Transcript AASLD Talk - Hepatitis C
Hepatitis C Choices in Care
HCV State of the Art Management for a Curable Disease
Robert G. Gish MD Robert G Gish Consultants LLC Member VHAC Founding member of CEVHAP Executive Committee (VP): NVHR Senior Medical Director: St Josephs Medical Center Phoenix Professor of Clinical Medicine University of Nevada Las Vegas
Complexity of Hepatitis C Patient Management
After HEPTIC EMR program Futur e
Why Treat Chronic Hepatitis C?
The disease Common, chronic, and potentially progressive Complications are becoming more common Liver failure Hepatocellular carcinoma (HCC) Decrease transmission Improve quality of life Systemic disease Improve survival due to the linkage of HCV to (non liver) all cause mortality Decrease immediate and long-term health care costs The treatment Viral cure, or sustained virologic response (SVR), is achievable SVR associated with histologic improvement and gradual regression of fibrosis 1 SVR leads to lower risk for liver failure and HCC, and improved survival 2,3 1. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 2. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 3. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.
Treatment starts NOW with behavior modification
Alcohol abstinence Weight loss of OW/Obese No THC use Stop IVDU
HCV as a Systemic Disease
Association between chronic HCV infection and: Diabetes/insulin resistance Cardiovascular disease HCV and Brain: decreased cognitive function and QOL Cancer Renal impairment Effects of antiviral therapy and SVR on prognosis: Clear mixed cryoglobulinemia Decrease liver-related mortality Abrogate non-liver-related mortality Stop graft loss in renal and liver transplant patients Change outcomes in immune suppressed patients with HIV and other treatments or disease states
SVR Reduces Risk of Development of Diabetes in Patients with HCV
Veterans Affairs Clinical Case Registry: 27,636 patients with HCV Followed for median 5 years Antiviral treatment initiated 1998-2007 HR = 0.77: 95% CI 0.71-0.84
Hyder S. and et al Digestive Disease week, 2013
Hyder S et al. DDW 2013; poster 608.
HCV+ individuals die 15 years sooner
Pinchoff J et al. IDWeek 2013; poster 1777.
CHeCS: Annual Rate of Length of Stay (days/year) by FIB4 score*, 2006-2010
10 7 6 9 8 5 2 1 4 3 0 2006 2007 2008 2009 2010
Year
*FIB4, calculated from ALT, AST, platelet count and patient age, increases with worsening fibrosis; values > 5.88 indicate cirrhosis and end-stage liver disease FIB4<=1.21
1.21 FIB4>5.88 Year 2006 2007 2008 2009 2010 Mortality rate (per 100 py) 1.4 2.1 2.8 3.2 4.4 From: R Mahajan et al, Abstract submitted to IDWeek 2013 Despite high death rates, only 19% of the 1600 confirmed chronic HCV patients in CHeCS had HCV infection noted on their death certificate; only 30% even of those dying with liver-related conditions 70% had pre-mortem ICD9 codes, liver biopsies, and FIB4 scores indicative of substantial liver damage This suggests that even if all HCV-infected patients are identified before death – clearly, not the case-- actual mortality in them exceeds 80 000/yr, most of it contributed to by underlying HCV related liver disease Whatever the listed cause of disease, HCV-infected persons died 15 years younger than everyone else * Reena Mahajan et al, ‘Rates and Causes of Mortality…”, Manuscript submitted; IDWeek 2013 abstr 1774 100 1986 1998 2001 2002 2011-13 80 70-75 60 54-56 42 39 40 34 20 16 6 0 IFN 6 mo IFN 12 mo Strader DB, et al. Hepatology 2004;39:1147-71. IFN/RBV 6 mo IFN/RBV 12 mo PEG-IFN 12 mo PEG-IFN /RBV 12 mo PEG-IFN /RBV + PI 6-12 mo 2014+ 90+% +/ INF RIBA PEG IFN/RBV + new therapies results in increased SVR rates, this may be accompanied by a higher incidence of Anemia, often requiring erythropoietin and/or transfusion Rash Taste abnormalities (dysgeusia) Fatigue Flu-like symptoms Nausea Pruritus/dry skin Neutropenia/thrombocytopenia Fever Depression +++ Poordad F, et al. N Engl J Med. 2011;364:1196-1206. Bacon BR, et al. N Engl J Med . 2011;364:1207-1217. Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2. Telaprevir NDA 201-917. April 28, 2011. Available at: www.fda.gov. Patients, n (% patients with at least one event) Serious adverse events (SAEs)* Premature discontinuation / due to SAEs Death Infection (Grade 3/4) † Telaprevir n = 295 535 in 160 patients (54.2%) 139 (47.1%) / 63 (21.3%) 7 (2.4 %) 27 (9.1 %) Hepatic decompensation (Grade 3/4) Rash (grade 3/SCAR) 15 (5.1 %) 16 (5.4 %) / 2 (0.6 %) Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9 %) EPO use / blood transfusion GCSF use 168 (57 %) / 53 (18 %) TPO use *SAEs in patients; SCAR: severe cutaneous adverse reaction † 3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection 8 (2.7 %) 6 (2 %) Patients, n (% patients with at least one event) Serious adverse events (SAEs)* Premature discontinuation / due to SAEs Death † Infection (Grade 3/4) Hepatic decompensation (Grade 3/4) Rash (grade 3/SCAR) Anemia (Grade 3/4: Hb < 8 g/dL) EPO use / blood transfusion GCSF use TPO use *SAEs in patients; SCAR: severe cutaneous adverse reaction † 1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia Boceprevir n = 190 321 in 97 patients (51.0%) 80 (42.1%) / 27 (14.2%) 3 (1.6 %) 8 (4.2 %) 9 (4.7 %) 2 (1.0 %) 19 (10.0 %) 119 (62.6 %) / 26 (13.7 %) 13 (6.8 %) 3 (1.6 %) Antiviral activity in all HCV genotypes All-oral combination regimen QD (or BID) dosing No/less selection of resistance Short treatment duration 6-12 weeks Excellent safety and tolerability Less or no DDI Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc. HCV Therapy —Past, Present, and Future IFN-free DAA Frequent combinations (G1) curability of Suppression of SVR 90-100% diverse HCV with DAA Ribavirin populations combination (PI + NI) without IFN Interferon Proof of concept for DAA (PI) Telaprevir and boceprevir Potential approval of other DAAs with IFN (eg faldaprevir) 1990 2000 2005 2010 2011 2012 2013 2014 2015 Pegylated interferons Thank you to Dr Ira Jacobson Curability of HCV without Interferon Target >90% SVR reached in Phase II and III trials Approval of simeprevir and sofosbuvir with IFN:G1, others? First approved IFN-free therapy: SOF+RBV: G2, 3 Simeprevir NS3 protease Inhibitor Q daily dosing Improved side effect profile No anemia Fewer DDIs Faldaprevir NS Protease inhibitor Q daily dosing Improved side effect profile No anemia 18 HCV-specific NS3/4A protease inhibitor Antiviral activity in patients infected with GT 1, 2, 4, 5, and 6 Oral, once-daily tablet Limited drug-drug interactions as CYP 3A4 inhibitor only at level of intestine Safe and well tolerated, n ~3800 patients Simeprevir —Completed Phase III Studies QUEST-1 and QUEST-2 Same study design, but conducted