UPDATES IN HEPATITIS C S A R A H N A I D O O, P H A R M, B C P S AP RI L 13, 2014 OBJECTIVES Be able to discuss changes in hepatitis c treatment Be able to provide recommendations to providers regarding hepatitis C treatment Be able to provide patient education on sofosbuvir and simeprevir STATISTICS Prevalence 2.7 million to 3.9 million persons in the US 45-85% are unaware that they are infected Most prevalent in those born from 1945-1965 Most likely infected during the 1970s-1980s http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1 Accessed 3/25/2014 1
BEHAVIORAL RISK FACTORS Injection drug use Blood transfusions (prior to 1992) Needle stick injuries in health care settings From pregnant mother to child Sex with an infected person Ineffective means of transmission Sharing personal items Ineffective means of transmission http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1 Accessed 3/25/2014 COMPLICATIONS If100 people become infected with Hepatitis C 75 85 will go on to develop chronic infection 60 70 will go on to develop chronic liver disease 5 20 will go on to develop cirrhosis over a period of 20 30 years 1 5 will die from the consequences of chronic infection (liver cancer or cirrhosis) Chronic hepatitis C is the leading indication for liver transplants in the US http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1 Accessed 3/25/2014 GENOTYPES Genotype1 US (60-70%) and Europe Genotype 2 US, Europe, Asia, South America, Africa Genotype 3 India, Far East and Australia Genotype 4 Africa and Middle East Genotype 5 South Africa Genotype 6 Hong Kong, Vietnam and Australia Chopra, S. Characteristics of the hepatitis C virus. In: UpToDate, Bloom, A (Ed), UpToDate, Waltham, MA 2014. 2
http://www.correlation-net.org/hep_c_trainers_manual/module06/slides/slide6_12.png Accessed April 2, 2014. TREATMENT Past Present Future TREATMENT PAST 3
TREATMENT TIMELINE 1957 Discovery of antiviral properties of interferon 1989 Discovery of hepatitis C virus 1991 1998 FDA approves first alfa interferon for treatment of hepatitis C Injected 3 times weekly x 48 weeks Rebetron approved (alfa interferon and ribavirin) Injected 3 times weekly x 24-48 weeks given with ribavirin HCV Advocate. 2010. A Brief History of Hepatitis C. http://www.hcvadvocate.org/hepatitis/factsheets_pdf/brief_history_hcv_10.pdf Accessed 4/1/2014 TREATMENT TIMELINE 2001 2002 2011 Peg-Intron approved (pegylated interferon alpha-2b) Peg-Intron plus ribavirin approved Inject 1 time weekly Pegasys approved (pegylated interferon alpha-2a) Inject 1 time weekly Protease inhibitors approved (telaprevir and boceprevir) Used in combination with pegylated interferon and ribavirin Approved for genotype 1 only HCV Advocate. 2010. A Brief History of Hepatitis C. http://www.hcvadvocate.org/hepatitis/factsheets_pdf/brief_history_hcv_10.pdf [Last accessed 03.09.12] http://img.medscape.com/fullsize/migrated/584/208/liv584208.fig1.gif Accessed April 3, 2014. 4
TREATMENT RESPONSE Yee, HS, et al. (2012) Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 107:669-689. TREATMENT PRESENT http://img.medscape.com/article/735/757/735757-fig1.jpg Accessed April 3, 2014. 5
GUIDANCE Recommendations for Testing, Managing, and Treating Hepatitis C hcvguidelines.org AASLD/IDSA This guidance should be considered a living document NS3/4A PROTEASE INHIBITORS Inhibitors of NS3/4A serine protease Enzyme involved in post-translational processing and replication of hepatitis C virus (HCV) Disrupt HCV by blocking the NS3 catalytic site or the NS3/4A interaction Blocks TRIF-mediated Toll-like receptor signaling and Cardifmediated retinoic acid-inducible gene 1 signaling 1 st Generation Boceprevir Telaprevir 2 nd Generation simeprevir Pockros, P. Direct acting antivirals for the treatment of hepatitis c virus infection. In: UpToDate, Bloom, A (Ed), UpToDate, Waltham, MA 2014. BOCEPREVIR 800 mg TID (available in 200 mg tablets) 12 tablets daily Approved for genotype 1 only Used in combination with peginterferon and ribavirin Treatment guided by an algorithm 6
Yee, HS, et al. (2012) Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 107:669-689. TELAPREVIR 1125 mg BID (available in 375mg tablets) 6 tablets daily Must be taken with 20 grams of fat Approved for genotype 1 only Used in combination with peginterferon and ribavirin Treatment guided by an algorithm Yee, HS, et al. (2012) Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 107:669-689. 7
SIMEPREVIR Approved November 2013 Genotype 1 patients with compensated liver disease (including cirrhosis) in combination with peginterferon alfa and ribavirin 150 mg once daily with food Food increases absorption by ~65% NS3 Q80K polymorphism Specific to genotype 1a subgroup If present, reduces efficacy of simeprevir Contains a sulfonamide moiety Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. SIMEPREVIR ADMINISTRATION Treatment-naïve and prior relapse patients including those with cirrhosis Prior non-responder patients (including partial and null responders) including those with cirrhosis Simeprevir + peg + ribavirin First 12 weeks First 12 weeks Peg + ribavirin Additional 12 weeks Additional 36 weeks Total Duration 24 weeks 48 weeks Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. SIMEPREVIR STOPPING RULES HCV RNA Treatment week 4: Greater than or equal to 25 IU/ml Treatment week 12: Greater than or equal to 25 IU/ml Treatment week 24: Greater than or equal to 25 IU/ml Action Discontinue simeprevir, peg and ribavirin Discontinue peg and ribavirin -simeprevir is complete at week 12 Discontinue peg and ribavirin *If peg or ribavirin is stopped for any reason simeprevir must be discontinued Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. 8
SIMEPREVIR DRUG INTERACTIONS Metabolized by CYP3A Mildly inhibits CYP1A2 and intestinal CYP3A4 CYP 3A Inhibitors CYP 3A Inducers EFFECT ON SIMEPREVIR CONCENTRATIONS INCREASES Increased risk of ADRs DECREASES Risk of reduced efficacy SELECT EXAMPLE Macrolides, antifungals, milk thistle, ritonavir Anticonvulsants, rifampin, dexamethasone, st johns wort, efavirenz SIMEPREVIR SPECIAL POPULATIONS Pregnancy category C Ribavirin is category X Hepatic Impairment No dose recommendation for patients with moderate or severe hepatic impairment Has not been studied post liver transplant Renal Impairment Not studied in CrCl <30 ml/min Race East Asian ancestry experience increased exposure No dose recommendations Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. SIMEPREVIR WARNINGS Photosensitivity Most frequently occurs in the first 4 weeks of treatment Exaggerated sunburn in areas exposed to light Use sun protection measures Rash Most frequently occurs in the first 4 weeks of treatment Most are mild to moderate and do not require discontinuation of simeprevir Sulfa allergy No increased incidence of rash or photosensitivity Insufficient evidence Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. 9
SIMEPREVIR ADRS ADR Simeprevir + peg-ifn + ribavirin First 12 weeks N=781 %(n) Rash/photosensitivity 28(218) 20(79) Pruritus 22(168) 15(58) Nausea 22(173) 18(70) Myalgia 16(126) 13(53) Dyspnea 12(92) 8(30) Placebo + peg-ifn + ribavirin First 12 weeks N=397 %(n) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. SIMEPREVIR PATIENT EDUCATION Should not be taken alone Females and males must use 2 forms of birth control during treatment and 6 months after Missed dose take within 12 hours of missing the dose Photosensitivity Rash Store in original bottle POOLED QUEST 1 & QUEST 2 Phase III Not yet published Genotype 1, treatment naïve, with compensated liver disease including cirrhosis N=785 Simep + peg-ifn + riba Peg-IFN + riba Genotype 1 419/521 (80%) 133/264 (50%) Genotype 1a 191/254 (75%) 63/131 (48%) Without Q80K 138/165 (84%) 36/83 (43%) With Q80K 49/84 (58%) 24/44 (55%) Genotype 1b 228/267 (85%) 70/133 (53%) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. 10
POOLED QUEST 1 & QUEST 2 Subgroup METAVIR Fibrosis Score Subgroup Simep + peg-ifn + riba % (n/n) Peg-IFN + riba % (n/n) F0-2 84 (317/378) 55 (106/192) F3-4 68 (89/130) 36 (26/72) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. PROMISE Phase III, not yet published Genotype 1, relapsed following previous interferon based therapy, with compensated liver disease including cirrhosis N=393 Simep + peg-inf +riba Peg-IFN + riba Genotype 1 26/260 (79%) 48/133 (36%) Genotype 1a 78/111 (70%) 14/54 (26%) Without Q80K 62/79 (78%) 8/34 (24%) With Q80K 14/30 (47%) 6/20 (30%) Genotype 1b 128/149 (86%) 34/79 (43%) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. PROMISE Subgroup METAVIR Fibrosis Score Subgroup Simep + peg-ifn + riba % (n/n) Peg-IFN + riba % (n/n) F0-2 82 (137/167) 41 (40/98) F3-4 73 (61/83) 24 (8/34) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December 2013. 11
ASPIRE Phase 2b Genotype 1, failed prior therapy with peg-ifn and ribavirin Simep 150 mg x 12 w + PR SVR24 % (n/n) Pooled simep 100 mg and 150 mg x 12w + PR SVR24 % (n/n) Placebo + PR SVR24 % (n/n) Prior relapser 77 (20/26) 83 (44/53) 37 (10/27) Prior partial responder Prior null responder 65 (15/23) 67 (31/46) 9 (2/23) 53 (9/17) 45 (15/33) 19 (3/16) Zeuzem S, Berg T, Gane E, et al. Simeprevir Increases Rate of Sustained Virologic Response Among Treatment- Experienced Patients with HCV Genotype-1 Infection: a Phase IIb Trial. Gastroenterology. 2013a ASPIRE Q80K polymorphism Genotype 1a Simep 150 mg + PR SVR24 Without Q80K 66.1% (39/59) With Q80K 60.9% (14/23) NS5B POLYMERASE INHIBITOR NS5B is an RNA dependent RNA polymerase involved in post translational processing Necessary for replication of HCV Enzyme has a catalytic site for nucleoside binding Sofosbuvir Pockros, P. Direct acting antivirals for the treatment of hepatitis c virus infection. In: UpToDate, Bloom, A (Ed), UpToDate, Waltham, MA 2014. 12
SOFOSBUVIR Approved December 2013 Approved for use in genotypes 1, 2, 3, and 4 Nucleotide analog NS5B polymerase inhibitor 400 mg once daily with or without food Dispense in original container Sovaldi [package insert]. Foster City; Gilead Sciences; December 2013. SOFOSBUVIR ADMINISTRATION Genotype Treatment Duration Genotype 1or 4 sofosbuvir + peg-ifn + ribavirin 12 weeks Genotype 2 sofosbuvir + ribavirin 12 weeks Genotype 3 Sofosbuvir + ribavirin 24 weeks Genotype 1 ineligible for peg-ifn Patients with hepatocellular carcinoma awaiting liver transplant Sofosbuvir + ribavirin Sofosbuvir + ribavirin 24 weeks Up to 48 weeks or until the time of liver transplant, whichever occurs first Sovaldi [package insert]. Foster City; Gilead Sciences; December 2013. SOFOSBUVIR DRUG INTERACTIONS Substrate of P-gp Inducers may decrease sofosbuvir plasma concentrations and decrease its therapeutic effects Do NOT coadminister decreases sofosbuvir concentrations Anticonvulsants Rifampin St. John s wort Tipranavir/ritonavir Drugs WITHOUT clinically significant interactions Cyclosporine Darunavir/ritonavir Efavirenz Emtricitabine Methadone Raltegravir Rilpivirine Tacrolimis Tenofovir Sovaldi [package insert]. Foster City; Gilead Sciences; December 2013. 13
SOFOSBUVIR SPECIAL POPULATIONS Pregnancy category B Ribavirin is category X Hepatic Impairment No dose adjustments needed for patients with mild, moderate or severe hepatic impairment Has not been studied post liver transplant Renal Impairment Not studied in CrCl <30 ml/min Sovaldi [package insert]. Foster City; Gilead Sciences; December 2013. SOFOSBUVIR ADRS Sovaldi [package insert]. Foster City; Gilead Sciences; December 2013. SOFOSBUVIR PATIENT EDUCATION Should not be taken alone Females and males must use 2 forms of birth control during treatment and 6 months after Keep in original container Take missed dose as soon remembered, but not more than 2 doses in one day Sovaldi [package insert]. Foster City; Gilead Sciences; December 2013. 14
NEUTRINO 12 weeks of sofosbuvir + peg-ifn + ribavirin in treatment naïve subjects with compensated liver disease including cirrhosis Genotypes 1 and 4 Phase 3 trial N=327 Genotype SVR Overall SVR 90% (295/327) 1 89% (261/292) 1a 92% (206/225) 1b 82% (54/66) 4 96% (27/28) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013b;368(20):1878-1887. NEUTRINO Selected subgroups Subgroup SVR Cirrhosis No 92% (252/273) Yes 80% (43/54) Race Black 87% (47/54) Non-black 91% (248/273) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013b;368(20):1878-1887. FISSION Genotypes 2 and 3, treatment naive Sofosbuvir + ribavirin for 12 weeks compared to peg-ifn + ribavirin for 24 weeks Phase 3 Genotype Sof + riba X 12 weeks N=253 peg/riba x 24 weeks N=243 Overall 2 & 3 67% (170/253) 67% (162/243) 2 95% (69/76) 78% (52/67) 3 56% (102/183) 63% (110/176) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013b;368(20):1878-1887. 15
FISSION Selected subgroup Cirrhosis Genotype 2 Genotype 3 Sof + riba X 12 w Peg + riba X 24 w Sof + riba X 12 w Peg + riba X 24 w Without 97% (59/61) 81% (44/54) 61% (89/145) 71%(99/139) With 83% (10/12) 62% (8/13) 34% (13/38) 30% (11/37) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013b;368(20):1878-1887. POSITRON Sofosbuvir + ribavirin x 12 weeks Genotypes 2 and 3 Patients who are interferon intolerant, ineligible or unwilling with compensated liver disease including cirrhosis Phase 3, placebo controlled Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. POSITRON Genotype Sofosbuvir + riba x 12 weeks N=207 Placebo X 12 weeks N=71 Difference [95% CI] Overall 2 & 3 78% (161/207) 0/71 78% [71,84] 2 93% (101/109) 0/34 93% [88,98] 3 61% (60/98) 0/37 61% [52,71] Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. 16
POSITRON Selected subgroups Cirrhosis Sofosbuvir + riba X 12 weeks Genotype 2 N=109 Sofosbuvir + riba X 12 weeks Genotype 3 N=109 No 92% (85/92) 68% (57/84) Yes 94% (16/17) 21% (3/14) Interferon Ineligible 88% (36/41) 70% (33/47) Intolerant 100% (9/9) 50% (4/8) Unwilling 95% (56/59) 53% (23/43) Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. FUSION Sofosbuvir and ribavirin for 12 or 16 weeks Phase 3 Genotype 2 or 3 who are treatment experienced with compensated liver disease including cirrhosis Genotype Sofos + riba X 12 weeks N=103 Sofos + riba X 16 weeks N=98 Difference [95% CI] Overall 50% (51/103) 71% (70/98) -22% [-35%,-9%] Genotype 2 82% (32/39) 59% (31/35) -7% [-23%,9%] Genotype 3 30% (19/64) 62% (39/63) -32% [-49%,-16%] Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. TREATMENT FU TU RE 17
SIMEPREVIR + SOFOSBUVIR? Not FDA approved COSMOS On-going phase II trial Simeprevir 150 mg and sofosbuvir 400 mg daily with or without ribavirin for 12 or 24 weeks Genotype 1 Published abstract Jacobson IM, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study. Hepatology: Special Issue: The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2013. 2013;58(4):1379A. COSMOS SVR4 Prior null responder to peg/riba and metavir score F0-2 Treatment naïve and prior null responders with metavir score F3-4 Prior null responder to peg/riba and metavir score F0-2 -w/ Q80K mutation Treatment naïve and prior null responders with metavir score F3-4 Sim + sofo w/o ribavirin X 12 weeks Sim + sofo w/ ribavirin X 12 weeks Sim + sofo w/o ribavirin X 24 weeks Sim + sofo w/ ribavirin X 24 weeks 13/14 (92.9%) 26/27 (96.3%) 14/15 (93.3%) 20/24 (83.3%) 14/14 (100%) 26/27 (96.3%) NA NA 13/14 (92.9%) 5/6 (83.3%) 26/27 (96.3%) 8/9/ (88.9%) 14/15 (93.3%) 4/4 (100%) NA NA NA NA 19/24 (79.2%) 8/12 (66.7%) DACLATASVIR NS5A replication complex inhibitor NS5A plays a role in viral replication and assembly of the hepatitis c virus Bristol-Myers Squibb 18
DACLATASVIR + SOFOSBUVIR Genotype 1, 2, 3 previously untreated patients sofosbuvir for 1 week, then daclatasvir and sofosbuvir for 23 weeks daclatasvir and sofosbuvir for 24 weeks daclatasvir, sofosbuvir, and ribavirin for 24 weeks Genotype 1 previous non responders to treatment with telaprevir or boceprevir daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks daclatasvir plus sofosbuvir, with or without ribavirin, for 24 weeks Sulkowski, M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-21. Sulkowski, M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-21. DACLATASVIR + SOFOSBUVIR Genotype 1 Prev untreated Sofo + dac X 12 weeks Genotype 1 Failed boc or telap Sofo + dac X 24 wees Genotype 2 Sofo + dac X 24 weeks Genotype 3 Sofo + dac X 24 weeks 98% 98% 92% 89% Sulkowski, M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-21. 19
ASUNAPREVIR NS3/4A protease inhibitor DACLASTASVIR + ASUNAPREVIR phase 2a, open-label, 24-week treatment study daclatasvir 60 mg once-daily AND genotype 1b patients received asunaprevir 200mg twice or once-daily genotype 1a and genotype 1b patients received asunaprevir twice or once-daily plus PegIFN/RBV genotype 1a and genotype 1b patients received asunaprevir twice-daily plus ribavirin Lok, A. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol. 2014 Mar;60(3):490-9. DACLASTASVIR + ASUNAPREVIR Lok, A. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol. 2014 Mar;60(3):490-9. 20
LEDIPASVIR NS5A inhibitor SOFOSBUVIR + LEDIPASVIR LONESTAR Genotype 1 Treatment naïve and treatment experienced with a protease inhibitor Sofosbuvir 400 mg and ledipasvir 90 mg SOFOSBUVIR + LEDIPASVIR Cohort A: treatment-naive patients Cohort B: patients previously treated with protease inhibitors Sofosbuvir Sofosbuvir Sofosbuvir Sofosbuvir Sofosbuvir plus ledipasvir plus ledipasvir plus ledipasvir plus ledipasvir plus ledipasvir with ribavirin with ribavirin for 8 weeks for 12 weeks for 12 weeks for 8 weeks for 12 weeks (n=20) (n=19) (n=19) (n=21) (n=21) Treatment week 4 20 (100%; 83 21 (100%; 84 19 (100%; 82 18 (95%; 74 21 (100%; 84 End of treatment 20 (100%; 83 21 (100%; 84 19 (100%; 82 19 (100%; 82 21 (100%; 84 SVR4 20 (100%; 83 21 (100%; 84 19 (100%; 82 18 (95%; 74 21 (100%; 84 19 (95%; 75 21 (100%; 84 18 * (95%; 74 18 (95%; 74 Lawitz, E. Sofosbuvir and ledipasvirfixed-dose combination with and without ribavirin in treatment-naïve and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomisedphase 2 trial. Lancet. 2014 Feb 8;383(9916):515-23. 21
COST Treatment Cost Interferon <$20,000 Peg-IFN + ribavirin $27,000 Telaprevir $79,000 Boceprevir $78,000 Simeprevir $66,360 Sofosbuvir $84,000 Fairpricingcoalition.com Accessed April 3, 2014 QUESTIONS? THANK Y OU! 22