Hepatitis C in Special Populations

Transcription

1 Hepatitis C in Special Populations David E. Bernstein, MD, FACG Vice Chairman of Medicine for Clinical Trials Chief, Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases Northwell Health System Professor of Medicine Hofstra Northwell School of Medicine Hepatitis C Special Populations Renal Disease Genotype 3 Pre-transplantation (decompensated disease) Post-transplantation Copyright 216 American College of Gastroenterology Page 1 of 21

2 TREATMENT OF HCV in PATIENTS WITH RENAL DISEASE Renal Disease and Hepatitis C Not Not caused by HCV Secondary to HCV Drugs PAN MPGN Copyright 216 American College of Gastroenterology Page 2 of 21

3 HCV and Renal Disease HCV can cause renal disease Cryoglobulinemia, MPGN HCV can be seen in CKD HTN, DM Interferon had been used with some success Significant side effect profile Adverse events of RBV enhanced with abnormal renal function Concern with use of all DAA s with CrCl < 3 except elbasvir/grazeprevir Stages of Chronic Kidney Disease CKD Stage Description GFR (ml/min/1.73 m 2 ) 1 Kidney Damage with Normal or GFR >9 2 Kidney Damage with Mild GFR Moderate GFR Severe GFR Kidney Failure <15 (or dialysis) Copyright 216 American College of Gastroenterology Page 3 of 21

4 Ruby-1 Study: HCV with stage 4/5 CKD Open-label Treatment SVR4 SVR12 GT1b GT1a Paritaprevir/r/Ombitsvir + dasabuvir Paritaprevir/r/Ombitsvir + dasabuvir + RBV Day 1 Week 12 Week 24 3D: Co-formulated OBV/PTV/r (25/15/1 mg QD) and DSV (25 mg BID) For GT1a: RBV 2 mg QD For GT1b: No RBV Pockros PJ, et al. AASLD 215. Ruby 1: Ombitasvir/Paritaprevir/r + Dasabuvir + RBV in G1 with stage 4/5 kidney disease /2 2/2 18/2 RVR EOTR SVR week treatment Non-cirrhotics 14 on dialysis 13 G 1a, 7 G1b 1 subject relapsed 49 yo AA, F3, IL28 B CT, BMI 37 < 92% medication adherence 1 subject died 14 days after treatment from heart disease Pockros et al AASLD 215 Abstract 139 Copyright 216 American College of Gastroenterology Page 4 of 21

5 C-SURFER: Grazoprevir/Elbasvir in Pts With GT1 HCV and Stage 4 or 5 CKD Treatment Wk 12 Follow-up Wk 4 Follow-up Wk 16 GT1 HCV-infected pts with stage 4/5 CKD (n = 224) Randomized period Grazoprevir/Elbasvir (n = 122) Placebo (n = 113) Open-label period Grazoprevir/Elbasvir (n = 113) Grazoprevir/elbasvir dosed orally 1 mg/5 mg once daily. Grazoprevir protease inhibitor Elabasvir NS5A inhibitor Roth D, et al. EASL 215. Abstract LP2. C-SURFER: SVR12: IMMEDIATE TREATMENT GROUP GZR/EBR 12 weeks 1 99% 94% Patients, (%) /116 Modified Full Analysis Set 115/122 Full Analysis Set Relapse 1* 1 Discontinued 6 unrelated to 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) Roth D, et al. EASL 215. Abstract LP2 Copyright 216 American College of Gastroenterology Page 5 of 21