independently of each other Treatment naïve GT 1 patients PROMISE Same study design as QUEST-1 and QUEST-2 GT 1 prior relapsers Jacobson I, et al. EASL 2013, Abstract 1425. Manns M, et al. EASL 2013, Abstract 1413. Lawitz E, et al. DDW 2013, Abstract 869b. Simeprevir/PEG/RBV PEG/RBV 100 80 80* 81* 79* 60 50 50 37 40 20 210/ 264 65/ 130 209/ 257 67/ 134 206/ 260 49/ 133 0 QUEST-1 QUEST-2 PROMISE *P <0.001 Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b. SIM+PR PR 100 90 94 80 83 70 71 78 76 65 60 60 52 49 42 40 28 24 20 152/ 183 54/90 54/77 11/40 105/ 147 36/74 105/ 117 29/56 72/77 29/37 114/ 150 32/76 24/37 4/17 0 F0-F2 Fibrosis F3-F4 1a 1b/other Genotype CC CT IL28B genotype Q80K polymorphism affected SVR Jacobson I, et al. EASL 2013;Abstract 1425. TT Simeprevir/PEG/RBV + PR PEG/RBV 100 85 80 67 65 60 51 53 40 40 20 0 165/195 52/102 F0-F2 24/36 F3 9/17 11/17 6/15 F4 (Cirrhosis) Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b. Placebo + PEG/RBV SMV 100 mg* + PEG/RBV SMV 150 mg* + PEG/RBV 100 85 85 80 75 60 57 51 46 40 37 19 20 9 n = 27 79 79 23 68 69 16 50 0 Relapsers Partial Responders Null Responders *For each dose, SVR for different treatment durations were similar so results were pooled. Abbreviation: SMV, simeprevir. 51 Zeuzem S, et al. EASL 2012;Abstract 2. Patient % Adverse Events SMV/PR (n = 257) Placebo/PR (n = 134) Grade 1 or 2 AE Grade 3 or 4 AE Serious AE AE leading to discontinuation of SMV * Most common AEs ( ≥25% in SMV arm) Headache Pyrexia Fatigue Influenza-like illness Other AEs of interest Rash (any type) Anemia 70.0 25.7 2.3 1.6 37.0 30.4 34.6 25.7 23.7 13.6 Pruritus 18.7 3.9 The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2 73.1 23.9 1.5 0.7 33.6 35.8 38.8 25.4 11.2 15.7 14.9 0.7 *Without regard to PEG IFN and RBV. Abbreviations: AE, adverse event; PR, PEG IFN + ribavirin; SMV, simeprevir. Manns M, et al. EASL 2013;Abstract 1413. Virtually all patients qualify for short-duration (24 weeks) therapy Limited drug-drug interactions Daily dosing GT 2 and 4 subtypes Phase III data in prior PEG/RBV partial and null responders Renal disease Pre and post transplant 100 80 60 81 87 97 98 100 100 73 50 40 20 0 2 Treatment Week 4 EOT SVR *Patients with previous non-response to IFN-based treatment Jacobson IM, et al. . N Engl J Med 2013;368:1867-77. Weeks of Treatment: 12 (N=100) 16 (N=95) 96 100 100 78 80 60 40 20 0 60 25/ 26 23/ 23 6/ 10 No Cx Genotype 2 Cx 7/ 9 63 61 37 14/ 38 25/ 40 19 5/ 26 14/ 23 No Cx Cx Genotype 3 Weeks of Treatment: 12 (N=100) 16 (N=95) Jacobson IM, et al. . N Engl J Med 2013;368:1867-77. Sofosbuvir + RBV VALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures G2 G3 SOF+RBV (n=73) SOF+RBV (n=250) SVR12 =93% Wk 24 Wk 0 100 80 SVR 12 (%) 60 93 Genotype 3 92 85 60 40 20 0 86/92 12/13 85/100 27/45 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naïve Treatment-experienced FDA Advisory Committee Meeting, Oct 25, 2013; Zeuzem S et al, AASLD 2013, #1085 99 99 100 80 60 40 20 0 91 2 4 Treatment Week Lawitz E, et al. N Engl J Med 2013;368:1878-87. EOT 90 SVR 100 90 80 70 60 50 40 30 20 10 0 24 week treatment 100 14/14 SMV/SOF 24 wks 1/24 4/24 4,2 16,7 79 100 90 80 70 60 50 40 30 20 10 19/24 SMV/SOF/RBV 0 24 wks SVR12 (SMV/SOF) SVR12 (SMV/SOF/RBV) Non-virologic failure Relapse 9 2 12 week treatment 7,8 1/14 13/14 SMV/ SOF… 12 wks 3,7 96 26/27 1/27 SMV/ SOF/RBV… 12 wks Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4 100 90 80 70 60 50 40 30 20 10 0 100 96,3 1/27 12 week treatment 100 100 100 93.3 1/15 14/14 26/27 7/7 12/12 7/7 14/15 Total Naives Nulls 9 naïve and 9 null responders METAVIR F4 patients Only relapser was a F4 prior null responder SVR4 (SMV/SOF) SVR4 (SMV/SOF/RBV) Relapse Treatment with SMV + SOF ± RBV results in: High SVR12 rates in HCV GT 1 null responder patients High SVR4 rates in naïve and null-responder patients with METAVIR F3-F4 These findings suggest that addition of RBV to SMV + SOF may not be necessary to achieve good virologic response in this patient population 12 weeks’ treatment may confer similar clinical benefit to 24 weeks’ treatment SMV + SOF ± RBV was generally well tolerated Daclatasvir + Sofosbuvir (N=41, GT-1) Simeprevir + Sofosbuvir COSMOS (N=80) Weeks 12 12 SVR 100% 100% Sulkowski MS, et al. EASL 2013; abstract 1417. Lawitz EM, et al. CROI 2013; abstract 155LB. ABT450/r + ABT267 + ABT333 + RBV (N=571) Sofosbuvir + ledipasvir + RBV (N=34) Faldaprevir + deleobuvir + RBV (GT1b, N=20) DCV + ASV + BMS-791325 (N=66) Weeks 12 8-12 16 12-24 SVR ~90% 95-100% ~95% 88-94% Kowdley K, et al. EASL 2013; abstract 3. Gane E, et al. CROI 2013; abstract 41LB. Zeuzem S, et al., APASL 2013. Everson GT, et al. IDSA 2013; abstract 1828. 2013 2014 BMS DCV/ASV/RBV* ---- GT1b Naïve/Tx-Exp/ IFN Intolerant COSMOS Study Off Label use SOF + SIM G-1 Sofosbuvir + RBV GT2/3 , Naïve/Tx EXP/ IFN Ineligible TX-Exp Daclatasvir Triple ---- Gt1. Naïve only Sofosbuvir + lepedisvir ---- GT1/2/3, Naïve/TX EXP/ IFN Ineligible Sofosbuvir Triple --- GT1, 4, 5, 6, Naive ABT 450/267/333/RBV --- GT1, Naïve/Tx-EXP Simeprevir Triple --- GT1, Naïve, Tx Exp Faldaprevir (BI201335) Triple --- GT1 Naïve, Tx-EXP 2015 2016 Triple IFN-Free Q1 Q2 Q3 Q4 2013 Q1 Q2 Q3 Q4 2014 Q1 Q2 Q3 Q4 2015 Q1 Q2 Q3 Q4 2016 * Precise timing TBD To Treat or not to Treat: A Constellation of Considerations Genotype virus Histologic stage To Treat or not to Treat: Q80K mutation or others 20%+ life time risk Of cirrhosis Duration of infection A Constellation of Considerations Personal plans (marriage, pregnancy) Age Family and other support Patient "mindset" Extrahepatic Features (Fatigue, EMC, PCT) COST HIV coinfection Occupation Contraindications & comorbidities Insulin ResistanceHCV-infected persons in CHeCS: Mortality rates also increasing*
The real impact of HCV mortality in the United States*
Current Treatment
The Evolution of HCV Therapy
Side Effects
INF + Riba +Telaprevir: SVR12 safety findings
INF + Riba + Boceprevir: SVR12 safety findings
HCV — The Revolution Has Begun
Two New Protease Inhibitors are coming in combination with PEG IFN/RBV
Simeprevir (TMC 435)
Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment Naïve and Prior Relapsers
QUEST-1 —SVR by Subgroup
QUEST-2 —SVR by Stage of Fibrosis
ASPIRE —Virologic Response to Simeprevir + PEG/RBV in Prior Partial and Null Responders
QUEST-2 —Safety Profile
Simeprevir —Benefits
Simeprevir —Data Gaps
All Oral: Sofosbuvir plus Ribavirin Genotype 2 and 3*
All Oral: Sofosbuvir plus Ribavirin Cirrhosis vs No Cirrhosis
Sofosbuvir/PegIFN/Ribavirin Genotype 1 (N=327)
Cohort 1: Null responders (F0-2)
Conclusion
IFN-free Summary Cross-company Studies
IFN-free Summary Phase 2 Study Results
Projected Timing for New Regimen Launches