Hepatitis C Difficult to Treat. Population. Disclosures

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1 Hepatitis C Difficult to Treat Populations Paul Y Kwo MD Professor of Medicine Director of Hepatology Stanford University School of Medicine 75 Welch Road #21 Palo Alto, CA 9434 Disclosures Advisory Board Member Abbvie, BMS, Gilead, Merck, Quest, Shareholder Durect Grant Recipient Abbvie, BMS, Gilead P (65) F (65) pkwo@stanford.edu Who is left who is difficult to treat Decompensated cirrhosis (challenges remain) DAA failures (routine) Renal failure (mostly routine) PWID (challenges remain) HCV/HCC (challenges remain) Post Liver transplant (routine) Many Special Populations are No Longer Special Population SVR Rate Black/Hispanic Race >95% HIV/HCV Coinfection >95% Post Orthotopic Liver Transplant >95% CKD/Dialysis >95% PWID/OST >95% Those with decompensated cirrhosis who have failed therapy remain one of the final special populations in need of additional therapies Protease inhibitors cannot be given in decompensated cirrhosis Treatment of HCV infection in decompensated cirrhosis patients Lower SVR rates than in those with compensated cirrhosis Comparable SVR rates in CTP B/C patients treated with 12- and 24- weeks of SOF-based therapies Improvement in MELD scores and CTP scores have been observed No data yet on improved survival High post-transplant SVR rates have been reported with multiple therapies More data required to offer best options to avoid MELD purgatory Use of HCV+ donors becoming routine Child-Turcotte-Pugh (CTP) Classification CTP score: Obtained by adding the score for each parameter CTP class: A=5-6 points; B=7-9 points; C=1-15 points 1

2 Dose Adjustments of DAAs in Cirrhosis Protease inhibitors should not be used in Childs B/C Why Higher Rates of Virologic Failure with Advanced Cirrhosis? Ledipasvir/ Childs Class Sofosbuvir Simeprevir Ribavirin Daily sofosbuvir A 4 mg 15 mg 1-12 mg/day 9mg/4mg B 4 mg No 6 mg 9mg/4mg C 4 mg No 6 mg 9mg/4mg Childs Class PTV/OMB/DSB Daclatasvir Grazoprevir/ Elbasvir Sofosbuvir/ velpatasvir Glecaprevir/ Pibrentasvir A 75/5/12.5 mg + 25 mg 6 mg 1/5 4mg/1mg 3/12 Decreased hepatocyte mass Decreased drug delivery B No 6 mg No 4mg/1mg No C No 6 mg No 4mg/1mg No Decreased drug uptake Bifano M, et al. AASLD 211. Abstract Garimella K, et al. Clinical Pharm 214. Abstract P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 212. Abstract 758. German, et al. AASLD 213. Abstract 467. Kirby R, et al. Clinical Pharm 213. Abstract PO2. First Line Treatment Options lead to good SVR rates (>85%) HCV genotype Decompensated Cirrhosis, RBV tolerant 1,4 LDV/SOF/RBV /RBV SOF/DAC/RBV 2/3 /RBV SOF/DAC/RBV 5, 6 LDV/SOF/RBV /RBV 12W 12W Decompensated Cirrhosis, RBV intolerant LDV/SOF SOF/DAC SOF/DAC LDV/SOF 24W 24W Start RBV 6 with SOF/LDV, SOF/DAC, full dose with (6 in CPT C) LDV/SOF + RBV: Genotype 1 and 4 with Advanced Liver Disease Week Week 12 LDV/SOF + RBV LDV/SOF + RBV SOLAR-1 Treatment naïve or experienced CPT Class B CPT Class C Post liver transplantation Week 24 Week 36 SOLAR-2: (greater G4 population) Treatment naïve or experienced CPT Class B CPT Class C Post liver transplantation Charlton M, et al. Gastroenterology, 215 [epub ahead of print] Reddy RT, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 8. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. SOLAR-1 and SOLAR-2 LDV/SOF + RBV: in Genotype 1 or 4 with Decompensated Cirrhosis (%) Comparable efficacy between SOLAR-1 and SOLAR-2 studies LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks / 24/ 19/ 18/ 2/23 22/23 17/2 n/n = n/n = /1 8 CTP B CTP C CTP B CTP C SOLAR-1: GT 1 and 4 [1.2] SOLAR-2: GT 1 [3] AE, adverse event; CTP, Child-Turcotte-Pugh; LDV, ledipasvir; RBV, ribavirin; SAE, serious adverse event; SOF, sofosbuvir. 1. Charlton M, et al. Gastroenterology, 215 [epub ahead of print] 2. Flamm SL, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. (%) n= 75 n= 75 n= 75 ASTRAL-4 Childs B Cirrhosis ± RBV 1-12 mg Wk Wkk24 + RBV Wk 36 Open-label, randomized (1:1:1) US study GT 1-6 treatment-naïve or -experienced patients with CPT B cirrhosis Eligibility criteria: CrCL >5 ml/min, platelets >3, x 1 3 /μl; no HCC or liver transplant Weight-based RBV dosing (1 or 12 mg/day) N Engl J Med. 215 Dec 31;373(27): doi: 1.156/NEJMoa

3 Results: in GT 1 Patients ASTRAL-4 Results: in GT 3 Patients ASTRAL SVR relapse 2 death 1 LTFU 1 relapse 2 deaths 3 relapse 3 LTFU SVR 4 6 relapses 2 1 death 1 breakthrough 1 relapse 1 breakthrough 4 relapse 1 death 6/68 65/68 + RBV 12 week 12 week N Engl J Med. 215 Dec 31;373(27): doi: 1.156/NEJMoa /71 24 week 7/14 SOF/V EL 12 week 11/13 + RBV 12 week 6/12 SOF/V EL 24 week Delisting patients who receive DAAs 183 individuals with decompensated cirrhosis and/or HCC treated with SOF based regimens Clinical and Biochemical responses post DAA therapy Coilly A, Pageaux GP, Houssel-Debry P, Duvoux C, Radenne S, de Ledinghen V at al. Improving liver function and delisting of patients awaiting liver transplantation for cirrhosis: do much to DAAs? Presented at 66th Annual Meeting of the American Association for the Study of Liver Diseases Boston, MA Nov MELD and Child-Pugh score changes over time in inactivated (N=34) and non-inactivated patients (N=68) Week 12 of therapy associated with higher rate of inactivation Which patients can you treat to achieve SVR and potentially delist? Achieving SVR with DAAs will reduce inflammation in the liver Reversal of fibrosis is required to reduce portal hypertension, may take years About 2% of those with MELD <2 may improve and be delisted with DAA therapy and these individuals should be considered for treatment Pay close attention to those with severe portal hypertension Those with MELD scores above 2 require careful assessment on individual basis More data required in this population Ribavirin free regimens are ideal, none yet available that give optimal SVR Journal of Hepatology , DOI: (1.116/j.jhep ) Copyright 216 European Association for the Study of the Liver Terms and Conditions 3

4 Recent ILTS/ATS recommendations We suggest that HCV-infected patients with decompensated cirrhosis with CTP Class B and/or MELD less than 2 on the waiting list for liver transplantation, who are without refractory portal hypertensive symptoms or other conditions requiring more immediate transplantation, should be treated with antiviral therapy 1 The efficacy, safety, and tolerability of DAA therapy make transplantation of HCV-viremic donors into HCVnegative recipients feasible to study 2. The transplantation of organs from HCV-viremic donor into nonviremic recipients should only be conducted under IRB-approved protocols with multistep informed consent processes 2. Other consideration is the increased use of HCV+ donors, don t want to treat patient twice HCV+ donors are being used with increasing frequency 3 HCV HCC risk 1Transplantation 217;11: ) 2American Journal of Transplantation 217; 17: Transpl Infect Dis. 218;2:e1289 Cure of Hepatitis C Reduces Liver Related Complications in those with hepatitis C Direct vs indirect mechanisms of carcinogenesis in the HCV-infected liver Van der Meer, et al. JAMA 212:38: Lemon et al GASTROENTEROLOGY 212;142: De Novo HCC After DAA Treatment: Multinodular presentation early post DAAs Pts, % Italian registry study of HCV-infected pts with no current or prior HCC, treated with DAAs Mean follow-up after starting DAA therapy: 3.8 ± 1 days 1 8 Single HCC Nodule 2-3 HCC Nodules > 3 Nodules/Infiltrative SVR yes SVR no SVR pending Romano A, et al. AASLD 216. Abstract 19. Pts, % Months After Initiation of DAA Therapy HCC Recurrence Following HCV DAA Therapy Retrospective study of pts with history of HCC before starting HCV DAAs (N = 15) AFP levels ranged from ng/ml in those who had response HCC Recurrence (%) Recurrence in Pts With Previous HCC Complete radiologic Response n/n = 36/1 24/77 9/2 All Pts Confirmed Radiologic Assessment Started DAA 4 Mos After CR 1 pts had second HCC recurrence or progression Endpoint Median time from DAA start to first recurrence, mos (IQR) Pts With Recurren ce (n = 24)* 3.5 (2-7.6) After Starting Median time from first to DAA second Among pts starting DAAs 4 mos 6 (3.2- recurrence/progression, after CR, 4 pts (2%) died 8.2) mos (IQR) 6/2 (3) Within 6 mos of first Deaths occurred in Months 9, 1, recurrence, n/n (%) 15, 16 after starting DAA 5 (2.8) Death, n (%) Reig M, et al. EASL 217. Abstract PS-31. Reproduced with *Pts from cohort with confirmed radiologic permission. assessment, no confounding factors. 4

5 Evolution of each patient in time periods Reig M, et al. EASL 217. Abstract PS-31.. HCC Recurrence Equivalent With DAAs and IFN Meta-analysis and meta-regression analysis comparing risk of HCC after SVR with DAA- vs IFN-based therapy in 41 studies (n = 13,875) Pts With First HCC Occurrence After SVR Characteristic DAA IFN Age, yrs 6 52 Cirrhosis, % 9 87 Child-Pugh Class B/C, % 34 Follow-up, yrs Dore G, et al. EASL 217. Abstract PS-16. Pts With HCC Recurrence After SVR Characteristic DAA IFN Pts with previous curative HCC 96 1 treatment, % Follow-up, yrs After adjusting for these factors, no difference in risk of HCC occurrence (arr:.75) or recurrence (arr:.62) between DAAs and IFN Impact of age and follow on HCC De Novo HCC After DAA Treatment in Pts With Cirrhosis Rate per 1 Pt-Yrs Pts with compensated or decompensated cirrhosis and SVR after SOF-based HCV treatment At baseline, 9/845 (1%) had HCC Median follow-up after end of DAA therapy: 85 wks (range: 8-187) Events n Exposure-Adjusted HCC Incidence Rates.5 Compensated Cirrhosis Muir A, et al. AASLD 216. Abstract Decompensated Cirrhosis 1 21 Survival Probability (No HCC Event) Pts at Risk, n CPTA 663 CPTB 177 CPTC 24 HCC Occurrence by Cirrhosis Status Yrs From Start of Treatment HCV/HCC risk in DAA patients De Novo HCC risk unlikely to be increased by HCV therapy, risk likely relates to underlying disease state Recurrent HCC, particularly after noncurative Rx is more controversial When aggressive recurrences are reported, they are early and often multinodular The mechanism is unclear It is possible that in cirrhotic patients, DAA therapy significantly reduced HCC immune response or that regeneration post clearance promotes HCC growth Wait until HCC controlled for 6-12 months prior to initiating HCV therapy Until further data discretion is the better part of valor DAA Failures If you cannot control HCC, eradicating HCV will not influence overall outcome Image just prior to initiation of therapy and 3 months into treatment Chase down all elevated AFP as it suggests there is viable HCC 5

6 The failure rate is low but how do we re-treat patients who do fail on new DAAs? Summary of Phase 3 studies of IFN-free therapy in GT 1 patients published in the Trial New England Regimen Journal of Medicine in 214* ION-1 LDV/SOF ± RBV ION-2 LDV/SOF ± RBV ION-3 LDV/SOF ± RBV SAPPHIRE-I SAPPHIRE-II PEARL-III PEARL-IV TURQUOISE-II 4% 368/ 3826 SVR Differing Rates of RAS Persistence Post-Therapy Median time to disappearance of NS3 RASs = ~8 months Majority of NS5A RASs remain detectable for more than 2 years Liang J, Ghany MG. N Engl J Med 214;37:243 7 *Included treatment-naïve and -experienced patients ± cirrhosis. Soriano V, AIDS Rev. 216 (%) POLARIS-1: /VOX for eeks in NS5A Inhibitor- Experienced HCV GT 1 6 Results by Genotype GT 1 1 relapse 1 breakthrough 1 withdrew consent 1 LTFU 97 Reference: 1. Bourliere M, et al. N Engl J Med. 217;376: relapses 74 1 relapse 1 withdrew consent GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT POLARIS-4: /VOX or for eeks in Non- NS5A Inhibitor DAA-Experienced HCV GT 1 4 (%) Results by Genotype /VOX 12 weeks (n = 182) 12 weeks (n = 151) relapse 1 death 2 LTFU relapses 1 relapse 1 breakthrough 8 relapses GT1a GT1b GT2 2 GT3 3 GT Reference: 1. Bourliere M, et al. N Engl J Med. 217;376: /VOX indications for treatment in US almost exclusively salvage strategy MAGELLAN-1, PART 2: GLECAPREVIR/PIBRENTASVIR FOR 12 OR 16 WEEKS IN PATIENTS WITH CHRONIC HCV GENOTYPE 1 OR 4 AND PRIOR DIRECT-ACTING ANTIVIRAL TREATMENT FAILURE Genotype 1, 2, 3, 4, 5, or 6 Patients Previously Treated with An NS5A inhibitor Duration 12 weeks Key baseline NS3 and NS5A substitutions were only present in patients with prior failure to both PI and NS5A inhibitors 1a or 3 Sofosbuvir without an NS5A inhibitor 12 weeks AASLD/IDSA additionally recommends /VOX-12 in treatment-naïve, geno-3, cirrhotics who have Y93H RAS as an alternative to -12 or G/P-12 AASLD/IDSA additionally recommends patients with genotype 3 and prior NS5A inhibitor failure and cirrhosis, to add weight-based ribavirin to /VOX 5/9 of these patients achieved Key NS3 positions: 155, 156, 168 Key NS5A positions: 24, 28, 3, 31, 58, 92, 93 OTVF: on treatment virologic failure Y93H/N at baseline: 1% (13/13) in patients with NS5A inhibitor experience (PI-naïve) 6

7 Glecaprevir/Pibrentasvir in treatment experienced individuals including DAA failures Genotype Patients Previously Treated With: Treatment Duration Compensated No Cirrhosis Cirrhosis (CPT-A) *An NS5A inhibitor 1 without prior treatment with an NS3/4A 16 weeks 16 weeks 1 PI An NS3/4A PI 2 without prior treatment with an NS5A 12 weeks 12 weeks inhibitor 1, 2, 4, 5, or 6 PRS 3 8 weeks# 12 weeks 3 PRS 3 16 weeks 16 weeks *AASLD/IDSA lists P/G as alternative to /VOX # AASLD/IDSA recommends 12 weeks, not 8 weeks treatment duration HCV in Renal Disease (CKD) 1. In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin. 2. In clinical Reference: trials, 1. Mavyret subjects [prescribing were information]. treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, AbbVie, Inc.; or 217. telaprevir with pegylated interferon and ribavirin 3. PRS=Prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor EXPEDITION-4: Glecaprevir/Pibrentasvir in CKD GT1 6 Stage 4/5 CKD +/- cirrhosis TN or TE Treatment Period G/P N = 14 Post-Treatment Period G/P is coformulated and dosed once daily as three 1 mg/4 mg pills for a total dose of 3 mg/12 mg Objective Determine the efficacy and safety of pangenotypic G/P for 12 weeks in patients with HCV GT1-6 and stage 4 or 5 chronic kidney disease (CKD) Gane, E., et al. "Efficacy And Safety Of Glecaprevir/Pibrentasvir (ABT-493/ABT-53) in patients with renal impairment and chronic hepatitis C virus genotype 1-6 infection." Hepatology 64 (216) 36 Weeks GRAZOPREVIR PLUS ELBASVIR IN NAIVE AND TREATMENT- EXPERIENCED PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION AND CHRONIC KIDNEY DISEASE GZR/EBR 12 weeks Patients, (%) % 94% / /122 Modified Full Analysis Full Analysis Set Set Relapse 1* 1 Discontinued unrelated to 6 Tx MFAS = primary efficacy analysis; FAS was a secondary analysis *Noncirrhotic, interferon-intolerant patient with HCV GT1b infection relapsed at FW12 lost to follow-up (n=2), n=1 each for death, non-compliance, withdrawal by subject, and withdrawal by physician (due to violent behavior) Lancet. 215 Oct 5. pii: S (15) Safety and Efficacy of Treatment With Once-Daily Ledipasvir/Sofosbuvir (9/4 mg) for eeks in Genotype 1 HCV-Infected Patients With Severe Renal Impairment 2 RBV free options post transplant (and pan genotypic) There was no clinically meaningful change in egfr: there was a 1.2-mL/min/1.73m 2 decrease from baseline to end of treatment Similar results #118: Sofosbuvir with NS5A Inhibitors in Hepatitis C Virus Infected Patients with Severe Renal Insufficiency Lawitz et al HEPATOLOGY (1). #1587 7

8 Safety and Efficacy of Glecaprevir/Pibrentasvir in Liver or Renal Transplant Adults with Chronic Hepatitis C Genotype 1-6 Infection Sofosbuvir/Velpatasvir for eeks in Genotype 1 4 HCV-Infected Liver Transplant Recipients One GT3a relapse at PTW4 One patient LTFU Reau et al EASL 217 excludes non-virologic failures No changes in immunosuppression were needed for rejection or suspected drug-drug interactions Agarwal et al HEPATOLOGY (1). #169 We can treat high risk populations (PWID) and achieve SVR with low rates of relapse If you are not having re-infection cases, you are not treating high risk populations HEPATITIS C VIRUS REINFECTION AND INJECTING RISK BEHAVIOR FOLLOWING ELBASVIR/GRAZOPREVIR TREATMENT IN PARTICIPANTS ON OPIATE AGONIST THERAPY: C-EDGE CO-STAR PART B Open to all participants who received 1 dose of EBR/GZR in Part A Assessments every 6 months HCV RNA Comparison of viral sequences at baseline and virologic recurrence to determine reinfection Urine drug screen Participant-reported behaviors Behavioral questionnaire: self-reported drug use Dore et al HEPATOLOGY (1). 195 Reinfection rates remain low in at risk populations Wyles et al: Similar rates of HCV recurrence in HCV/HIV and HCV infected participants who achieved SVR after DAA treatment Interim report median time since completion of HCV therapy was weeks and 11.1 weeks for HCV/HIV and HCV participants, respectively Sylvestre et al: No Evidence of 1-Year Reinfection after Treating HCV at a Methadone Program Summary The number of difficult to treat populations to treat is shrinking We can cure most people with hepatitis C we encounter if they comply with therapy Optimal management of decompensated patients still not yet defined, but we are getting closer, work with your transplant center Rigorously survey HCV cirrhosis patients/hcc patients whom you treat HCV with DAAs Work with centers of excellence on these patients Post SVR, risks of progressive liver disease/hcc remain, though are reduced Effective treatment of opiate addiction appears to lower risk of reinfection Wyles et al HEPATOLOGY (1).978 Sylvestre et al HEPATOLOGY (1) We will need to treat populations that have not been historically treated 8