Formulary Management of the Protease Inhibitors Boceprevir and Telaprevir for Chronic Hepatitis C Virus

Transcription

1 formulry Mngement Formulry Mngement of the Protese Inhiitors Boeprevir nd Telprevir for Chroni Heptitis C Virus Alexndr Tungol, PhrmD; Kellie Rdemher, PhrmD; nd Jeremy A. Shfer, PhrmD, MBA ABSTRACT Bkground: Heptitis C virus (HCV) is the most ommon hroni loodorne illness in the United Sttes. The inidene of ute heptitis C in the United Sttes peked ner 50,000 ses in the lte 1980s ut hs stilized sine 2003 to less thn 5,000 ses nnully. The omintion of pegylted interferon (peginterferon) nd rivirin hs een the stndrd reommended tretment for HCV. Protese inhiitors telprevir nd oeprevir were pproved y the FDA in My 2011 for the tretment of heptitis C genotype 1 in omintion with peginterferon nd rivirin. Ojetive: To review the phse 3 trils for telprevir nd oeprevir nd provide mnged re onsidertions. Methods: A MEDLINE review ws performed for rtiles pulished nd ville through Septemer 15, 2011, using keywords oeprevir or telprevir with n emphsis on phse 3 trils. The literture serh ws limited to rtiles in English, linil trils, rndomized ontrolled trils, nd reserh onduted in humns. Additionl informtion ws otined from the FDA wesite. Results: Three phse 3 trils re ville for telprevir, whih provided dt tht were the sis for FDA pprovl. Boeprevir demonstrted effiy nd sfety in 2 pivotl phse 3 trils. Both gents demonstrted sttistilly signifintly higher rtes of virologi response ompred with the stndrd of re involving peginterferons nd rivirin. Telprevir nd oeprevir lso demonstrted effiy in the tretment of ptients who hd previously filed dul therpy for heptitis C. Sfety onerns for oth gents inlude nemi, drug intertions, skin rshes, nd gstrointestinl dverse events. Conlusions: Deision mkers hve mny ftors to onsider in developing strtegy round heptitis C. Inresed drug osts, ptient mngement, dherene, omprtive sfety nd effiy, nd pproprite utiliztion mngement ontrols re importnt issues. Pyers my onsider developing linil progrms to enourge dherene nd pproprite use nd leverge n pproprite hnnel to ensure ost-effetive therpy. J Mng Cre Phrm. 2011;17(9): Copyright 2011, Ademy of Mnged Cre Phrmy. All rights reserved. Wht is lredy known out this sujet Historilly, the stndrd of re for the tretment of heptitis C hs een pegylted interferon (peginterferon) nd rivirin. The protese inhiitors telprevir nd oeprevir were pproved y the FDA in My 2011 for the tretment of heptitis C genotype 1 in omintion with peginterferon nd rivirin. Neither protese inhiitor my e used s monotherpy for heptitis C. Wht this review dds The urrent Amerin Assoition for the Study of Liver Diseses (AASLD) Prtie Guidelines (2011) reommend triple therpy with protese inhiitor, peginterferon, nd rivirin s the stndrd tretment for heptitis C. Both telprevir nd oeprevir hve een studied in tretmentnïve nd previous prtil responders, ut only telprevir hs een studied in prior null responders. Mnged re onsidertions of heptitis C pertinent to deision mkers inlude inresed totl drug tretment osts nd potentil inrese in utiliztion, ptient mngement nd dherene, omprtive sfety nd effiy, nd pproprite utiliztion mngement ontrols. The 12-week regimen of telprevir therpy hs wholesle quisition ost (WAC) in 2011 of $49,200 (dded to $17,175 WAC for 24 weeks of peginterferon plus rivirin [PR] or $34,349 for 48 weeks of PR). The oeprevir WAC in 2011 is $26,410 for the 24-week regimen (dded to $20,037 WAC for PR for 28 weeks, $25,762 for 36 weeks, or $34,349 for 48 weeks). Rtes of nemi were 36% in the telprevir-treted ptents versus 17% for ptients treted only with peginterferon nd rivirin. Anemi ourred in 45%-50% of oeprevir-treted ptients versus 20%-30% of ptients treted only with peginterferon nd rivirin; erythropoiesis-stimulting gents were used to mnge nemi in 43% of oeprevir-treted ptients versus 24% of ptients treted only with peginterferon nd rivirin. Heptitis C virus (HCV) is the most ommon hroni loodorne illness in the United Sttes. Approximtely 3.9 million people in the United Sttes hve hroni infetion. 1 HCV is leding use of liver trnsplnt nd liver ner in the United Sttes nd worldwide. 2,3 The inidene of ute heptitis C in the United Sttes peked ner 50,000 ses in the lte 1980s ut hs stilized sine 2003 to less thn 5,000 ses nnully. 4 The progressive deline my e result of inresed edution nd puli wreness of trnsmissile risk ftors. 4 Wong et l. (2000) estimted tht diret medil expenditures for HCV would grow to $10.7 illion over the period despite stle disese rte. 5 HCV is trnsmitted y exposure to infeted lood or lood produts with injetle drug use eing the leding use. 6 HCV hs t lest 6 genotypes nd 50 different sutypes (i.e., HCV sutype 1, 1, et.), with genotype 1 eing the most Vol. 17, No. 9 Novemer/Deemer 2011 JMCP Journl of Mnged Cre Phrmy 685

2 TABLE 1 FDA-Approved Inditions, Dose, Administrtion, nd Drug Cost for Telprevir nd Boeprevir for HCV Infetion Drug Dose nd Administrtion, FDA-Approved Indition Peginterferon + Rivirin Drug Cost Telprevir (Inivek) 375 mg tlets Boeprevir (Vitrelis) 200 mg psules 2 tlets (750 mg) 3 times dily (7-9 hours prt) for 12 weeks (ll ptients) INCIVEK must e dministered with oth peginterferon lf nd rivirin for ll ptients for 12 weeks, followed y response-guided regimen of either 12 or 36 dditionl weeks of peginterferon lf nd rivirin depending on virl response nd prior response sttus. Initite therpy with peginterferon lf nd rivirin for 4 weeks prior to strting oeprevir (led-in phse) At tretment week 4, dd oeprevir 800 mg (four 200 mg psules) orlly 3 times dily (every 7-9 hours) with food ( mel or light snk) VICTRELIS must e dministered in omintion with peginterferon lf nd rivirin. 