Eliminating Hepatitis C from New Zealand Catherine Stedman Associate Professor of Medicine, University of Otago, Christchurch Gastroenterology Department, Christchurch Hospital
Disclosures I have the following financial relationships to disclose within the past 12 months: Advisory board committees or speaking for Gilead Sciences, Abbvie 2
Hepatitis C in NZ Estimated 50000 in NZ with Hepatitis C Approximately 50% diagnosed The silent epidemic This virus can be cured
Who is at risk for Hepatitis C in New Zealand? Factor concentrates pre-1987 Jackson, 2000 Active injecting drug user Robinson. 1995 Prison inmates (female) Brunton, 2000 Blood transfusion pre-1992 Brullen, 2000 Haemodialysis Marshall 1999 STD clinic McKenna,1992 6% 3% 2.5% 30% 75% 89% Caucasian blood donors Bullen, 1999 0.9% Maori/PI blood donors Woodfield, 2000 ESR Report, 2000 0.49% New Zealand population 1.2% 0% 25% 50% 75% 100% 4 Prevalence Rate WHAD, July 28th 2015
Decreasing Incidence of HCV in Australia/NZ Related to falling incidence in Injecting Drug Use 15,000 Number of new infections 10,000 5,000 0 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 Dore et al. HCV Projections Working Group 2007 Other IDU Migrants 5
Characteristics of the local HCV Population Age and Gender Christchurch Community Clinic HCV Prevalence 5.0% 4.5% 4.0% 3.5% 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 0.0% Males (2013) Females (2013) Brunton C (unpublished) 6
Characteristics of the local HCV Population Age and size of population 50,000 infected, median age of 47 years 8,000 Total Viremic Infected (2013) 7,000 6,000 5,000 4,000 3,000 2,000 1,000 - Most have been infected for 20-30 years at time of diagnosis WHAD, 28 July, 2015 Gane E, et al. NZ Med J 2014; Dec 2014 7
Characteristics of the local HCV Population Proportion with Cirrhosis HCV Pilots in Bay of Plenty and Wellington 788 Fibroscans performed in community Nil Moderate F0 F2 63% Unsuccessful 12% 16% have established cirrhosis 25% have at least severe fibrosis Severe Fibrosis F3 9% Cirrhosis F4 16% 8
The total number of HCV infections is expected to decline in New Zealand while the disease burden is expected to increase 60,000 50,000 40,000 30,000 20,000 10,000 - Total Infected Cases (Viremic) 450 400 350 300 250 200 150 100 50 - Liver related Deaths Base Base 500 450 400 350 300 250 200 150 100 50 - HCC 1,200 1,000 800 600 400 200 - Decompensated Cirrhosis Base Base Gane E, Stedman C, Brunton C, Radke S, Henderson C, Estes C, et al. Impact of improved treatment on disease burden of chronic hepatitis C in New Zealand. N Z Med J 2014;127:61-74. 9
HCC deaths Incident HCC cases In fact, national estimates show an increase in HCC cases and HCC deaths 60.0 50.0 40.0 30.0 20.0 Males (Ministry of Health) Females (Ministry of Health) Males (model) Females (model) 10.0-1950 1960 1970 1980 1990 2000 2010 45.0 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 Males (Ministry of Health) Females (Ministry of Health) Males (model) Females (model) - 1950 1960 1970 1980 1990 2000 2010 10
HCC deaths Incident HCC cases In fact, national estimates show an increase in HCC cases and HCC deaths 60.0 50.0 40.0 30.0 Males (Ministry of Health) Females (Ministry of Health) Males (model) 20.0 Females (model) Current liver cancer (HCC) rates 10.0 - are increasing 1950 1960 1970 1980 by 1990 10% 2000 2010 per year in 45.0 New Zealand 40.0 35.0 Males (Ministry of Health) 30.0 25.0 20.0 15.0 10.0 5.0 Females (Ministry of Health) Males (model) Females (model) - 1950 1960 1970 1980 1990 2000 2010 11
Number of HCCs per annum Incidence of Liver Failure from HCV is rising more rapidly than projected in 2000 ESR Report 80 70 Patients with decompensated HCV cirrhosis referred for Liver Transplant 60 50 40 HCV 30 20 10 0 65 52 48 46 40 35 31 14 8 1 0 3 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 12
Thousands Thousands Global: HCV is now the leading cause of liverrelated morbidity and mortality Global Burden of Disease 2013 estimated age-sex-specific all-cause mortality 450 Cirrhosis 400 Liver cancer 400 350 300 250 200 150 100 50 Cirrhosis HBV Cirrhosis HCV Cirrhosis other 350 300 250 200 150 100 50 Liver cancer HBV Liver cancer HCV Liver cancer other 0 1990 1995 2000 2005 2010 2013 0 1990 1995 2000 2005 2010 2013 Deaths due to HCV more than doubled between 1990 2013; Liver cancer deaths due to HCV increased 300% Cowie BC, et al. EASL 2015; Poster #P1256; Global Burden of Disease 2013. Lancet 2015;385:117 71 WHAD, 28 July, 2015 13
Median age at death (years) HCV-infected adults are at increased risk of premature death 100 80 60 40 Premature death (<65 years) and median age at death among all deaths, NYC (2000 2011) 25% died prematurely 78 yrs 64% died prematurely 60 yrs 94% died prematurely 52 yrs 20 0 No HCV or HIV HCV mono-infected HCV/HIV co-infected Pinchoff J, et al. Clin Infect Dis 2014;58:1047 54 14
Current treatment options cannot meet the unmet medical need in New Zealand patients with HCV 1. Poor tolerability Side-effects of interferon Not suitable for elderly, or advanced disease 2. Complex dosing regimen Large number of pills Frequent monitoring Interfere with commonly prescribed drugs 3. Limited Efficacy WHAD, 28 July, 2015 15
Numbers started on treatment Peg-IFN for GT1 Peg-IFN for GT 2/3 Boceprevir for GT 1 Treatment Rate by Year In New Zealand 1000 900 800 700 600 500 400 300 200 100 0 894 766 711 611 560 575 539 529 540 478 488 479 420 380 265 105 102 135 120 24 31 23 32 25 35 15 30 55 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 WHAD, 28 July, 2015 PHARMAC data on file ACS, CCST data on file 16
Receptor binding and endocytosis Targets in the HCV Life Cycle for Direct Acting Antiviral Agents Transport and release Fusion and uncoating Virion assembly Translation and polyprotein processing (+) RNA LD ER lumen LD NS5A inhibitors ER lumen Membranous web LD RNA replication NS3 Protease Inhibitors Non-Nuc NS5B inhibitors NUC NS5B inhibitors
Proof of Concept HCV Studies Inform-1 Study Dual HCV oral antivirals can suppress Hepatitis C and prevent resistance ELECTRON Study Proof of concept that HCV can be cured in interferon-free regimen of sofosbuvir + ribavirin Gane, Roberts, Stedman et al Lancet 2010 Gane E, Stedman C et al. N Engl J Med 2013
Fixed Dose Combination Ledipasvir Picomolar potency against HCV GT 1a and 1b 1 Effective against NS5B RAV S282T 2 Once daily, oral, 90 mg LDV NS5A inhibitor Sofosbuvir Potent antiviral activity against HCV GT 1 6 High barrier to resistance Once-daily, oral, 400-mg tablet approved for use with other agents to treat HCV infection SOF nucleotide polymerase inhibitor Ledipasvir/Sofosbuvir FDC Once-daily, oral, fixed-dose (400/90 mg) combination tablet No food effect LDV NS5A inhibitor SOF nucleotide polymerase inhibitor 1. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172. 19
SVR12 (%) Ledipasvir/Sofosbuvir in HCV Genotype 1 Phase 3 Trials: ION-1, ION-2, ION-3 LDV/SOF LDV/SOF+RBV 100 99 97 98 99 94 93 95 94 96 99 99 80 60 40 20 0 211/ 214 211/ 217 212/ 217 215/ 217 202/ 215 201/ 216 12 Weeks 24 Weeks 8 Weeks 12 Weeks 12 Weeks 24 Weeks ION-1 GT 1 treatment-naïve including cirrhotics ION-3 GT 1 treatment-naïve non-cirrhotic ION-2 GT 1 treatment-experienced including cirrhotics and PI failures 206/ 216 102/ 109 107/ 111 108/ 109 110/ 111 97% (1886/1952) overall SVR rate Error bars represent 95% confidence intervals. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print] Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print] Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print
Hepatitis C Genotype 1: Ledipasvir/Sofosbuvir Harvoni One pill Once daily 8-12 weeks 97% cure LDV SOF
Hepatitis C Genotype 1: Sofosbuvir/Ledipasvir Single Tablet Regimen One pill Once daily 8-12 weeks LDV SOF 97% cure >$27000 NZ per month
Sofosbuvir/Ribavirin in Genotypes 2 & 3 HCV: VALENCE Study Zeuzem S, et al. AASLD 2013 Poster 1085
Abbvie VIEKIRA PAK Combination regimen for Genotype 1 HCV HCV Receptor binding and endocytosis Transport and release 3. MID-/LATE LIFECYCLE INHIBITION - NS5A inhibitor Ombitasvir (OBV) 1. EARLY INHIBITION - NS3/4A protease inhibitor Paritaprevir (PTV) Translation and polyprotein processing Fusion and uncoating (+) RNA ER ER GOLGI RNA replication Replication, virion assembly, and egress 2. MID-LIFECYCLE INHIBITION - non-nucleoside NS5B polymerase inhibitor Dasabuvir (DSV) Lindenbach & Rice. Nature 2005:436;933 38. 2 4
Abbvie Viekira Pak 12 week all oral regimen Coformulated paritaprevir /ritonavir (PTV/r) 150 mg/100 mg plus Ombitasvir (OBV) 25 mg (QD) Dasabuvir (DSV) 250 mg (BID) ± Ribavirin (RBV) weight-based dose (BID) RBV RBV Ritonavir boosting Allows twice daily dosing Drug-drug interactions http://hep-druginteractions.org
SVR12 (%) Viekira Pak in HCV Genotype 1 non-cirrhotic patients 100 90 80 100 100 100 96 96 100 100 100 100 94 95 96 70 60 50 40 30 20 10 Subtype GT1a Gt1b 0 Treatment history Treatment-naïve Treatmentexperienced Prior relapse Prior partial Prior null response response Overall results AbbVie Pty Ltd. Viekira Pak. Dossier submitted to Medsafe July 2014.
