3Learning ObjectivesReview epidemiologic trends of liver-related morbidity and mortality in chronic HCV infectionDiscuss HCV-related management approaches for patients with advanced fibrosis and cirrhosisDiscuss HCV-related management approaches for patients who are candidates for liver transplantation
4Advanced Liver Disease: Basic Principles Hepatic fibrosisNot reliably diagnosed by ultrasound or other imaging modalitiesLiver fibrosis ratesNot predictable or linearProgression from compensated cirrhosis to decompensated liver diseaseOccurs in 5% of patients per yearHepatocellular carcinomaDevelops in 1% to 2% of patients with hepatitis-related cirrhosis each yearSlide: Advanced Liver Disease: Basic PrinciplesHepatic fibrosis is not reliably diagnosed by ultrasound or other imaging modalities.1Liver fibrosis rates are not predictable or linear.1Progression from compensated cirrhosis to decompensated liver disease occurs in 5% of patients per year.1Hepatocellular carcinoma develops in 1% to 2% of patients with hepatitis-related cirrhosis each year.1ReferenceSherman KE. Advanced liver disease: what every hepatitis C virus treater should know. Top Antivir Med. 2011;19:Sherman KE. Top HIV Med. 2011;19:
5Chronic HCV Infection: Natural History Exposure(Acute phase)15%-45%55%-85%5%-30%Over YearsChronicCirrhosisResolvedSlide: Chronic HCV Infection: Natural HistoryThis slide illustrates the natural history of HCV infection.A small percentage of individuals will go on to spontaneous resolution—about 15%—whereas 85% develop chronic disease. Of this 85% who develop chronic disease, about 80%, (68% of all infected individuals), will have stable chronic hepatitis without significant progression over the next 20 years. By contrast, 20% of those who develop chronic disease (17% of all infected individuals) will develop cirrhosis over the next years. Of these cirrhotic patients, many will continue to progress slowly, and about 25% will rapidly develop hepatocellular carcinoma (HCC) or liver failure. Thus, liver cancer and liver failure occur in approximately 4% of patients who are exposed to HCV over a 20- to 25-year period.ReferencePoynard T, Bedossa P, Opoion P, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:Co-morbiditiesLiver Decompensation (5%/year)HCC (2%-8%/year)Poynard T, et al. Lancet. 1997;349:
6Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir) No FibrosisStage 1Stage 2Fibrous expansion ofsome portal areasFibrous expansion of most portal areas with occasional portal to portal bridgingStage 3Stage 4Slide: Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir)This slide contains examples of the progression of fibrosis according to the Metavir system.1ReferenceFaria SC, Ganesan K, Mwangi I, et al. MR imaging of liver fibrosis: current state of the art. Radiographics. 2009;29:Fibrous expansion of portal areaswith marked bridging (portal-to-portal and portal-to-central)CirrhosisCirrhoticLiverFaria SC, et al. Radiographics. 2009;29: Adapted from Everson GT.
7FibroScan FibroScan (kPa) 8.8 9.6 14.6 F0-F1 F2 F3 F4 Liver Fibrosis The probe induces an elastic wave through the liverThe velocity of the wave is evaluated in a region located from2.5 to 6.5 cm below the skin surfaceDiagnostic accuracy:Significant fibrosis: 0.79Advanced fibrosis: 0.91Cirrhosis: 0.97FibroScan (kPa)Slide: FibroScanThe FibroScan is a noninvasive method based on transient elastography that is designed to measure liver stiffness. Ziol and colleagues evaluated the use of liver stiffness measurement (LSM) in HCV patients with liver fibrosis (n=327). Patients underwent liver biopsy and LB and LSM.1LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P<0.0001).1>F2: 0.79 ( ).>F3: 0.91 ( ).>F4: 0.97 ( ).The optimal LSM cutoff values of 8.7 and 14.6 kPa showed >F2 and F4, respectively.1ReferenceZiol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41:48-188.8.131.524.6F0-F1F2F3F4Liver Fibrosis(METAVIR)Ziol M, et al. Hepatology. 2005;41:48-54.
8Projected Burden of Advanced Fibrosis Over the Next Decade 1990 77.6% F0/1; cirrhosis =5%2010 41.8% F0/1; cirrhosis =25%2020 cirrhosis = 37.2%Davis GL, Gastroenterology. 2010;138:
9Progressive Increase in Incidence of HCV-Related Cirrhosis and HCC in US Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected VeteransEl-Serag HB. Gastroenterology 2012;142:1264–1273.
10Natural History of HCV Cirrhosis 10080604020CompensatedSurvivalprobability(%)After 1st complicationDeathsLiver-related (70%)Other cause (30%)12345678910Years after diagnosisAdapted from Fattovich G et al. Gastroenterology. 1997;112:
11By 2007, Deaths From HCV Surpassed Those From HIV Change in Mortality Rates From 1999 to 20077654321HIV15,10612,734Hepatitis CRate per 100,000 PeopleHepatitis B1,815199920002001200220032004200520062007YearLy KN, et al. Ann Intern Med. 2012;156(4):
12Risk Factors for Progressive Fibrosis and Cirrhosis Persistently elevated ALT levelsLonger duration of infectionAlcohol excess (>50 g/day)Age >40 years at time of infectionHIV or HBV coinfectionHigh BMIMale genderPresence of steatosis on biopsySlide: Risk Factors for Progressive Fibrosis and CirrhosisRisk factors associated with progressive fibrosis and cirrhosis include:1,2Persistently elevated ALT levels.Longer duration of infection.Alcohol excess (>50 g/day)>3 standard drinks defined as 12 fluid ounces of regular beer, 5 fluid ounces of wine, or 1.5 fluid ounces of distilled spirits (80 proof) and contains approximately 0.5 ounces (14 grams) of pure alcohol.Age >40 years at time of infection.HIV or HBV coinfection.High BMI.Male gender.ReferencesPoynard T, Bedossa P, Opoion P, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:Kim WR, Poterucha JJ, Benson JT, et al. The impact of competing risks on the observed rate of chronic hepatitis C progression. Gastroenterology. 2004;127:Poynard T, et al. Lancet. 1997;349:Kim WR, et al. Gastroenterology. 2004;127:
13Incremental All-Cause Costs HCV Incremental All-Cause Health Care Costs by Liver Disease Severity (USD 2009)27,845(965)No liver disease (n=26,977)Compensated cirrhosis (n=1521)Decompensated cirrhosis (n=4249)15,464(710)Incremental All-Cause Costs(per-patient-per-year)Slide: HCV Incremental All Cause Health Care Costs by Liver Disease Severity (USD 2009)Costs for these HCV cohorts were significantly higher than those of the matched comparison cohorts with a mean difference of $5,870, $5,330, and $27,845 PPPY for HCV without liver disease and HCV, compensated cirrhosis, and decompensated cirrhosis, respectively.ReferenceMcAdam-Marx C, McGarry LJ, Hane CA, et al. : all-cause and incremental per patient per year cost associated with chronic hepatitis C Virus and associated liver complications in the United States: A managed care perspective. J Manag Care Pharm. 2012;17:5879(157)5818(292)5330(491)4526(213)3102(157)2659(41)1721(123)1893(123)810(49)974(194)1081(275)641(37)93(130)Total HealthCare CostsInpatientOutpatientPhysicianServicesPharmacyCostsPlace of ServiceDifference between HCV and non-HCV matched controls.Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:
14HCV Can Now Be Cured in Most Patients Unlike HIV and HBV infection, HCV infection is a curable diseaseWhat does cure mean?Sustained Viral ResponseUndetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infectionLong term morbidity and mortality benefitsGhany MG, et al. Hepatology. 2009;49(4):
16SVR Was Associated With Reduced Long-Term Risk of All-Cause Mortality in an International, Multicenter StudyAll-Cause MortalityPercentTime (years)International, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada. Patients with chronic HCV infection started an interferon-based treatment regimen between 1990 and 2003 (n=530).van der Meer AJ, et al. JAMA. 2012;308:
17SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study Genotype 1(n=12,166)Genotype 2(n=2904)Genotype 3(n=1794)SVR rate: 35%SVR rate: 72%SVR rate: 62%Cumulative Mortality (%)YearsYearsYearsRetrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility ( ).SVR=sustained virological response.Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:
18SVR Was Associated With Improved Long-Term Liver-Related Outcomes in the HALT-C Trial Database Cumulative Incidence of Any Liver-Related Outcome Among Patients With Bridging Fibrosis or CirrhosisPercentAnalysis of liver outcomes (decompensation, HCC, or death) in the HALT-C trial database. All comparisons P<.0001.*Detectable HCV RNA at treatment week 20 (combination therapy was discontinued at week 24). HALT-C=Hepatitis C Antiviral Long-Term Treatment against Cirrhosis. Morgan TR, et al. Hepatology. 2010;52:
19Hepatocellular Carcinoma in HCV UntreatedInterferon0.60.5Cumulative incidence0.40.30.20.112345678910YearsYoshida H et al. Ann Intern Med. 1999;131:178.
20AASLD/IDSA Recommendations: HCV-Related Cirrhosis Treatment-naive patients with compensated cirrhosis, including those with HCCShould receive the same treatment as recommended for patients without cirrhosisAASLD and IDSA. Available at: Version January 29, 2014.
21CDC & USPSTF recommend 1-time testing of baby boomers (born 1945-1965) HCV-Infected Persons in the US: Estimated Rates of Detection, Referral to Care and CureCDC & USPSTF recommend 1-time testing of baby boomers (born )50%X1000 persons32-38%20-23%7-11%5-6%Infected Diagnosed Referred HCV RNA Treated ‘Cure’to care testHolmberg S, N Engl J Med 2013; 368: 1859
22Barriers to Cure for Hepatitis C: Data From a Large Integrated Health System Evaluate linkages between HCV screening and treatmentCalculate the “missed opportunity” at each transition of careAnalyze patient characteristics which may influence the “missed opportunity” at each transition of careBrown et al, AASLD 2013
23Brown et al, AASLD 2013 HCV Ab+ N=566 Death < 365 Days Testing N=39 Left System <6 mo TestingN=69RNAScreen?N=458No RNA ScreenN=87 (19%)RNA ScreenN=371 (81%)Negative RNAN=63 (17%)Positive RNAN=308 (83%)Brown KA. et al., AASLD 2013Brown et al, AASLD 2013
24with positive HCV-RNA were seen by Gastroenterology HCV Ab+(586 patients)Death <365 days testing(39 patients)Excluded458Left system <6 mo testing(69 patients)RNAScreenNo RNA87 (19%)RNA Screen371 (81%)Referral?N=308No ReferralN=125 (41%)Self ReferralN=3 (1%)ReferredN=180 (58%)Gastro Visit?N=183Only 38% (117/308) of patientswith positive HCV-RNA were seen by GastroenterologyNo VisitN=66 (36%)VisitN=117 (64%)Brown KA. et al., AASLD 2013Brown et al, AASLD 2013RNA negative (3)Substance Abuse (14)No follow up (11)Transplant evaluation (15)Co-morbidities (23)External follow up VA (3)Waiting for new treatment (6)Patient declined (12)Previous treatment (9)Treat-mentNoTreatment96 (82%)Treatment21 (18%)NoSVR13 (62%)SVR8(38%)
25with positive HCV-RNA were treated HCV Ab+(586 patients)Death <365 days testing(39 patients)Excluded458Left system <6 mo testing(69 patients)RNAScreenNo RNA87 (19%)RNA Screen371 (81%)Negative RNA63 (17%)Positive RNA308 (83%)ReferralNo Referral125 (41%)Self Referral3 (1%)Referred180 (58%)Treatment DecisionN=117Only 6.8% (21/308) of patientswith positive HCV-RNA were treatedOnly 2.6% (8/308) SVRNoTreatment*N=96 (82%)TreatmentN=21 (18%)No SVRN=13 (62%)SVRN=8(38%)*Reasons for No Treatment: RNA negative (3); substance abuse (14); no follow up (11); transplant evaluation (15); co-morbidities (23); external follow up VA (3); waiting for new treatment (6); patient declined (12); previous treatment (9)Brown KA. et al., AASLD 2013Brown et al, AASLD 2013
26HCV treatment considerations in advanced fibrosis and cirrhosis
27French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1) Prospective cohort, HCV genotype 1, compensated cirrhosisRelapse or prior partial responders to PRSVR12Telaprevir: 40% (range: 29%-53%)Boceprevir: 41% (range: 11%-51%)Discontinuations: 47%Serious adverse events: 40%Early treatment discontinuation: 21.3%Death: 2.0%Anemia (<9.0 g/dL): 29.4%Hepatic decompensation: 2.4%Factors Associated WithDeath and Severe Complications (n=62)AdjustedOdds RatioPlatelet <100,000/mm33.1 (P=0.0105)Serum albumin <35 g/dL6.33 (P=0.0001)Slide: French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1)The French National Early Access Program is a prospective cohort of HCV genotype 1 patients with compensated cirrhosis who had a prior relapse or prior partial responders to PR. The overall SVR rates with telaprevir- and boceprevir-based triple therapy were 40% (range: 29% to 53%) and 41% (range: 11%-51%), respectively.1-3SVR12 predictors included those who had a prior partial response to PR (versus relapse) and genotype 1b (versus 1a).This cohort found a high incidence of serious adverse events (40%), discontinuations (47%) and early treatment discontinuation (21.3%). There was also a high incidence of death (2.0%), anemia (<9.0 g/dL) (29.4%), and hepatic decompensation (2.4%).1-3Death or severe complications were related to platelets count <100,000/mm3 (Odds ratio: 3.11; P=0.0105) and albumin <35 g/dL (Odds ratio: 6.33; P=0.0001), with a risk of 44.1% in patients with both.3ReferencesFontaine H, Hezode C, Dorival C, et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 455 cirrhotic non responders treated in the French early access program (ANRS CO2O-CUPRIC). J. Hepatol. 2013;58(suppl 1): S27. Abstract 60.Hezode C, Dorival C, Zoulim F, et al. Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 455 cirrhotic non responders. Week 16 analysis of the French early access program (ANRS CO2O-CUPRIC) in real-life setting. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT J Hepatol. 2013;59:Risk of Death or Severe Complications (%)Platelets (/mm3)>100,000<100,000Albumin (g/dL)>35 (n=298/69)3.44.3<35 (n=28/34)7.144.1Fontaine H, et al. J Hepatol. 2013;58(suppl 1):S27. Abstract 60.Hezode C, et al. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.Hezode C, et al. J Hepatology. 2013;59:
28Sofosbuvir + RBV + PegIFN: SVR12 by Fibrosis Stage (Genotypes 1-6) Retrospective analysis of 4 phase 3 clinical trialsBaseline fibrosis stage by FibroTest/FibroSureF0-F2 (55%), F3 (17%), F4 (28%)General decline in SVR with advancing fibrosisSVR12 rates among patients with thrombocytopenia (platelets <125/mm3) were similar to rates in cirrhotic patients across all HCV genotypesSlide: Sofosbuvir + RBV + PegIFN: SVR12 by Fibrosis Stage (Genotypes 1-6)Patel and colleagues conducted a retrospective analysis of SVR12 rates and safety data across four phase 3 clinical trials (FISSION, POSITRON, FUSION, and NEUTRINO) by degree of liver fibrosis (F0-F4) and extent of thrombocytopenia.1The SVR12 rates among patients with thrombocytopenia (platelets <125/mm3) were similar to rates in cirrhotic patients across all HCV genotypes. Data by fibrosis will be shown in the next slides.1ReferencePatel K, Gordon SC, Sheikh AM, et al. Efficacy and safety of sofosbuvir in patients according to fibrosis stage: an analysis of phase 3 data. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.
29Sofosbuvir + RBV + PegIFN (Multiple Genotypes): SVR12 by Baseline Fibrosis Stage (FibroTest) Sofosbuvir + RBV (FUSION)(16 weeks, treatment-experienced)Sofosbuvir + PR (NEUTRINO)(12 weeks, treatment-naïve)Genotype Genotype 3Genotypes 1, 4-6100%100%97%96%89%85%80%80%79%67%63%Slide: Sofosbuvir + RBV + PegIFN (Multiple Genotypes): SVR12 by Baseline Fibrosis Stage (FibroTest)A similar trend was observed among HCV patients receiving sofosbuvir + RBV for 16 weeks or sofosbuvir + PR for 12 weeks. SVR12 rates tended to be lower among those with cirrhosis at baseline, especially in patients who were HCV genotype 3.1ReferencePatel K, Gordon SC, Sheikh AM, et al. Efficacy and safety of sofosbuvir in patients according to fibrosis stage: an analysis of phase 3 data. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.Patients (%)Patients (%)40%F0(n=4/5)F1-F2(n=14/21)F3(n=5/10)F4(n=9/27)F0(n=78)F1-F2(n=105)F3(n=54)F4(n=86)PR: pegIFN + RBV.Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.
30COSMOS Subgroup Analysis: HCV Genotype 1, METAVIR F3-F4 Phase 2aOpen-labelGenotype 1Prior PR null responderor treatment-naïveMETAVIR F3-F4No BMI limit<70 years of ageSimeprevir + Sofosbuvir qd (n=14)Simeprevir + Sofosbuvir qd+ RBV (n=27)Simeprevir + Sofosbuvir qd (n=16)Simeprevir + Sofosbuvir qd + RBV (n=30)Slide: COSMOS Subgroup Analysis: HCV Genotype 1, METAVIR F3-F4COSMOS was an open-label, phase 2a study of 12- or 24-weeks of simeprevir (150 mg qd) and sofosbuvir (400 mg qd) in prior PR null responders with genotype 1. The analysis by Lawitz and colleagues focused on patients who had cirrhosis (F3-F4) at baseline.1ReferenceLawitz E, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior null-responder/treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with metavir F3–4 (cohort 2). J Hepatol. 2014;60(suppl 1):S524. Abstract O165.WeekSofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).Weight-based ribavirin dosing ( mg).Baseline demographics and disease characteristics:Male: 67%; age: 58 years; black: 9%.Genotype 1a: 78%.Genotype 1a with Q80K: 40%.IL28B non-CC: 79%.Cirrhosis: 47%.HCV RNA (log10 IU/mL): 6.6.Prior PR null responders: 54%.Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
31COSMOS Subgroup Analysis: SVR12 in HCV Genotype 1, METAVIR F3-F4 SVR12 by HCV SubtypeSimeprevir + sofosbuvirNo RBV With RBVSimeprevir + sofosbuvir + RBV100%100%98%95%96%95%93%93%93%94%SVR12 (%)1.1% DiscontinuationSVR12 (%)Slide: COSMOS Subgroup Analysis: SVR12 in HCV Genotype 1, METAVIR F3-F4SVR12 rates were high (93%-96%) among the 12- and 24-week arms regardless of RBV use. The presence of Q80K and IL28B TT genotype did not appear to negatively impact SVR12 rates.1ReferenceLawitz E, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior null-responder/treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with metavir F3–4 (cohort 2). J Hepatol. 2014;60(suppl 1):S524. Abstract O165.12 Weeks(n=14/27)24 Weeks(n=16/30)1b1a1a +Q80KCCCTTTIL28B Genotype(n=17/48/19)Genotype(n=18/40/26)Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
32LDV/SOF Phase 2 and 3 Program An Integrated Safety and Efficacy Analysis of >500 Patients with compensatedCirrhosis Treated with Ledipasvir/Sofosbuvir with or without RibavirinWk 0Wk 12Wk 36Wk 24SVR12LDV/SOFLDV/SOF + RBVn=118n=204n=133n=58The next study we would like to highlight is also being presented by Dr. Bourliere, on Sunday.this is a retrospective, pooled analysis of 513 patients with compeansted cirrhosis.513 patients with HCV GT 1, compensated cirrhosisPooled data from Phase 2 and 3 LDV/SOF ± RBV studiesLONESTAR, ELECTRON, ELECTRON-2, (Japan), ION-1, ION- 2, SIRIUSPrimary efficacy endpoint: SVR12Bourliere et al, AASLD 2014
33SVR12 Overall and by Treatment Duration LDV/SOF Phase 2 and 3 Program: Cirrhotic SubjectsSVR12 (%)493/513305/322188/191Overall12 Weeks24 WeeksOut of 513 patients, 20 failed to achieve SVR1218 Relapsed1 LTFU, 1 Death (presumed infection)Bourliere et al, AASLD 2014Error bars represent 95% confidence intervals.
34Treatment Experienced SVR12 by Regimen and Duration LDV/SOF Phase 2 and 3 Program: Cirrhotic SubjectsTotalTreatment NaïveTreatment ExperiencedOverall SVR12Duration12 wk24 wkRegimenLDV/SOFLDV/SOF + RBVDuration/± RBVLDV/SOF 12 wkLDV/SOF + RBV 12 wkLDV/SOF 24 wkLDV/SOF + RBV 24 wk96%98%95%95%97%94%98%99%98%95%96%95%97%99%96%-The SVR among TE cirrhotic patients treated for 12 weeks was 90%-But when RBV was added or treatment duration extended to 24 weeks, SVR rates of % were observed.92%96%90%96%98%96%98%97%98%100%100%100%SVR12, %Bourliere et al, AASLD 2014
35‡Relapse Among Cirrhotic Subjects LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects513failedSVR12493(96.1%)20(3.9%)LTFU;Deathrelapse218Plts ≥ 75Plts < 75135Of the 513 patients evaluated, only 20 failed to achieve a SVROf these 20, 1 patient died on treatment, and 1 patient was lost to follow up after a single visitThis leaves 18 patients out of 513 who were true relapsers.Of these, 5, had a platelet count of less than 75, and 4 of these were treated with LDV/SOF for 12 weeks –In this group, the Relapse rate was 27% -- which contrasts with the 2-5% relapse rate observed in all other groups.FDC 12OtherFDC 12Other410293734151224%(1.1%-9.7%)2%(1.1%-4.5%)27%(7.8%-55.1%)5%(0.1%-22.8%)FDC 12 = LDV/SOF for 12 weeksOther = LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeksLTFU = Lost to Follow Up (n=1)Bourliere et al, AASLD 2014
36SIRIUS Study Double-blinded 0 wk12 wk24 wk36 wkLDV/SOF + RBVPlaceboSVR12LDV/SOF + Placebo RBVSVR12The Goal of the SIRIUS study, which is the brainchild of Dr. Bourliere,was to take “CUPIC-like failures”, cirrhotic patients who had failed PEG-RBV, and then a PI+PEG+RBV, and treat them with one of two regimens:LDV SOF + RBV for 12 weeks, or LDV/SOF for 24 weeks.Double-blindedTreatment-experienced patients with compensated cirrhosis who did not achieve SVR following sequential PEG + RBV and PI + PEG + RBV regimensBourliere et al, AASLD 2014
37Demographics SIRIUS (GS-US-337-0121) Placebo 12 Weeks → LDV/SOF+RBV 12 Weeks n=77LDV/SOF + Placebo RBV 24 Weeks n=78Total N=155Mean age, y (range)56 (39–74)57 (23–77)56 (23–77)Male, n (%)58 (75)56 (72)114 (74)White, n (%)76 (99)75 (96)151 (97)Mean BMI, kg/m2 (range)28 (20–47)26 (19–40)27 (19–47)IL28B non-CC, n (%)73 (95)72 (92)145 (94)Varices, n (%)16 (21)25 (32)41 (26)Mean platelets (range)153 (54–316)141 (59–278)147 (54–316)Platelets <100 x 103 /µL14 (18)13 (17)27 (17)Mean albumin g/dL3.9 (3.2–4.6)3.9 (3.0–4.9)Albumin <3.5 g/dL, n (%)6 (8)14 (17)20 (13)155 TE patients with compensated cirrhosis were enrolled in this study – consistent with their compensated status, the mean platelet count was around 150, and the mean albumin was around 4.Bourliere et al, AASLD 2014
38Disposition SIRIUS (GS-US-337-0121) Randomized N=155Placebo 12 wk n=78D/C treatmentdue to AE (n=1)LDV/SOF + RBV 12 Wk n=77LDV/SOF 24 Wk n=77*Of note, 1 subject discontinued therapy due to septic arthritis, while on placebo, and has been excluded from the efficacy analysis.Completed study treatmentn=77Completed study treatmentn=77Completed follow-up wk 12 n=77Completed follow-up wk 12 n=77*1 patient was randomized to receive placebo 12 weeks then LDV/SOF+RBV for 12 weeks but received LDV/SOF for 24 weeks. Efficacy is assessed as ITT; for demographics and safety, they are analyzed according to treatment received.Bourliere et al, AASLD 2014
39SVR12 SIRIUS (GS-US-337-0121) LDV/SOF+RBV 12 Weeks LDV/SOF 24 Weeks The SVR12 results are shown here; with 96 and 97% of patients achieving a sustained virologic response in the two arms. in total,74/7775/77LDV/SOF+RBV 12 WeeksLDV/SOF 24 WeeksError bars represent 95% confidence intervals.Bourliere et al, AASLD 2014
40Adverse Events ≥15% SIRIUS (GS-US-337-0121) Preferred term, n (%)Placebo 12 Wk → LDV/SOF + RBV 12 WkLDV/SOF 24 WkPlacebo 12 Wkn=77LDV/SOF +RBV 12 Wkn=76Overall Period n=77First 12 Wkn=78Overall Period n=78Asthenia24 (31)29 (38)45 (58)28 (36)35 (45)Headache16 (21)13 (17)21 (27)27 (35)31 (40)Pruritus14 (18)11 (14)22 (29)4 (5)7 (9)Insomnia9 (12)17 (22)Nausea8 (10)8 (11)Fatigue3 (4)5 (7)7(9)15 (19)Dry skin6 (8)12 (16)Arthralgia5 (6)12 (15)Bronchitis1 (1)Two adverse events occurred more frequently with LDV/SOF than Placebo – Headache and FatigueMost AEs mild or moderate in severityBourliere et al, AASLD 2014
41HCV infection before liver transplantation: Treatment of decompensated patients strategies to prevent recurrence of hcv post liver transplant
42AASLD and IDSA Recommendations: HCV-Related Cirrhosis Patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C)Should be referred to a medical practitioner with expertise in that condition (ideally in a liver transplant center)Preferred RegimenAny GenotypeSofosbuvir + RBV for up to 48 weeks(consider creatinine clearance and hemoglobin)Slide: AASLD and IDSA Recommendations: HCV-Related CirrhosisThis slide lists the AASLD/IDSA HCV regimens for patients with HCV-related cirrhosis.1ReferenceAASLD and IDSA. Recommendations for testing, managing, and treating hepatitis C. Available at: Version January 29, 2014.Regimens Not RecommendedAny GenotypeAny IFN-based therapyMonotherapy with pegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimensAASLD and IDSA. Available at: Version January 29, 2014.
43Antiviral Therapy Before Liver Transplantation ChallengesPoor toleranceIncreased adverse eventsRisk of hepatic decompensationSuboptimal SVR ratesHCV treatment in this patient population requires significant oversight and input in an experienced practiceExpectations???Slide: Antiviral Therapy Before Liver Transplantation for HCV-Infected Recipients With Advanced Fibrosis and CirrhosisThe use of anti-viral HCV therapy in patients with advanced liver disease is problematic, with poor tolerance, increased side effects including risk hepatic decompensation and less sensitivity to interferon resulting in suboptimal SVR rates.1-5Treatment for these groups of patients requires significant oversight and input and should only be undertaken in experienced transplant centers.1-5ReferencesAgarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Engl J Med. 2002;347:Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:Bruno S, Shiffman ML, Roberts SK, et al. Efficacy and safety of peginterferon alfa-2a (40 KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 2010;51:Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Fried MW, et al. N Engl J Med. 2002;347:Manns MP, et al. Lancet. 2001;358:Hadziyannis SJ, et al. Ann Intern Med. 2004;140:Bruno S, et al. Hepatology. 2010;51:
44Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation Open-LabelGenotypes 1-4Treatment-naïve andexperiencedCompensated cirrhosis(Child-Pugh 5-6, A)Decompensated cirrhosis(Child-Pugh 7-9, B)Esophageal or gastric varicesHepatic venous gradient(HVPG): >6 mm Hg)Sofosbuvir qd + RBV(n=25)Observation(n=25)Sofosbuvir qd + RBVWeekCurrent AnalysisSlide: Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + DecompensationAfdhal and colleagues conducted an open-label study to evaluate the safety and efficacy of 48 weeks of sofosbuvir and RBV in patients with HCV cirrhosis and portal hypertension (CTP 5–10).1Outcomes included on-treatment virologic response, safety, and change in CTP, MELD, and HVPG. Rapid virologic response at treatment weeks 4 (RVR4) and 8 (RVR8) were defined by HCV RNA <25 IU/mL.1ReferenceAfdhal N, Everson G, Calleja JL, et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV ( mg).HVPG at day 0 and 48 in the sofosbuvir-treated patients.Baseline demographics and disease characteristics:Male: 72%-80%; age: years; white: 84%-96%, treatment-naive: 68%-92% .Genotype 1a, 1b, 2, 3, 4: 36%-40%, 24%-36%, 4%-8%, 8%-32%, 4%-8%.IL28B non-CC: 72%-88%.HVPG >12 mm Hg: 76%-80%.CTP score 5-6, 7-9: 36%-44%, 56%-60%.MELD <10, 10-15: 32%, 56%-60%.Albumin: g/dL; platelets: x103.ALT, AST: , U/mL.Ascites: 24%-36%.Encephalopathy 8%-20%.Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
45Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation High rates of virologic suppression irrespective of severity of liver diseaseDecreased necroinflammation with ALT normalizationImprovementsPlatelet count and albuminAscites and hepatic encephalopathyLow rates of treatment discontinuation due to adverse events (4%)Outcomes at Week 24Sofosbuvir+ RBV(n=25)ObservationHCV RNA <LLOQ (%)CTP A (n=7)CTP B (n=15)10090--ChangePlatelets (103/µL)CTP ACTP BAlbumin (g/dL)Bilirubin (mg/dL)ALT (U/L)1710.50.4-0.2-72-75-9-1-0.10.213Slide: Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + DecompensationHigh rates of virologic suppression were achieved with 48 weeks of sofosbuvir + RBV irrespective of severity of liver disease (90%-100%). There was also a decrease in necroinflammation markers and ALT normalization. Other improvements were seen with platelet count, serum albumin, ascites, and hepatic encephalopathy.1Overall, there was a low rate of treatment discontinuation due to adverse events (4%).1ReferenceAfdhal N, Everson G, Calleja JL, et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
46SOLAR-1 (Decompensated Cirrhosis) GT 1 and 4, CPT Class B and C LDV/SOF + RBVWk 0Wk 12Wk 24SVR12Wk 36108 patients randomized 1:1 to 12 or 24 Weeks of TreatmentBroad inclusion criteriaTotal bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dLCLcr ≥ 40 mL/min, platelets > 30,000 x 103/µL,CPT ≤ 12Stratified by CPT score B or CWith this picture in mind, We’d like to turn to patients with decompensated cirrhosis.These patients are being evaluated in the first cohort of SOLAR-1.And will be discussed by Dr. Flamm on Tuesday.All patients received LDV/SOF+RBV – for either 12 or 24 weeks.Both CPT B and C patients were includedHowever CPT C patients with a score of were excluded due to their high near term mortality.Flamm, et al, AASLD 2014
47Baseline Disease Characteristics GT 1 and 4, CPT Class B and C CPT BCPT C12 Weeksn=3024 Weeksn=29n=23n=26MELD score, n (%)<106 (20)8 (28)10‒1521 (70)16 (55)16 (70)13 (50)16-203 (10)5 (17)7 (30)12 (46)21-251 (4)Ascites, n (%)17 (57)17 (59)22 (96)25 (96)Encephalopathy, n (%)20 (67)21 (91)23 (88)Median bilirubin, mg/dL (range)2.0 ( )1.4 ( )2.9 ( )3.8 ( )Median albumin, g/dL (range)2.9 ( )3.0 ( )2.6 ( )2.6 ( )Median INR, (range)1.3 ( )1.3 ( )1.4 ( )1.4 ( )Median platelets, x 103/µL (range)88 (36-212)73 (30-154)81 (39-177)71 (32-179)Consistent with a cohort of subjects with decompensated cirrhoris:The prevalence of ascites or encephalopathy at baseline was high in CPT B patients, and nearly universal for CPT C patients.Flamm, et al, AASLD 2014
48SVR12 GT 1 and 4, CPT Class B and C LDV/SOF + RBV 12 WeeksLDV/SOF + RBV 24 WeeksSVR12 (%)Overall, almost 90% of subjects with decompensated disease achieved a SVRBeing treated for 12 versus 24 weeks did not appear to impact SVR12 ratesSimilar SVR12 rates were observed between CPT B and CPT C subjects.3 relapses1 death1 relapse2 deaths2 death1 LTFU1 relapse1 death45/5242/4726/3024/2719/2218/20OverallCPT BCPT C6 subjects (2 CPT B/24 Wk, 1 CPT C/12 Wk and 3 CPT C/24 Wk) excluded (transplant on study);3 subjects CPT C/24 Wk have not reached SVR12..Flamm, et al, AASLD 2014
49Change in MELD Score Baseline Through Follow-up Week 4 GT 1 and 4, CPT Class B and C CPT BCPT C12 wk (n=30)*24 wk (n=29)*12 wk (n=23)*24 wk (n=26)*(+10)n=5n=5n=2n=3Virologic Supression was also associated with an improvement in MELD score.Seen here is a waterfall plot, where each bar represents a difference patient and their change in MELD score.Patients with increased MELD scores were not enriched with relapsersPatient who increased by 10 was due to an AE of increased INR – up to 3.2Flamm, et al, AASLD 2014*Missing FU-4: n=2 CPT B 12 wks; n=4 CPT B 24 wks; n=2 CPT C 12 wk; n=7 CPT C 24 wk.(-8)
50Safety Summary GT 1 and 4, CPT Class B and C CPT BCPT CPatients, n (%)12 Weeksn=3024 Weeksn=29n=23n=26Overall SafetyAE29 (97)27 (93)23 (100)26 (100)Grade 3‒4 AE2 (7)8 (28)6 (26)11 (42)Serious AE3 (10)10 (34)6 (26)Serious and related AEs2 (8)Treatment DC due to AE1 (3)Death2 (9)1 (4)With respect to Safety,There were few treatment realted SAEs,Related SAEs: Anemia (2), Hepatic Encephalopathy, Peritoneal HemorrhageFlamm, et al, AASLD 2014
51Cumulative HCC by Age Group Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic FibrosisMeta-analysis (n=1000)10 cohorts, individual patient dataSVR with IFN-based therapyBridging fibrosis or cirrhosis51 events of HCC over 5.1 years of follow-upPatients with HCV-induced cirrhosis who achieve SVR remain at risk for HCCRisk increased with age, severity of liver disease, and presence of diabetes mellitusCumulative HCC by Age GroupAge Group<45 years45 to 60 years>60 years12.2%9.7%P=0.006Rate (%)Slide: Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic FibrosisVan der Meer and colleagues conducted a meta-analysis of 10 cohorts using individual patient data (n=1000) to assess SVR rates with IFN-based therapy. Patients had bridging fibrosis or cirrhosis without HIV or HBV coinfection.1There were a total of 51 events of HCC over 5.1 years of follow-up post achievement of an SVR with IFN-based therapy. These data illustrated the concern that patients with HCV-induced cirrhosis who achieve SVR remain at risk for HCC. This risk increased with age, severity of liver disease, and presence of diabetes mellitus.1ReferenceVan der Meer AJ, Feld JJ, Hafer H, et al. The risk for hepatocellular carcinoma among patients with chronic HCV infection and advanced hepatic fibrosis following sustained virological response. Hepatology. 2013;58(suppl 1):280A. Abstract 143.2.6%Years After SVRvan der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143.
52Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL) First, randomized, controlled trial of pre-transplant PR (LADR) to prevent recurrent HCV post-transplantRandomized to either pegIFN + RBV (LADR) or control (untreated)Primary endpointPost-transplant HCV RNA undetectable at week 12Baseline CharacteristicsTreatment(n=63)Control(n=16)Male (%)7381Age (years)56Genotype (%)1/4 or 62/347/424/2588/120/0HCV RNA (log10 IU/mL)5.7HCC upgrade (%)5494MELD12.0CPT score7.06.3Hemoglobin (g/dL)13.113.5ANC (/µL)794531Platelets (x103/µL)9293Previous IFN treatment (%)Slide: Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL)The Adult-to-Adult Living Donor Liver Transplantation Cohort Study is the most recent trial evaluating standard-duration interferon-based therapy pre-transplantation.1This study included patients who had been listed for either living donation or HCC with MELD exception, underwent treatment with a standard duration PR and were compared to untreated controls.Exclusion criteria included prior null responders, creatinine (>2.2 mg/dL); hemoglobin (<10 g/dL); ANC (<750/µL); and platelets (<35K/µL).The primary endpoint was post-transplant HCV RNA undetectable at week 12.ReferenceEverson GT, Terrault NA, Lok AS, et al. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology. 2013;57:PR: pegIFN + RBV; LADR: low accelerating dose regimen.Everson GT, et al. Hepatology. 2013;57:
53A2ALL Study: Virologic Response With PR by GenotypeVirologic Responseby Treatment DurationHCV RNA UndetectableAt liver transplantationWeek 12 post-transplantHCV RNA UndetectableAt liver transplantationWeek 12 post-transplant67%68%64%59%52%50%Treated Patients (%)Treated Patients (%)Slide: Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL)A total of 57 patients underwent transplantation (44 treated and 13 controls).59% and 25% of treated patients had undetectable HCV RNA at the time of transplant and at post-transplant week 12, respectively.Treatment response increased with increasing duration of therapy pre-transplant.ReferenceEverson GT, Terrault NA, Lok AS, et al. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology. 2013;57:29%25%25%22%18%0%Overall(n=44)1, 4, 6(n=23)2, 3(n=21)<8(n=8)8 to 16(n=22)>16(n=14)HCV GenotypePegIFN + RBV Duration (Weeks)Per protocol analysis. PR: pegIFN + RBV.Everson GT, et al. Hepatology. 2013;57:
54HCV Treatment Before Liver Transplantation in Patients With Decompensated Cirrhosis G1(%)Child-PughTreatmentEOTRG1/non-G1 (%)SVRHCV RNA NegativePost Transplant (%)Crippin 2002(pilot study; n=15)7311.9IFN + RBV33(overall)NAThomas 2003(single cohort; n=20)6710.0IFN6020Everson 2005(single cohort; n=124)707.4(LADR)30/8213/5026Forns 2003(single cohort; n=30)A (50%);B (43%); C (7%)30Carrion 2009(case controlled; n=51)80A (45%);B (43%); C (4%)PR20/100Everson 2013(randomized,controlled; n=79)567.041/5325Slide: HCV Treatment Before Liver Transplantation in Patients With Decompensated CirrhosisThis slide summarizes the key studies in the use of standard-duration interferon-based therapy administered pre-transplantation to prevent HCV recurrence post-transplantation.1-6ReferencesCrippin JS, McCashland T, Terrault N, et al. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:Thomas RM, Brems JJ, Guzman-Hartman G, et al. Infection with chronic hepatitis C virus and liver transplantation: a role for interferon therapy before transplantation. Liver Transpl. 2003;9:Everson GT, Trotter J, Forman L, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology. 2005;42:Forns X, Garcia-Retortillo M, Serrano T, et al. Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol. 2003;39:Carrion JA, Martinez-Bauer E, Crespo G, et al. Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: a retrospective study. J Hepatol. 2009;50:Everson GT, Terrault NA, Lok AS, et al. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology. 2013;57:G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen.Crippin JS, et al. Liver Transpl. 2002;8: ; Thomas RM, et al. Liver Transpl. 2003;9: ;Everson GT, et al. Hepatology. 2005;42: ; Forns X, et al. J Hepatol. 2003;39: ;Carrion JA, et al. J Hepatol. 2009;50: ; Everson GT, et al. Hepatology. 2013;57:
55Pre-Liver Transplant Sofosbuvir + RBV: Prevention of Recurrent HCV Open-label, phase 2 study conducted at 16 sites (n=61)Deceased donor liver transplantation candidates with HCVHCC meeting MILAN criteriaMELD exception for HCCCPT <7Exclusion: decompensated cirrhosis, prior solid organ transplantation, HBV or HIV coinfection, renal impairmentUp to 48 weeks of sofosbuvir 400 mg + RBV ( mg) pre-transplantBaseline CharacteristicsTreatment(n=61)Male (%)80Age (years)59BMI <30 kg/m2 (%)43Genotype (%)1a/1b2/3439/3413/12HCV RNA >6 log10 IU/mL (%)41IL28 B non-CC (%)78MELD8CPT score 5-7 (%)95%Prior HCV treatment (%)75Slide: Pre-Liver Transplant Sofosbuvir + RBV: Prevention of Recurrent HCVCurry and colleagues conducted an open-label, phase 2 study to assess the efficacy and safety of up to 48 weeks of sofosbuvir 400 mg qd + RBV in patients with chronic HCV infection of any genotype listed for liver transplantation due to hepatocellular carcinoma (Milan criteria and well compensated cirrhosis [Child-Pugh-Turcotte score of <7).1The primary endpoint was HCV RNA <25 IU/mL 12 weeks after liver transplantation.The post-liver transplantation immunosuppressive regimen was tacrolimus plus prednisone with or without mycophenolate mofetil.ReferenceCurry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
56Pre-Liver Transplant Sofosbuvir + RBV: Virologic Response in HCV Genotypes 1-4 HCV recurrence prevented in 64% of patients HCV RNA <LLOQ at time of transplantationOn treatment HCV RNA suppression was rapid (1 week)HCV RNA Undetectable93%91%64%Patients (%)Slide: Pre-Liver Transplant Sofosbuvir + RBV: Virologic Response in HCV Genotypes 1-4HCV recurrence prevented in 64% of patients HCV RNA <LLOQ at time of transplantation. On-treatment HCV RNA suppression was rapid (1 week).Factors associated with HCV recurrence (multivariate exact odds ratio) included days continuously TND prior to transplantation: 1.04 (1.01, 1.08; P=0.0007).1ReferenceCurry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.Overall(n=44)>12 WeeksTreatment(n=33)Post-TransplantWeek 12(n=39)At TransplantTND: target not detected.Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
57Individual Patient Data HCV RNA Continuously TND (Days) Pre-Liver Transplant Sofosbuvir + RBV: Target Not Detected and Safety in Genotypes 1-4Median days TNDNo HCV recurrence (n=28): 95HCV recurrence (n=10): 5.5 (P<0.001)Sofosbuvir + RBV was generally well toleratedDiscontinuations due to adverse events: 3% (none related to sofosbuvir)Days Continuously TND Before Liver Transplant and Preventing HCV RecurrenceHCV recurrence (n=10)No HCV recurrence (n=28)>30 days TNDIndividual Patient DataSlide: Pre-Liver Transplant Sofosbuvir + RBV: Target Not Detected and Safety in Genotypes 1-4The days of continuously target not detect prior to transplant was predictive of HCV recurrence. No HCV recurrence occurred in patients who had a median of 95 continuous days of TND prior to transplant.1Overall, sofosbuvir + RBV was generally well tolerated, with only discontinuations due to adverse events in 3% (none related to sofosbuvir). Selected incidence of adverse events included fatigue (38%), anemia (23%), headache (23%), nausea (16%), and rash (15%).1ReferenceCurry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.HCV RNA Continuously TND (Days)TND: target not detected.Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
58HCV Treatment Considerations for Transplant Recipients Achieving sustained virologic responsePossible in some well-selected patients with HCV and decompensated cirrhosisPost-transplantation recurrence of HCV may be prevented if SVR is achieved pretransplantPotential benefits of HCV therapy need to be balanced against the risk of sepsis, hepatic failure, and deathChild’s C cirrhoticsRisks usually outweigh benefitsTransplantation evaluationComplete before initiating HCV treatment begins (in case patient should decompensate)Slide: HCV Treatment Considerations for Transplant RecipientsThe use of low-accelerating dose regimen can yield sustained virologic responses in select HCV patients with cirrhosis and who had a decompensating event. Achievement of a sustained virologic response in such patients can prevent posttransplantation HCV recurrence. However, the associated risks of this approach needs to considered (ie, risk of sepsis, liver failure, and death) in relation to the potential benefits.1The risks of this approach usually outweigh the benefits in advanced cirrhotics, particularly those with Child-Turcotte-Pugh’s C grade cirrhosis.1To this end, patients should undergo a transplantation evaluation prior to considering a low-accelerating dose regimen.1ReferenceGhany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:Ghany MG, et al. Hepatology. 2009;49:
60Early Antiviral Therapy to Prevent HCV Recurrence After Liver Transplantation G1(%)Treatment Initiation Post-Transplant (weeks)TreatmentSVRTreatment Discontinuation (%)Rejection (%)Mazzafero 2001(single cohort; n=36)833IFN + RBV33(G1/4: 20 G2/3: 100)Sugawara 2004(single cohort; n=21)439(G1/4: 33 G2/3: 100)2526Chalasani 2005(phase 3b study; n=54)74PRUntreated8(G1/4: 5 G2/3: 14)31321221Shergill 2005(randomized,controlled; n=54)NR2 to 6pegIFN4.518.24122.7Bzowej 2011controlled; n=115)7910 to 2622285.6Slide: Early Antiviral Therapy to Prevent HCV Recurrence After Liver TransplantationThe use of early IFN-based therapy to prevent HCV recurrence yields an SVR rate that ranges from 8% to 39% (median 16%), in 5% to 33% of genotype 1 patients and 14% to 100% of genotype 2/3 patients, respectively. The main drawbacks are that treatment can only be administered to a low proportion of patients, and that drug dose reduction and discontinuation are necessary in approximately 70% and 30% of patients respectively.1-5ReferencesMazzaferro V, Tagger A, Schiavo M, et al. Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment. Transplant Proc 2001;33:Sugawara Y, Makuuchi M, Matsui Y, et al. Preemptive therapy for hepatitis C virus after living-donor liver transplantation. Transplantation. 2004;78:Chalasani N, Manzarbeitia C, Ferenci P, et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology. 2005;41:Shergill AK, Khalili M, Straley S, et al. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am J Transplant. 2005;5:Bzowej N, Nelson DR, Terrault NA, et al. PHOENIX: a randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl. 2011;17:PR: pegIFN + RBV; G: genotype; NR: not reported.Mazzafero V , et al. Transplant Proc. 2001;33: ; Sugawara Y, et al. Transplantation. 2004;78: ; Chalasani N, et al. Hepatology. 2005;41: ; Shergill AK, et al. Am J Transplant. 2005;5: ;Bzowej N, et al. Liver Transplant. 2011;17:
61Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation Advantages of delaying treatment until established HCV recurrenceReduced risk of acute cellular rejectionBetter graft functionLower doses of immunosuppressionNumerous studies with PRSVR rates: 8% to 45%ChallengesHigh discontinuation ratesPoor tolerability (fatigue, asthenia, pyrexia, cytopenias), especially in severe hepatitis post-transplantSlide: Delayed Antiviral Therapy to Treat HCV Recurrence After Liver TransplantationThe advantages of delaying treatment until established HCV recurrence occurs is that there is a reduced risk of acute cellular rejection, higher chances for better graft function, and the need for lower doses of immunosuppression.1-3There are numerous studies with PR in this treatment setting, with SVR rates ranging from 8% to 45%.1-3However, challenges do exist, such as high discontinuation rates and poor tolerability (fatigue, asthenia, pyrexia, cytopenias), especially in severe hepatitis post-transplant.1-3There are a limited studies with direct-acting antiviral therapy in this setting, however early results are promising and establish the feasibility of this approach.1-3ReferencesAgarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol. 2012;26:Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int. 2011;32(suppl 1):PR: pegIFN + RBV.Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26:Roche B, et al. Liver Int. 2011;32(suppl 1):
62Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation G1(%)AdvancedFibrosis (%)Treatment Initiation Post-Transplant (months)TreatmentSVRTreatment Discontinuation (%)Dumortier 2004(single cohort; n=20)80NR28PR4520Oton 2006(2-center cohort; n=55)91336344(G1: 40)24Angelico 2007(randomized, controlled;n=42)83pegIFN3829Carrion 2007n=81)9015Untreated481940Picciotto 2007(single center; n=61)874625Hanouneh 2008(retrospective, medicalrecords; n=53)793526Slide: Delayed Antiviral Therapy to Treat HCV Recurrence After Liver TransplantationEarlier studies that evaluated this strategy reported low SVR rates between 12% and 24% with peginterferon monotherapy.1-6Studies utilizing PR show SVR rates for all genotypes ranging between 8% and 45%, with SVR rates in genotype 1 patients being considerably lower (range: 13% and 33%).1-6These study cohorts were heterogeneous with wide variation in the time from liver transplantation to the start of treatment and the percentage of patients with advanced fibrosis. Despite this, high discontinuation rates and poor tolerability were consistently high in these studies.1-6ReferencesDumortier J, Scoazec JY, Chevallier P, et al. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol. 2004;40:Oton E, Barcena R, Moreno-Planas JM, et al. Hepatitis C recurrence after liver transplantation: viral and histologic response to full-dose PEG-interferon and ribavirin. Am J Transplant. 2006;6:Angelico M, Petrolati A, Lionetti R, et al. A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver transplant recipients with recurrent hepatitis C. J Hepatol. 2007;46:Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology. 2007;132:Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol. 2007;46:Hanouneh IA, Miller C, Aucejo F, et al. Recurrent hepatitis C after liver transplantation: on-treatment prediction of response to peginterferon/ribavirin therapy. Liver Transplant. 2008;14:53-58.PR: pegIFN + RBV; G: genotype; NR: not reported.Dumortier J, et al. J Hepatol. 2004;40: ; Oton E, et al. Am J Transplant. 2006;6: ; Angelico M, et al. J Hepatol. 2007;46: ; Carrion JA, et al. Gastroenterology. 2007;132: ; Picciotto FP, et al. J Hepatol. 2007;46: ; Hanouneh IA, et al. Liver Transplant. 2008;14:53-58.
63Direct-Acting Antiviral Agents to Treat HCV Recurrence After Liver Transplantation Telaprevir or boceprevir + PRPromising preliminary SVR rates in genotype 1Significant dose reductions required for cyclosporine and tacrolimusIncreased adverse event profileAnemia occurs in most patientsRBV dose reduction and hematologic growth support factors/blood transfusionsNo data on viral resistance and impact on post-transplant periodIFN-free regimensSimplified dosingPromising preliminary SVR rates in multiple genotypesNo drug interactions with common immunosuppressant agents (?SMV)Lower incidence of adverse events, including anemiaSlide: Direct-Acting Antiviral Agents to Treat HCV Recurrence After Liver TransplantationThe use of DAAs in the post-transplant setting has been limited. Early pharmacokinetic data tempered expectations of the use of these agents in the liver transplant setting. Data on the use of telaprevir in healthy volunteers resulted in a significant increase in cyclosporin (5-fold) and tacrolimus levels (70-fold) due to the inhibition of the P4503A cytochrome. At present the data are based on mono-centric experiences and specific recommendations are difficult to make, aside from demonstrating that PI based triple therapy is feasible in this challenging population, albeit with a significant cumulative burden of side effects and drug–drug interactions.1-4The development of side-effects, in particular anemia, is universal, requiring the combination of ribavirin dose reduction, the use of hematological growth support factors and/or blood transfusion. Also no data are currently available regarding the development of viral resistance and its impact in the post-transplant period.The use of IFN-free regimens with simplified dosing has shown promising preliminary SVR rates in multiple genotypes. These regimens appear to have no or limited drug interactions with common immunosuppressant agents and are associated with a lower incidence of adverse events, including anemia.1-4ReferencesLucey MR, Terrault N, Ojo L, et al. Long‐term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. 2013;19:3-26.Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol. 2012;26:Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int. 2011;32(suppl 1):PR: pegIFN + RBV.Lucey MR, et al. Liver Transplant. 2013;19:3-26; Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26: ; Roche B, et al. Liver Int. 2011;32(suppl 1):
64REFRESH Study: Telaprevir + PR in HCV Genotype 1 Liver Transplant Recipients Interim results with telaprevir + PR show promising efficacyAnemiaMild or moderate: 41%Severe: 6.5%RBV dose reduction: 43%Erythropoietin/blood transfusions: 30%/6.5%No reports ofRejections, autoimmune hepatitis, or deathsSevere or potentially life-threatening cases of rash or pruritusInterim ResultsPatients(n=46)HCV RNA <25 IU/mL (%)Week 4Week 125360Serious adverse events (%)15Adverse events (%)FatigueAnemiaHeadacheNauseaAnorectalDiarrheaRashPruritus59484641373522Grade 3/4 creatinine increase (%)4Renal failure11Slide: REFRESH Study: Telaprevir + PR in HCV Genotype 1 Liver Transplant RecipientsInterim results with telaprevir + pegIFN + RBV in this challenging patient population show promising efficacy. Undetectable HCV RNA levels were achieved in 53% and 60% of patients at week 4 and 12, respectively.1Mild or moderate anemia was reported in 41% of patients and severe anemia in 6.5% of patients. RBV dose reduction was required in 43% of patients and erythropoietin use or blood transfusions was needed for 30% and 6.5%, respectively.1There were no reports of rejections, autoimmune hepatitis, or deaths or of severe or potentially life-threatening cases of rash or pruritus.1ReferenceBrown K, Fontana RJ, Russo MW, et al. Twice-daily telaprevir in combination with peginterferon alfa-2a/ribavirin in genotype 1 HCV liver transplant recipients: interim week 16 safety and efficacy results of the prospective, multicenter REFRESH study. Hepatology. 2013;58(suppl 1):209A. Abstract 3.PR: pegIFN + RBV.Brown K, et al. Hepatology. 2013;58(suppl 1):209A. Abstract 3.
65CRUSH-C: Virologic Response in HCV Genotype 1 eRVR is highly predictive of SVR12Treatment duration <36 weeks negatively affects SVR12 ratesAdverse events led to treatmentDiscontinuations: 20%Interruption: 7%SVR12eRVRNo eRVR93%†86%59%50%Patients (%)Slide: CRUSH-C: Virologic Response in HCV Genotype 1The overall SVR12 rate was 59%, with the highest SVR12 rates being seen among patients who achieved an eRVR and had received >36 weeks of therapy and achieved an eRVR.1Adverse events led to treatment discontinuation and interruption in 20% and 7% of patients, respectively.1ReferenceStravitz R, Levitsky J, Dodge JL, et al. Higher sustained virologic response (SVR-12) achievable in liver transplant (LT) recipients with hepatitis C (HCV) treated with protease inhibitor (PI) triple therapy (TT). Hepatology. 2013;58(suppl 1):429A. Abstract 461.33%‡16%5%Overall(n=90)Yes(n=56)No(n=32)<36(n=5/10)>36(n=46/11)*P<0.001 versus not achieving an eRVR.†P=0.04 versus <36 weeks (eRVR).‡P=0.003 versus <36 weeks (no eRVR).AchievedeRVRTreatment Duration (weeks)Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.
66CRUSH-C (All Patients): Safety in HCV Genotype 1 High rates of hospitalizations (27%) and >0.5 mg/dL increase in creatinine (41%)Anemia is a significant problemPegIFN + RBV dose reduction: 38%/86%Erythropoietin/blood transfusions: 84%/56%Death (7%)Mainly due to liver-related causes, usually in patients with advanced diseaseSlide: CRUSH-C (All Patients): Safety in HCV Genotype 1There were high rates of hospitalizations (27%) and cases of >0.5 mg/dL increase in creatinine (41%).1Anemia was a significant problem during the study, with pegIFN and RBV dose reduction being required by 38% and 86%, respectively and erythropoietin use and need for blood transfusions by 84% and 56% of patients, respectively.1Death occurred in 7% of patients and was mainly due to lever-related causes, usually in patients with advanced disease.1ReferenceStravitz R, Levitsky J, Dodge JL, et al. Higher sustained virologic response (SVR-12) achievable in liver transplant (LT) recipients with hepatitis C (HCV) treated with protease inhibitor (PI) triple therapy (TT). Hepatology. 2013;58(suppl 1):429A. Abstract 461.Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.
67Baseline Characteristics Sofosbuvir Compassionate Use Program: Recurrent HCV Following Liver TransplantationPatients with severe recurrent HCV infection following liver transplantationLikely to have <1 year life expectancySofosbuvir 400 mg qd + RBV + pegIFN for up to 48 weeksBaseline CharacteristicsPatients(n=104)Male (%)73Age (years)55Genotype (%)1a/1b2/3/428/491/7/8/ALT (IU/L)71Bilirubin (mg/dL)3.1Albumin (g/dL)INR1.3MELD score15Time from liver transplantation (months)17Slide: Sofosbuvir Compassionate Use Program: Recurrent HCV Following Liver TransplantationForns and colleagues reported on the compassionate use of sofosbuvir 400 mg qd with RBV and with or without pegIFN for 48 weeks n in patients with severe recurrent HCV infection following liver transplantation. Patients in this study were likely to have less than a 1 year life expectancy.1The recommended time of clinical assessments were:1On treatment: weeks 4, 12, 24, 36, and 48.Follow-up: weeks 4, 12, and 24.ReferenceForns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.PR: pegIFN + RBV.Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
68Sofosbuvir Compassionate Use Program: Initial Treatment Evaluations Overall, liver function tests significantly improved over timeMost patients improved clinically or remained stableAll serious adverse events (48%)Leading to treatment discontinuation (13%)Deaths (13%) were mostly a result of disease progression in this very sick populationOn treatment (n=8)Post treatment follow-up (n=5)Treatment Outcomes62%62%Patients (%)Slide: Sofosbuvir Compassionate Use Program: Initial Treatment EvaluationsThe overall SVR12 rate was 62%, with a higher SVR12 rate being achieved among patients receiving sofosbuvir + RBV versus pegIFN + RBV.1Overall, liver function tests significantly improved over time. Most patients improved clinically or remained stable (62% and 21%, respectively), with 21% having declining clinical condition or died.1There was a low incidence of treatment-related adverse events leading to discontinuation (3%). Deaths (13%) were mostly a result of disease progression in this very sick population.1ReferenceForns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.21%21%SVR12(n=85)Improved*StableWorseClinical Outcomes(n=104)*Improved: improvement in decompensation events(ie, significant decrease in hepatitic encephalopathyepisodes, improvement or disappearance of ascites, and improvement in liver-related laboratory values.Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
69Sofosbuvir + RBV: Treatment of Recurrent HCV After Liver Transplantation Key ResultsOpen-label studyGenotype 1(83%), 3 (15%), 4 (3%)CTP <7 and MELD <17Time liver transplantation: 4.3 yearsMETAVIR F3/F4: 23%/40%Sofosbuvir 400 mg qd + RBV (starting at 400 mg) for up to 24 weeksSafetyNo deaths, graft losses, or rejectionDiscontinuations due adverse events: 5%Patients(n=40)HCV RNA <25 IU/mL (%)Week 4SVR4SVR12SVR241007370Concomitant immunosuppression (%)TacrolimusMycophenolate mofetilPrednisoneCyclosporinAzathioprine3528255Adverse events (%)FatigueHeadacheArthralgia23Grade 3/4 laboratory abnormalities (%)25/28Slide: Sofosbuvir + RBV: Treatment of Recurrent HCV After Liver TransplantationSamuel and colleagues reported interim results of an ongoing single-arm, open-label interferon-free pilot study of HCV naïve and treatment-experienced patients with recurrent HCV infection (any HCV genotype) after liver transplantation. Patients received up to 24 weeks of sofosbuvir 400 mg qd + RBV.1Genotype 1(83%), 3 (15%), 4 (3%).Prior HCV treatment (88%).CPT <7 and MELD <17.Time liver transplantation: 4.3 years.METAVIR F3/F4: 23%/40%The interim SVR12 rate was 70% with no reports of deaths, graft losses, or rejection. Discontinuations due adverse events were low for this patient population (5%) and RBV dose escalation was manageable. No drug-drug interactions were noted with the variety of common immunosuppressant agents used.1ReferenceSamuel D, Charlton M, Gane E, et al. Sofosbuvir and ribavirin for the treatment of recurrent hepatitis C infection after liver transplantation: results of a prospective, multicenter study. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.Samuel D, et al. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.
70SOLAR: GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C Wk 0Wk 12Wk 24Wk 36LDV/SOF + RBVSVR12LDV/SOF + RBVSVR12223 patients randomized 1:1 to 12 or 24 weeks of treatmentGT 1 or 4 treatment-naïve or -experienced post-transplant patients≥ 3 months from liver transplantRBV dosingF0–F3/CPT A cirrhosis: weight-basedCPT B and C cirrhosis: dose escalation, 600–1200 mg/dWith respect to post-transplantation patients,These patients are being evaluated in the second cohort of SOLAR-1.And will be discussed by Dr. reddy on Sunday.Five groups of patients are beign evaluated, spanning the post-transplant spectrum”:F0-F3, Compensated Cirrhosis, CPT B and CPT C Decompensated cirrhosis, and FCH- FCH patients will be presented at EASL and not discussed here.Reddy et al, AASLD 2014
71Baseline Disease Characteristics – 12 and 24 Weeks GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C CPT Bn=52CPT Cn=9MELD (n, %)<10N/A28 (55)13 (25)1 (11)10-1520 (39)33 (63)5 (56)16-203 (6)4 (8)2 (22)21-252 (4)Ascites, n (%)2 (2)40 (77)9 (100)Encephalopathy, n (%)1 (1)23 (44)7 (78)Median bilirubin, mg/dL (range)0.7 ( )0.8 ( )1.2 ( )2.1 ( )Median albumin, g/L (range)3.8 ( )3.7 ( )3.2 ( )2.4 ( )Median INR (range)1.0 ( )1.1 ( )1.2 ( )1.3 ( )Median platelets, x 103/µL (range)146 (71-429)108 (41-358)93 (32-225)79 (54-189)Median hemoglobin, g/dL (range)14.0 ( )13.6 ( )12.9 ( )11.5 ( )Median CLCr, mL/min (range)65.0( )62.1( )58.9( )66.6( )Baseline disease characteristics are shown here.As expected, as the patients’ clinical status worsens, their bilirubin increase, and their albumin drops.Reddy et al, AASLD 2014
72SVR12 GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C LDV/SOF + RBV 12 WeeksLDV/SOF + RBV 24 WeeksSVR12 (%)Here are the SVR rateswhether patients were treated for 12 or 24 weeks did not appear to impact SVR rates.Also, the differences obsereved between CPT B and C patients are likely due to the small number of CPT C patients that were studied – only 8 in total.53/5555/5625/2624/2522/2615/183/52/3F0–F3CPT ACPT BCPT C*Subject completed 8 days of treatment and withdrew consent8 CPT B 24 Week and 1 CPT C 24 Week subjects have not reached the Week 12 post treatment visit..Reddy et al, AASLD 2014
73Deaths GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C Cause of DeathTreatment Duration(Weeks)Treatment RelatedCPT AProgressive multifocal leukoencephalitis12NoUnknown†24CPT BThoracic aorta aneurysm dissectionSepsisMulti-organ failure/intestinal perforationInternal bleeding – esophageal varicesComplications of cirrhosis (sepsis, thrombosis)In total, there were 7 deaths – but there was no pattern to these deaths.Observation Period: Day 1 through Post-treatment Week 12†per family requestReddy et al, AASLD 2014
74CORAL-I Study: ABT-450/r/Ombitasvir + Dasabuvir + RBV for HCV Genotype 1 After Liver Transplantation Ongoing phase 2 study of 24 weeks of ABT-450/r/ombitasvir + dasabuvir + RBVHCV genotype 1 (n=34)Liver transplantation due to HCV infectionMedian time from txp moMETAVIR <F2, no prior PISVR 97%Relapse 1No deaths, graft losses, rejectionRBV dose reduction: No impact on overall SVRSlide: CORAL-I Study: ABT-450/r/Ombitasvir + Dasabuvir + RBV for HCV Genotype 1 After Liver TransplantationMantry and colleagues reported on an ongoing phase 2 study on 24 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV for HCV genotype 1 recurrence after liver transplantation due to HCV infection (n=34).1Therapy with PR was permitted prior to transplantation.Treatment-naïve post transplantation.METAVIR <F2On stable immunosuppression: tacrolimus (85%), cyclosporine (15%).The primary outcome was SVR12.1ReferenceMantry PS, Kwo PY, Coakley E, et al. High sustained virologic response rates in liver transplant recipients with recurrent HCV genotype 1 infection receiving ABT-450/r/ombitasvir+dasabuvir plus ribavirin. Hepatology. 2014;60(suppl 1):298A-299A. Abstract 198.ABT-450/ritonavir/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV ( mg).Tacrolimus: 0.5 mg once weekly or 0.2 mg every 3 days.Cyclosporine: 1/5 of daily dose given once daily prior to HCV therapy.Mantry PS, et al. Hepatology. 2014;60(suppl 1):298A-299A. Abstract 198.
75Summary HCV eradication in advanced liver disease Reduces decompensationDoes not prevent HCCPrevents HCV recurrence post transplantIFN-based therapy is suboptimal in decompensated cirrhosisLower SVR rateHigher toxicityData with new DAAs evolvingPromise for IFN-free therapy pre- and post-transplant in the futureSlide: SummaryHCV eradication in advanced liver disease reduces decompensation, does not prevent HCC, and prevents HCV recurrence post transplant.IFN-based therapy is suboptimal in decompensated cirrhosis as it associated with lower SVR rates and higher toxicity burden.Data with new DAAs is evolving, with future promise for IFN-free therapies administered both pre- and post-transplant .