24 weeks for undetetle HCV RNA t weeks 8 nd 24 for tretment-nïve ptients 32 weeks for undetetle HCV RNA t weeks 8 nd 24 for prior-relpse nd prtil-responder ptients 32 weeks for detetle (>9.3 IU per ml) HCV RNA t week 8 nd undetetle t week 24 for tretment-nïve, prior-relpse nd prtil-responder ptients Ptients with irrhosis: 4 weeks peginterferon lf nd rivirin (led-in phse) followed y 44 weeks oeprevir 800 mg (four 200 mg psules) 3 times dily (every 7-9 hours) in omintion with peginterferon lf nd rivirin In omintion with peginterferon lf nd rivirin, for the tretment of genotype 1 hroni heptitis C (CHC) in dult ptients with ompensted liver disese, inluding irrhosis, who re tretment-nïve or who hve een previously treted with interferon-sed tretment, inluding prior null responders, prtil responders, nd relpsers. INCIVEK must not e used s monotherpy nd must only e used in omintion with peginterferon lf nd rivirin. A high proportion of previous null responders (prtiulrly those with irrhosis) did not hieve SVR nd hd telprevir resistne-ssoited sustitutions emerge on tretment with INCIVEK. INCIVEK effiy hs not een estlished for ptients who hve previously filed therpy with tretment regimen tht inludes INCIVEK or other HCV NS3/4A protese inhiitors. For the tretment of hroni heptitis C (CHC) genotype 1 infetion, in omintion with peginterferon lf nd rivirin, in dult ptients ( 18 yers of ge) with ompensted liver disese, inluding irrhosis, who re previously untreted or who hve filed previous interferon nd rivirin therpy. 24 weeks for undetetle HCV RNA t weeks 4 nd 12 for tretmentnïve nd prior-relpse ptients 48 weeks for detetle (1,000 IU per ml or less) HCV RNA t weeks 4 nd 12 for tretmentnïve nd prior-relpse ptients 48 weeks for undetetle HCV RNA t weeks 4 nd 12 for tretmentnïve ptients with irrhosis 48 weeks for ll prior-prtil nd nullresponder ptients 28 weeks for undetetle HCV RNA t weeks 8 nd 24 for tretmentnïve ptients 36 weeks for undetetle HCV RNA t weeks 8 nd 24 for priorrelpse nd prtilresponder ptients 48 weeks for detetle HCV RNA t week 8 nd undetetle t week 24 for tretment-nïve, prior-relpse nd prtilresponder ptients $49,200 for 12 weeks telprevir $17,175 for 24 weeks PR $34,349 for 48 weeks PR $26,410 for 24 weeks oeprevir $35,213 for 32 weeks oeprevir $20,037 for 28 weeks PR $25,762 for 36 weeks PR $34,349 for 48 weeks PR Sme s ove 48 weeks $48,418 for 44 weeks oeprevir $34,349 for 48 weeks PR Soure: Produt lels with presriing informtion for telprevir 11 nd oeprevir. 10 Tretment durtion for telprevir depends on response. Cost estimtes sed on wholesle quisition ost (WAC) prie in Septemer PR regimen ssumed peginterferon lf-2 nd rivirin dosed t 1,200 mg dily. FDA = U.S. Food nd Drug Administrtion; HCV = heptitis C virus; IU = interntionl unit; mg = milligrm; ml = milliliter; PR = peginterferon + rivirin; RNA = rionulei id; SVR = sustined virologi response. ommon in the United Sttes. 3 For every 100 people infeted with HCV, people will develop hroni infetion; will develop hroni liver disese; 5-20 will develop irrhosis; nd 1-5 will die of irrhosis or liver ner. 7 Aute HCV illness mnifests symptomtilly in 20%-30% of ptients. 4 Possile symptoms inlude dominl pin, fever, ftigue, loss of ppetite, nuse, nd vomiting. The remining 70%-80% of ptients my e symptomti or experiene only mild symptoms. 4 The Amerin Assoition for the Study of Liver Diseses (AASLD) Prtie Guidelines (2011) represent the gold stndrd for guidne on the mngement of heptitis C. 6 These guidelines were pproved nd re supported y the AASLD, the Infetious Diseses Soiety of Ameri, nd the Amerin College of Gstroenterology. 6 The omintion of pegylted interferon (peginterferon) nd rivirin hs een the stndrd reommended tretment for HCV prior to the relese of the protese inhiitors. 6 Telprevir nd oeprevir were pproved y the U.S. Food nd Drug Administrtion (FDA) in My 2011 in omintion with peginterferon lf nd rivirin for the tretment of genotype 1 hroni heptitis C in dult ptients with ompensted liver disese, inluding irrhosis, who re tretment-nïve or who hve een previously treted with interferon-sed tretment (Tle 1). 8,9 Both gents inhiit the NS3/4A serine protese essentil for replition of HCV. 10,11 The introdution of the protese inhiitors, or diretly ting ntivirls, signifintly hnges the lndspe of HCV mngement for oth tretmentnïve nd tretment-experiened ptients. 686 Journl of Mnged Cre Phrmy JMCP Novemer/Deemer 2011 Vol. 17, No. 9

3 FIGURE 1 Key word telprevir for pulition through Septemer 15, rtiles identified 50 rtiles exluded for not eing in English or out humns 131 rtiles exluded for not eing phse 3 linil trils or RCTs Flowhrt of Literture Seletion Limits: English, humn, linil tril, or rndomized ontrolled tril Key word oeprevir for pulition through Septemer 15, rtiles identified 43 rtiles exluded for not eing in English or out humns 79 rtiles exluded for not eing phse 3 linil trils or RCTs 3 rtiles for review 2 rtiles for review Drug Telprevir (Inivek) 11 TABLE 2 Boeprevir (Vitrelis) 10 Lel Wrnings Serious skin retions (drug rsh with eosinophili nd systemi symptoms, Stevens-Johnson Syndrome), rsh, nemi Anemi, neutropeni Sfety Wrnings for Telprevir nd Boeprevir Other Adverse Retions Hemorrhoids, noretl disomfort, nl pruritus, dysgeusi, ftigue, pruritus, nuse, dirrhe Ftigue, nuse, hedhe, dysgeusi Contrindited Meditions Speifi to Telprevir or Boeprevir torvsttin rmzepine, phenoritl, phenytoin, drosperinone Contrindited Meditions for Both Telprevir nd Boeprevir lfuzosin, rifmpin, dihydroergotmine, ergonovine, ergotmine, methylergonovine, ispride, St. John s Wort, lovsttin, simvsttin, pimozide, sildenfil, tdlfil, trizolm, orl midzolm RCT = rndomized ontrolled tril. The purpose of this rtile is to () provide n overview of the linil dt for telprevir nd oeprevir, inluding the phrmokinetis, phse 3 pivotl tril effiy, nd sfety; nd () offer insight to mnged re deision mkers on mngement strtegies for HCV sed on ftors tht inlude linil dt, ost, need for dherene, nd overge determintion. Serh Method nd Results A MEDLINE review ws performed for rtiles pulished nd ville through Septemer 15, 2011, using keywords telprevir nd oeprevir with n emphsis on pulished rndomized ontrolled trils (Figure 1). The literture serh ws limited to rtiles in English, linil trils, rndomized ontrolled trils, nd reserh onduted in humns; review rtiles nd met-nlyses were exluded. Additionl informtion ws otined from the FDA wesite. Phrmokinetis Telprevir. Telprevir is ioville nd sored in the smll intestine. 