SVR12, % patients Abbvie Viekira Pak in HCV Genotype 1 patients with cirrhosis: Viekira Pak + RBV 88.6% 94.2% 98.5% 100% 380 patients with GT1 HCV. All patients with established cirrhosis 124 /140 GT 1a 114 /121 67 /68 GT 1b 12 weeks 24 weeks 51 /51 Poordad F et al. N Engl J Med 2014:370;1973 82. Asselah T et al. J Hepatol 2014; 61:1430 33.
New therapies open up new horizons
What would it take to reduce the health burden associated with chronic hepatitis C? Reduce morbidity and mortality Funding of new oral therapies for all cirrhotics Capacity to treat 2%/year Fibroscan access - to identify cirrhotics Eliminate HCV infection Funding of new oral therapies for everyone Capacity to treat 10%/year Identify the 30,000 New Zealanders who are undiagnosed Treat those who are transmitting HCV (PWID, prisoners) i.e. treatment as prevention 29
Impact of Different Scenarios Total Infected Cases (Viremic) Liver related Deaths 60,000 450 50,000 400 350 40,000 300 30,000 250 200 20,000 150 10,000 100 50 - - Base SVR Only Elimination Base SVR Only Elimination Elimination - 1yr delay Elimination - 2 yr delay Elimination - 1yr delay Elimination - 2 yr delay HCC Decompensated Cirrhosis 500 450 400 350 300 250 200 150 100 50-1,200 1,000 800 600 400 200 - Base SVR Only Elimination Base SVR Only Elimination Elimination - 1yr delay Elimination - 2 yr delay Elimination - 1yr delay Elimination - 2 yr delay Gane E, Stedman C, Brunton C, Radke S, Henderson C, Estes C, et al. Impact of improved treatment on disease burden of chronic hepatitis C in New Zealand. N Z Med J 2014;127:61-74. 30
Viremic Prevalence (000) Healthcare Costs - 2014 NZD (M) Total viremic infections peaked in 2010, but HCV related healthcare costs will continue to increase past 2035 under current Tx paradigm 70,000 70 60,000 50,000 40,000 30,000 20,000 10,000 0 60 50 40 30 20 10 0 In 2015, estimated annual healthcare costs of $25 million NZD By 2035, annual healthcare costs will increase 71% to $42 million NZD per year Total cumulative healthcare costs during 2015-2035 are estimated at $700 million NZD Annual healthcare costs peak in 2038 at $43 million NZD 31
Increasing the number of cured HCV individuals will lead to a reduction in HCV-related healthcare costs $45 $40 $35 $30 $25 $20 $15 $10 $5 $0 Total Healthcare Costs Base Elimination - no delay Elimination - 2 yr delay SVR Only Elimination - 1 yr delay Percent Reduction in Healthcare Costs in 2015-2035 (Million NZD) Reduction in Liver Related Deaths in 2015-2035 Increase SVR 10% ($73) 655 Lives lost due to delay Elimination (no delay) 53% ($375) 2,980 Elimination (1 year delay) 49% ($342) 2,715 265 Elimination (2 years delay) 44% ($311) 2,450 530 32
Hepatitis C: Conclusions HCV disease burden will increase over time even though the total number of HCV infections is expected to decline Hepatitis C is curable with short duration all-oral regimens» major shift away from interferon-based therapy» Drug costs and availability are limiting implementation of new therapy The increase in HCV related disease burden can be mitigated through higher cure rate therapies» Delaying access to treatment results in loss of lives There is potential for Hepatitis C elimination in NZ 33
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