6 ELBASVIR / GRAZEPREVIR GT 1 FDA APPROVAL GT 1a TN or PEG/RBV TE without baseline RAV s Treatment Elbasvir/grazeprevir Duration 12 weeks GT 1a TN or PEG/RBV TE with baseline RAV s Elbasvir/grazeprevir + 16 weeks RBV GT 1b TN or PEG/RBV TE Elbasvir/grazeprevir 12 weeks GT 1a/1b PEG/RBV/PI TE Elbasvir/grazeprevir 12 weeks Zepatier PI Merck January 28, 216 AASLD/IDSA Dosing Considerations in With Renal Impairment with Current Therapies egfr/crcl 3-5 ml/min No adjustment needed 15-3 ml/min No adjustment needed < 15 ml/min or hemodialysis OMV/PTV/RT LDV/SOF [2] SMV + SOF, [3] RBV [5] ELB/GRZ 6 V + DSV [1] DCV + SOF [4] Safety and efficacy not ] established No adjustment needed Safety and efficacy not established Safety and efficacy not established No adjustment needed No adjustment needed for SMV or DCV; Safety and efficacy of SOF not established Safety and efficacy not established Alternating 2 mg and 4 mg every other day No adjustment needed 2 mg/day No adjustment needed 2 mg/day No adjustment needed 1. OMV/PTV/RTV + DSV [package insert]. 2. LDV/SOF [package insert]. 3. AASLD/IDSA/IAS-USA. Recommendations for testing, managing, and treating hepatitis C. 4. DCV [package insert]. 5. RBV [package insert]. 6. ELB/GRZ [package insert] Copyright 216 American College of Gastroenterology Page 6 of 21

7 TREATMENT OF GENOTYPE 3 GT 3 Is Associated With a Significantly Higher Risk of Cirrhosis and HCC vs GT 1 VA HCV Clinical Case Registry (2-29) 88,348 patients with genotype 1 (8%) 13,77 genotype 2 (12%) 8,337 genotype 3 (7.5%) Mean follow-up 5.4 years After adjustment for demographic, clinical and antiviral treatment factors, comparison between genotypes 3 and 1 Hazard Ratio Confidence Interval Cirrhosis HCC Conclusion: GT 3 is associated with a significantly higher risk of cirrhosis and HCC vs GT 1, independent of age, diabetes, BMI or antiviral treatment Kanwal F et al, Hepatology 214;6:98-15 Copyright 216 American College of Gastroenterology Page 7 of 21

8 Treatment of Genotype 3: 12 and 16 weeks of therapy Fission Naive SOF/RBV 12 wks PEG/RBV 24 wks Fusion Treatment Experienced SOF/RBV 12 wks SOF/RBV 16 wks Lawitz E, et al. N Engl J Med. 213; 368: Jacobson et al. NEJM 213,368: VALENCE: Sofosbuvir and Ribavirin for 24 weeks Week GT 3 Sofosbuvir + RBV (n = 25) SVR 12 Drug Dosing Sofosbuvir 4 mg once daily Ribavirin (weight-based and divided bid): 1 mg/day if < 75 kg or 12 mg/day if 75 kg Zeuzem S, et al. NEJM 214;37: Copyright 216 American College of Gastroenterology Page 8 of 21

9 VALENCE: 24 Wks SOF + RBV in GT 3 Patients SVR12 (%) /25 86/92 12/13 Overall Naive, Naive, Non-cirrhotic Cirrhotic 87/1 Experienced, Non-cirrhotic 27/45 Experienced, Cirrhotic Extending treatment duration to 24 weeks did not significantly increase the incidence of AEs Zeuzem S, et al. NEJM 214;37: Genotype 3: ALLY-3 Study Design Treatment-naive N = 11 Treatment-experienced N = 51 DCV 6 mg + SOF 4 mg QD DCV 6 mg + SOF 4 mg QD Follow-up Day 1 Week 12 Week 24 Week 36 Primary endpoint: SVR12 SVR12 Eligible patients Age 18 years with chronic GT 3 infection and HCV RNA 1, IU/mL Treatment-naive or -experienced (prior treatment failures), including patients with cirrhosis Those who received prior treatment with NS5A inhibitors were excluded Nelson et al. Hepatology 215; 61: Copyright 216 American College of Gastroenterology Page 9 of 21

10 DCV/SOF for GT 3: SVR12 in Treatment-naïve and Treatmentexperienced patients Treated for 12 Weeks (ALLY-3) SVR12 (%) /11 44/51 Treatment-naive Treatment-experienced Nelson DR, Hepatology 215; 61: SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3) 1 Overall Tx-naive Tx-experienced 8 SVR12 (%) No Yes No Yes No Yes Cirrhosis Nelson DR, Hepatology 215; 61: Copyright 216 American College of Gastroenterology Page 1 of 21