12 For optiml exposure, telprevir must e tken with food (not low ft). Systemi exposure (re under the urve [AUC]) is inresed y 237% in onjuntion with stndrd ft mel (533 kilolories nd 21 grms ft) ompred with the fsted stte. When o-dministered with peginterferon, mximum onentrtion t stedy stte (C mx,ss ) nd AUC re inresed y 43% nd 38%, respetively. Rivirin does not ffet telprevir plsm onentrtions, nd mximum plsm onentrtions re rehed in 4 to 5 hours fter dose. 13 In vitro studies hve shown telprevir to e sustrte nd inhiitor of P-glyoprotein (P-gp) nd CYP3A, resulting in linilly signifint drug intertions (see Tle 2). 13 Telprevir is 59% to 76% ound to plsm proteins (lph-1-id glyoprotein nd lumin). In the phse 2 studies PROVE 2 nd PROVE 3, popultion phrmokineti nlysis ws performed using phrmokineti dt from ll sujets. After orl dministrtion, the pprent totl lerne ws out 31.6 liters (L) per hour nd 37.5 L per hour in PROVE 2 nd PROVE 3, respetively. 13 Telprevir undergoes hepti metolism, nd primry route of elimintion is fel. Elimintion hlf-life is 4 to 4.7 hours. Boeprevir. Boeprevir should e tken with food, ut type of mel nd timing re not ruil. Clinil trils demonstrted oeprevir AUC inresed up to 65% when tken with food. 14 Boeprevir rehes mximum plsm onentrtion 3 hours fter dose. An in vitro study showed oeprevir to e P-gp sustrte. 14,10 Boeprevir is lso CYP3A4/5 sustrte nd strong inhiitor nd is pproximtely 75% plsm protein ound (see Tle 2 for linilly signifint drug intertions). 14 In vitro studies showed oeprevir to e primrily metolized through the ldoketoredutse (AKR)-medited pthwy to ketone-redued metolites (intive). Men pprent lerne of oeprevir is 157 L per hour, nd its elimintion hlflife is pproximtely 3.4 hours. The primry route of elimintion is fel. Effiy nd Sfety Telprevir. The effiy nd sfety of telprevir ws studied in three phse 3 pivotl trils: ADVANCE (Telprevir for Previously Untreted Chroni Heptitis C Virus Infetion), 15 ILLUMINATE (Response-Guided Telprevir Comintion Tretment for Heptitis C Virus Infetion), 16 nd REALIZE (Telprevir for Retretment of HCV Infetion). 17 The study designs, smples, nd effiy nd sfety outomes re shown in Tle 3. Vol. 17, No. 9 Novemer/Deemer 2011 JMCP Journl of Mnged Cre Phrmy 687

4 TABLE 3 Effiy nd Sfety Results from Phse 3 Trils of Telprevir Study/Drug Regimens Design/Smple Results ADVANCE 15 T12PR: Triple therpy (telprevir with peginterferon lf-2 plus rivirin [PR]) for 12 weeks After the first 12 weeks, ptients with extended RVR d reeived 12 dditionl weeks of PR lone (totl tretment durtion 24 weeks) Ptients lking extended RVR d reeived 36 dditionl weeks of PR lone (totl tretment durtion 48 weeks) T8PR: Triple therpy for 8 weeks followed y pleo plus PR for 4 weeks After the first 12 weeks, ptients with extended RVR d reeived 12 dditionl weeks of PR lone (totl tretment durtion 24 weeks) Ptients lking extended RVR d reeived 36 dditionl weeks of PR lone (totl tretment durtion 48 weeks) PR: Pleo plus PR for 12 weeks followed y PR lone for n dditionl 36 weeks (totl tretment durtion 48 weeks) The following doses were used: telprevir 750 mg orlly every 8 hours with food peginterferon lf mg suutneously weekly rivirin 1,000 mg orlly dily (ptients weighing < 75 kg) or rivirin 1,200 mg orlly dily (ptients weighing 75 kg) Therpy ws stopped if HCV RNA levels were > 1,000 IU per ml t week 4 (T12PR nd T8PR groups; only telprevir disontinued); < 2 log 10 derese from seline in HCV RNA levels ourred t week 12 (disontinue ll drugs); or hd detetle HCV RNA t ny time etween weeks 24 nd 40 (disontinue ll drugs). ILLUMINATE 16 T12PR24: Triple therpy (telprevir plus PR) for 12 weeks, followed y PR lone for 12 weeks (totl tretment durtion 24 weeks) T12PR48: Triple therpy for 12 weeks, followed y PR lone for 36 weeks (totl tretment durtion = 48 weeks) The following doses were used: telprevir 750 mg orlly with food every 8 hours peginterferon lf mg suutneously weekly rivirin 1,000 mg orlly dily (ptients weighing < 75 kg) or rivirin 1,200 mg orlly dily (ptients weighing 75 kg) Therpy ws stopped if HCV RNA levels were > 1,000 IU per ml t week 4 (only telprevir disontinued); < 2 log 10 derese in HCV RNA from seline ourred t week 12; or hd detetle HCV RNA etween weeks 24 nd 36. Phse 3, doule-lind, pleoontrolled RCT Inlusion Criteri 18 to 70 yers of ge HCV genotype 1 infetion with evidene of hroni heptitis, s onfirmed y mens of liver iopsy within 1 yer efore sreening for the study (inluding ptients with ompensted liver irrhosis) Seronegtivity for heptitis B surfe ntigen nd the sene of ntiodies ginst humn immunodefiieny virus types 1 nd 2 Asolute neutrophil ounts t lest 1,500 per mm 3 Pltelet ounts t lest 90,000 per mm 3 Hemogloin levels t lest 12 gm per dl for women or t lest 13 gm per dl for men Exlusion Criteri Deompensted liver disese Liver disese from other uses Heptoellulr rinom Bseline Chrteristis Well lned etween tretment groups 58% mle, 9% lk,11% Hispni 21% ridging firosis or irrhosis 59% HCV sutype 1 40% HCV sutype 1 1% HCV sutype unknown Averge HCV RNA (log 10 IU per ml): 6.3 in ll groups 77% with HCV RNA 800,000 IU per ml Phse 3, open-lel, rndomized, noninferiority tril. Results of HCV RNA testing were doule-linded through week 24. Inlusion Criteri Age etween 18 nd 70 yers Presene of hroni infetion with HCV genotype 1, indited y dignosis t more thn 6 months efore the sreening visit, with detetle HCV RNA level t the visit, s well s no previous tretment for HCV infetion Seronegtive test for heptitis B virus nd humn immunodefiieny virus Asolute neutrophil ount of 1,500 or more per mm 3 Pltelet ount of 90,000 or more per mm 3 Hemogloin level of 12 gm or more per dl for femle ptients or 13 gm or more per dl for mle ptients Liver iopsy within 1 yer efore sreening visit or underwent the proedure during the sreening period unless iopsy more thn 1 yer previously showed evidene of irrhosis Exlusion