Activity Overview. Target Audience

Transcription

1 Activity Overview In this activity, Dr. Kwo discusses treatment approaches for the few populations in which HCV remains difficult to treat, including patients who have not responded to direct acting antiviral treatment, those with advanced renal disease, and those who have undergone transplantation. Target Audience This activity is intended for primary care clinicians.

2 Accreditation / Designation Statements In support of improving patient care, Indiana University School of Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Indiana University School of Medicine designates this enduring material for a maximum of.5 AMA PRA Category Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure Policy In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members participating in an IUSM sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity. Indiana University School of Medicine and Med IQ require any person in a position to control the content of an educational activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines relevant financial relationships as those in any amount occurring within the past 2 months, including those of a spouse/life partner, that could create a conflict of interest (COI). Individuals who refuse to disclose will not be permitted to contribute to this CME activity in any way. Med IQ has policies in place that will identify and resolve COIs prior to this educational activity. Med IQ also requires faculty to disclose discussions of investigational products or unlabeled/unapproved uses of drugs or devices regulated by the US Food and Drug Administration. Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.

3 Disclosure Statements The content of this activity has been peer reviewed and has been approved for compliance. The faculty and contributors have indicated the following financial relationships, which have been resolved through an established COI resolution process, and have stated that these reported relationships will not have any impact on their ability to give an unbiased presentation. Paul Y. Kwo, MD Consulting fees/advisory boards: AbbVie Inc., Gilead Sciences, Inc., Merck & Co., Inc. The peer reviewers and activity planners have no financial relationships to disclose. Acknowledgment of Commercial Support This activity is supported by educational grants from AbbVie Inc. and Gilead Sciences, Inc. Copyright 28 The Indiana University School of Medicine

4 Instructions to Receive Credit To receive credit, read the introductory CME material, listen to the audiocast, and complete the evaluation, attestation, and post test, answering at least 7% of the post test questions correctly Contact Information Call (toll free) iq.com Please visit us online at IQ.com for additional activities provided by Med IQ.

5 Learning Objectives Upon completion, participants should be able to: Outline the treatment potential and limitations for difficult to treat HCV cases Paul Y. Kwo, MD Professor of Medicine Chief of Hepatology Stanford University Stanford, CA Faculty

6 Activity Planners Sara C. Miller, MS Director, QI Institute, CE Strategy and Content Med IQ Baltimore, MD Jill Phillips Compliance and Meeting Planning Specialist Indiana University School of Medicine Indianapolis, IN Samantha Gordon CME Specialist Med IQ Baltimore, MD Who Left Is Difficult to Treat? Decompensated cirrhosis (challenges remain) DAA failure (routine) Renal failure (mostly routine) PWID (challenges remain) HCV/HCC (challenges remain) Post liver transplant (routine) AASLD IDSA. hcvguidelines.org.

7 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/Opioid Agonist Therapy > 95% Those with decompensated cirrhosis who have failed therapy remain one of the few special populations in need of additional therapies Protease inhibitors cannot be given in decompensated cirrhosis HCV Treatment in Patients With Decompensated Cirrhosis Lower SVR rates than in those with compensated cirrhosis Comparable SVR rates in CTP B/C patients treated with 2 and 24 weeks of sofosbuvir based therapies Improvements in MELD scores and CTP scores have been observed No data yet on improved survival High posttransplant SVR rates have been reported with multiple therapies More data required to offer best options to avoid MELD purgatory Use of HCV positive donors becoming routine

8 Child Turcotte Pugh Classification Points 2 3 Encephalopathy None Grade 2 (or precipitant induced) Ascites None Mild/Moderate (diuretic responsive) Grade 3 4 (or chronic) Severe (diuretic refractory) Bilirubin (mg/dl) < > 3 Albumin (g/dl) > < 2.8 PT (see prolonged) or INR < 4 < > 6 > 2.3 CTP score: CTP class: Obtained by adding the score for each parameter A = 5 6 points; B = 7 9 points; C = 5 points Pugh RN, et al. Brit J Surg. 973;6: Dose Adjustments of DAAs in Cirrhosis Protease Inhibitors Should Not Be Used in CTP B/C CTP Class Sofosbuvir Simeprevir Ribavirin Ledipasvir/ Sofosbuvir A 4 mg 5 mg,,2 mg 9 mg/4 mg B 4 mg No 6 mg 9 mg/4 mg C 4 mg No 6 mg 9 mg/4 mg CTP Class PTV/OMB/DSB Daclatasvir Elbasvir/ Grazoprevir Sofosbuvir/ Velpatasvir Glecaprevir/ Pibrentasvir A 75/5/2.5 mg + 6 mg 5 mg/ mg 4 mg/ mg 3 mg/2 mg 25 mg B No 6 mg No 4 mg/ mg No C No 6 mg No 4 mg/ mg No Bifano M, et al. AASLD 2. Abstract 362; Garimella K, et al. Clinical Pharm 24. Abstract P43; Sofosbuvir [package insert]; Simeprevir [package insert]; Khatri A, et al. AASLD 22. Abstract 758; German P, et al. AASLD 23. Abstract 467; Kirby R, et al. Clinical Pharm 23. Abstract PO2.

9 Why Are Rates of Virologic Failure Higher in Advanced Cirrhosis? Decreased hepatocyte mass Decreased drug delivery Decreased drug uptake First Line Treatment Options Lead to Good SVR Rates (> 85%) HCV Genotype Decompensated Cirrhosis, RBV a Tolerant, 4 LDV/SOF/RBV SOF/VEL/RBV SOF/DAC/RBV 2, 3 SOF/VEL/RBV SOF/DAC/RBV 5, 6 LDV/SOF/RBV SOF/VEL/RBV 2 wk 2 wk 2 wk 2 wk 2 wk 2 wk 2 wk Decompensated Cirrhosis, RBV Intolerant LDV/SOF SOF/VEL SOF/DAC SOF/VEL SOF/DAC LDV/SOF SOF/VEL 24 wk 24 wk 24 wk 24 wk 24 wk 24 wk 24 wk Adverse Events (DAAs without RBV) (occurring in % of patients) Fatigue, headache, nausea Fatigue, headache, nausea, anemia Fatigue, headache, nausea Fatigue, headache, nausea, anemia Fatigue, headache, nausea Fatigue, headache, nausea Fatigue, headache, nausea, anemia Start RBV 6 mg with LDV/SOF or SOF/DAC, full dose with SOF/VEL (6 mg in CTP C) a Primary toxicity associated with ribavirin is hemolytic anemia AASLD IDSA. hcvguidelines.org.

10 LDV/SOF + RBV: SVR2 in Genotype and 4 Patients With Decompensated Cirrhosis SVR2, % (72 95) (74 97) Comparable Efficacy Between SOLAR and SOLAR 2 Studies (68 96) (7 96) (7 96) 8 SVR2, % (8 ) 85 (66 96) 78 (6 9) 2 n/n = 26/ 3 24/ 27 9/ 22 2/ 23 CTP B CTP C SOLAR : GT and 4 2 n/n = LDV/SOF + RBV 2 weeks LDV/SOF + RBV 24 weeks 2/23 22/23 7/2 CTP B CTP C SOLAR 2: GT 8/23 Charlton M, et al. Gastroenterology. 25;49:649 59; Manns M, et al. Lancet Infect Dis. 26;6: ASTRAL 4: SVR2 in Genotype Patients With CTP B SVR2, % relapses 2 deaths LTFU relapse 2 deaths 3 relapses 3 LTFU 6/68 SOF/VEL 2 weeks 65/68 SOF/VEL+ RBV 2 weeks 65/7 SOF/VEL 24 weeks Curry MP, et al. N Engl J Med. 25;373:

11 ASTRAL 4: SVR2 in Genotype 3 Patients With CTP B SVR2, % relapses death 5 breakthrough relapse 5 breakthrough 4 relapses death 7/4 SOF/VEL 2 weeks /3 SOF/VEL+ RBV 2 weeks 6/2 SOF/VEL 24 weeks Curry MP, et al. N Engl J Med. 25;373: HCC Risk

12 Curing HCV Reduces Liver Related Complications All Cause Mortality, % No. at risk Without SVR With SVR HCC, % No. at risk Without SVR With SVR Without SVR With SVR P <. 2 3 All Cause Mortality Time, years Without SVR With SVR P <. 2 3 HCC Time, years Liver Related Mortality or Liver Transplantation, % No. at risk Without SVR With SVR Liver Failure, % No. at risk Without SVR With SVR Liver Related Mortality or Liver Transplantation Without SVR With SVR P < Time, years Without SVR With SVR P <. 2 3 Liver Failure Time, years van der Meer AJ, et al. JAMA. 22:38: De Novo HCC After DAA Treatment: Multinodular Presentation Early Post DAAs Italian registry study of HCV infected patients with no current or prior HCC, treated with DAAs Mean follow up after starting DAA therapy: 3.8 ± days 8 Single HCC nodule 2 3 HCC nodules > 3 nodules/infiltrative 8 Patients, % Patients, % SVR yes SVR no SVR pending Months After Initiation of DAA Therapy Romano A, et al. AASLD 26. Abstract 9.

