Information Magazine for people with Hepatitis C and HIV. Hepatitis C - Treatment in people with haemophilia, the results to date

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1 Positive News Information Magazine for people with Hepatitis C and HIV Hepatitis C - Treatment in people with haemophilia, the results to date From July 2012 to October 2013, a total of fifteen persons with haemophilia or related bleeding disorder with Genotype 1 Hepatitis C had commenced triple therapy treatment consisting of Pegylated Interferon, Ribavirin and a ProteateInhibitor(eitherIncivoorVictrelis).TheIrishHaemophilia Societyhasprovided,andcontinuestoprovide,support,encouragement,assistanceandinformationtoallourmembersontreatment.Todate,atotalofsevenpeoplewithhaemophiliahavecompleted the course of treatment with two individuals requiring a twentyfourweekcourseoftreatmentandfiveindividualsrequiring afortyeightweekcourse.allsevenindividualswerenegativefor thehepatitiscvirusattheendoftheirtreatment(anendoftreatmenttesponse-eotr).ofthesesevenindividuals,threearenow at six months post completion of treatment, and all 3 have achievedasustainedvirologicalresponse(svr)which,effectively, is a cure.a further four individuals are continuing their treatment.thetreatmentfailedforthreeindividualswiththeirtreatment beingstoppedandunfortunately,afourthindividualdiedwhileon treatment.wewillcontinuetomonitorandreporttheoutcomeof treatmentinthehaemophiliagroup. The Irish Haemophilia Society Representing people in Ireland with haemophilia and related bleeding disorders. Support from the Irish Haemophilia Society Ifyouareontreatment,andthereissomethingthattheSocietycanhelpyouwith,pleasedonot hesitatetocontacttheofficeon WearecommittedtoofferingpracticalsupportandassistancetomembersonHepatitisCtreatment. Someofthesupportsavailabletomembersare: AccommodationFacility FinancialAssitance PersonalSupport PleasecontactAnneDuffyon ifyouhaveanyconcernsorqueriesinrelationtotreatment.Weare heretogiveasmuchsupportaspossible,duringyourcourseoftreatment. Edition: December 2013

2 Getting through treatment the Irish experience In 2011, two new treatments for Hepatitis C genotype 1, were licensed. These were Boceprevir (Victrelis) and Telaprevir (Incivo), used in combination with Interferon and Ribavirin. In late 2011, the first Irish person with haemophiliastartedthesetreatmentsandbymarch2013,elevenpeoplehadstartedorfinishedtreatment.studies haveshownthatapproximately20%ofpeoplestoppedtreatmentearlyasaresultofthesideeffectsofthesedrugs. However,withintheIrishgroupofpeoplewithhaemophiliaonHepatitisCtreatment,nobodystoppedtreatmentearly asaresultofsideeffects.theirishhaemophiliasociety(i.h.s.)askedthesememberswhattheyhaddonetopreparefortreatment,whattheirexpectationsoftreatmentwereandhowthosechangedduringtreatment.thesemembersfilledoutaquestionnaireinmarchthisyearandwereaskedtotakepartinadiscussiongroupinaprilwhichwas guidedbytheresultsofthequestionnaires.anumberofthesepeoplewithhaemophilia,andtheirpartnerstookpart. Thequestionnairelookedatpreparationforsideeffects,preparationforimpactondailylifeincludingwork,dailyactivitiesandthesubsequentrealityoftreatment. Someoftheearlyresultsshowthatthebiggestfactorinthedecisiontostarttreatmentwasduetotheavailabilityof newtreatments.discussionswiththehepatologynursesandcliniciansabouttheircurrentclinicalpositionhadalarge impact.theperson sagehadtheleasteffectonthedecision.thebiggestsourceofinformationthatpeopleusedto getagraspoftheroadaheadwastheinformationmeetingsorganisedbythei.h.s.thiswasfollowedbyinformationbythehepatologycliniciansandnurses.ati.h.s.meetings,thosewhospokeweremainlycliniciansandthenurseswhowouldbecaringforpeoplewhenontreatment.attendingthesemeetingsallowedmostpeopletogetanswers toquestionsthattheyhadn teventhoughtaboutinrelationtotreatment,sideeffectsandcoping.theleastfrequent informationsourceusedwaspharmaceuticalindustryleaflets. Inpreparationforthesideeffects,somepeopleinformedspecificfamilymembersandfriendsthattheywerestarting treatment.theypreparedthemselvesmentallyfortreatment.inrelationtothetreatmentitself,asskinrasheswere assumedtobeamajorpotentialsideeffect,throughdiscussionwiththehepatologynursesandpeoplewhohaddone treatment,peoplemoisturisedorwashedtheirskinwithnon-perfumedcreams(e.g.silcock sbaseore45).some preparedalistofmedicationsthatcouldassistwithsideeffectsbeforetheybecameamajorproblem.peopledid thingsthatsavedeffortortroublelatersuchas,arrangedhomehelp,preparedfrozenmeals,orfixedminorproblems aroundthehouse.specificallyfortelaprevir(incivo),peoplepreparedforthedietof20goffatwitheachtablet.they didthisbyfiguringoutwhatwas20goffatincertainfoods,andhavingalternativesforthetimeswhentheydidnot wantaspecificfoodtype. Fromaworkpointofview,mostwereeithernotworkingorreducedtheirworkload.Forthosewhowereworking theyreducedtheirworkloadsignificantlybybetween25-50%.inrelationtotelaprevir(incivo),reducingworkload wasmoreinthefirst12weeksandlessfortheremainingtime.withboceprevir,itrequiredaslessofareductionfor mostofthelengthoftreatment.72%ofrespondentsratedtheimpactofthetripletherapytreatmentsasseveretovery severeandthesamenumbersaidthatsideeffectsweremoresevereormuchmoreseverethanhadbeenanticipated.thepeginteferonandriabvirinhadrelativelywellcharacterisedsideeffects,whichareflu-likesymptoms,depression,fatigue,reducedconcentration,moodswings,coughing,breathlessnessandsleepdisruptionthatappearedwith varyingdegreesindifferentpeople.addinginathirddrugtenderedtoaddormagnifythesesideeffects. With Boceprevir, a constant metallic taste in their mouth was described, and some people used plastic cutlery to reducetheproblemsfromthissideeffect.analdiscomfortoritchingwasdescribedinassociationwithtelaprevir. However,thismayhavebeenduetoindividualsnottakingthefull20goffatwiththetablets.Somefeltthatincreasingtheamountto21-22ghelped.Skinrasheswerenotascommonasexpected,butitchingandskinirritationwere. Commonplacesforthesewerewherethereseemedtobetheleastamountofmuscleorfat,i.eankle,hands,fingers, ears,etc.thiswasgenerallydealtwithbymoisturisingand/ormedicationsprescribedbythehepatologyteam.the mostsignificantside-effectofboceprevirandtelaprevirwasaraisedrateofanaemia(lackofredcells,andtherefore oxygen,intheblood),whichledtooneofthemainsideeffectswhichwasfatigue.oneoftheindividualssaid although you are told about the side effects, I don t think anyone can really tell you how sick you can feel on a bad day. Howeverinfurtherdiscussionsthesameindividualsaid thesideeffectshavebeentolerablebuttherehavebeen somehardweeks. Thismessagereallygetstotheheartofthematter.Obviouslythereisnopointinsayingthat thesetreatmentsareeasy.somedayscanbeverydifficultbutthereisanendandaverygoodreasonyouaredoing this,whichisthefocusandthedriveforalotofpeople. 2 Thisalsoleadsontotheimportanceofsupport.Whentheseindividualswereaskedaboutwhatwerethemajorsupportsduringthistimethethreetopresponseswerefirstlyyourpartner/spouse/familymembers,secondlythesupport ofthestaffinhepatologyandthirdlymeetingwithotherpeoplewhowereontreatment.asstatedalreadytheseare theearlyresultsofhowtheindividualsthemselvescopedontreatment.inafutureissuesof PositiveNews wewill bediscussingtheseinmoredetailaswellastheideasandthoughtsofthepartnerswhoalsohadtogothroughthe treatment,justinadifferentway.

3 The future is speeding towards us, and it looks promising Youknowthatfeelingwhenyouhavewaitinghours for the bus to come and then two come along together. Well that is what it has been like in Hepatitis C treatment for the last ten years. The onlydifferencereallyisthatafterthosetwothereis anentirefleetthatmaybecomingbehindthem.it reallyisafascinatingtimeinhepatitisctreatment. A little tip, to get the most out of this article you should know, your genotype, IL28B combination, howyourespondedtotreatmentlasttimeandyour fibrosisstage(seethereminderssection). Current Treatments At present, the regimen for treating Hepatitis C consists of two or three drugs in combination depending on the genotype, each with their own side-effects. Genotypes - 2, 3, 4, 5, 6 Acombinationofpegylatedinterferonandribavirin(pIFN/RBV)isstilltheonlytreatmentavailableforthesegenotypesatthemoment.ThemainreasonisthefocushasbeenonGenotype1asitisthemostcommon.TheSVR ratesingenotype2and3arearound80%withthepifn/rbv.thepegylatedinterferon(pifn)isasub-cutaneous injectiononceaweekandtheribavirin(rbv)istakenintabletformtwiceaday.thetreatmentcurrentlylastsfor either24weeksor48weeks. Reminders / Glossary of Terms SVR - stands for sustained virological response and means there is no Hepatitis C virus evident in the blood 24 weeks after treatment has ended, currently the accepted definition of a cure. Subsequent relapses are very rare. If there is no virus evident twelve weeks after treatment has ended, in over 99% of cases this is still the case after 24 weeks. It is sometimes written with a number after it. The number stands for the number of weeks after the treatment is finished. Example: SVR4 is 4 weeks after the end of treatment. Genotype (G1a, 1b, 2, 3, 4 etc.) - Hepatitis C comes in many different genotypes (varieties), with very different rates on how effective treatment is. In general, G1 and G4 (especially G1a) are the hardest to treat though now with new drugs G1b in particular is more treatable. G3 is next hardest to treat and G2 the easiest to treat. IL-28B Is a protein in the body that plays a role in the defence against viruses. There is one point on this protein where there are 3 possible combinations. These are CC, CT and TT. Individuals with the CC configuration have the best response to treatment followed by those with CT and those with TT have the worst response. Naïve Never tried treatment before. Null Responder Is someone who has tried treatment before but it had little or no effect on the viral load and the viral load was never undetectable during their treatment. Relapsing Responder Is someone who has tried treatment before, the virus was undetectable at the end of treatment but it came back in the six months between finishing and week 24 (SVR24). So, they do not achieve an SVR and this person is referred to as a relapsing responder. Fibrosis - Scarring to the liver (but the liver is still largely able to do its job). There are various grades of fibrosis. Cirrhosis - Large portions of the liver are replaced with scar tissue; blood flow through the liver is restricted and the person will probably be suffering from symptoms caused by poor liver function. pifn stands for the drug pegylated (longer lasting) Interfereon. Injection once a week. RBV Stands for the drug Ribavirin. Tablets twice a day. pifn/rbv Stands for both together. 3

4 Genotype 1 Genotype 1 has two sub genotypes, G1a and G1b. The previous treatment was the same as with all other Genotypes:PegylatedInterferonandRibavirin(pIFN/RBV).TheSVRrateshoweverweremuchlessat40-50%for peoplewithhepatitiscaloneandabout30-40%forpeoplewhoareco-infectedwithhivandhepatitisc.in2011, two new drugs were licenced to tackle this more difficult Genotype. These were known as G1 specific protease inhibitors. These are tablets taken in conjunction with the pifn/rbv. These are called Telaprevir (Incivo) and Boceprevir(Victrelis).Wehavediscussedtheseindetailinprevious PositiveNews newsletters,sopleasecheck outourwebsiteorcontactusformoreinformation.forthefirsttime,peoplewithg1haveachieved67%to75%svr ratesinstudies.however,thelikelihoodofsvrdependsonsomeone sindividualsituation.peoplewhoalready havecirrhosisrespondtotreatmentlessoftenthanpeopleinearlierstagesofliverdisease.ifprevioustreatmenthad littleornoeffect(nullresponders),theprospectsarenotasgoodifthesamemedicationsaretakenagainwiththe additionoftheextradrug.instudiestodate,nullresponderswithcirrhosiswhotookthetelaprevirtripletherapyonly had 14% response rates. On the other hand, Relapsers with Genotype 1 have good prospects. In pre-licencing approvalstudieswithboceprevirandtelaprevir,75to88%ofrelapsersachievedansvr. Note: Telaprevir Until now Telaprevir tablets have had to be taken three times a day and at eight-hour intervals, in order to avoid the virus from becoming resistant to the drugs. Telaprevir must also be taken with 20g of fat. This is not easy for many people as Hepatitis C treatment can cause nausea and loss of appetite. A new study has shown that Telaprevir can be taken twice a day, resulting in the same SVR rates. Side-effects were similar in groups on twice a day and three times a day, regardless of whether people had cirrhosis or not. However, anaemia occurred slightly more often in the twice-daily dose. This appears to be good news as it may turn a regimen that is difficult into a more manageable one. HIV / HCV Co-Infection Peoplewhoareco-infectedwithHIVandHepatitisChaveagreaterriskofdevelopinglate-stageliverdiseasesuch ascirrhosisandlivercancer.previoustreatmentswithpifn/rbvwerelesssuccessfulforpeopleinthissituation.a newstudynowrevealsthattripletherapywithtelaprevir,pifn/rbvhassimilarsvrratesinthosewithhivco-infectionasinpeoplewithhepatitiscalone.in74%ofpreviouslyuntreatedpeople,hepatitiscwaseliminatedusingtriple therapy,whereasonly45%oftrialsubjectsachievedthisusingdualtherapy.asecondstudybythesameteamhas founda62.5%svr12responseratewithboceprevir.thenewdrugsaremostlybeingusedinpeoplewhohavehepatitisconly(mono-infection),howeverthereareafewclinicaltrialsinco-infection.astherecanbemanyinteractions withhivdrugs,itisimportantthatthistreatmentismonitoredbydoctorswhoareexperiencedintreatingbothhiv andhepatitiscandwhocancustomisetherangeofhivmedications. Cirrhosis Peoplewithcirrhosis,whoarealreadyseriouslyill,havelesstimetowaitforfuturetreatmentsbutrespondlessoften tocurrenttripletherapiesandalsohaveasignificantlyhigherriskofcomplications.inafrenchstudyofpeopleon Telaprevir or Boceprevier, triple therapies, 50% of people with cirrhosis had complications such as infections, and morethan4%progressedtodecompensatedcirrhosis.thereweretendeaths.severecomplicationsusuallyoccurred inpeoplewhoseliverfunctionwasalreadysignificantlyimpairedbeforetreatmentwasstarted.asyoumayexpect, themorediseasedtheliverthegreaterthetreatment-relatedrisks.withouttreatment,however,peoplewithcirrhosis areatriskofdyingwithinafewyears.thedecisionfororagainststartingthecurrenttripletherapyisthereforenot easyforthosewhohavecirrhosis.individualcasesshouldbediscussedingreatdetailwithyourdoctorandtreatment shouldbewellsupervised.thefurtheradvancedthecirrhosis,themorelikelythepossibilitythatatransplantwillalso beconsidered. Side Effects Thereisadrawbacktothenewtripletherapies.Thereisanincreasednumberofside-effectsreported.ThepIFN/RBV therapyhasagenerallywelldefinedsetofsideeffects(interferoncausesflu-likeillnessanddepression,amongst otherthings,andribavirincausesanaemia).theadditionofathirddrughasmagnifiedsomeofthesesideeffects andaddedsomeadditionalonesdependantonwhichnewdrugyoumaybeon. 4 WithBoceprevir,ametallictaste,inparticular,wasobservedmorefrequentlythanwithdualtreatment.WithTelaprevir, skinrashesaremorecommon,sometimesrequiringtreatment.inaddition,discomfortanditchingintheanalareais frequentlyreported.themostsignificantside-effectofboceprevirandtelaprevirisprobablyaraisedrateofanaemia (lack of red cells, and therefore oxygen, in the blood). If Boceprevir or Telaprevir are added then ribavirin-related anaemiacanincrease.ontheupside,anaemiaisasignthattreatmentisworking.peoplewhoexperienceanaemia asaside-effectachievesvrmoreoftenthanpeoplewhodonot.itwasreportedfromthreeamericanclinicsthatup to21%ofpeopletakingtelaprevirstoppedtreatmentearly.thishasnotbeencaseintheirishpeoplewithhaemophiliacohortsofar,withnoonestoppingtreatmentasaresultofsideeffects.youcanreadadescriptionofthesideeffects andcopingskillsusedbythemembersoftheihsingettingthroughtreatments(seepagetwo).

5 Not everyone with Genotype 1 requires three medications. One study suggests that some people, despite having Genotype1,wouldhaveagoodchanceofeliminatingtheirHepatitisCwithtwomedications.Thisgroupischaracterised as having had no previous treatment, no cirrhosis, low viral load(<600,000 before treatment) and no viral detectabilityafterfourweeksoftreatment.ifallthesefavourablefactorscometogether,thechancesofsuccessinthe studywerejustashighregardlessofwhetherthetrialparticipantsaddedboceprevirornotafterthefourthweek(90 versus89%).thisappliedtoaroundatenthofpeoplewithgenotype1. What the future may hold? Numerousnewdrugsarebeingexplored.Thefirstinnovationswecanexpectwillbemoretripletherapies,inwhich anotherdrugwithfewerside-effectsisaddedtopifn/rbv,whileforparticularlystubborninfections,quadrupletherapieswillbetested.it simportanttorememberthatthenewdrugsdon tworkequallywellforeveryone,andinparticular,someonlywork,orworkwell,withcertainhcvgenotypes.inthefuture,doctorsandpatientswillhavetoconsiderthechoiceofmedicationsverycarefully.inaddition,anovelversionofinterferoncalledpegylatedinterferon lambdaisbeingresearched.thisproducesfewerside-effectsthanpegylatedinterferonalfa(usedincurrenttreatment). Direct Acting Antivirals (DAA s) Thedevelopmentofdirect-actingantivirals(DAAs)hasbeendescribedbymanyasrevolutionary.TheseareverydifferentinthewaytheyworkcomparedtopIFN/RBV.Basically,thepIFN/RBValterstheabilityofyourownbodyto attackthevirus.thesenewdaa saredifferent,asthenamesuggests,astheydirectlyattackthevirusitselftoprevent it from replicating (copying itself). There are 3 main types at the moment, Protease inhibitors, Polymerase inhibitorsandns5ainhibitors.thesehavedifferentmechanismsofpreventingreplicationbypreventingdifferentsectionsofthevirusfromdoingwhattheyaresupposedtodo.theycangenerallybedistinguishedbythename HCVProteaseinhibitors endingin'previr' HCVPolymeraseinhibitors endingin'buvir' NS5Ainhibitors endingin'asvir' ThefirstapprovedDAAs,wereproteaseinhibitorsboceprevir(Victrelis)andtelaprevir(Incivo).ManyofthenextgenerationHepatitisCdrugsnowinthepipelinearebettertolerated,moreconvenientandraiseSVRratesevenfurther often into the 90 to 100% range for people with the right predictors.as add-ons, they improve the efficacy of Interferon-basedtherapy,buttherealrevolutionwillbeall-oral,interferon-freeregimens.Table1belowshowshow thefuturemaylook,basedoncurrentstudies.

6 TherearecurrentlyelevendrugsinphaseIIIclinicaltrialsforHepatitisC.Behindtheseareanother22drugsandcombinationsinphaseIIclinicaltrialsforthetreatmentofHepatitisC.However,notalloftheseareexpectedtomakeit tothemarket.historically,only50%ofinphaseiiand70%ofcompoundsinphaseiiihavereachedthemarket. Next to Market Janssen and MedivirAB have won the race to be next to the market. They received approval for simeprevir in November2013intheUSAandCanada.Simeprevirisaonce-dailyproteaseinhibitorusedwithpeginterferonand ribavirininhepatitiscgenotype1.adecisiononthisineuropeisexpectedin2014. Gileadsubmittedanapplicationforapprovalofsofosbuvir,forusewithribavirininHepatitisCgenotypes2and3,and incombinationwithpeginterferonandribavirinforallotherhepatitiscgenotypes.adecisiononthisisexpectedin theusaondecember8.inlateoctober2013,anfdausaadvisorypanelvotedinfavourofapprovalofthedrug inpatientswithgenotype2and3incombinationwithribavirin.thepanelalsovotedunanimouslytoapprovethe druginpatientswithgenotype1and4incombinationwithribavirinandinterferoninpatientswhohavenotreceived priortherapy.theyalsoappearedtosupporttheuseofsofosbuvirinpatientswhofailedpriortreatment.theyhave alsourgedgileadtomakethedrugavailabletoothercompaniestostudyincombinationwithotheroralregimens. TheFDAisnotobligedtoacceptalltherecommendationsfromtheadvisorypanelbuttheygenerallydo. 6 In Europe, sofosbuvir is expected to be licensed in early to mid However, in October 2013 the European MedicinesAgency s(ema)hasgivenanopinionontheuseofsofosbuvir,inacompassionate-useprogramme.itis thethirdtimeacompassionate-useprogrammehasbeenassessedattheeulevel.suchprogrammes,setupatthe nationallevel,areintendedtogivepatientswithalife-threatening,long-lastingorseriouslydisablingdiseasewho havenoavailabletreatmentoptions,accesstodrugsthatarestillunderdevelopmentandthathavenotyetbeen authorised.thespecificconditionssuggested: peoplewhoareactivelyonthewaitinglistforlivertransplantationandrequiretreatmenttopreventgraftnew liverreinfectionwithhepatitisc, peoplewhohaveundergonelivertransplantationandhaveaggressive,recurrenthcvinfectionresultingin progressiveandworseningliverdiseaseandareathighriskofdeathordecompensatedliverfailurewithin twelvemonthsifleftuntreated.

7 Current Clinical Trials Beforeyoureadmuchfurtheraboutclinicaltrialsinthecomingpagesthereareanumberoftableswithsummarised informationfromanumberofthecurrenttrialsthatlookpromising.thetablesaresplitintothekeygroupsbygenotypeandwhereappropriatebyspecifictreatmentstatus(naive,nullresponderetc.)thesemaylookcomplicated becauseofthewayclinicaltrialsare.itisactuallyprettysimple.findthetablespecifictoyoursituationandinthe diagrambelowitgivesthedetailsofhoweachboxworksusingthetables. HCV Genotype 1 - Treatment - Naive PegInterferon-freeandPegInterferon-sparing(havetousePeg-interferonbutonlyforthetermofthenewdrug)combinations have been highly effective against Hepatitis C Genotype 1, regardless of subtype(g1a or G1b), IL28B genotype,andhepatitiscviralload.withtheseregimens,treatmentdurationisfixed,ratherthandependentonthe response to viral load and most are taken for 12 weeks. Extending treatment to 24 weeks does not appear to increasesvrrates.after12weeksoftreatment,56%to100%ofparticipantsinclinicaltrialshadnon-detectable viralloads,mosttreatmentsachievedsvrratesofatleast80%.table2showstheinterferonfreeregimensand Table3showstheInterferonSparingRegimens.AlthoughsofosbuvirmaybecomeabackboneformanyInterferonfreeregimens,theinitialindicationinGenotype1(andgenotype4)isfor12weeksincombinationwithpIFN/RBV. Withthisregimen,cureratesreached89%(and80%inpeoplewithcirrhosis). 7

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9 Hepatitis C Genotype 1 - Treatment - Experienced Quad trials(twodaaspluspeginterferonandribavirin)orresponse-guidedtherapyaregraduallybeingreplaced bypeginterferon-freeregimensintreatment-experiencedpeople.re-treatmentwitha12or24weekregimenof two,three,four,orfivedrugsisbeingexploredintreatment-experiencedpeoplewithhepatitiscgenotype1(table 4).MosttrialshavebeenconductedinpeoplewhowereunsuccessfullytreatedwithpIFN/RBV.Tworegimens (sofosbuvirandanns5ainhibitor[eitherdaclatasvirorledipasvir],withorwithoutribavirin)havebeenstudiedin peoplewhowereunsuccessfullytreatedwithpifn/rbvandanhepatitiscproteaseinhibitor.curerateshave rangedfromadismal11%to100%withmostregimenshavingsvr saround90%oftreatment-experienced.the majoritywithpoorindicatingfactorssuchasil28bctorttgenotype,hepatitiscgenotype1a,andhighhepatitis Cviralloads. 9

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11 Hepatitis C Genotypes 2 and 3 UntiltheDAAera,genotypes2and3wereconsideredeasilycured.ItiseasiertoachieveanSVRwithGenotype 2 regardless of cirrhosis or prior treatment failure. However, Genotype 3 is proving to be a challenge. Only one peginterferon-free regimen (sofosbuvir plus daclatasvir), with or without ribavirin has yielded cure rates above 65%,after24weeksoftreatment.AddingpIFNtoa12-weekcourseofsofosbuvirandribavirinseemstoboostSVR rates.addingpeginterferontosofosbuvirandribavirinfor4or8weekspushedcureratesto100%inhepatitisc Genotype3.(Table5) 11

12 Hepatitis C Genotypes 4-6 OngoingtrialsareexploringdifferentregimensinGenotype4.Finaldataisavailable,after12or24weeksoftreatmentwithsofosbuvirpluspeginterferonandribavirin.Only39peoplewithgenotype4weretreated.After24weeks (SVR)theresultswere82%andafter12weeks(SVR-12)were96%.Todate,sofosbuvirandpIFN/RBVistheonly regimentohavebeenstudiedinhepatitiscgenotypes5,albeitinonly13people,onewithgenotype5. 12

13 HIV/Hepatitis C Co/Infection HepatitisCco-infectionincreasesAIDS-related,liver-related,andall-causemortalityamongpeoplewithHIV,despite the use of antiretroviral therapy(art).the incidence of Hepatitis C related complications has been rising among HIV/HepatitisCco-infectedpeople.Clearly,peoplewhoareHIV/HepatitisCco-infectedshouldbeaprioritypopulationforDAAtrials,sincetheyareatriskformorerapidHepatitisCprogression.Althoughcompaniesstandtobenefit from supporting these trials, development of peginterferon-free trials has been lagging.as of May 2013, only one peginterferon-freetrial(sofosbuvirandribavirin)wasopentohiv/hepatitisc-coinfectedpeople.ongoingtrialswith simeprevir,faldaprevir,anddaclatasvirarepeginterferon-based.however,thegoodnewsisthat,initialreportssuggestthathivdoesnotappeartobeasignificantfactorwhenadaaisaddedtopeginterferonandribavirin.thishas been supported by data from trials of telaprevir-based treatment, as well as interim reports from 2 other trials, STARTVerso4(faldaprevir-basedtreatment)andtheTMC435-C212(simeprevir-basedtreatment)study. Interferon Sparing - Faldaprevir plus PEG-IFN/RBV STARTVerso4isanongoing,308-person,phaseIIItrialoffaldaprevirpluspeginterferonandribavirininHIV/Hepatitis Cco-infectedpeoplewithHepatitisCGenotype1whoweretreatment-naiveorrelapsers.17%werecirrhotic.NoHIV virologicalbreakthroughoccurred.byweek12,hepatitiscviralloadwasundetectablein82%oftreatment-naiveparticipants and 91% of relapsers. The most common side effects were nausea, fatigue, diarrhoea, and headache. Seriousadverseevents(<1%)reportedwerefever,abdominalpain,rash,vomiting,dehydration,gastroenteritis,anemiaandneutropenia.Threedeathsoccurredinthestudy,twowerenotconsideredrelatedtothestudydrug,andthe thirdwasduetodrugreactionwitheosinophiliaandiscurrentlyunderreview. Interferon Sparing - Simeprevir plus PEG-IFN and RBV TMC435-C212isanongoingHepatitisCtreatmenttrialin106treatment-naiveortreatment-experiencedpeoplecoinfectedwithHIVandHepatitisCGenotype1.NoHIVvirologicalbreakthroughoccurred.Interimresultsarepromising.SVR-12was75%(9of12).RelapsehasbeenreportedonlyinpeoplewithHepatitisCGenotype1a.Atthetime ofanalysis,64%ofnullrespondersremainedontreatment.thesafetyofthisstudyisdescribedassimilartothat reportedinhepatitiscmono-infection,withfourpeoplediscontinuingforadverseevents.commonsideeffectswere fatigue,headache,nausea,pruritus,andrash. A Novel Approach - MicroRNAs MicroRNAsarepresentinhumancellsandtheirjobistoregulategeneexpression.MicroRNA122(miR-122)isfound inlivercellsanditbindstothehepatitiscvirus,stabilizingitandstimulatingviralreplication.adrugtargetingmir- 122,calledmiravirsen,isbeingstudiedinHepatitisCGenotype1(althoughitisusefulforallgenotypes).Miravirsen haspotentialasasupplementaltherapyandcouldbeadministeredoncemonthlyandisnotexpectedtohavesignificantdrug-druginteractionswithdaa sorothercommonlyusedmedications. Cirrhosis HepatitisCpatientsawaitinglivertransplantsareinneedoftreatmentbutoftencannottolerateinterferon-basedtherapy.Ontheotherhandleftuntreated,HepatitisCalmostalwaysinfectsthenewliversoonaftertransplantation,which canleadtocirrhosis,graftfailureanddeath.demonstratingthatdaaswereeffectiveinnullresponderswasthefirst areaforpeginterferon-sparingandpeginterferon-freeregimens.butcirrhosisisthetruetestwithaneedforhepatitis C treatment that is safe and effective for people with cirrhosis and will work at least as well for everyone else. PrioritisingpeoplewithmoreseriousliverdamageforHepatitisCtreatmentisbothethicalandsensible.Thismay preventtransplantationanddeathfromliverdisease.yetpatientswithadvancedliverdiseasehavebeenunderrepresentedin,orexcludedfrom,manyclinicaltrials.drugsarebeingbroughttomarketwithlimiteddatainpeoplewith cirrhosis,whoaremostlikelytobetreatedfirst.serioussideeffectsandfatalitieshavebeenreportedfromtrialsof boceprevir-andtelaprevir-basedregimensinpeoplewithcompensatedcirrhosis.aphaseiitrial,sound-c,isan exampleofaproactiveapproachtoincludethisgroup,sinceitincludedasubsetof33peoplewithcompensatedcirrhosisandreportedsvrratesinthisgroupashighas67%. Pre-Transplant AstudywascarriedoutontheuseofsofosbuvirandribavirintopreventHepatitisCrecurrencefollowinglivertransplantation.Thisstudyenrolled61people,mostlyintheUS.Participantshadcompensatedliverdiseaseandwere listedfortransplantationduetohepatocellularcarcinoma(hcc),atypeoflivercancer.peoplewithhepatitisborhiv co-infection,decompensatedcirrhosisorkidneyimpairmentwereexcluded.theoriginalregimenwas24weeksbut thiswaslaterextendedto48weeks.thelastdosewastakenonthedayoftransplantation.theyreceivedstandard immunosuppressivetherapytopreventrejectionofthenewliver.atotalof41participantsunderwenttransplantation withundetectableviralloadwhilethreepeopledidsowhileviralloadwasstilldetectable.tendiscontinuedtreatment, fourfinishedtreatmentbutwerestillawaitingtransplantsandonewasstillontherapywhilewaiting. 13

14 HepatitisCviralloaddeclinedrapidlyafterstartingsofosbuvirandribavirin.Mostpatientswhoreceivedtreatmentfor any duration (93%) or for at least 12 weeks (91%) had an undetectable viral load at the time of transplantation. AmongthosewithundetectableHepatitisCattransplantation,64%maintainedviralsuppressionat12weeksposttransplant.PeoplewhodidnotexperienceHepatitisCrecurrencehadundetectableviralloadforamedianof95days beforetransplantationcomparedwithjust5.5daysforthosewhodidhavearecurrence.only1patienthadarecurrenceafterhavinganundetectableviralloadfor30daysormore.sofosbuvirandribavirinwasgenerallysafeand welltoleratedinthisdifficult-to-treatpopulation.therewere11seriousadverseevents.noneofwhichwereconsideredrelatedtosofosbuvir.thereweretwodiscontinuationsduetoadverseevents(3%).threepeoplediedbefore transplantation and five afterwards. The most common side-effects were fatigue (38%), anaemia (23%) and headache(23%). Post Translplant Thesecondstudy,lookedatsofosbuvirandribavirinfortreatmentofHepatitisCrecurrenceafterlivertransplantation. Thisincluded40participantsinFrance,Germany,NewZealand,SpainandtheUS.Participantshadundergoneliver orcombinedliverandkidneytransplantsbetweensixmonthsand12years(medianfouryears)beforeanddidnot experienceorganrejectionorhavesignsofliverdecompensation.participantsweretreatedwithsofosbuvirfor24 weeks.theyalsostartedwithalowdoseofribavirinwhichwasgraduallyincreasedbasedontolerability(determined byhaemoglobinlevels).hepatitiscviralloadagaindeclinedrapidlyafterstartingtherapy.atweek4andattheend of treatment all participants had undetectable viral load. Four weeks after completing treatment 77% had no detectableviralload.thisisapromisingresult,buttooearlytodetermineasacureasrelapsehasbeenseenafter thispointinothersofosbuvirstudies.nointeractionswerereportedbetweensofosbuvirandanyimmunosuppressant agents including tacrolimus (used by 70%), mycophenolate mofetil (35%), prednisone (28%) or cyclosporin (25%),thoughfourpeopledidincreasetheirtacrolimusdosewhileonsofosbuvir. Toward Collaboration Financial considerations play a significant role in Hepatitis C drug development. Competition for market share is fierce, since experts estimate that the Hepatitis C market in Japan, the United Kingdom, Germany, France, Italy, Spain,andtheUnitedStateswillreachUS$14-20billionby2018.Mostpharmaceuticalcompaniesaredevelopinginhousecombinationstoavoidsharingthemarket.Asaresult,onlythreetrialshavecombinedDAAsfromdifferent companies.sofosbuvir(gilead)hasbeenpairedwithdaclatasvir(bms)andsimeprevir(janssen).sofosbuvirand daclatasvirhavebeentestedwithorwithoutribavarinandresultswerespectacular.svrratesrangedfrom88-100% after12or24weeksoftreatment,regardlessoftreatmenthistory,ribavirinuse,hepatitiscgenotypeorsubtype, IL28B genotype, or treatment duration. The study included 170 non-cirrhotic, treatment-naive participants with HepatitisCGenotypes1,2,and3,and41treatment-experiencedparticipantswithHepatitisCGenotype1. Anothertrial,usesacombinationofsimeprevirandsofosbuvir(nexttwotomarket)for12or24weeks,withorwithoutribavirin.ThisincludestwogroupsofnullresponderswithHepatitisCgenotype1.Group1werepeoplewith verymildtomoderateliverscarringandgroup2werepeoplewithextensiveliverscarringandcirrhosis.although mostofgroup1hadpoorindicatingfactors(il28bnon-ccgenotypeandhepatitiscgenotype1a),earlyresultswere very good 8 weeks after treatment finished, 96% in the sofosbuvir/simeprevir/rbv arm, and 92% in the sofosbuvir/simeprevirarmachievedansvr.therewerenodiscontinuations,buttworelapsesoccurred,oneineach arm.sofar,24peoplehavebeenfolloweduntil12weeksaftertreatment,and100%remainundetectable.theregimenwassafeandtolerable.thesecondgroupwasfullyenrolledasofmarchof2013andisstillunderinvestigation.unfortunately,itislikelythatgilead spartnershipwithjanssenorbmswillbeshort-lived,regardlessofthefinal resultsofeitherstudyastheyaredevelopingtheirownns5ainhibitor,ledipasvir,possiblyinasinglepillwithsofosbuvir. 14 Simepreviranddaclatasvirarebeingtested,withorwithoutRBV,for12or24weeks(plusanoptionalextra24weeks of pifn/rbv if needed), in an ongoing trial of 180 treatment-naive and prior null responders with Hepatitis C Genotype1,includingpeoplewithcirrhosis.Off-labeluseofthesedrugsmaybepossible,althoughitwillbedifficult topersuadehealthauthoritiestopayfordrugsfromtwoseparateregimestobeusedatthesametimeinthesame patientunlessthiswasarecognisedandlicencedcombination. Summary TreatmentforHepatitisCvirusinthefutureshouldbesimpler,shorter,andmoreeffective.All-oralcombinationsof direct-actingantivirals(daas)havepushedsvrratesinhepatitiscgenotype1toover90%.however,wearefar from having a single-tablet regimen suitable for everyone. Peginterferon-free treatment is less effective against HepatitisCGenotype3,andverylittleisknownabouttreatinggenotypes4,5,and6withDAA s.

15 Moreinformationisneededonthesafety,efficacy,andtolerabilityofDAA sinthoselikelytobeprioritizedforhepatitis Ctreatment,suchasHIVco-infectionandcirrhosis.Despitedozensofongoingtrials,dataonDAAbasedregimens inpeoplewithcirrhosis,especiallythosewhoaretreatment-experiencedarelimited.asofmay2013,therewasonly onepeginterferon-freetrialavailabletopeopleco-infectedwithhivandhepatitisc.somekeypoints: NewDirectActingAntivirals(DAA )areaveryexcitingandrealprospectbutitwillbesometimebeforewe seealotofthem. ThenextDAAtomarketinEuropeshouldbeinearly2014andthisisforallgenotypes.Therewillbetwo morecominglaterin2014andearly2015butthesearejustforgenotype1. MoreworkneedstobedoneonpatientswhowillbeprioritisedsuchasHIVco-infection,cirrhosisandpre andpostlivertransplantations. TheIrishHaemophiliaSocietywillcontinuetomonitorthesedevelopmentsandkeepyouinformedinastimelyamanneraspossibleaboutchangesandupdatesinupcomingnewsletters.Wewillalsobeactivelyadvocatingfortheinclusionofpeoplewithhaemophiliainclinicaltrialsandearlyaccessprogramsforthosethatareinmostneedoftreatment.WewillcontinuetomakesubmissionsonbehalfofpeoplewithhaemophiliatotheHTAbodywhoassessthe costeffectivenessandrecommendwhetherthesenewdrugsshouldbere-imbursed.ifthesenewproductsfollowthe samepathasthelasttwodaa sthenextnewdruginirelandforhepatitisccouldbeassessedanddependingon therecommendationbeavailableinsecondhalfof2014. ICORN and the Consultative council on Hepatitis C TheStatutoryConsultativeCouncilonHepatitisCwasestablishedin1996andwassetuptoprovideinputand recommendationstothehealthauthoritiesonallaspectsoftreatmentandcareforpersonswhowereinfectedwithhepatitiscviabloodorbloodproductssuppliedbythestate.thecouncilinitiallyhadrepresentatives fromthefourpatientorganisationswhosememberswereinfectedwithhepatitiscviabloodproducts.thesewere: PositiveAction representingwomenwhowereinfectedviaantid, TransfusionPositive representingpeopleinfectedviabloodtransfusion,the IrishKidneyAssociation representingthosewhowereinfectedviarenaldialysisand ofcoursethe IrishHaemophiliaSociety representingthoseinfectedbybloodproductsorfactorconcentrates.the initialcouncilhadtworepresentativeseachfrompositiveactionandtransfusionpositivewithoneeachfromthe IrishKidneyAssociationandtheIrishHaemophiliaSociety.TheCouncilalsohadhepatologists,anursearepresentativefromtheHSEandageneralpractitionerandwaschairedbyaHepatologist,Dr.LizKenny.TheCouncilhas beeninactiveforthepasttwoyearsandtheclinical/patientorganisationinterfacewasnotworking. AspartoftheconditionsattachedtothereimbursementofthenewtherapiesforHepatitisCin2012,theHealth TechnologyAssessmentrecommendedthatthecliniciansestablishaseparateclinicalgroup-theIrishHepatitisC OutcomesResearchNetwork(ICORN).Thecliniciansestablishedthisgroupin2012.ItconsistsoftheHepatologists andinfectiousdiseaseconsultantsfromthehospitalswheretherearespecifichepatologycentres.inaddition,the grouphasrepresentativesfromthevirusreferencelaboratory,thehse(micheletait),hepatologynurses(helena Irish)andarepresentativeofthepatientorganisations(BrianO Mahony).TheICORNgroupmonitorstheoutcome oftreatment,hasestablishedatreatmentregistryandcollectivelyreviewanddecideonbestpracticeintreatment and dealing with side effects and laboratory parameters. It is a very welcome addition to the management of HepatitisCinIrelandandallowsformorecollaborativeandcohesivethinkingbetweenthecliniciansonanational basis.aseparatearticleinthisedition(seepage15)onicornisincludedwrittenbyprofessorsuzannenorris, ChairoftheICORNGroup. TheConsultativeCouncilonHepatitisChasnowbeenestablishedinamoreslimmeddownformatwitheightmembers-twoeachfromPositiveAction,TransfusionPositive,andtheIrishHaemophiliaSocietyandonefromtheIrish KidneyAssociationandischairedbyMicheleTaitfromtheHSE.TheSocietyisrepresentedonthenewCouncilby BrianO MahonyandAnneDuffy.ThefirstmeetingwasheldinJulyandmeetingswilltakeplacesixtimesperyear. ThenextstageoftheprocessisfortheCounciltostrategicallyplantheworkforthecomingthreeyears.Ihopethat wecanconcentrateonsubstantivepolicyissueswhichwillhavearealbearingontheabilityofthosewithhepatitis Ctolivewiththeconditionorideallybesupportedthroughtreatmenttoclearthevirus.Overthecomingmonths,I alsohopethatregularliaisonwiththeicorngroupcanfacilitateseparatebutcomplementaryprogrammesofwork tobenefitpeoplewithhepatitisc. 15

16 ItistheintentiontohavethechairofICORNinvitedtoattendsomeCouncilmeetingswhenspecificclinicalareas areontheagendaandtoreceiveupdatesontheworkandapproachoficorn.thiscommunicationwillalsobe facilitatedbythefactthatcouncilchairmicheletaitandibotharemembersoficorninadditiontothecouncil. Patienteducationandeducation,viamaterialsandconferences,willbekeyareasofwork.Thespecificareasthe Councilwillworkoninthecomingyearswillinclude: Patientfriendlyinformationontreatment. AdvocacyforrequirementsofthosewithHepatitisCviabloodorbloodproducts. MonitoringofreviewandworkingofentitlementsunderHAAcardandTravelandLifeInsuranceSchemes. AgreecollaborationandliaisonwithICORNandNationalStrategyGroup(whichwillbelookingatissues suchaspreventionofnewcasesofhepatitiscinthepopulation). Datacollection(research)byindividualpatientorganisations-co-operationandcollaborationwhere possible. Datacollection-settingprioritiesforHPSCdatabasewhichcollectsdataontheprogressionofHepatitisC inthosewhowereinfectedviabloodorbloodproducts. Brian O Mahony, Chief Executive. ICORN Group HepatitisCisaworld-widepublichealthproblemresultinginasignificantimpactonhealthcareresourceutilisationandcosts.InIreland,9,282casesofHepatitisCwerenotifiedbetween2004and2010.However,thetrue prevalenceofhepatitiscinirelandisunknown.inarecentpaperlinkingnotificationstovirologylaboratoryresults, Thorntonetalestimatedthatthereareapproximately30,000-50,000patientsinfectedwithchronicHepatitisCin Ireland,withthemajorityofinfectedpatientsundiagnosed.Ofthe6knownHepatitisCgenotypes,genotype1is themostcommongenotype,accountingforapproximately55%ofinfectionsinireland.complicationsofchronic HepatitisCinfectionincludetocompensatedcirrhosis,decompensatedliverdisease,hepatocellularcarcinoma anddeath.hepatitiscinfectionthereforerepresentsasignificantburdenofcaretotheirishhealthcaresystem. In2012,patientsinfectedwithHepatitisCvirusGenotype1wereprovidedwiththeoptionofenhancedtherapeuticoutcomewiththeavailabilityofdirectly-actingantiviralagents(DAA s)asadd-ontherapytoabackbonetodual therapywithpegylatedinterferonandribavirin.efficacydatafromrandomisedcontrolledtrialsreportedsignificantlyimprovedcureratesintermsofachievementofasustainedviralresponse(sur)inbothtreatmentnaïve andtreatmentexperiencedpatients.clinicalefficacyandeconomicoutcomedataarecurrentlyderivedfromrandomisedcontrolledtrials,however,isrecognisedthatthereisaneedtoassesstheeffectivenessoftheagentsin therealworldsetting. 16 Given the complexity of protease inhibitor-based treatment paradigms, and the requirement for a co-ordinated nationalapproachtotheintroductionofthenewtherapeuticagents,theirishhepatitiscoutcomesandresearch Network(ICORN)wasestablishedinFebruary2012.Thisnationalnetworkcompriseshepatologistsfromallseven nationalhepatologycentres,consultantsininfectiousdiseases,virologists,epidemiologists,scientists,expertsin biostatisticalanalysis,theh.s.e.,andpatientorganisations.thisuniqueclusterofclinicalandresearchexpertise isunitedinrealisingtheunderlyingaimoficorn enhancingthequalityofcareforallpatientstreatedwithproteaseinhibitorsthroughthedevelopmentofanationalgovernancestructureforantiviralstewardship.throughthe establishmentofaclinicaladvisorygroup,icorndevelopednationalhcvtreatmentguidelinesinseptember 2012, which is informing the rollout of the national Hepatitis C Protease Inhibitor Treatment Programme. Additionally,ICORNmembersrecognisedtheneedforanationalresearchdatabasetoprospectivelycollectand collatedataontreatedpatientstoallowtrueclinicalandeconomicoutcomestobeassessedfollowingtheintroductionoftheseagentsinroutineclinicalpractice,withoutthestrictinclusion/exclusioncriteriaappliedintheclinicaltrialsetting.consequently,theicornhepatitisctreatmentandoutcomesregistrywasdevelopedin2012, andaprospective,longitudinal,observationaloutcomesresearchstudyforpatientswithhepatitisctreatedwith direct-actingantiviralagentscommenced. DatagatheredprospectivelyinthisHepatitisCobservationaloutcomesstudy,underthestewardshipofICORN, willproviderealworldevidenceoftheclinicaleffectiveness,economicimpactandsafetyoftripletherapyregimens whenusedinroutineclinicalpractice,withtheaimofinformingclinicalpracticeandrefininghealthpolicystrategiesfortheirishhepatitisccohortofpatients.thisprojectwilladditionallyfulfilseveraloftherecommendations outlinedinthenationalhepatitiscstrategy document. Professor Suzanne Norris, Consultant Hepatologist. IrishHaemophiliaSociety, FirstFloor,CathedralCourt, NewStreet,Dublin8. Tel: Fax: info@haemophilia.ieWebsite: