Patients with Cirrhosis: Managing the HCV Peri-Transplant Patient Fred Poordad, MD Professor of Medicine University of Texas Health Science Center VP, Academic and Clinical Affairs The Texas Liver Institute San Antonio, TX Disclosures
• Grant/Research support: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol- Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics • Speaker: Gilead, Kadmon, Janssen, Merck, Onyx/Bayer, Genentech, Salix and Vertex • Consultant/Advisor: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol- Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance and Vertex. Hepatitis C is the Leading Cause for Liver Transplant in the US
Berg et al. Am J Transplant. 2009;9(part 2):907. Numbers of HCV Patients With Decompensated Cirrhosis and HCC Are Expected to Peak in 2020 in the US
• Increasing prevalence of decompensated cirrhosis and HCC could increase number of patients on liver transplant waiting list
160,000 Hepatocellular cancer
140,000 Decompensated cirrhosis
120,000
100,000
80,000
60,000
Number of Cases 40,000
20,000
0 1950 1960 1970 1980 1990 2000 2010 2020 2030 Year Curves indicate gender and age at time of initial HCV infection. Data are for the United States. Davis et al. Gastroenterology. 2010;138:513. El El a Studies Base 2010 cost ($/patient/year) Khoury Costs of Liver Liver of Costs Transplant Costs Higher Than Much
use a patient cohort model to estimate total cost costusing and transition probability for each et al. of Less of Less C Hepatitis for Sequelae Advanced J Viral Summary of Studies Reporting Incremental Cost by Sequela (In 2010 US $) 2010 (Inby Sequela Cost Incremental Reporting Studiesof Summary Hepat . 2012;19:153.
sequela .
a
Costs of Liver Transplants Vary Around the World
Canada UK $113,280 ($61,490-$165,070) $97,040 ($52,490-$164,390)
United States Japan $201,110 $163,140 ($173,760- ($74,920-$299,690) $223,460) Spain Taiwan $253,460 $23,150 ($132,260-$443,700) ($15,430-$30,860) Australia $132,040 Brazil ($127,920-$136,170) $64,170 New Zealand $82,530
The lowest transplantation costs have been reported in Taiwan and the highest in Western Europe El Khoury et al. J Med Econ. 2012;15:887. Widespread Use of Effective Therapy Could Significantly Reduce Need for Transplants
Potential Transplant Need
180,000 162,559 162,747
160,000 150,617
140,000 126,296 120,000 100,000 91,310 80,000 60,000 49,013
Number Number of Persons 40,000
20,000 25,573 27,175 26,207 24,258 21,994 0 18,193 0 5 10 15 20 25 30 Year in Model No treatment 25% 50% 75% treated All treated Desai et al. The Liver Meeting 2013. Abstract 1427. Numbers of HCV Patients on Liver Transplant: HCC Numbers Have Nearly Doubled Since 2007
12
Incidence rate ratioa for HCC: 1.118 (95% CI, 1.107–1.130); P<0.001
10 HCC 8 ESLD
6
IR per 100,000per IR
a 4
2 Adjusted
0 2003 2004 2005 2006 2007 2008 2009 2010 • The number of HCV patients wait-listed for HCC has risen by 12% per year on average (from 623 in 2003 to 1379 in 2010, or from 2.1 to 4.6 per 100,000) • In contrast, wait-listing due to end-stage liver disease (ESLD) has remained relatively stable over the study period (0.7% rise, from 1451 to 1674, or from 4.8 to 5.6 per 100,000) aAdjusted for age and sex. Fleming et al. The Liver Meeting 2013. Abstract 12. Pre-Transplant Therapy SOF + RBV to Prevent HCV Recurrence Post-LT
SOF 400 mg + RBV 1000‒1200 mg (n=61) pTVR12
• N=61 DDLT candidates with MELD exception for HCC – Genotypes 1-4 – CPT ≤7 (43% CP=5) – Median MELD =8 (8-14) – CrCl ≥60 mL/min – Rx-naïve (25%) or experienced (75%) – Absence of HIV or HBV
Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation Virological Response
SOF + RBV to Prevent HCV Recurrence Post-Transplant
Rate Rate (%) Viral Response Viral
• On-treatment HCV RNA suppression was rapid and similar to other patient populations on SOF regimens • Treatment with SOF + RBV was generally safe and well tolerated
*3 subjects were >LLOQ at transplant †1 subject has not reached pTVR12, 1 subject lost to follow up at Week 8 post transplant Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation Analysis of Post-Transplant Recurrence in GT 1–4 Days HCV RNA Continuously TND Prior to Transplant
No Recurrence (n=29) Recurrence (n=10)
No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days Median days TND • No recurrence: 99 • Recurrence: 5.5 p <0.001*
28
*Wilcoxon rank sum test. Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation SOF+RBV for Chronic HCV with Cirrhosis and Portal HTN ± Decompensation
• Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation for 6 months in patients with HCV cirrhosis
and portal HTN (CTP 5–9) SOF + RBV Observation n=25 n=25 Male, n (%) 18 (72) 20 (80) Wk 0 Wk 24 Wk 48 Wk 72 Wk 96 Median age, y (range) 56 (43‒69) 55 (44‒69) BMI ≥30 kg/m2, n (%) 8 (32) 7 (28) Mean HCV RNA, log IU/mL (range) 6.1 (4.4‒7.0) 6.1 (3.8‒6.9) SVR12 10 Arm 1 SOF 400 mg + RBV GT, n (%) 1000‒1200 mg n=25 1a 10 (40) 9 (36)
SVR12 1b 9 (36) 6 (24) Arm 2 SOF 400 mg + RBV Observation 2 2 (8) 1 (4) n=25 1000‒1200 mg 3 2 (8) 8 (32)
Preliminary 4 2 (8) 1 (4) results IL28B non-CC, n (%) 22 (88) 18 (72) Prior HCV treatment, n (%) 17 (68) 23 (92) Mean HVPG mmHg, n (range) 16.9 (9‒29) 16.2 (7‒27) Afdhal N, EASL, 2014, O68 HVPG >12 mmHg, n (%) 19 (76) 20 (80) Afdhal *1 patient HCV RNA < LLOQ (%)
N, EASL, 2014, O68
was a non - responder
at Week at Week 8. Virologic Response
Week
Laboratory and Clinical Event Changes
SOF+RBV Observation 24 weeks Platelets (103/µL) Albumin (g/dL) ALT (U/L) p=0.001 p=0.003 p=0.001 p=NS
CTP A CTP B
Ascites Hepatic Encephalopathy SOF + RBV Observation SOF + RBV Observation Patients, n n=25 n=25 n=25 n=25 Baseline 6 9 5 2 Week 12 5 8 3 3 Week 24 0 7 0 4 Afdhal N, EASL, 2014, O68 Post Transplant Therapy Sofosbuvir Compassionate Use Program: Patient Disposition
Severe acute hepatitis/early recurrence Post transplant compensated and (<12 months from liver transplant with typical decompensated cirrhosis [liver biopsy biochemical and histological findings) (F4) or clinical decompensation] n=48 n=56
Discon due to AE n=7 Liver transplant SOF Compassionate Use Program n=12 SOF+RBV±PEG n=104 Death N=13
Completed 24-48 weeks treatment N=72 Forns, et al. EASL 2014 Results: Baseline Characteristics
Overall Demographics (n=104) Male, n (%) 76 (73) Median age, y (range) 55 (16-76)
Median HCV RNA, log10 IU/mL (range) 8.4 (1.3-8.9) GT, n 1/1a/1b 8/29/51 2/3/4 1/7/8 Median bilirubin, mg/dL (range) 3.1 (0.4-45) Median albumin, g/dL (range) 3.1 (1.3-12.2) Median INR (range) 1.3 (0.8-4.5) Median ALT, IU/L (range) 71 (8-1162) Median platelets, x103/µL (range) 78 (19-340) Median MELD (range) 15 (6-43) Median months from LT to treatment (range) 17 (1-262) Forns, et al. EASL 2014 Results: Overall Virologic Response
81/93 53/85
Patients were excluded from this analysis if received a liver transplant (n=8 at EOT; n=12 at SVR12) Forns, et al. EASL 2014 Results: Overall Virologic Response
100 8/93 4/85
4/93 13/85 Lost to follow-up 80 Death
15/85 HCV RNA>LLOQ )
HCV RNA 60 40 Patients 20 81/93 53/85 0 Forns, et al. EASL 2014 EOT SVR12 Results: Clinical Outcomes 100 80 ) 62 (% 60 40 Patients 21 21 20 0 60/104 22/104 22/104 Improved* Stable Worsened/Deceased • All patients who received ≥1 dose of SOF are included *Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver- related laboratory values. Forns, et al. EASL 2014 Results: Laboratory Tests (Median and Interquartile Ranges) 12 5 L) ) 10 / 4 L (g bin d / u 8 g in 3 m m ( Bilir 6 u 2 4 Alb 1 2 Baseline EOT FU Wk12 Baseline EOT FU Wk12 0 0 2 25 1.5 20 NR I 1 ELD 15 0.5 M 10 0 Baseline EOT FU Wk12 5 Baseline EOT FU Wk12 Forns, et al. EASL 2014 0 SOF+RBV for Established Recurrent HCV Post-Liver Transplant TN & TE with N=40 SVR 12 recurrent HCV SOF 400 mg + RBV 400–1200 mg 0 24 Study Week Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels Study inclusion criteria – Liver transplant ≥ 6 months and ≤ 150 months – CTP ≤ 7 and MELD ≤ 17 Exclusion: Prednisone >5 mg/day Key baseline characteristics – 55% GT1a, 28% GT1b, 15% GT3, 3% GT4 – 88% treatment experienced (23% PI/PEG/RBV failures) – 40% F4 cirrhotic Samuel D, EASL, 2014, P1232 Virologic Response 40/40 40/40 29/40 28/40 28/40 • Relapse was not influenced by RBV dose or exposure • No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC dosing due to improved liver function Samuel D, EASL, 2014, P1232 Adverse Events and Lab Abnormalities SOF + RBV, SOF + RBV, Adverse Events, n (%) N=40 Grade 3 and 4 Lab Abnormalities, n (%) N=40 SAEs* 6 (15) Overall Grade 3 11 (28) AEs that led to D/C of study treatment† 2 (5) Overall Grade 4 11 (28) AEs in ≥ 15% of patients Lymphocytes (5 G3; 9 G4) 13 (33) Fatigue 12 (30) Hemoglobin (G3) 8 (20) Diarrhea 11 (28) Hyperglycemia (3 G3; 1 G4) 4 (10) Headache 10 (25) White blood cell count (G3) 3 (8) Arthralgia 9 (23) Hyperbilirubinemia (G4) 1 (3) Nausea 8 (20) Lipase (G4) 1 (3) Anemia 8 (20) Neutrophils (G3) 1 (3) Cough 7 (18) AST (G3) 1 (3) *All SAEs assessed as unrelated to SOF: ascites, pyrexia (2 cases), jaundice, pneumonia, urinary tract infection, hemarthrosis, osteoporotic fracture, confusion, hallucination; †Recurrence of hepatocellular carcinoma and pneumonia. AST, aspartate aminotransferase; DC, discontinuation; G, grade; SAE, serious adverse event. Samuel D, EASL, 2014, P1232 ABT-450/r/ABT-267 + ABT-333 + Ribavirin in Liver Transplant Recipients With Recurrent HCV SVR12 3D + RBV (N=34) Day 0 Week 24 To Week 72 • 