13 HCC Recurrence Following DAA Treatment Retrospective study of patients with a history of HCC before starting DAAs (N = 5) AFP levels ranged from 369 ng/ml in those who had a response HCC Recurrence, % Recurrence in Patients With Previous HCC Radiologic CR n/n = 36/ 24/77 9/2 All patients Confirmed Started DAAs radiologic 4 months assessment after after CR starting DAAs Endpoint Among patients starting DAAs 4 months after CR, 4 (2%) died Deaths occurred in months 9,, 5, and 6 after starting DAA a Patients from cohort with confirmed radiologic assessment, no confounding factors. Patients Had Second HCC Recurrence or Progression Median time from DAA start to first recurrence, months (IQR) Median time from first to second recurrence/progression, months (IQR) Within 6 months of first recurrence, n/n (%) Death, n (%) Patients With Recurrence (n = 24) a 3.5 (2 7.6) 6 ( ) 6/2 (3) 5 (2.8) Reig M, et al. EASL 27. Abstract PS 3. Reproduced with permission. 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 4 studies (N = 3,875) Patients With First HCC Occurrence After SVR Characteristic DAA IFN Age, years 6 52 Cirrhosis, % 9 87 CTP class B/C, % 34 Follow up, years. 5.5 Patients With HCC Recurrence After SVR Characteristic DAA IFN Patients with previous curative HCC treatment, % 96 Follow up, years.3 5. After adjusting for these factors, no difference in risk of HCC occurrence (arr,.75) or recurrence (arr,.62) between DAAs and IFN Dore G, et al. EASL 27. Abstract PS 6.

14 HCC Risk and DAA Therapy De novo HCC risk unlikely to be increased by HCV therapy; risk likely relates to underlying disease state Small percentage of patients may have undetected HCC that transitions to an aggressive presentation Recurrent HCC, particularly after noncurative treatment, 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 reduces HCC immune response or regeneration post clearance promotes HCC growth Wait until HCC is controlled for 6 2 months prior to initiating HCV therapy Until further data, discretion is the better part of valor If you cannot control HCC, eradicating HCV will not influence overall outcome Image just prior to therapy initiation and 3 months into treatment Chase down all elevated AFP as it suggests there is viable HCC DAA Failure

15 Retreatment of Patients Who Fail on New DAAs Summary of phase 3 studies of IFN free therapy in genotype patients published in the New England Journal of Medicine in 24 a Trial ION ION 2 ION 3 SAPPHIRE I SAPPHIRE II PEARL III PEARL IV TURQUOISE II Regimen LDV/SOF ±RBV LDV/SOF ±RBV LDV/SOF ±RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV 4% 3,68/ 3,826 a Included treatment naïve and experienced patients ± cirrhosis. SVR Liang TJ, et al. N Engl J Med. 24;37: Differing Rates of Posttreatment RAS Persistence RAVs, % NS5A inhibitors Non nucleoside polymerase inhibitors Protease inhibitors Sofosbuvir Median time to disappearance of NS3 RASs = ~8 months Majority of NS5A RASs remain detectable for more than 2 years % Days Months Years Soriano V, et al. AIDS Rev. 26;8:8 8.

16 POLARIS : SOF/VEL/VOX for 2 Weeks in NS5A Inhibitor Experienced Patients With Genotypes 6 SVR2 Results by Genotype SVR2, % GT relapse breakthrough withdrew consent LTFU relapses relapse withdrew consent GT a GT b GT 2 GT 3 GT 4 GT 5 GT Overall SVR was 96%, which was significantly superior to prespecified performance goal of 85% (P <.) Bourliere M, et al. N Engl J Med. 27;376: POLARIS 4: SOF/VEL/VOX or SOF/VEL for 2 Weeks in Non NS5A Inhibitor Experienced Patients With Genotypes 4 8 SVR2 Results by Genotype SOF/VEL/VOX 2 weeks (n = 82) SOF/VEL 2 weeks (n = 5) SVR2, % relapse death 5 relapses relapse breakthrough 3 3 GT a GT b GT 2 GT 3 GT LTFU relapses Bourliere M, et al. N Engl J Med. 27;376:

17 SOF/VEL/VOX Indications for Treatment: In US, Almost Exclusively Salvage Strategy Genotype Previous Treatment Duration, 2, 3, 4, 5, or 6 An NS5A inhibitor 2 weeks a or 3 Sofosbuvir without an NS5A inhibitor 2 weeks AASLD IDSA additionally recommends SOF/VEL/VOX for 2 weeks in treatment naïve, genotype 3 patients with cirrhosis who have Y93H RAS as an alternative to SOF/VEL for 2 weeks or glecaprevir/pibrentasvir for 2 weeks AASLD IDSA additionally recommends adding weight based ribavirin to SOF/VEL/VOX for genotype 3 patients with cirrhosis and prior NS5A inhibitor failure AASLD IDSA. hcvguidelines.org. MAGELLAN, PART 2: Glecaprevir/Pibrentasvir for 2 or 6 Weeks in Patients With Chronic HCV Genotype or 4 and Prior DAA Failure SVR2, % Baseline Substitutions 3 3 None 2 2 NS3 only 3 relapses OTVF 2 24 NS5A only 3 3 None 4 4 NS3 only OTVF NS5A only Key baseline NS3 and NS5A substitutions were present only in patients with prior failure to both PI and NS5A inhibitors 5/9 of these patients achieved SVR2 Key NS3 positions: 55, 56, 68 Key NS5A positions: 24, 28, 3, 3, 58, 92, 93 Regimen G/P: 2 Weeks G/P: 6 Weeks Y93H/N at baseline: % (3/3) SVR2 in patients with NS5A inhibitor experience (PI naïve) Poordad F, et al. Hepatology. 28;67:253 6.

18 Glecaprevir/Pibrentasvir in Treatment Experienced Patients, Including DAA Failures Treatment Duration Genotype Previous Treatment Compensated No Cirrhosis Cirrhosis (CTP A) An NS5A inhibitor without prior NS3/4A PI a 6 weeks 6 weeks An NS3/4A PI 2 without prior NS5A inhibitor 2 weeks 2 weeks, 2, 4, 5, or 6 PRS 3 8 weeks b 2 weeks 3 PRS 3 6 weeks 6 weeks. In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin 2. In clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin 3. 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 a AASLD IDSA lists G/P as alternative to SOF/VEL/VOX. b AASLD IDSA recommends 2 weeks, not 8 weeks, as treatment duration MAVYRET [package insert]. AbbVie, Inc.; 27. HCV in Renal Disease (CKD)

19 EXPEDITION 4: Glecaprevir/Pibrentasvir in CKD Treatment Period Posttreatment Period GT 6 SVR2 Stage 4/5 G/P CKD N = 4 +/ Cirrhosis TN or TE Weeks G/P is coformulated and dosed once daily as three mg/4 mg pills for a total dose of 3 mg/2 mg Objective Determine the efficacy and safety of pan genotypic G/P for 2 weeks in patients with HCV genotypes 6 and stage 4 or 5 CKD SVR2, % 98% ITT Breakthrough Relapse Discontinuation LTFU Gane E, et al. N Engl J Med. 27;377: Grazoprevir Plus Elbasvir in Treatment Naïve and Experienced Patients With HCV Genotype and CKD 99% GZR/EBR 2 weeks 94% SVR2, % /6 5/22 Modified FAS FAS Relapse a Discontinuation unrelated to Tx 6 b Modified FAS was the primary efficacy analysis; FAS was a secondary analysis. a Noncirrhotic, interferon intolerant patient with HCV GTb infection relapsed at FW2. b LTFU (n = 2), n = each for death, noncompliance, withdrawal by subject, and withdrawal by physician (due to violent behavior). Roth D, et al. Lancet. 25;386:

20 Safety and Efficacy of Treatment With Once Daily LDV/SOF (9 mg/4 mg) for 2 Weeks in Genotype Patients With Severe Renal Impairment SOF AUC Ʈ, h, ng/ml LDV/SOF 2 Weeks, n = 8 Mean age, years (range) 57 (32 66) Male, n (%) 2 (67) White, n (%) 8 (44) Black, n (%) (56) Mean BMI, kg/m 2 (range) 3 (2 39) Mean egfr, ml/min/.73 m 2 (range) 24.9 ( ) Cirrhosis, n (%) 2 () HCV GT (total), n (%) 8 () a 4 (78) b 4 (22) IL28B non CC, n (%) 7 (94) Mean HCV RNA, log IU/mL (range) 6.2 (5. 7.),, SOF AUC Phase 2/3 Severe RI GS 337 AUC Ʈ h, ng/ml,,,, GS 337 AUC Phase 2/3 Severe RI There was no clinically meaningful change in egfr: there was a.2 ml/min/.73 m 2 decrease from baseline to end of treatment Similar results reported in #8: sofosbuvir with NS5A inhibitors in HCV infected patients with severe renal insufficiency Lawitz E, et al. Hepatology. 27;66:Abstract 587. SVR2, % LDV AUC Ʈ, h, ng/ml, 8/8 LDV/SOF 2 weeks,, LDV AUC Phase 2/3 Severe RI 2 RBV Free Options Posttransplant (and Pan Genotypic)

