1 / 38

Hepatitis C Choices in Care

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

dale
Download Presentation

Hepatitis C Choices in Care

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. Complexity of Hepatitis C Patient Management Future After HEPTIC EMR program

  3. 1. PoynardT, 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. 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 fibrosis1 • SVR leads to lower risk for liver failure and HCC, and improved survival2,3

  4. Treatment starts NOW with behavior modification • Alcohol abstinence • Weight loss of OW/Obese • No THC use • Stop IVDU

  5. 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

  6. Hyder S et al. DDW 2013; poster 608. 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

  7. HCV+ individuals die 15 years sooner Pinchoff J et al. IDWeek 2013; poster 1777.

  8. CHeCS: Annual Rate of Length of Stay (days/year) by FIB4 score*, 2006-2010 *FIB4, calculated from ALT, AST, platelet count and patient age, increases with worsening fibrosis; values > 5.88 indicate cirrhosis and end-stage liver disease

  9. HCV-infected persons in CHeCS:Mortality rates also increasing* From: R Mahajan et al, Abstract submitted to IDWeek 2013

  10. The real impact of HCV mortality in the United States* • 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

  11. Current Treatment

  12. The Evolution of HCV Therapy StraderDB, et al. Hepatology 2004;39:1147-71. 1998 2001 2002 2011-13 1986 2014+ 90+% +/-INF RIBA 70-75 54-56 SVR (%) 42 39 34 16 6 PEG-IFN /RBV 12 mo PEG-IFN /RBV + PI 6-12 mo IFN 6 mo IFN 12 mo IFN/RBV 6 mo IFN/RBV 12 mo PEG-IFN 12 mo

  13. Side Effects 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.

  14. INF + Riba +Telaprevir: SVR12 safety findings • *SAEsin patients; SCAR: severecutaneous adverse reaction • †3 septicemia, 1 varicealhemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection

  15. INF + Riba + Boceprevir: SVR12 safety findings *SAEs in patients; SCAR: severecutaneous adverse reaction †1 pulmonary infection, 1 anevrysmalbeeding, 1 septicemia

  16. HCV — The Revolution Has Begun • Antiviral activity in all HCV genotypes • No/less selection of resistance • All-oral combination regimen • Short treatment duration 6-12 weeks • QD (or BID) dosing Excellent safety and tolerabilityLess or no DDI • Applicable in difficult-to-treat populations: • Transplant • Coinfection • End-stage renal disease, etc.

  17. HCV Therapy—Past, Present, and Future IFN-free DAA combinations (G1) SVR 90-100% Frequent curability of diverse populations without IFN Ribavirin Suppression of HCV with DAA combination (PI + NI) Potential approval of other DAAs with IFN (egfaldaprevir) Proof of concept for DAA (PI) Telaprevir and boceprevir Interferon 1990 2000 2005 2010 2011 2012 2013 2014 2015 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 Pegylated interferons Thank you to Dr Ira Jacobson

  18. Two New Protease Inhibitors are coming in combination with PEG IFN/RBV • 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

  19. Simeprevir (TMC 435) • 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

  20. 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.

  21. Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment-Naïve and Prior Relapsers 81* 80* 79* 50 50 37 210/ 264 209/ 257 65/ 130 67/ 134 206/ 260 49/ 133 *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.

  22. QUEST-1—SVR by Subgroup 94 90 83 78 76 71 70 65 60 52 49 42 28 24 152/ 183 105/ 147 105/ 117 114/ 150 54/90 54/77 11/40 36/74 29/56 72/77 29/37 32/76 24/37 4/17 Fibrosis Genotype IL28B genotype Q80K polymorphism affected SVR Jacobson I, et al. EASL 2013;Abstract 1425.

  23. QUEST-2—SVR by Stage of Fibrosis 85 67 65 53 51 40 165/195 52/102 24/36 9/17 11/17 6/15 Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b.

  24. ASPIRE—Virologic Response to Simeprevir + PEG/RBV in Prior Partial and Null Responders SMV 150 mg* + PEG/RBV Placebo + PEG/RBV SMV 100 mg* + PEG/RBV 100 85 85 80 75 60 57 51 46 SVR24 (%) 37 40 19 20 9 27 79 79 23 68 69 16 50 51 n = 0 Relapsers Partial Responders Null Responders *For each dose, SVR for different treatment durations were similar so results were pooled. Abbreviation: SMV, simeprevir. Zeuzem S, et al. EASL 2012;Abstract 2.

  25. QUEST-2—Safety Profile Patient % • Data for the first 12 weeks of treatment are shown • The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2 *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.

  26. Simeprevir—Benefits • Virtually all patients qualify for short-duration (24 weeks) therapy • Limited drug-drug interactions • Daily dosing

  27. Simeprevir—Data Gaps • GT 2 and 4 subtypes • Phase III data in prior PEG/RBV partial and null responders • Renal disease • Pre and post transplant

  28. Jacobson IM, et al. . N Engl J Med 2013;368:1867-77. All Oral: Sofosbuvir plus RibavirinGenotype 2 and 3* Weeks of Treatment: (N=100) (N=95) *Patients with previous non-response to IFN-based treatment

  29. Jacobson IM, et al. . N Engl J Med 2013;368:1867-77. All Oral: Sofosbuvir plus RibavirinCirrhosis vsNo Cirrhosis Weeks of Treatment: (N=100) (N=95) 25/26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 Genotype 2 Genotype 3

  30. Sofosbuvir + RBVVALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures SVR12 =93% SOF+RBV (n=73) G2 G3 SOF+RBV (n=250) Wk 24 Wk 0 Genotype 3 93 92 85 SVR 12 (%) 60 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

  31. Lawitz E, et al. N Engl J Med 2013;368:1878-87. Sofosbuvir/PegIFN/RibavirinGenotype 1 (N=327)

  32. Cohort 1: Null responders (F0-2) 1/24 24 week treatment 12 week treatment 4/24 1/27 1/14 Patients (%) 14/14 19/24 SMV/SOF 24 wks SMV/SOF/RBV 24 wks 13/14 26/27 SMV/SOF12 wks SMV/SOF/RBV12 wks Non-virologic failure SVR12 (SMV/SOF) SVR12 (SMV/SOF/RBV) Relapse

  33. Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4 9 naïve and 9 null responders METAVIR F4 patients Only relapser was a F4 prior null responder 12 week treatment 1/27 1/15 SVR4 (SMV/SOF) SVR4 (SMV/SOF/RBV) Patients (%) Relapse 7/7 12/12 7/7 14/15 26/27 14/14

  34. Conclusion • 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

  35. Sulkowski MS, et al. EASL 2013; abstract 1417. Lawitz EM, et al. CROI 2013; abstract 155LB. IFN-free SummaryCross-company Studies

  36. 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. IFN-free SummaryPhase 2 Study Results

  37. Projected Timing for New Regimen Launches BMS DCV/ASV/RBV* -----GT1b Naïve/Tx-Exp/IFN Intolerant Triple COSMOS Study Off Label use SOF + SIM G-1 IFN-Free Daclatasvir Triple-----Gt1. Naïve only Sofosbuvir + RBV GT2/3, Naïve/Tx-EXP/ IFN Ineligible TX-Exp 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 * Precise timing TBD

  38. To Treat or not to Treat: A Constellation of Considerations Genotype virus Genotype Patient (IL28) Q80K mutation or others Histologic stage 20%+ life time risk Of cirrhosis Duration of infection To Treat or not to Treat: A Constellation of Considerations Personal plans (marriage, pregnancy) Age Family and other support Patient "mindset" COST Occupation Contraindications & comorbidities Insulin Resistance Extrahepatic Features (Fatigue, EMC, PCT) HIV coinfection

More Related