Hepatitis C No Barriers to Cure

Transcription

1 2018 Digestive Diseases Conference Kansas Hepatitis C No Barriers to Cure Dr. Mauricio Lisker Melman Professor of Medicine Director Hepatology Program Division of Gastroenterology Disclosure The following are my disclosures. Potential conflicts of interest have been resolved. Research Support / Grants Speakers Bureau / Honoraria NIH Abbvie Gilead Merck SimplySpeaking 1

2 Number of HCV Cases (millions) Over 5.2 Million People Living With Chronic HCV in the US Conservative estimate Upper limit of estimate 3.2 NHANES Estimate 1.9 HCV Cases Not Included in NHANES* *Homeless (n=142, ,6100); incarcerated (n=372, ,826); veterans (n=1,237,461-2,452,006); active military (n=6805); healthcare workers (n=64, ,234); nursing home residents (n=63,609); chronic hemodialysis (n=20,578); hemophiliacs (n=12,971-17,000) Estimated Total HCV Cases Chak E, et al. Liver Int. 2011; 31: WHO Target for HCV 2030 Is it a dream? 2

3 The CDA Foundation. Hepatitis C USA. Lafayette, CO: CDA Foundation, Available from (Accessed ) The CDA Foundation. Hepatitis C USA. Lafayette, CO: CDA Foundation, Available from (Accessed ) 3

4 There is a wide range of prevalence, diagnosis rates, and treatment rates across the European Union 12.0% 10.0% DEU FRA Treatment Rate 8.0% 6.0% 4.0% LTU CZE POL ROU BGR HRV PRT AUT ESP NLD IRL LVA GBR EST ITA 2.0% SVN FIN MLT SVK HUN GRC BEL 0.0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Diagnosis Rate DNK SWE LUX Bubble Diameter: HCV Prevalence 2% 1% 0.5% Source: Polaris Observatory ( 7 The virus and Sustained Virologic Response 4

5 Sustained Virologic Response () Treatment Regimen 0 EOT* Treatment Duration weeks (8, 12, 16, 24) Off Treatment Observation weeks (12) *EOT: End of treatment M. Lisker Melman, 2017 is significantly associated with reduction in all-cause mortality rate: 35% Genotype 1 (n=12,166) Genotype 2 (n=2904) rate: 72% Genotype 3 (n=1794) rate: 62% Non- Cumulative Mortality (%) P< Non- Cumulative Mortality (%) P< Non- Cumulative Mortality (%) P< Years Years Years Retrospective analysis of veterans who received pegifn + RBV at any VA medical facility ( ). Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:

6 Impact of on HCC and liver-related complications 100 HCC Liver-Related Complications 100 Cumulative Incidence (%) Non- P< Follow-Up (Years) Cumulative Incidence (%) Non- P< Follow-Up (Years) Single-center cohort. Non- in 67% of patients treated with pegifn + RBV. Median follow-up: 3.5 years. Total patients (n=307). Number of events: HCC (n=46); liver-related complications (n=31). Cardoso A-C, et al. J Hepatol. 2010;52: is associated with improved outcomes Sustained viral response Durable 99% stay HCV negative for >10 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. 2010;51: Veldt BJ, et al. Ann Intern Med. 2007;147: Maylin S, et al. Gastroenterology. 2008;135:

7 HCV Therapy: A Successful History HCV Therapy: A Successful History Ribavirin 1998 Interferon 1991 Pegylated Interferons Pre-DAA Era: Overall rates 40-50% Genotype 1 M. Lisker Melman,

8 HCV Treatment Challenges in the IFN Era Up to 48 Weeks Lower efficacy between 40%-50% for GT 1 Lower real-world efficacy compared with clinical trials Longer courses of therapy Up to 48 weeks Response-guided therapy needed for shorter courses Tolerability and toxicity IFN and RBV Frequent monitoring More complicated regimens Multiple pills daily Weight-based dosing Hepatitis C in the USA 100% 3.2 million 75% 50% 25% 0 HCV in USA 50% 1.6 million Diagnosed 32-38% million Referred to care 7-11% to Treated 5-6% to Successfully Treated NEJM 2013;368:

9 HCV Therapy: A Successful History Ribavirin 1998 Interferon 1991 Pegylated Interferons 2001 Telaprevir and boceprevir 2011 Simeprevir or sofosbuvir with IFN (GT1) Sofosbuvir+RBV with IFN (GT1) Pre-DAA Era: Overall rates 40-50% Genotype 1 Early-DAA Era: Overall rates 65-75% Genotype 1 Early-DAA Era Telaprevir, Boceprevir Genotype 1 activity Improve rates even further XFirst generation DAAs Increase the burden of AEs 9