11 ALLY 3+ Study: SOF/DCV/RBV for 12 vs 16 weeks in F3/4 patients 1 9 SVR 12 in Patients with Advanced Fibrosis /6 14/14 8/8 Overall 12 weeks 16 weeks Leroy et al AASLD 215 Oral LB-3 ALLY 3+ Study: SOF/DCV/RBV for 12 vs 16 weeks in F3/4 patients SVR 12 in Patients with Compensated Cirrhosis /18 31/36 16/18 Overall 12 weeks 16 weeks Leroy et al AASLD 215 Oral LB-3 Copyright 216 American College of Gastroenterology Page 11 of 21

12 Therapies in Development for Genotype 3: Not FDA approved Sofosbuvir + Velpatasvir Sofosbuvir (SOF) 1,2 Potent antiviral activity against HCV GT 1 6 Once-daily, oral, 4-mg tablet SOF Nucleotide polymerase inhibitor Velpatasvir 3-5 Picomolar potency against HCV GT 1 6 PK supports once-daily dosing GS-5816 NS5A inhibitor SOF + Velpatasvir 6 Treatment for 12 weeks resulted in high SVR in treatment-naïve patients with HCV GT 1 6 without cirrhosis SOF + GS Jacobson IM, et al. New Engl J Med 213;368: ; 2. Lawitz E, et al. New Engl J Med 213;368: ; 3. Cheng G, et al. EASL 213, poster 1191; 4. German P, et al. EASL 213, poster 1195; 5. Lawitz E, et al. EASL 213, poster Everson G, et al. EASL 214, oral presentation. Copyright 216 American College of Gastroenterology Page 12 of 21

13 ASTRAL 3 Results: SVR 12 p <.1* SVR12 (%) / /275 SOF/VEL 12 Weeks SOF + RBV 24 Weeks *p-value for superiority of SOF/VEL compared with SOF+ RBV. Error bars represent 95% confidence intervals. Foster et al. NEJM 215 ASTRAL 3: Results: SVR12 by Cirrhosis and Treatment History 1 8 SOF/VEL SOF + RBV SVR12 (%) No Error bars represent 95% confidence intervals. Yes Treatment Naïve No Yes Treatment Experienced Cirrhosis Foster et al NEJM Copyright 216 American College of Gastroenterology Page 13 of 21

14 SURVEYOR-II Part 1 (GT3): Study Design Open-label, phase 2 trial evaluating the safety and efficacy of coadministered ABT-493 (PI) and ABT-53 (NS5a inhibitor), at varying doses, ± ribavirin (RBV), in patients with HCV GT3 infection Day 1 Week 12 PT Week 24 Treatment period Post-treatment (PT) period n=3 n=3 a n=31 n=3 ABT mg + ABT mg ABT mg + ABT mg mg mg + RBV b ABT mg + ABT-53 4 mg ClinicalTrials.gov: NCT N=121. a Includes one patient who was incorrectly assigned to treatment in the GT2 cohort. b Daily dose of 1 mg or 12 mg RBV dosed BID based on patient body weight being <75 kg or 75 kg. Kwo et al AASLD 215 SURVEYOR-II Part 1 (GT3): Per Protocol SVR12 Rates by Treatment* ABT ABT-53 3 mg + 12 mg *Excluding non-virologic failures. Kwo et al AASLD mg + 12 mg 2 mg + 12 mg + RBV 2 mg + 4 mg Copyright 216 American College of Gastroenterology Page 14 of 21

15 TREATMENT OF DECMPENSATED DISEASE LDV/SOF + RBV: Genotype 1 and 4 with Decompensated Cirrhosis Week Week 12 Week 24 Week 36 LDV/SOF + RBV SVR12 LDV/SOF + RBV SVR12 SOLAR-1 Treatment naïve or experienced CPT Class B CPT Class C Post liver transplantation 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. Copyright 216 American College of Gastroenterology Page 15 of 21

16 LDV/SOF + RBV: SVR12 in Genotype 1 or 4 with Decompensated Cirrhosis LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks SVR12 (%) SVR12 (%) n/n = 26/ 3 24/ 27 CTP B SOLAR-1 [1.2] 19/ 22 18/ 2 CTP C 2 n/n = 2/ 23 22/ 23 CTP B 17/ 2 SOLAR-2 [3] 13/ 18 CTP C 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. Solar 2: LDV/SOF + RBV: Change in MELD Score from Baseline to Follow-up Week 4 in CPT B or C Disease 4 Pre/Post-Transplantation (CPT B and C; n = 136)* * (8) Change in MELD Score n = 18-1 (-11) (-17) ** *Missing FU-4: n = 24. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract SOLAR-2 G2. Copyright 216 American College of Gastroenterology Page 16 of 21

17 European Compassionate Use Program (CUP): SOF + DCV ± RBV for 24 Weeks SVR12, % 24-wk DCV + SOF 24-wk DCV + SOF + RBV All patients / 19/ 58/ 24/ 21/ 45/ n/n = 4 1/1 1/1 2/ A B C CP Score Treatment naive or treatment experienced CP Category: 57% CP A; 36% CP B; 6% CP C MELD Scores: >5% had MELD Scores 9 and < 15 DCV dose determined by country; inclusion of RBV based on physician discretion Welzel TM, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract P772. ASTRAL-4: Childs B Cirrhosis Wk Wk12 Wk24 Wk 36 n=75 SOF/VEL SVR12 n=75 SOF/VEL + RBV SVR12 n=75 SOF/VEL SVR12 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) Curry et al NEJM 215 Copyright 216 American College of Gastroenterology Page 17 of 21

18 ASTRAL 4: Results: SVR12 in GT SVR relapse 2 death 1 LTFU 1 relapse 2 deaths 3 relapse 3 LTFU 6/68 SOF/VEL 12 week Curry et al. NEJM /68 65/71 SOF/VEL+ RBV 12 week SOF/VEL 24 week ASTRAL 4: Results: SVR12 in GT SVR relapses 1 death 1 breakthrough 1 relapse 5 1 breakthrough 4 relapse 1 death Curry et al. NEJM 215 7/14 SOF/VEL 12 week 11/13 6/12 SOF/VEL+ RBV 12 week SOF/VEL 24 week Copyright 216 American College of Gastroenterology Page 18 of 21

19 TREATMENT POST LIVER TRANSPLANTATION SOLAR-1: SVR12 Rates in OLT Patients Receiving LDV/SOF + RBV SVR12 (%) wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 2 n/n = 53/ 55 55/ 56 25/ 26 24/ 25 22/ 15/ /5 2/3 F-F3 CPT A CPT B CPT C In the 24-week arm, 8 patients with CPT B and 1 patient with CPT C have not reached the follow-up week 12 visit MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CPT A and 8/41 patients with CPT B disease Reddy RT, et al. Hepatology. 214;6(suppl): Abstract 8. Copyright 216 American College of Gastroenterology Page 19 of 21

20 Ally-1: SOF + DCV + RBV 6 mg Post OLT SVR 12 by HCV Genotype N = SVR12, % /53 3/31 9/1 1/11 1/1 Overall 1a 1b 3 6 Genotype Poordad F, et al. Presented at: EASL 215; Abstract LO8. CORAL-1: PrOD for 24 weeks: SVR in GT1 Post Liver Transplant 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 1% 97% 97% 97% EOTR SVR4 SVR12 SVR24 33/34 had SVR One patient had a relapse (post-treatment day 3) At the time of relapse, this patient had R155K in NS3 protease, M28T+Q3R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline Kwo et al NEJM 214 RBV use at discretion of treater Copyright 216 American College of Gastroenterology Page 2 of 21

21 Conclusions: Treatment in Special Populations Renal Disease Genotype 3 Pre-transplantation Post-transplantation All have high SVR with new DAA therapies No more special populations!! Copyright 216 American College of Gastroenterology Page 21 of 21