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID • RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol Kwo, et al. EASL 2014 Calcineurin Inhibitor (CNI) Dosing With 3D Regimen • A phase 1 drug-drug interaction study demonstrated that dosing tacrolimus (TAC) or cyclosporine (CYA) with the 3D regimen compared to either alone resulted in a – 7-fold increase in TAC half-life – 3-fold increase in CYA half-life • Based on these findings, recommended dosing during 3D treatment was – TAC • 0.5 mg once weekly or • 0.2 mg every 3 days – CYA • 1/5 of the daily pre-3D treatment dose given once daily Kwo, et al. EASL 2014 Eligibility Criteria • 18 to 70 years of age, inclusive • HCV GT1 infection • Liver transplantation due to HCV infection >12 months before screening • Treatment-naïve after transplantation – PegIFN/RBV treatment prior to transplantation was permitted • Screening liver biopsy-confirmed Metavir score Kwo, et al. EASL 2014 Baseline Patient Characteristics 3D + RBV (N=34) Mean time since transplantation, months 47.9 Male (%) 79.4 Black/white race (%) 11.8 / 85.3 Hispanic or Latino ethnicity (%) 17.6 Mean age (years) 59.6 Mean BMI (kg/m2) 29.7 Fibrosis stage (%) F0-F1/F2 53 / 47 IL28B non-CC (%) 76.5 HCV subtype (%) GT1a/GT1b 85.3 / 14.7 Mean HCV RNA (log10 IU/mL) 6.6 Immunosuppressive medication (%) Tacrolimus/cyclosporine 85.3 / 14.7 Mean creatinine clearance (mL/min) 90.5 Mean creatinine (mg/dL) 1.1 Mean ALT/AST/GGT (U/L) 78.9 / 63.9 / 170.3 Kwo, et al. EASL 2014 Preliminary Efficacy Results 100% 100% 97.0% 96.2% % Patients % 34/34 34/34 32/33 25/26 RVR EOTR SVR4 SVR12 (Week 4) (Week 24) No patient had breakthrough; One patient had a relapse (post-treatment day 3) Kwo, et al. EASL 2014 Adverse Events Occurring in >15% of Patients 3D + RBV Event, n (%) (N=34) • No episodes of acute or chronic Any AE 33 (97.1) rejection Headache 15 (44.1) • 1 patient discontinued study drug due to Fatigue 14 (41.2) AEs (moderate rash, memory Cough 10 (29.4) impairment, and anxiety) after week 18 Insomnia 9 (26.5) – Patient achieved SVR12 Asthenia 8 (23.5) • 2 patients had serious AEs Diarrhea 8 (23.5) – Hypotension and tachycardia associated Nausea 8 (23.5) with initiation of tamsulosin after elective surgery Rash 7 (20.6) – Moderate peripheral edema and pain in Anemia 6 (17.6) extremity in a diabetic patient with history of Dizziness 6 (17.6) peripheral edema Muscle spasms 6 (17.6) Pyrexia 6 (17.6) Kwo, et al. EASL 2014 Hemoglobin Effect 3D + RBV Event, n (%) (N=34) Kwo, et al. EASL 2014 Ribavirin Dose Modifications 3D + RBV Baseline End of Treatment RBV total daily dose (mg), n (%) (N=34) (N=34) 400 3 (8.8) 4 (11.8) 600 to 800 19 (55.9) 25 (73.5) 1000 to 1200 12 (35.3) 5 (14.7) • 600 to 800 mg daily was the most frequent RBV dosage both at baseline and end of treatment Kwo, et al. EASL 2014 Pre-Treatment and On-Treatment Tacrolimus Ctrough Concentrations • Ctrough levels were comparable pre- 16 treatment and on-treatment 14 • TAC dose was 0.5 to 1.0 mg at 1-2 12 week intervals for most patients 10 • 4 patients experienced a TAC level 8 >15 ng/mL (15.7-34.0 ng/mL) 6 4 – All 4 patients had TAC dosing 2 errors 0 – 2 patients had associated Tacrolimus Concentration (ng/mL) Concentration Tacrolimus Pre-Treatment On-Treatment creatinine increases (1.8 and (Treatment Weeks 1-4) 1.4 mg/dL), which normalized Kwo, et al. EASL 2014 when dosing was corrected Pre-Treatment and On-Treatment Cyclosporine Ctrough Concentrations • CYA levels were 200 maintained within the 150 desired range with the recommended dosing 100 regimen (N=5 patients) Cyclosporine Cyclosporine • On-treatment CYA dose 50 Concentration (ng/mL) Concentration was 1/5 of the pre- Pre-Treatment On-Treatment treatment dose in these patients Kwo, et al. EASL 2014 Future Therapies Sulkowski Sulkowski et al. • HCV RNA SafetyHighlights Patients, % – N DCV+ SOF has an acceptable tolerabilityprofile Engl • • SVR Rates in Multiple Genotypes LI LI SOF +DCV 16 14 J Med weremild The most common adverse eventswere fatigue (29% Only 2/211 (<1%) patients receiving SOF + DCV with and without RBV discontinued therapydue to adverse events GT2/3 . 2014;370:211. + DCV 14 14 SOF - to - moderate +RBV +SOF DCV 14 12 24 wk treatment 24 wk of Treatment Patients AchievingSVR12 LI LI SOF +DCV 15 15 - naive; - 040 Study Shows High +SOF DCV 14 14 - 50%), (16%headache +RBV +SOF DCV 15 15 12 wk treatment 12 wk of Treatment +SOF GT1a/1b 41 41 DCV - naive; +RBV +SOF - DCV 38%), and nausea (10% 41 39 DCV +SOF 24 wk treatment24 wk of Prior PI failures; failures; Prior PI 21 21 - 32%), which DCV +SOF +RBV 20 19 DCV + SOF: ALLY 1 Cirrhosis and Post-Transplant Study Design • Objective: Assess the efficacy and safety of DCV 60 mg QD + SOF 400 mg QD in treatment-naive or -experienced GT1–6 patients with advanced liver disease awaiting liver transplantation, or with recurrent HCV post-transplant • Primary end point: SVR12 0 12 24 36 Study Week Pre-transplant DCV 60 mg QD + 24-wk follow-up (n=60) SOF 400 mg QD Therapy up to 12 wk OR Transplant 24-wk follow-up 3 mo – 12 y Post-transplant DCV 60 mg QD + SOF 24-wk follow-up (n=50) 400 mg QD SVR12 AI444-215. www.ClinicalTrials.gov/ct2/show/NCT02032875. Study Design of DCV + SMV + RBV • Objective: Assess the effect of DCV + SMV on the pharmacokinetics of cyclosporine and tacrolimus and the efficacy and safety of DCV + SMV + RBV in post–orthotopic liver transplantation participants with recurrent HCV genotype 1b infection • Primary end point: SVR12 Metavir Score Week 24 SVR12 Recurrent HCV F1-F2 Part 1: DCV + SMV + RBV Follow-up GT 1b (n=40) F1-F4 Part 2: DCV + SMV + RBV Follow-up • Inclusion criteria – Liver transplant between 6 months and 10 years prior to screening visit – Screening HCV RNA level >10,000 IU/mL – No post–orthotopic liver transplant anti-HCV treatment – Receiving stable immunosuppressant therapy with cyclosporine or tacrolimus for >3 months prior to the screening visit SMV = simeprevir. NCT01938625; http://clinicaltrials.gov/ct2/show/study/NCT01938625. Conclusion • Peri-transplant patients are an important group of HCV patients, although small in numbers overall • Eradication in this population will “free up” organs for other liver indications • IFN no longer has an indication in this population • Multiple all oral therapies appear effective