10 The HCV Genome 5 IRES ~9.6 kb 3 NCR Protease TranslationReplicative Complex 3,000 Inhibitors AA polyprotein Inhibitors C E1 E2 P7NS2 NS3 4A 4B NS5A NS5B Structural Proteins Non-structural Proteins Polymerase Inhibitors DAA Era Timeline of Recent DAA Therapies August 2017 Glecaprevir/Pibrentasvir July 2017 Sofos/Velpatas/Voxilaprevir January 2016 Elbasvir/Grazoprevir July 2015 Paritaprevir/ritonavir, Ombitasvir July 2015 Daclatasvir June 2016 Sofosbuvir/Velpatasvir X X X December 2014 Paritaprevir/ritonavir, Ombitasvir, Dasabuvir, Ribavirin October 2014 Sofosbuvir/Ledipasvir X 10

11 DAA Era Regimens Pan-genotypic activity Impact on viral resistance Improve rates even further Second generation DAAs Reduce the burden of AEs Suitable for some difficult-to-cure patients Sofosbuvir: First in Class NS5B Nucleotide Active against all genotypes ~90% Weeks Shorter duration compared with earlier regimens 1 pill, once daily, in combination with other anti-hcv agents High for most patients High barrier to resitance Well tolerated 11

12 Hepatitis C in the USA 100% 3.2 million 75% 50% 25% 0 HCV in USA 50% 1.6 million Diagnosed 32-38% million Referred to care 7-11% to Treated Since sofosbuvir was launched 5-6% to Successfully Treated 750 K Cured NEJM 2013;368: Prevalence by Patient Type (Genotype 1-6) Nationwide Chart Audit by Phisicians that Treat HCV 11% N = % 4% 74% Treatment Naïve Non-Cirrhotic Treatment Naïve Compensated Cirrhotic All Treatment Experienced Decompensated Cirrhotic 12

13 Challenges Met With New-Based Regimens for Most Patients Higher efficacy 95% Real-world evidence confirms clinical-trial data Shorter courses of therapy As short as 8 weeks of therapy with SOF/LDV 12 weeks of SOF/VEL for genotype 1-6 patients Better tolerability and fewer toxicities Few discontinuations in randomized clinical trials Lower rates of adverse events compared with earlier regimens Fewer drug interactions Less complicated regimens Single-tablet regimens No RBV for most patients pifn-free for most patients No baseline resistance testing Chronic Hepatitis C DAA Treatment Today Viral load Genotype/Subtype Tx Naïve or experienced Cirrhosis and CPT score Before or After OLT Renal Function (egfr) HIV, HBV Co-Infection Drug-to-drug Interactions Viral Resistance 13

14 Chronic Hepatitis C Treatment Challenging Issues Spontaneous HBV Reactivation with Second Generation DAA s HBsAg + HBV DNA + Treat HBV DNA low / - Observe Treat if change HBsAg Anti-HBc + Monitor ALT ALT HBV DNA + Treat 14

15 Drug drug interactions: Most Frequent Outpatient-Drugs Prescribed The 10 most common drug classes in regular outpatient medication list Percentage (%) Proton pump inhibitors 24.1 Beta-blockers (selective) 18.4 Aldosterone antagonists 16.9 Thyroid hormones 16.5 Angiotensin II antagonists 13.0 ACE inhibitors 11.1 Dihydropyridine derivatives 10.7 Thiazides 10.0 Sulphonamides 9.2 Beta-blockers (non-selective) 8.0 Maasoumy B, et al. ISVHLD 2015; Poster presentation P140. Real-world Studies: Describe how a medication will perform in a broader population Populations Studied Utlization Randomized vs Real-world Clinical Trials ü Differing age groups groups ü Race, ethnicity, and gender ü Comorbid conditions ü Concomitant drugs ü Lifestyle, smoking and drinking ü Disease severity ü Adherence Phases I-III Post-approval Research 15

16 HCV Therapeutic Development In Pursuit of Perfectovir Requirements Perspective Extremely High Treatment Efficacy Pan-genotypic activity (similar dosing and duration) Maintenance of high efficacy in all patients categories including decompensated and peri-transplant settings Minimal toxicities and broad documented safety including renal failure and children High genetic barrier with minimal HCV resistance Easy of dosing, preferably 1 tablet per day Limited Drug-to-Drug interactions Short treatment duration Affordability G J Dore, JJ Feld. 16