for RBV Abergel, EASL, 2015, O056 35 SVR12 (%) 20/21 19/20 31/32 8/9 Treatment Status Cirrhosis No subjects D/C study due to AEs
AASLD Treatment for HIV and HCV co-infections 1) Treatment for HIV and HCV coinfected patients is the same as persons without HIV infection
AASLD Guidelines # 6 and 7 Is the USA a country with Resources so Limited that we cannot afford to eliminate up to 95% of HCV from the population? 1) Antiviral treatment is recommended for all HCV positive patients, except those with limited life expectancy due to non-hepatic causes. 2) If resources limit the ability to treat all patients then it is most appropriate to treat only those at greatest risk of complications of the disease.
BLUE CROSS AND MEDICAID RESTRICTIONS ON HEPATITIS C TREATMENT
Florida Medicaid Requirements for Treatment 1) Treatment Naïve without cirrhosis have to be Stage 3 fibrosis or > 2) Treatment experienced without cirrhosis Have to be stage 3-4 fibrosis 3) Treatment experienced with Cirrhosis Have to be stage 4
Blue Cross Requirements for Treatment One of the following must be met 1) Metavir score of F3 or greater 2) Fibroscan score F3 or greater 3) HCC awaiting Liver transplant 3) S/P Liver Transplant 4)Type 2 or 3 Cryoglobulinemia with end organ damage 5) Requested agent is Peginterferon
Effectiveness of HCV Therapy Has Been Reduced by Eligibility Restrictions and Low Rates of Initiation Results of a Literature Review on the Course of HCV Treatment in Clinical Care Settings North CS, et al. Gen Hosp Psych. 2013;35:122-128.
Annals of Internal Medicine June 30 th 2015 Restrictions (To paying for the treatment) do not seem to conform with the recommendations from professional organizations.. Current restrictions seem to violate federal Medicaid law, which requires states to cover drugs consistent with their U.S. FDA labels.