21 Safety and Efficacy of Glecaprevir/Pibrentasvir in Liver or Renal Transplant Patients With Chronic HCV Genotype 6 Infection 8 98% (95.3% %) 99% (97% %) Noninferiority threshold SVR2, % 6 4 SVR2, ITT One genotype 3a patient relapsed at PTW4 One patient LTFU SVR2, mitt Reau N, et al. Hepatology. 28. [epub ahead of print]. Sofosbuvir/Velpatasvir for 2 Weeks in Genotype 4 HCV Infected Liver Transplant Recipients Week 2 24 SVR2 N = 79 SOF/VEL Mean time since transplant, years 8.7 ( ) (range) Immunosuppressant use, n (%) Tacrolimus 56 (7) Cyclosporine (4) Sirolimus 8 () Everolimus 5 (6) Mycophenolate 9 (24) Azathioprine 9 () Prednisolone () No changes in immunosuppression were needed for rejection or suspected drug drug interactions SVR2, % Relapse OTVF Other 98% SVR Total 2 7% No RAS 55/79 NS5A RAS 3% RAS 24/ GT GT a 98% SVR2 GT b 96% SVR2 NS5B NI RAS 8% RAS 6/77 92% No RAS 7/77 % SVR2 54/55 22/24 68/7 6/ GT 2 2 virologic relapses occurred in patients with baseline NS5A RASs Genotype 3b patient with A3K+L3M at baseline Genotype a patient with K24R at baseline 4 patients with baseline Y93H RASs (3 genotype 3 and genotype b) GT GT 4 Agarwal K, et al. J Hepatol. 28. [epub ahead of print]

22 We Can Treat High Risk Populations (eg, PWID) and Achieve SVR With Low Rates of Relapse If you are not seeing reinfection cases, you are not treating high risk populations HCV Reinfection and Drug Related Risk Behavior Following Elbasvir/Grazoprevir Treatment in Participants on Opioid Agonist Therapy: C EDGE CO STAR Part B Open to all participants who received 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: selfreported drug use Reinfection rate was 2.3/ personyears, with a persistent reinfection rate of.6/ person years Participants, % Reinfection Free Survival, % of Participants Visit No. at risk month follow up (n = 9) month follow up (n = 78) Persistent reinfections (n = 7) All reinfections (n = ) Mean duration of follow up: 75 weeks (range, 36 weeks) EOT Duration of Follow Up, weeks FW2 FW24 6m FU 2m FU 8m FU Noninjecting drug use previous 6 months Noninjecting drug use previous month Injecting drug use previous 6 months Injecting drug use previous month 8 month follow up (n = 73) 24m FU month follow up (n = 8) Reinfection with subsequent clearance (n = 3) Persistent reinfection (n = 7) Time to Reinfection Post EOT (weeks) 8, 9, 9 9,, 24, 32, 52, 84, 25 Dore G, et al. Hepatology. 27;66:Abstract 95.

23 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 2.9 weeks and. weeks for HCV/HIV and HCV participants, respectively Follow up, person years HCV recurrences, n HCV/HIV HCV 9.6 Incidence rate (95% CI).35/ p y (..94) Sylvestre et al: No evidence of year reinfection after treating HCV at a methadone program Patients With > 9% Adherence, % / p y (. 2.92) > 9% Adherence vs Substance Use Virologic Response No Yes EtOH Heroin Cocaine Methamphetamine Cannabis ETR SVR 2 SVR yr Effective treatment of opiate addiction appears to lower risk of reinfection Patients, % ITT As treated Wyles D, et al. Hepatology. 27;66:Abstract 978; Sylvestre DL, et al. Hepatology. 27;66:Abstract LB 8. Summary The number of difficult to treat populations is shrinking We can cure most people with HCV if they adhere to therapy Optimal management of decompensated patients still not yet defined, but we are getting closer; work with your transplant center Rigorously survey HCV patients with cirrhosis or HCC whom you treat with DAAs Work with centers of excellence on these patients Post SVR, risks of progressive liver disease/hcc remain, though are reduced We will need to treat populations that have not been historically treated

24 28 Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors.