Challenges in managing hepatitis C virus infection

Challenges in managing hepatitis C virus infection Ahmed Alwassief MDCurrent situation

FDA Approval of HCV Treatments 1991 Interferon (IFN) 1998 IFN and ribavirin 2001 Pegylated IFN 2011 Boceprevir and telaprevir 2013 Sofosbuvir and simeprevir

Current situation Current situation

Regimens with one DAA + PEG-IFN alfa/RBVRegimens with two DAAs ( PEG-IFN alfa and/or RBV)IFN-free regimensABT-072, -333 (NNIs)ABT-450 (PI)BI201335 (PI)Daclatasvir (NS5A)Asunaprevir(PI)Danoprevir (PI)Mericitabine (NI) GS-7977 (NI)Tegobuvir (NNI)TMC-435 (PI)Alisporivir (Cyp)GS-9526 (PI) + tegobuvirDaclatasvir + AsunaprevirVX-222 (NNI) + telaprevir

GS-7977 + RBVDaclatasvir + GS-7977Daclatasvir + Asunaprevir RBVABT-450/r + ABT-072 + RBVABT-450/r + ABT-333 + RBVBI-201335 + BI-207127 RBVMericitabine + Danoprevir/r + RBVGS-5885 + GS-9451 + Tegobuvir + RBVAlisporivir RBVSample of Investigational HCV RegimensNNI = non-nucleoside NS5B inhibitor, NI = nucleoside NS5B inhibitor, PI = protease inhibitor, RBV = ribavirin, NS5A = replication complex inhibitor Cyp= cyclophilin inhibitor, r= ritonavir5

Essential Goals to Eliminate HCV Prevent sequelae of advancing liver disease in those already infected Baby Boomers, born 1945-1965 Many dont know they are infected Prevent new or incident infections Persons who inject drugs (PWID) Unsafe healthcare practices Sexual exposures in immunocompromised individuals

Essential Goals to Eliminate HCV MicroRNAsDefinition ??miR-122 is a highly abundant, liver-expressed miRNA that is implicated in the egulation of hepatic cholesterol, lipid and iron metabolism and in maintaining liver cell identity.miR-122 was shown to function as an important host factor for hepatitisC virus (HCV) propagation by an unusual mechanism, in which twomiR-122 molecules bindes to HCV genome at tow sites forming a complex that protects the HCV from nucleolytic degradation and thereby promotes viral RNA stability and propagation Furthermore, both miR- 122 binding sites are conserved in all six HCV genotypes

Tow drugs had been developed Phase 2a study with combination therapy of miravirsen 4 weeks + PR 8 weeks on 12 patients showed SVR in 58% and a recommendation with longer Tx protocole was instituted.chronic loss of miR-122 function in Mir122germline knockout and liver-specific knockout mice, respectively,resulted in increased incidence of steatohepatitis and hepatocellularcarcinoma with ageThe reported adverse events were infrequent andmostly mild, such as headache, coryza, fatigue and nausea, and noserious adverse events or clinically significant changes in safety testThe other drug is still in phase 1 trials

Challenges in managing hepatitis C Cirrhotic patients Post transplantChildrenPregnancyNon responders/ Null responders Logistics and economic challengesTreat or wait

Challenges in managing hepatitis C Cirrhotic patients Post transplantChildrenPregnancyLogistics and economic challengesTreat or wait

Limited Data and Lower SVR Rates With Advanced Fibrosis SVR (%)123/328213/319211/313 48 PR381008060402006767n/N = SVR (%)9/2414/3422/42381008060402004152n/N =Poordad F, et al. N Engl J Med. 2011;364:1195-1206. F0-2F3/4BOCRGT BOC48 48 PRBOCRGT BOC48 BOC, boceprevir; PR, peginterferon/ribavirin; RGT, response-guided therapy; SVR, sustained virologic response.

12CirrhosisFISSION 2013 RCTSofo + PR VS PR G 2 & 3OPTIMIZE 2012 Tel RGT + PR G 1SVR12 Cirrhotics 51%Non Cirrhotic 77%NEUTRINO 2013 Single open lableSofo+ PRG 1,4,5,6CUPICSOUND-C2: Faldaprevir + BI-207127 R

Hzode severv serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed.

safety profile was poor and patients with platelet count 100,000/mm(3) and serum albumin 100.000Platelet Count < 100.000Albumin > 3.5 g/dL3.3%4.8%Albumin < 3.5 g/dL7.1%40.6%Hezode C et al EASL 2013 Submitted Safety in cirrhotics:Clinical Trials vs Real World

n=530n=323n=734n=727n=159n=296Clinical trials(including cirrhotics)Real world(cirrhotics only)Treatment-naveTreatment-experiencedTreatment-experiencedTelaprevirBoceprevirn=132n=80n=363n=361PegIFN/RBV(courtesy F. Poordad)19Ribavirin + Sofosbuvir + PEGIFNData in 153 cirrhosisSummary of Fusion (68 HCVG2&3 experienced), Fission (100 HCV G2&3 naives) , Positron (31 HCV G2/3 IFN intolerant) and Neutrino (54 G1&4-6 naives) Studies

Lawitz E NEJM 2013; Jacobson IM NEJM 2013Boceprevir + PR for G1 F 4 Calleja 2014SVRw12 rate was 67.0%Perfectives were Response to prior treatment (relapsers), >1log decrease in viral load in the lead-in phaseBaseline albumin >3.5g/dl.36.5% at least one serious adverse events = Infection & Hepatic decompensationPerfectives of SAEPatients with albumin 2 mg/dlOther AE Neutropenia (57.6%), Anaemia (47.6%) and gradeThrombopenia (25.9%).

Spaine21

DAAs in the real world

conclusionDDAs generally are better than PR Treatment3DDAs regiment is better than 2 DDAsSafety profile is largely undetermined especially that real world experience looks significantly different than trials

Challenges in managing hepatitis C Cirrhotic patients Post transplantChildren..??Pregnancy..??Non responders/ Null responders Logistics and economic challengesTreat or wait

Challenges in managing hepatitis C Cirrhotic patients Post transplantChildrenPregnancyNon responders/ Null responders Logistics and economic challengesTreat or wait

Sofosbuvir + PR II LONESTAR-2study of pegylated IFNa, ribavirin, and sofosbuvir (400mg/day for 12 weeks) in treatment-experienced patients,rates of SVR were 96% (22 of 23) in patients with genotype2 infection and 83% (20 of 24) in those withgenotype 3 infection.61 There are limited data on the effectsof this combination in treatment-experienced patientsinfected with HCV genotypes 1 or 46, particularlyfor those who did not respond to pegylated IFNa orribavirin alone.IFN Free Regimen for Experienced Patients1. Poordad, et al. EASL 2012. Abstract. 2. Kowdley KV, et al. AASLD 2012. Abstract LB-1. 63594*47020406080100NaiveNonrespondersSVR (%)31/34n/N =8/176/1703/34273/113/6 null5/11 partialStatistical fluke ordue to previous NR,RBV resistance?98020406080100NaiveSVR (%)n/N =77/79Nulls9342/4573/4511/7900SVR NR Relapse*Different doses of ABT450/r combined.Very high SVR rates in 12 wksPotent combination may overcome null response to PR3D RegimenABT450/r (PI) + ABT-333 (NNI) + RBV x 12 wks[1]4D RegimenABT-450/r (PI) + ABT-333 (NNI) +ABT-267 (NS5A) + RBV x 12 wks[2]NR, nonresponder; PI, Optemistic VS realistic protease inhibitor; PR, peginterferon/ribavirin; r, ritonavir;RBV, ribavirin; SVR, sustained virologic response.278462/7493*[2]38/41Previous Null Responders: Quad Therapy100806040200SVR12 or 24 (%)90[1]9/10Quad therapy may be a good option for null respondersWell tolerated BUT cirrhotics excluded*Asunaprevir QD and BID combined.88% GT1an/N = 100806040200SVR12 (%)61% GT1an/N = Daclatasvir (NS5A) + Asunaprevir (PI) + PegIFN/RBV x 24 wks (Quad)Danoprevir/r (PI) + Mericitabine (Nuc)+ PegIFN/RBV x 24 wks (Quad)[3]1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Lok AS, et al. AASLD 2012. Abstract 79. 3. Feld JJ, et al. AASLD 2012. Abstract 81. BID, twice daily; GT, genotype; PegIFN, peginterferon; PI, protease inhibitor; PR, peginterferon/ribavirin; QD, once daily; RBV, ribavirin; r, ritonavir; SVR, sustained virologic response.

IS ther a role for IFN Tx in experienced patients

2864 14/22IFN Ineligible/Intolerant or Unwilling100806040200SVR 24 (%)9119/21PreviousNullsIFNIntolerant/IneligibleBreakthrough correlated with low plasma drug concentrationsChallenges beyond AEs of IFNTherapy only works if you take your medicationsn/N =Daclatasvir (NS5A) + Asunaprevir (PI) x 24 Wks (IFN Free)Suzuki F, et al. EASL 2012. Abstract 14.HCV RNA (log10 IU/mL)876543210N = 21Null Responders480246810121620242836EOTSVR24LLOQ = 15 IU/mLTime (wks)Daclatasvir + AsunaprevirFollow-up876543210N = 22PegIFN/RBV Ineligible/Intolerant480246810121620242836EOTSVR24Daclatasvir + AsunaprevirFollow-upBelow LLOQ UndetectableEOT, end of treatment; IFN, interferon; LLOQ, lower limit of quantitation; PegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; SVR, sustained virologic response.29PROPORTION OF EXPERIENCED HCV GENOTYPE 1 PATIENTS WITHOUT RESPONSE AFTER TREATMENT020406080100SVR (%)RelapsersPartial Responders17-31PegIFN + RBVBacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Vierling JM, et al. AASLD 2011. Abstract 931.

NullResponders BOC or TVR + PegIFN + RBV71-7641-6085-9362-715 95

Setting % without ResponseHCV G1 naive25-37HCV G1 relapsers17-31HCV G1 partial responders41-60HCV G1 null responders63-71It is rational to use IFN free TX in experienced patients 30REALIZE: Very Low SVR in Cirrhotic Previous Null RespondersPrevious RelapsersPrevious Partial RespondersPrevious Null Responders2/15n/N =53/62144/16712/380/510/1834/473/170/915/3811/321/5No, Minimal, or Portal FibrosisCirrhosisStagePooled T12/PR48Pbo/PR482/1548/5724/591/187/501/10BridgingFibrosisNo, Minimal, or Portal FibrosisCirrhosisBridgingFibrosisNo, Minimal, or Portal FibrosisCirrhosisBridgingFibrosisREALIZE: TVR + PegIFN/RBV in GT1 Previous Relapsers and NonrespondersZeuzem S, et al. EASL 2011. Abstract 5. 100060SVR (%)804020863285138413721856034204163901410Double trouble 31Sofosbuvir + Ribavirin in HCV G2 &3 Non responders: Fusion StudyHCV genotype 2 or 3 patients who failed prior interferon-based therapy were randomized (1:1) to receive either a 12-week (n=103) or 16-week (n=98) course of sofosbuvir 400 mg once daily plus RBV (1,000 or 1,200 mg/day). 63% HCV genotype 3.34% CirrhosisHistorical control group: 25% SVR

Jacobson IM NEJM 2013% SVRSimeprevir + Sofosbuvir + RBVGenotype 1 F0-F2 non respondersSimeprevir Sofosbuvir RBVSimeprevir SofosbuvirSimeprevir SofosbuvirRBVSimeprevirSofosbuvir24 weeks24 weeks12 weeks12 weeksNumber24152714RVR %81668557UND EOTR8388100100SVR84/6 66%5/5 100%26/27 96%13/14 (92%)Anemia %250110Bilirubin increase2020CAVEAT SVR w8 mild fibrosisLawitz CROI 2013SVR Daclatasvir + Sofosbuvir + RBVG1 Telaprevir /Boceprevir failureDCV +SOFDCV + SOF + RBVN2120EOT UNDETECTABLE21/21 (100%)19/20 (95%)SVR 421/21 (100%)20 (100%)SVR 12Non cirhosis, breakthrough, relapsers and non responders 1a 80% IL28b; nonCC 98%; > F2 83%Sulkowski EASL 2013Contingency plan Secret weapon for DAAs faliure 34Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options

Suzuki J Hepatol 2013POSITRON Efficacy of a 12-Week of Sofosbuvir Plus Ribavirin for Chronic Hepatitis C Patients HCV G2 or 3 who are Unable or Unwilling to Take InterferonStudy population: HCV G2 or G3 were interferon intolerant, interferon ineligible or unwilling to take interferon randomized (3:1) to receive 12 weeks of either sofosbuvir 400 mg once daily plus weight-based RBV twice daily (n=207) or matching placebo (n=71). 207 patients randomized to the sofosbuvir/RBV arm, 15 percent had compensated cirrhosis (more advanced liver disease) 53 percent were infected with genotype 2.

0/7159/97102/110Jacobson IM NEJM

Challenges in managing hepatitis C Cirrhotic patients Post transplantChildrenPregnancyNon responders/ Null responders Logistics and economic challengesTreat or wait

Logistics and economic challengesA socioeconomic situation (costs)

Currently, access to treatment for HCV is limited, Treatment rates are lowest in resource-limited countries including those countries with the highest prevalence. key reasons for limited treatment access have been the cost, and complexity, with unknown effectiveness of treatment in relation to genotypes.Ideal treatment plane Simplification of treatment regimensStandardization of treatment regimensService deliveryAccess to affordable medicinesAs of September 2014, six drugs were approved by the FDA forthe treatment of HCV standard interferon (IFN) or pegylatedinterferon alpha (PegIFN), ribavirin (RBV), three protease inhibitors(boceprevir, simeprevir, and telaprevir), and the nucleotideanalogue and polymerase inhibitor sofosbuvir.38Ideal treatment plane Simplification and Standardizationof treatment regimensService deliveryAccess to affordable medicines

Situation now is like the HIV at the beginning of this melinium as many drugs are being tested Simplification over 41 drugs with about 25 combinations are being tested this will naturally evolve into a limited number of combination therapy mostly according to Genotype .

Service delivery mean to initiate a sustainable plan of mangment with judicial use of resources so examples in australia with the limited number of doctor nurses were trained to deploy treatment under non immediate physician supervision

Nations should not start Eradication plane and then interrupt it because of non realistic goals

Prevention plan with Screening of risk groups and combatting vertical transmission

Prioratization of patient groups to target the potentially infectious 1st like health care workers sexually active patients Patient self-managementHCV treatmentshould be formulated as an oral, pan-genotypic, interferon free,fixed-dose combination therapy.39Access to affordable medicines

HCV treatment is expensive, costing as much as US$84,000 and Monopolized by Multinational companies>Lessons from HIV tX evolution Use of WTO agreements for either Compulsory licensing or patent oppositions Increased price transparency.. WHO Global Price Reporting allowed countries and agencies to monitor the prices of generics all over the world which can be used by pressure groups Patent sharing arrangements

DrugDrug InteractionsCYP3A4PIMetabolitesSubstrates and Inhibitors of CYP3A4Interactions with many common drugsStatinsOCPSSRISildenafilMany moreOCP, oral contraceptive pill; PI, protease inhibitor.41We did not detect the S282T mutation (the onlyvariant known to be associated with resistanceto sofosbuvir)Cirrhosis:Most urgent need response = short term survivalHCV Treatment Based on Individualized Risk-Benefit AnalysisTreat nowTriple therapy substantially increases SVR ratesSuccessful treatment may arrest progression of liver diseaseEarlier treatment has higher success ratesUncertainty about timelines for approval and reimbursementDecrease Infection load will decrease transmission rate and prevent future infectionsDeferCurrent Tx are imperfectComplex regimens (TID, lead-in) Challenging adverse eventsUnsuccessful treatment may reduce subsequent treatment success Induce resistanceNext-wave DAAs may achieveHigher cure rates Shorter treatment duration Improved safety and tolerabilityIFN-free treatmentBetter resistance profileActivity in non-GT143Classification Description

Class I Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective

Class II Conditions for which there is conflicting evidence and/or a divergence of opinion aboutthe usefulness and efficacy of a diagnostic evaluation, procedure, or treatment

Class IIa Weight of evidence and/or opinion is in favor of usefulness and efficacy

Class IIb Usefulness and efficacy are less well established by evidence and/or opinion

Class III Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful

Level of Evidence Description

Level A Data derived from multiple randomized clinical trials or meta-analysesLevel B Data derived from a single randomized trial, or nonrandomized studiesLevel C Consensus opinion of experts, case studies, or standardGrading System Used to Rate the Level of the Evidence and Strength of theRecommendationSafety Outcome, n (%)TVR-Based Treatment (n = 292)BOC-Based Treatment(n = 205)Serious AEs132 (45.2) 67 (32.7)Premature discontinuationFrom serious AEs66 (22.6)43 (14.7)54 (26.3)15 (7.3)Death*5 (2.6)1 (0.5)Infection (grade 3/4)19 (6.5) 5 (2.4) RashGrade 3/SCAR14 (4.8)0Hepatic decompensation6 (2.0)6 (2.9)Blood transfusions47 (16.1)13 (6.3)Hezode C, et al. EASL 2012. Abstract 8. *Causes of death in patients treated with TVR: septicemia, septic shock, pneumopathy, esophageal varices bleeding, endocarditis; causes of death in patients treated with BOC: pneumopathy.Preliminary Real-World Safety Findings: CUPICPIs in Patients With CirrhosisAE, adverse event; BOC, boceprevir; PI, protease inhibitor; SCAR, severe cutaneous adverse reaction; TVR, telaprevir.

451. Chen EY, et al. AASLD 2012. Abstract 133. 2. Bichoupan K, et al. AASLD 2012. Abstract 1755. 50403020100Patients (%)n/N =18498 GT1 Patients Evaluated[1]Started Therapy22171169/40789/40743/407Did Not StartPatientChoiceWait forBetterTherapiesMildDiseaseHigher Discontinuation Rates in Real-World Settings Than in Clinical TrialsD/CBeforeWk 122140302010091/498D/C TVR < 12 wks58/17433[2]2136/174174 GT1 Patients StartedTVR-Based Triple Therapy[2]Due to AEsAE, adverse event; D/C, discontinued; GT, genotype; TVR, telaprevir.46Challenges of Current PI-Based TherapyEfficacyVery dependent on the IFN responseTolerabilityAdditional AEs beyond pegIFN/RBVRegimensComplicated (lead-in, RGT)/pill burdenDDIsMany with both agents to common drugsGenotype/special populationsLimited activity in non-GT1, limited data HIV/OLTx, ESRDAE, adverse event; DDI, drugdrug interaction; ESRD, end-stage renal disease; GT, genotype; IFN, interferon; OLTx, orthotopic liver transplantation; pegIFN, peginterferon; PI, protease inhibitor; RGT, response-guided therapy.

47GlossaryDAA: Direct Acting Agent. Anti-HCV medications that target specific aspects of HCV viral replicationPEG: Pegylated interferonRBV: RibavirinPR: PEG + ribavirinGenotype: Strains of HCV that affect treatment response (1-6) Genotypes 1&4 harder to cure than 2&3IL28b human gene that contributes to response to IFN-based treatmentResponse from best to worst: CC>CT>TT

Glossary (2) SVR: Sustained virologic response (HCV viral load undetectable off of treatment) SVR12 and SVR24 considered curesNull response: Failure to attain at least 2 log10 drop in HCV after 12 weeks of treatmentResponse Guided Therapy: Shortening therapy based on good early virologic response (1st 12 weeks)

Recommended regimen for treatment-naive patients with HCV genotype 1 who are eligible to receive IFN.

Daily sofosbuvir (400 mg) and weight-based RBV

(1000 mg [