Criteri Hepti deompenstion Clinilly signifint liver disese from nother use Ative ner within the previous 5 yers (exept treted sl-ell rinom) Bseline Chrteristis Well lned etween tretment groups 60% mle, 14% lk, 10% Hispni or Ltino 16% ridging firosis 72% HCV sutype 1 27% HCV sutype 1 1% HCV sutype unknown 79% with HCV RNA 800,000 IU per ml Tretment Group T12PR T8PR PR P Vlue Versus PR n = 363 n = 364 n = 361 Effiy outomes, % (n) SVR t 24 weeks 75 (271) 69 (250) 44 (158) < Undetetle HCV RNA t 72 weeks 73 (265) 67 (243) 44 (158) RVR 68 (246) 66 (242) 9 (34) Extended RVR d 58 (212) 57 (207) 8 (29) Relpse e 6 (17) 7 (18) 27 (51) Sfety outomes, % (n) Rsh f 37 (133) 35 (129) 24 (88) DC due to rsh 7 (24) 5 (17) 1 (2) Anemi g 37 (135) 39 (141) 19 (70) DC due to AEs 10 (36) 10 (37) 7 (26) Sustined virologi response. Undetetle (lower limit of detetion 10 IU per ml) plsm HCV RNA 24 weeks fter the lst plnned study dose of ptient s ssigned tretment. Primry endpoint. Lower limit of detetion 10 IU per ml. Rpid virologi response, defined s undetetle HCV RNA t week 4. d Undetetle HCV RNA t weeks 4 nd 12. e Undetetle HCV RNA levels t the end of the tretment period, ut onfirmed detetle HCV RNA levels some time etween the end of tretment nd 24 weeks fter lst study dose. f Rsh ws ezemtous nd reversed y disontinuing telprevir. Stevens-Johnson syndrome ourred in 1 ptient out 11 weeks fter ompleting telprevir tretment. g Hemogloin level <10 gm per dl: ESAs were not used to mnge nemi; the rivirin dose ws redued in ordne with produt leling (the effiy of the regimen is not ompromised if rivirin is redued; rivirin onentrtions hieved re similr to tht of full dosing in nonnemi ptient). DC = disontinution. Rndomly Assigned to T12PR24 Rndomly Assigned to T12PR48 Tretment Group n = 162 n = 160 Effiy outomes, % (n) SVR t 24 weeks 92 (149) 88 (140) RVR 100 (162) 99 (159) Extended RVR 100 (162) 99 (159) Relpse d 6 (9) 3 (4) Sfety outomes, % (n) Rsh 37 (60) 39 (62) DC due to rsh 9 (14) 6 (10) Anemi e 42 (68) 41 (66) DC due to AEs 13 (21) 12 (20) Sustined virologi response. Undetetle (lower limit of detetion pproximtely 10 to 15 IU per ml) plsm HCV RNA level t end of tretment phse nd 24 weeks fter the lst plnned study dose. Primry endpoint. Overll, 72% (n = 540) of enrolled ptients hieved SVR. Undetetle HCV RNA level t week 4. Undetetle HCV RNA level t week 4 nd week 12. d Undetetle HCV RNA t end of tretment, ut detetle fter the end of tretment. e Determined y investigtors opinion. ESAs were not used to mnge nemi; the rivirin dose ws redued in ordne with produt leling (the effiy of the regimen is not ompromised if rivirin is redued; rivirin onentrtions hieved re similr to tht of full dosing in nonnemi ptient). DC = disontinution. 688 Journl of Mnged Cre Phrmy JMCP Novemer/Deemer 2011 Vol. 17, No. 9

5 TABLE 3 Effiy nd Sfety Results from Phse 3 Trils of Telprevir (ontinued) Study/Drug Regimens Design/Smple Results REALIZE 17 T12PR48: Triple therpy (telprevir plus PR) for 12 weeks, followed y pleo plus PR for 4 weeks, nd then PR lone for 32 weeks (totl tretment durtion 48 weeks) Led-in T12PR48: Pleo plus PR for 4 weeks, followed y triple therpy for 12 weeks nd then PR lone for 32 weeks (totl tretment durtion = 48 weeks) PR48 (ontrol): Pleo plus PR for 16 weeks, followed y PR for 32 weeks (totl tretment durtion = 48 weeks) The following doses were used: telprevir 750 mg orlly every 8 hours peginterferon lf mg suutneously weekly rivirin 1,000 mg orlly dily or 1,200 mg orlly dily (weight sed) Ptients were strtified y seline virl lod (HCV RNA < 800,000 or 800,000 IU per ml) nd type of previous response to peginterferon-rivirin (no response, prtil response, or relpse). Therpy ws stopped if HCV RNA levels were > 100 IU per ml t weeks 4, 6, nd 8 fter strt of telprevir tretment (T12PR48 nd led-in T12PR48 groups; only telprevir disontinued); < 2 log 10 derese from seline in HCV RNA levels ourred t week 12 (T12PR48 group nd ontrol groups) or week 16 (led-in T12PR48 group); or hd detetle HCV RNA t week 24 or 36. Phse 3 doule lind, pleo-ontrolled RCT Inlusion Criteri 18 to 70 yers of ge Chroni HCV genotype 1 infetion Did not hve SVR to 1 previous ourse of PR despite reeiving t lest 80% of the intended dose Detetle HCV RNA Liver iopsy within 18 months efore sreening Asolute neutrophil ount 1,200 per mm 3 Pltelet ount 90,000 per mm 3 Hemogloin levels t lest 12 gm per dl for women or t lest 13 gm per dl for men Exlusion Criteri Deompensted liver disese Liver disese from other uses Heptoellulr rinom Bseline Chrteristis Well lned etween tretment groups 70% mle, 5% lk, 11% Hispni 26% irrhosis 53% previous relpse 19% prtil response 28% no response 45% HCV sutype 1 45% HCV sutype 1 HCV sutype unknown (1 ptient) Averge seline HCV RNA (log 10 IU per ml): 6.6 in ll groups 88.5% with HCV RNA 800,000 IU per ml Tretment Group Led-in T12PR48 T12PR48 PR48 n = 266 n = 264 n = 132 P Vlue Versus PR48 SVR t 24 weeks, % (n) Previous relpse 83 (121/145) 88 (124/141) 24 (16/68) < No response or prtil 41 (50/121) 41 (51/123) 9 (6/64) < response to previous therpy Previous prtil response 59 (29/49) 54 (26/48) 15 (4/27) < No previous response d 29 (21/72) 33 (25/75) 5 (2/37) < All ptients < Relpse, % (n) Previous relpse 7 (10/135) 7 (9/138) 65 (30/46) Lk previous virologi response Previous prtil response 21 (8/39) 25 (9/36) 0 No previous response 27 (8/30) 25 (9/36) 60 (3/5) Sfety outomes: ll ptients, % (n) Rsh 37 (99) 36 (95) 19 (25) DC due to rsh 5 (12) 4 (10) 0 Anemi e 30 (79) 36 (94) 15 (20) DC due to AEs 15 (39) 11 (29) 3 (4) SVR is the primry endpoint defined s undetetle (lower limit of detetion 10 IU per ml) HCV RNA 24 weeks fter lst plnned study dose. Undetetle HCV RNA t the end of previous ourse of therpy with HCV RNA positivity therefter. 2 log 10 derese in HCV RNA fter 12 weeks of therpy ut with detetle HCV RNA. d < 2 log 10 derese in HCV RNA fter 12 weeks of therpy. e Determined y investigtors opinion. ESAs were not used to mnge nemi; the rivirin dose ws redued in ordne with produt leling (the effiy of the regimen is not ompromised if rivirin is redued; rivirin onentrtions hieved re similr to tht of full dosing in nonnemi ptient). DC = disontinution. AE = dverse event; dl = deiliter; ESA = erythropoiesis-stimulting gent; gm = grm; HCV = heptitis C virus; kg = kilogrm; IU = interntionl units; mg = mirogrm; mm 3 = ui millimeters; PR = peginterferon+rivirin; RCT = rndomized ontrolled tril; RNA = rionulei id; RVR = rpid virologi response; SVR = sustined virologi response. Boeprevir. The effiy nd sfety of oeprevir ws studied in two phse 3 pivotl trils: SPRINT-2 (Boeprevir for Untreted Chroni HCV Genotype 1 Infetion) nd RESPOND-2 (Boeprevir for Previously Treted Chroni HCV Genotype 1 Infetion). The study designs, smples, nd effiy nd sfety outomes re shown in Tle 4. Mnged Cre Considertions The rrivl of the protese inhiitors hs hd signifint impt on the mngement of genotype 1 heptitis C. Both gents hve demonstrted signifintly improved sustined virologi response (SVR) rtes ompred with onventionl dul therpy with peginterferon nd rivirin. However, oth protese inhiitors introdue issues tht mnged re deision mkers will need to ddress in order to optimize ost-effetive use. Deision mkers need to onsider inresed totl drug tretment osts, ptient mngement nd dherene, omprtive sfety nd effiy, nd pproprite utiliztion mngement ontrols when deiding on strtegy for heptitis C tretment. Hed-to-hed omprtive linil trils re lking etween telprevir nd oeprevir. Both gents hve studies in tretment-nïve nd previous prtil responders, ut only telprevir hs een studied in prior null responders. 17 AASLD guidelines reommend the use of telprevir for prior null responders. 6 Although oth gents were studied with peginterferon, telprevir ws used with peginterferon lf-2 while oeprevir trils used peginterferon lf-2. There my e speultion tht the overll effiy of the protese inhiitors ould e ffeted y hoie of peginterferon euse there re effiy differenes etween peginterferon lf-2 nd lf-2 in the heptitis C popultion. Some pyers my require the use of one speifi peginterferon in utiliztion mngement progrm, regrdless of the protese inhiitor used. Current literture nd FDA leling for the protese inhiitors does not support the use of one distint peginterferon produt over the other. The rtionle for peginterferon preferred produt seletion y pyer ould e multifeted, inluding produt ost, mnufturer disounts, hnnel steerge, nd linil differenes. In ross-tril omprisons, telprevir ppers to hve Vol. 17, No. 9 Novemer/Deemer 2011 JMCP Journl of Mnged Cre Phrmy 689

6 TABLE 4 Effiy nd Sfety Results from Phse 3 Trils of Boeprevir Study/Drug Regimens Design/Smple Results SPRINT-2 18 Phse 3 pleo-ontrolled RCT Control: PR for 4 weeks (led-in period), followed y pleo plus PR for 44 weeks (totl tretment durtion 48 weeks) Response-guided: PR for 4 weeks (led-in period), followed y oeprevir plus PR for 24 weeks Ptients would end therpy if HCV levels were undetetle (lower limit of detetion 9.3 IU per ml) from week 8 through 24 (totl tretment durtion 28 weeks) Otherwise, ptients reeived pleo plus PR for n dditionl 20 weeks (totl tretment durtion 48 weeks) Fixed durtion: PR for 4 weeks (led-in period), followed y oeprevir plus PR for 44 weeks (totl tretment durtion = 48 weeks) The following doses were used: oeprevir 800 mg orlly 3 times dily with food peginterferon lf mg per kg suutneously weekly rivirin weight-sed dosing 600 to 1,400 mg orlly dily in divided doses in morning nd evening Ptients were enrolled seprtely into 2 ohorts: lks nd nonlks, due to differenes in SVR etween the groups. They were strtified y genotype 1 sutype ( or ) nd HCV RNA level ( 400,000 IU per ml or > 400,000 IU per ml). Ptients disontinued tretment if they hd detetle HCV RNA level t week 24. Inlusion Criteri 18 yers of ge or older Chroni infetion with HCV genotype 1 with no previous history of HCV tretment Plsm HCV RNA level 10,000 IU per ml Weight 40 to 125 kg Exlusion Criteri Liver disese not relted to heptitis C Deompensted irrhosis Renl insuffiieny HIV or heptitis B infetion Pregnny or urrent restfeeding Ative ner Bseline Chrteristis Well lned etween tretment groups 60% mle, 14% lk, 82% white, 4% other 64% HCV sutype 1 33% HCV sutype 1 3% HCV sutype unknown 85% with HCV RNA > 800,000 IU per ml Tretment Group Response- Fixed Control Guided Durtion n = 363 n = 368 n = 366 P Vlue Versus Control SVR t 24 weeks, % (n) All ptients 38 (137) 63 (233) 66 (242) < Nonlk ohort 40 (125/311) 67 (211/316) 68 (213/311) < Blk ohort 23 (12/52) 42 (22/52) 53 (29/55) 0.040; Relpse, % (n) All ptients 22 (39/176) 9 (24/257) 9 (24/265) < Sfety outomes: ll ptients, % (n) Anemi 29 (107) 49 (182) 49 (179) < ESA use 24 (87) 43 (159) 43 (159) < Men durtion of ESA in dys DC due to nemi 1.1(4) 1.6 (6) 1.9 (7) Neutrophil ount 500 to 14 (50) 24 (87) 25 (90) < < 750 per mm 3 (grde 3) Dysguesi 18 (64) 37 (137) 43 (156) < DC due to AEs 16 (57) 12 (45) 16 (60) SVR is the primry endpoint defined s undetetle (lower limit of detetion 9.3 IU per ml) HCV RNA levels for 24 weeks fter ompleting therpy. Detetle HCV RNA levels during follow-up despite undetetle levels t the end of tretment. Hemogloin < 10 gm per dl. Rivirin dose ws redued or ESA dministered t the disretion of investigtors (the effiy of the regimen is not ompromised if rivirin is redued; rivirin onentrtions hieved re similr to tht of full dosing in nonnemi ptient). DC = disontinution. RESPOND-2 19 Control: PR for 4 weeks (led-in period), followed y pleo with PR for 44 weeks (totl tretment durtion 48 weeks) Response-guided: PR for 4 weeks (led-in period), followed y oeprevir with PR for 32 weeks Ptients would end therpy if HCV RNA levels were undetetle (lower limit of detetion 9.3 IU per ml) t week 8 nd 12 (totl tretment durtion 36 weeks) Ptients with detetle level t week 8 ut undetetle t week 12 reeived PR for n dditionl 12 weeks (totl tretment durtion 48 weeks) Fixed durtion: PR for 4 weeks (led-in period), followed y oeprevir with PR for 44 weeks (totl tretment durtion = 48 weeks) The following doses were used: oeprevir 800 mg orlly 3 times dily with food peginterferon lf mg per kg suutneously weekly rivirin weight-sed dosing 600 to 1,400 mg orlly dily in divided doses t morning nd evening Ptients were strtified y previous response to therpy (nonresponse or relpse) nd HCV sutype (1 or 1). Nonresponse ws defined s derese in the HCV RNA level t lest 2 log 10 IU per ml y week 12 ut with detetle level during therpy period. Relpse ws defined s undetetle (lower limit of detetion 9.3 IU per ml) HCV RNA level t the end of tretment, ut detetle levels during follow-up. Ptients disontinued ll tretment if they hd detetle HCV RNA level t week 12. Phse 3 pleo-ontrolled RCT Inlusion Criteri 18 yers of ge or older Chroni infetion with HCV genotype 1 nd prior response to interferon (minimum 12-week durtion of therpy) Plsm HCV level 10,000 IU per ml Weight 40 to 125 kg Exlusion Criteri Heptitis B or infetion with humn immunodefiieny virus Liver disese not relted to heptitis C Deompensted liver disese Unontrolled dietes mellitus Severe psyhitri disorder Ative sustne use Bseline Chrteristis 67% mle, 12% lk, 86% white, 2% other 47% HCV sutype 1 44% HCV sutype 1 9% HCV sutype unknown 12% irrhosis 88% with HCV RNA > 800,000 IU per ml Tretment Group Response- Fixed Control Guided Durtion n = 80 n = 162 n = 161 P Vlue Versus Control Effiy outomes, % (n) SVR t 24 weeks 21 (17) 59 (95) 66 (107) < Erly response 9 (7) 46 (74) 52 (84) SVR mong erly responders 100 (7/7) 86 (64/74) 88 (74/84) Relpse 31 (25) 15 (17) 12 (14) Sfety outomes, % (n) Anemi d 20 (16) 43 (70) 46 (74) < ESA use e 21 (17) 41 (66) 46 (74) 0.003; < DC due to nemi (5) Neutrophil ount 500 to 9 (7) 19 (30) 20 (32) 0.060; < 750 per mm 3 (grde 3) Dysgeusi 11 (9) 43 (69) 45 (72) < DC due to AEs 2 (2) 8 (13) 12 (20) 0.150; Primry endpoint defined s undetetle (lower limit of detetion 9.3 IU per ml) HCV RNA levels t week 24 fter ompleting therpy. Undetetle HCV RNA level t week 8. Undetetle HCV RNA level t the end of tretment, ut detetle levels during follow-up. d Hemogloin level <10 gm per dl. Rivirin dose ws redued or n ESA dministered t the disretion of investigtors. Effiy of the regimen is not ompromised if rivirin is redued; rivirin onentrtions hieved re similr to tht of full dosing in nonnemi ptient. e A totl of 16 ptients who reeived ESA lso reeived red lood-ell trnsfusion. DC = disontinution. AE = dverse event; dl = deiliter; ESA = erythropoiesis-stimulting gent; gm = grm; HCV = heptitis C virus; HIV = humn immunodefiieny virus; kg = kilogrm; IU = interntionl units; mg = mirogrm; ml = milliliter; PR = peginterferon + rivirin; RCT = rndomized ontrolled tril; RNA = rionulei id; RVR = rpid virologi response; SVR = sustined virologi response. 690 Journl of Mnged Cre Phrmy JMCP Novemer/Deemer 2011 Vol. 17, No. 9

7 signifintly elevted risk of rsh ompred with oeprevir (22% vs. 2% in previously untreted ptients). 10,11 Stevens- Johnson syndrome ourred in 1 ptient out 11 weeks fter ompleting telprevir tretment. 15 Anemi ppered to our t similr rtes with telprevir nd oeprevir in ross-tril omprisons (19% vs. 20% in previously untreted ptients). 10,11 Although nemi ws mnged differently in the linil trils (telprevir ptients reeived rivirin dose/frequeny modifitions, nd oeprevir ptients reeived erythropoiesis-stimulting gents [ESAs]), prtitioners will likely onsider the use of ESAs with either protese inhiitor depending on their own linil experiene with these gents. 15,17-19 Mnged re pyers my inlude provisions in utiliztion mngement progrms tht mnge nemi in ptients reeiving either of the protese inhiitors with rivirin dose redution (effiy of the regimen is not ompromised if the rivirin dose is redued; rivirin onentrtions hieved will e similr to tht of full dosing in nonnemi ptient) nd llow the use of ESAs t prtiulr hemogloin levels if rivirin dose redution is insuffiient to mnge nemi. Comprtive trils nd studies in different ptient sugroups, inluding those with humn immunodefiieny virus (HIV) oinfetion, re needed to fully understnd the differenes etween the protese inhiitors. Drug Cost Telprevir nd oeprevir will ring sustntil new phrmy osts to the mngement of heptitis C. The wholesle quisition ost (WAC) of telprevir is $97.62 per 375 milligrm (mg) tlet nd $13.10 per 200 mg tlet of oeprevir. 20 Full tretment osts will vry onsiderly depending on tretment durtion, drug hoie, nd ptient mix. Bsed on WAC priing, the ost of 12 weeks of telprevir would e $49,200.48, nd oeprevir WAC would rnge from $26, for 24 weeks to $48, for 44 weeks of therpy, in ddition to the osts for peginterferon plus rivirin (Tle 1). Telprevir s higher ost my e lned y the signifintly esier dosing regimen of telprevir (12 weeks in ll ses) versus the more onfusing, response-guided oeprevir regimen. Additionl osts will e inurred in the mngement of dverse effets from the orl gents. Anemi mnged y ESAs would dd signifint ost to the regimen versus mngement vi rivirin dose redution. Rtes of nemi were 36% in the telprevir-treted ptients versus 17% for ptients treted only with peginterferon nd rivirin. 11 Anemi ourred in 45%-50% of oeprevir-treted ptients versus 20%-30% of ptients treted only with peginterferon nd rivirin. 10 In the SPRINT-2 tril, nemi with oeprevir ws mnged vi ESA 40,000 units dministered weekly, with men durtion of 94 weeks of ESA therpy in the response-guided group nd 156 weeks in the fixed-durtion group versus 121 weeks in the peginterferon-rivirin group. 18 Forty-three perent of oeprevir-treted ptients reeived ESAs ompred with 24% of ptients reeiving only peginterferon plus rivirin in linil trils. 10 The WAC of vil of 40,000 units of ESA is $ Depending on the durtion of therpy, ESAs ould dd signifintly to the totl osts of the regimens of the protese inhiitors. Lortory monitoring nd lini visits my lso e inresed s ptients re monitored for response nd dherene. Prior to the pprovl of the protese inhiitors, MAdm- Mrx et l. (2011) found tht verge totl ll-use osts were $19,665 per ptient per yer (PPPY) in 2009 dollrs for HCVinfeted ptients. 21 The ost of HCV mngement will more thn doule or triple for ptients with genotype 1 infetion treted with triple therpy. Additionlly, WAC priing does not ount for mrk-ups in phrmy provider hnnels or drug mnufturer retes. Due to the inresed osts, pyers should strongly onsider implementtion of utiliztion nd re mngement progrms tht help ensure tht the right ptients reeive the pproprite therpy nd re dherent to therpy. Utiliztion Mngement A linilly foused, omprehensive utiliztion mngement progrm is impertive in the mngement of heptitis C. The utiliztion mngement riteri should inlude the following ftors: pproprite ptient seletion, onomitnt therpy, sfety onsidertions, dosing, nd ontinution of therpy. Approprite ptient seletion my exlude groups not studied in phse 3 trils with the orl protese inhiitors, inluding virl genotypes other thn 1 nd individuls with HIV oinfetion. In these groups, tretment with the stndrd dul therpy my e pplile. Conomitnt therpy with peginterferon nd rivirin is ritil to the suess of protese inhiitor therpy. Utiliztion mngement progrms my e used to mndte triple therpy in ptients with genotype 1 infetion unless they hve ontrinditions to the protese inhiitors. A utiliztion mngement progrm should lso ensure pproprite dosing of protese inhiitors nd peginterferon s well s pprovl of therpy durtions limited to wht is neessry to omplete tretment. Both telprevir nd oeprevir hve numerous ontrinditions nd serious drug intertions. Coverge riteri should onsider sreening for these situtions prior to pproving therpy. Finlly, oth protese inhiitors hve guidelines regrding tretment futility (Figure 2). These riteri predit tretment filures sed on virl lods t speifi time points. Mngement progrms my inlude these stopping points vertim to ensure ptients re eing monitored nd responding to therpy. However, if mnged re deision mkers deide to follow the futility rules, 2 points must e onsidered. First, overge pprovls should extend eyond required lortory heks to llow for reporting of virl lods without the ptient running out of medition. Seond, meeting the futility rules should stop overge of oth the protese inhiitor nd the peginterferon. Vol. 17, No. 9 Novemer/Deemer 2011 JMCP Journl of Mnged Cre Phrmy 691

8 FIGURE 2 Heptitis C Tretment Algorithm: Telprevir nd Boeprevir Telprevir Futility Rules Week 4 HCV RNA level 1,000 IU per ml DISCONTINUE ALL THERAPY Week 12 HCV RNA level 1,000 IU per ml DISCONTINUE ALL THERAPY Week 24 HCV RNA level 10 IU per ml DISCONTINUE ALL THERAPY Week 1 Triple therpy: telprevir + PR PR Disontinue telprevir Continution Rules Tretment-nȉve* nd prior-relpse ptients: Week 24 Week 48 Not detetle t week 4 nd week 12 ontinue PR through week 24 *for ptients with irrhosis ontinue PR through week 48 unless detetle t week 24 Detetle t week 4 nd/or week 12 ontinue PR through week 48 unless detetle t week 24 Prior prtil- nd null-responder ptients: Week 48 Not detetle t week 4 nd week 12 ontinue PR through week 48 unless detetle t week 24 Boeprevir Futility Rules Week 1 Week 8 HCV RNA level (Undetetle: 9.3 IU per ml) Week 4 Begin oeprevir Week 12 HCV RNA level 100 IU per ml DISCONTINUE ALL THERAPY Week 28 HCV RNA level 9.3 IU per ml DISCONTINUE ALL THERAPY PR Triple therpy: oeprevir + PR Continution Rules Tretment-nȉve ptients: Week 28 Not detetle t week 8 nd week 24 ontinue triple therpy with oeprevir + PR through week 28 Week 48 Detetle t week 8 nd not detetle t week 12 omplete oeprevir t week 36 nd ontinue PR through week 48 Prior-relpse nd prtil-responder ptients: Week 36 Not detetle t week 4 nd week 24 ontinue triple therpy with oeprevir + PR through week 36 Week 48 Detetle t week 8 nd not detetle t week 12 omplete oeprevir t week 36 nd ontinue PR through week 48 Ptients with irrhosis: Week 48 4 weeks of PR followed y 44 weeks of triple therpy with oeprevir + PR Soure: Telprevir (Inivek) presriing informtion. 11 Soure: Boeprevir (Vitrelis) presriing informtion. 10 HCV = heptitis C virus; IU = interntionl units; ml = milliliter; PR = peginterferon + rivirin; RNA = rionulei id. 692 Journl of Mnged Cre Phrmy JMCP Novemer/Deemer 2011 Vol. 17, No. 9

9 Ptient dherene is ruil to the ost-effetive use of the protese inhiitors in heptitis C. Nondherent ptients re t signifint risk of tretment filure nd resistne development. 22 Mnged re deision mkers my implement re mngement progrm in onjuntion with utiliztion mngement riteri to ensure ptients re monitored for pproprite use nd dherene to therpy. Mny speilty phrmies hve experiene in re mngement of heptitis C. Idelly, re mngement progrm would inlude regulr (weekly or monthly) lls from phrmist to the ptient to ssess urrent dherene to therpy. Presription lims ould lso e monitored to ensure onsistent filling, nd ll ould e pled to memers suspeted of hving gp in re. Pyers my onsider limiting distriution of heptitis C tretments to speilty phrmy tht offers omprehensive re mngement to ptients. Finlly, mnged re deision mkers should edute the speilty phrmy nd prtitioners on the speifis of the utiliztion mngement riteri, whih will redue potentilly duplitive efforts y the pyer nd the speilty phrmy in re requirements, suh s lortory tests, or potentilly inonsistent periods for pproved durtion of therpy. Provider edution ould e delivered vi trining modules nd/or hving sujet mtter expert ville to nswer questions on the riteri. The relese of telprevir nd oeprevir mrks unique event in whih 2 disese-hnging therpies reeived FDA pprovl within dys of eh other. Suh events provide pyers with the opportunity to gther informtion nd dt on how new therpies re dopted, lter existing utiliztion of estlished therpies, nd impt medil nd phrmy osts. Prime Therpeutis reported tht the utiliztion of drugs for heptitis C deresed y 22.1% in 2010 ompred with 2009, ontriuting to 15.2% derese in drug ost for these drugs (-$0.03 per memer per month), 9% of whih ws in medil enefit osts nd 91% ws in phrmy enefit osts. 23 Although phrmy osts will inrese with the use of the protese inhiitors, the totl ost of ring for ptients with heptiti C infetion should derese due to the inresed ure rtes with the protese inhiitors. The relese of the protese inhiitors will use the first surge in use of heptitis C gents s tretment-nïve nd previously treted ptients ttempt therpy. Pyers should gther dt on the hnges in utiliztion nd how the different produts perform (e.g., use of presription lims to determine utiliztion trend, ost per lim fter pplile disounts, nd medil lims informtion to monitor for dverse events suh s nemi). This informtion ould prove useful in determining the vlue tht the mrket ples on different spets of ompeting drugs inluding dosing, sfety profile, ost, nd effetiveness of utiliztion mngement tools. Additionlly, omprehensive dt olletion ould further define the true ost of the 2 gents when tking into onsidertion disounts, hnnel, nd dverse events. Conlusions With FDA pprovl of the new protese inhiitors, deision mkers hve mny ftors to onsider in developing strtegy round heptitis C. Inresed drug osts, ptient mngement, dherene, omprtive sfety nd effiy, nd pproprite utiliztion mngement ontrols re importnt issues. Despite the gret dvnement in heptitis C tretment, the protese inhiitors hve signifint dverse effet profile nd pill urden. An pproprite utiliztion mngement strtegy should e implemented to ensure ptients reeive optiml enefit from therpy. Authors Alexndr Tungol, PhrmD, is Phrmy Resident; Kellie Rdemher, PhrmD, is Senior Clinil Phrmist; nd Jeremy A. Shfer, PhrmD, MBA, is Senior Diretor of Utiliztion Mngement, Prime Therpeutis LLC, Egn, Minnesot. AUTHOR CORRESPONDENCE: Jeremy A. Shfer, PhrmD, MBA, Prime Therpeutis LLC, 1305 Corporte Center Dr., Egn, MN Tel.: ; Fx: ; E-mil: jshfer@primetherpeutis.om. DISCLOSURES There ws no externl funding for this mnusript. The uthors re employees of Prime Therpeutis LLC, phrmy enefits mngement ompny whose ownership inludes helth plns. Conept nd design were performed y Tungol nd Shfer. Dt olletion nd interprettion were performed primrily y Tungol with the ssistne of Rdemher nd Shfer. The mnusript ws written primrily y Tungol nd Shfer nd revised primrily y Tungol nd Rdemher. REFERENCES 1. Colvin HM, Mithell AE, eds. Committee on the Prevention nd Control of Virl Heptitis Infetions. Heptitis nd Liver Cner: A Ntionl Strtegy for Prevention nd Control of Heptitis B nd C. Wshington, DC: Institute of Mediine, The Ntionl Ademies Press; Aville t: np.edu/tlog.php?reord_id= Aessed Otoer Europen Assoition for the Study of the Liver. EASL Clinil Prtie Guidelines: mngement of heptitis C virus infetion. Journl of Heptology. 2011;55(2): Aville t: files/47d873f9f_file.pdf. Aessed Otoer 28, U.S. Centers for Disese Control. Heptitis C informtion for helth professionls. Mrh 14, Aville t: index.htm. Aessed Otoer 28, Ferguson M. Current therpies for hroni heptitis C. Phrmotherpy. 2011;31(1): Wong JB, MQuilln GM, MHuthison JG, Poynrd T. Estimting future heptitis C moridity, mortlity, nd osts in the United Sttes. Am J Puli Helth. 2000;90(10): Aville t: pm/rtiles/pmc /?tool=pumed. Aessed Otoer 28, Vol. 17, No. 9 Novemer/Deemer 2011 JMCP Journl of Mnged Cre Phrmy 693

10 6. Ghny MG, Nelson DR, Strder DB, Thoms DL, Seeff LB. An updte on tretment of genotype 1 hroni heptitis C virus infetion: 2011 prtie guideline y the Amerin Assoition for the Study of Liver Diseses. Heptology. 2011;54(4): U.S. Centers for Disese Control. Heptitis C. June Aville t: Aessed Otoer U.S. Food nd Drug Administrtion. FDA news relese. FDA pproves Inivek for heptitis C. My 23, Aville t: NewsEvents/Newsroom/PressAnnounements/um htm. Aessed Otoer 28, U.S. Food nd Drug Administrtion. FDA news relese. FDA pproves Vitrelis for heptitis C. My 13, Aville t: NewsEvents/Newsroom/PressAnnounements/um htm. Aessed Otoer 28, Vitrelis (oeprevir) psules. Merk. My Aville t: Aessed Otoer 28, Inivek (telprevir) film oted tlets. Vertex. My Aville t: Aessed Otoer 28, Perni RB, Almquist SJ, Byrn RA, et l. Prelinil profile of VX-950, potent, seletive, nd orlly ioville inhiitor of heptitis C virus NS3-4A serine protese. Antimiro Agents Chemother. 2006;50(3): Aville t: d&id=pmid: Aessed Otoer 28, U.S. Food nd Drug Administrtion. Center for Drug Evlution nd Reserh. Clinil phrmology nd iophrmeutis review of telprevir. Applition numer July 8, Aville t: Aessed Otoer 28, U.S. Food nd Drug Administrtion. Center for Drug Evlution nd Reserh. Clinil phrmology nd iophrmeutis review of oeprevir. Applition numer June 14, Aville t: essdt.fd.gov/drugstfd_dos/nd/2011/202258orig1s000clinphr mr.pdf. Aessed Otoer 28, Joson IM, MHuthison JG, Dusheiko G, et l., for the ADVANCE Study Tem. Telprevir for previously untreted hroni heptitis C virus infetion. N Engl J Med. 2011;364(25): Aville t: nejm.org/doi/full/ /nejmo Aessed Otoer 28, Shermn KE, Flmm SL, Afdhl NH, et l., for the ILLUMINATE Study Tem. Response-guided telprevir omintion tretment for heptitis C virus infetion. N Engl J Med. 2011;365(11): Aville t: Aessed Otoer 28, Zeuzem S, Andreone P, Pol S, et l., for the REALIZE Study Tem. Telprevir for retretment of HCV infetion. N Engl J Med. 2011; 364(25): Aville t: NEJMo Aessed Otoer 28, Poordd F, MCone J Jr, Bon BR, et l., for the SPRINT-2 Investigtors. Boeprevir for untreted hroni HCV genotype 1 infetion. N Engl J Med. 2011;364(13): Aville t: NEJMo Aessed Otoer 28, Bon BR, Gordon SC, Lwitz E, et l., for the RESPOND-2 Investigtors. Boeprevir for previously treted hroni HCV genotype 1 infetion. N Engl J Med. 2011;364(13): Aville t: full/ /nejmo Aessed Otoer 28, Wolters Kluwer Helth. Medi-Spn Mster Drug Dt Bse v2.5 (MDDB). Aessed Septemer 20, MAdm-Mrx C, MGrry LJ, Hne CA, Biskupik J, Deniz B, Brixner DI. All-use nd inrementl per ptient per yer ost ssoited with hroni heptitis C virus nd ssoited liver omplitions in the United Sttes: mnged re perspetive. J Mng Cre Phrm. 2011;17(7): Aville t: spx?id= Lo Re V 3rd, Tel V, Lolio AR, Amoros VK, Kpln DE, Gross R. Reltionship etween dherene to heptitis C virus therpy nd virologi outomes: ohort study. Ann Intern Med. 2011;155(6): Prime Therpeutis Drug Trend Insights. August Aville t: pdf. Aessed Otoer 28, Journl of Mnged Cre Phrmy JMCP Novemer/Deemer 2011 Vol. 17, No. 9