Antiviral Therapy 2015; 20: (doi: /IMP2825)

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1 Antivirl Therpy 2015; 20: (doi: /IMP2825) Originl rticle Cost-effectiveness of boceprevir co-dministrtion versus pegylted interferon-2b nd ribvirin only for ptients with heptitis C genotype 1 in Singpore Yock Young Dn 1 *, Shnnon A Ferrnte 2, Elmin H Elbsh 2, Tun-Ying Hsu 3 1 Deprtment of Medicine, Yong Loo Liu School of Medicine, Ntionl University of Singpore, Singpore 2 Helth Economic Sttistics, Merck & Co., Inc., Whitehouse Sttion, NJ, USA 3 Medicl Affirs, MSD Phrm (Singpore) Pte Ltd, Singpore *Corresponding uthor e-mil: yock_young_dn@nuhs.edu.sg Bckground: Ptients infected with chronic HCV genotype 1 experience liver complictions s the disese progresses. This study ims to project the long-term reduction of liver complictions nd cost-effectiveness of tretment strtegies, including co-dministrting boceprevir (BOC) with pegylted interferon-α2b (PEG-IFN) nd ribvirin compred with stndrd of cre (SOC) of PEG-IFN nd ribvirin only. Methods: A Mrkov model ws creted to estimte the expected costs nd qulity-djusted life-yers (QALYs) ssocited with tretment strtegies outlined in the BOC pckge insert in Singpore. Ptient chrcteristics were from pivotl trils, the trnsition probbilities nd QALYs were estimted from publictions, nd the phrmceuticl nd helth sttus costs were obtined from public hospitl in Singpore. The threshold of cost-effectiveness ws chosen s 65,000 SGD for this study. Results: For tretment-nive ptients, BOC is highly cost-effective compred with SOC (179 SGD/QALY) nd cost-sving for ptients who hve filed prior tretment, due to higher QALYs from better sustined virologicl response (SVR) nd lower costs from voidnce of complictions. Sub-group nlyses show tht BOC is cost-effective for non-cirrhotic tretment-experienced ptients nd null responders. It out-performs SOC for tretment-nive non-cirrhotic nd cirrhotic ptients who hve filed prior tretment. Even fter djusting for higher prevlence of fvourble IL28B genotype in Asins, BOC is cost-effective compred with SOC. Only untreted cirrhotic ptients showed inconclusive costeffectiveness for BOC. Conclusions: Compred with SOC, BOC prevents more HCV liver complictions from HCV genotype 1, prticulrly in ptients who hve filed previous SOC. Improved SVR nd shortened durtion of tretment result in BOC being potentilly cost-sving or cost-effective in n Asin popultion. Introduction Heptitis C is mjor cuse of liver disese, ccounting for 350 thousnds deths worldwide. There re pproximtely 150 million [1] ptients chroniclly infected with HCV, with 3 4 million new HCV infections nnully. The prevlence rte [2] of HCV is pproximtely 1.3% in North Americ, % in Ltin Americ, % in Afric, 2.4% in Europen countries, 3.4% in South Asi nd 3.7% in Est Asi. Chronic HCV prevlence is exceptionlly high in Egypt (15%), Pkistn (4.8%) nd Chin (3.2%) [1]. The burden on society lies in the chronic sequele of chronic heptitis C liver cirrhosis nd heptocellulr crcinom (HCC). HCV ccounts for lmost 25% of HCC nd is mjor etiology for liver trnsplnttion for decompensted liver disese, but the economic burden of complictions of chronic heptitis C hs not been well studied in Asin Pcific countries. It ws estimted tht the nnul tretment cost of liver complictions ws 1,175 SGD for stble or compensted cirrhosis, 15,390 SGD for decompensted cirrhosis, 12,314 SGD for HCC nd 106,589 SGD for the first yer of liver trnsplnt, s well s 11,841 SGD for the subsequent yer [3]. Tretment of heptitis C, unlike heptitis B, cn induce sustined virologicl response (SVR) nd thus vert the long-term problems of chronic liver diseses. Pegylted 2015 Interntionl Medicl Press (print) (online) 209

2 YY Dn et l. interferon-α2b (PEG-IFN) nd ribvirin hve been the bckbone of nti-hcv tretment for mny yers, but tretment for genotype 1 hs been suboptiml. The vilbility of direct-cting ntivirls in combintion gretly increse the SVR rtes of HCV genotype 1. Of the two new ntivirls licensed by the US FDA, boeceprevir, novel peptidomimetic ketomide protese inhibitor tht binds reversibly to the HCV non-structurl 3 ctive sites, is the only one vilble in most prts of Asi. The sfety nd efficcy of dding boceprevir to stndrd-ofcre (SOC) ws evluted in two Phse III rndomized double-blind plcebo-controlled trils: the SPRINT-2 tril [4] ws conducted with 1,097 HCV genotype 1 ptients (938 non-blck nd 159 Blck) who were tretment-nive, wheres the RESPOND-2 tril [5] studied 403 ptients with prior tretments. Dt from SPRINT-2 showed tht SVR cn be incresed from 38% to 63%, wheres RESPOND-2 showed tht this enhnced SVR rte (21% versus 59%) is lso beneficil for ptients who hve filed prior PEG-IFN/ribvirin tretment. In Western communities, these drugs hve been shown to be cost-effective. This outcome hs resulted in triple therpy being ccepted s SOC tretment for genotype 1 HCV ptients (EASL nd AASLD), lthough the APASL guidelines in 2012 hve not been updted yet. However, in Asi where helth-cre resources hve lwys been limited with mny competing demnds on the helth budget, the cost-effectiveness hs not been dequtely studied. Added to this is tht Asins hve higher prevlence of the IL28B genotype, which could predict good responses to conventionl PEG-IFN/ribvirin, nd so the cost-effectiveness of triple therpy becomes less strightforwrd. Here, we imed to perform cost-effectiveness study on combintion of boceprevir nd PEG-IFN plus ribvirin ginst PEG-IFN plus ribvirin in n Asin popultion represented by Singpore. Methods This study ims to investigte the cost-effectiveness of boceprevir combined with PEG-IFN plus ribvirin by simulting ptients disese progression nd tretment pttern ccording to the lbel indiction in Singpore. The tretment protocol is s presented in the Additionl file 1 for both tretment-nive nd tretment-experienced ptients. A Mrkov model ws developed to cpture the disese progression nd to project the lifetime cumultive incidence of dvnced liver-relted complictions (decompensted cirrhosis nd HCC) nd liver trnsplnt in order to be consistent with current understnding of the biology of chronic HCV-relted liver disese nd ssocited tretment (Additionl file 1) [6,7]. Different stges (F0 F4) of chronic HCV infection were defined by the METAVIR scoring system nd ptients were ssumed to progress into more severe stges or remin in the sme stte without successful tretment. Correspondingly, successful tretment cn result in n SVR, which is considered cure for HCV ptients. Ptients with compensted cirrhosis re t risk for developing decompensted cirrhosis nd HCC. Although there re different modes of decompenstion (tht is, scites, vricel hemorrhge nd encephlopthy) they re modelled s one helth stte here becuse these decompensted modes re not mutully exclusive. If ptient develops decompensted cirrhosis nd/or HCC then the ptient my receive liver trnsplnt. Owing to differentil mortlity between the immedite nd lte phses following trnsplnttion, the liver trnsplnt helth stte is divided into two sttes: the liver trnsplnt (lsts for 1 yer) nd the post-liver trnsplnt stte. With the exception of ptients with decompensted cirrhosis, HCC nd liver trnsplnt, who re subject to excess mortlity compred with the generl popultion, ll other ptients fce the sme mortlity risk s the generl popultion. The trnsition probbilities nd SVR rtes we used were from observed rtes of triple therpy nd PEG-IFN/ ribvirin mong non-blck subjects from SPRINT-2 nd RESPOND-2 in our bse cse study. To djust for possible differences in SVR rte in Asin popultions, which hs been reported with 73% prevlence of good IL28B genotype in met-nlysis, we performed second-stge nlysis djusting the SVR for Asin popultions bsed on the results of Cucsin subjects. The chrcteristics of ptients (verge 50 yers old in the cohort nd 62% mle), efficcy nd complince were bsed on observtions from SPRINT-2 nd RESPOND-2. The distribution of fibrosis stges for tretment-nive nd tretment-experienced ptients were bsed on dt from SPRINT-2 nd RESPOND-2, respectively. Inputs relted to ll-cuse mortlity rte nd tretment costs were specific to Singpore (Tble 1). The unsubsidized cost of liverssocited helth sttus ws collected from hospitl finncil records of tertiry not-for-profit hospitls in Singpore. Actul rel-life cost dt mke the results of this study good reference from public perspective. Expected costs nd qulity-djusted life-yers (QALYs) ssocited with the tretment strtegies were clculted over the rest of ptients lifetime. Results Bse cse Ptients previously untreted For ptients who were tretment (PEG-IFN nd/or ribvirin)-nive, the boceprevir-bsed regimen is estimted to reduce the cumultive incidence of liver-relted Interntionl Medicl Press

3 Cost-effectiveness of boceprevir in HCV G1 ptients in Singpore Tble 1. Model inputs nd rnges used in sensitivity nlysis Prmeter Bse cse Lower cse Upper cse Reference Dist Clinicl inputs: nnul trnsition probbilities Fibrosis progression F0 F ( ) [14] Bet F1 F ( ) [14] Bet F2 F ( ) [14] Bet F3 F ( ) [14] Bet Cirrhosis Compensted to decompensted ( ) [15 20] Bet Compensted to HCC ( ) [15 23] Bet Decompensted to HCC ( ) [24] Bet Probbility of receiving liver trnsplnt Decompensted cirrhosis ( ) [25,26] Bet HCC ( ) [27,28] Bet Probbility of cured ptient (SVR) progressing to Decompensted cirrhosis ( ) [29] Bet HCC ( ) [29] Bet Mortlity rtes All-cuse mortlity b [30] Liver-relted mortlity ssocited with ( ) [28] Bet decompensted cirrhosis (first yer) Liver-relted mortlity ssocited with ( ) [16] Bet decompensted cirrhosis (subsequent yers) Liver-relted mortlity ssocited with HCC ( ) [15] Bet Liver trnsplnt (first yer) ( ) [31] Bet Liver trnsplnt (subsequent yers) ( ) [31] Bet Economic input Weekly ntivirl drug therpy-relted costs Pegylted interferon/ribvirin, SGD 372 c Boceprevir, SGD 990 c Erythroprotein (to tret nemi), SGD d Monitoring costs over 48 weeks, SGD 2,900 e Annul helth stte costs F0 F3, SGD ,050 NUHS e Gmm Compensted cirrhosis, SGD 5,880 4,410 7,350 NUHS e Gmm Decompensted cirrhosis (first yer), SGD 14,000 10,500 17,500 NUHS e Gmm Decompensted cirrhosis (subsequent yers), SGD 19,000 14,250 23,750 NUHS e Gmm HCC (first yer), SGD 36,040 27,030 45,050 NUHS e Gmm HCC (subsequent yers), SGD 22,060 16,545 27,575 NUHS e Gmm Liver trnsplnt (first yer), SGD 154, , ,500 NUHS e Gmm Liver trnsplnt (subsequent yers), SGD 12,500 9,375 15,625 NUHS e Gmm Utility input Bseline utility weights for generl popultion 1.0 Antivirl drug-therpy-relted utility weights Pegylted interferon/ribvirin, no side effects 0.9 [32] (bseline fibrosis-stge utility) Pegylted interferon/ribvirin + boceprevir, 0.9 [32] no side effects (bseline fibrosis-stge utility) Antivirl-relted nemi ( ) [32,33] (bseline fibrosis-stge utility) Helth stte utility weights F0 F ( ) [32,34] Bet F2 F ( ) [32,34] Bet Compensted cirrhosis 0.90 ( ) [32,34] Bet The prmeters of the distributions (Dist) ssumed re vilble upon request. b Age/gender-specific. c Pegylted interferon/ribvirin re pckged free with no cost to the pyer when ptients re tking boceprevir together with pegylted interferon/ribvirin. d Bsed on n verge dose of 20,000 IU/ml per week. e Hospitl finncil records. HCC, heptocellulr crcinom; SVR, sustined virologicl response. Antivirl Therpy

4 YY Dn et l. Tble 1. Continued Prmeter Bse cse Lower cse Upper cse Reference Dist Decompensted cirrhosis (first yer) 0.80 ( ) [32,34] Bet Decompensted cirrhosis (subsequent yers) 0.80 ( ) [32,34] Bet HCC 0.79 ( ) [32,34] Bet Liver trnsplnt (first yer) 0.84 ( ) [32,34] Bet Liver trnsplnt (subsequent yers) 0.84 ( ) [32,34] Bet SVR 1.00 ( ) Discount rte, % disese (including decompensted cirrhosis, HCC nd liver trnsplnt), mortlity nd liver trnsplnt by 41 42%, with n incrementl cost-effectiveness rtio (ICER) equl to 179 SGD. Ptients who filed prior tretment Moreover, boceprevir lso works on ptients who hve been treted with SOC yet filed to chieve SVR. The boceprevir-bsed strtegy is projected to decrese the cumultive incidence of liver-relted disese nd mortlity, nd liver trnsplnt by 48 51%. Under the current economic costs for complictions, the boceprevir-bsed regimen is cost-sving compred with SOC due to the significnt reduction in the number of liver trnsplnts, which is very costly in Singpore setting. Tble 2 summrizes the results. Subset nlysis: ptients under different stges of fibrosis Non-cirrhotic ptients who were tretment-nive For ptients who were tretment-nive with non-cirrhotic liver condition, the boceprevir regimen tretment ws projected to reduce 47% of liver complictions. Under the current pricing scheme, boceprevir is costsving compred with SOC s result of mrked reduction in liver complictions, prticulrly liver trnsplnt. Cirrhotic ptients who were tretment-nive The difference of efficcy between the co-dministrtion of boceprevir nd PEG-IFN plus ribvirin versus SOC on ptients who rech cirrhotic liver sttus without prior tretment is not s significnt s other subsets of ptients due to smller mrgin of benefit. Non-cirrhotic ptients who filed prior tretment Ptients who were treted yet filed to chieve SVR nd styed t non-cirrhotic sttus benefited from the boceprevir tretment regimen by hving 53% lower incidence rte of liver complictions. The ICER ws 1,291 SGD. Cirrhotic ptients who filed prior tretment Among cirrhotic ptients who filed previous tretment with SOC, boceprevir-bsed tretment is projected to hve 40 52% lower incidence rte of liver complictions, prticulrly with mrked reduction on liver trnsplnt, HCC nd liver-relted mortlity. At its current qulity nd QALY gin, the boceprevir regimen is projected to be cost-sving compred with SOC. Null responders For null responders with HCV virl lods tht did not decrese by t lest 2 log during the first 12 weeks of tretment, boceprevir-bsed tretment is projected to reduce the incidence rte of liver compliction by 30 32%, nd the ICER is in the relm of being costeffective. All the results re summrized in Tble 3. Sensitivity nlyses The sensitivity nlyses were conducted with clinicl inputs, cost of helth sttus nd utility vlues corresponding to the qulity of life in order to compre the cost nd benefit between two tretment schemes. In order to simulte the results of input chnge due to exogenous custion, we took the uncertinty of clinicl input (tht is, trnsition probbilities between different stges of liver compliction), utility nd tretment cost into considertion. The lower nd upper vlues of clinicl inputs nd utility vlues re referred to s the bounds of 95% confidence intervl, while the vlues of helth sttus cost re estimted s 25% lower nd higher compred with the bseline vlue. All input vlues for sensitivity nlysis re summrized in Tble 1. The ICER does vry nd minimum nd mximum vlues re summrized in the Additionl file 1. All simultions with input vrition within the 95% confidence intervl showed tht boceprevir tretment is still costeffective even with systemtic uncertinty tken into ccount nd cost-sving for most of scenrios for treting ptients who filed prior tretment. Sensitivity nlysis of the cost-effectiveness nlysis show tht boceprevir ws certinly cost-effective tretment strtegy for tretment-nive ptients with the threshold set t 65,000 SGD nd cost-sving tretment from 50% of probbilistic simultions. Also, with ptients who filed the previous tretment, boceprevir ws cost-sving compred with SOC in bout 80% of simultions nd cost-effective in ll Interntionl Medicl Press

5 Cost-effectiveness of boceprevir in HCV G1 ptients in Singpore Tble 2. Projected number of liver complictions, cost, QALY nd ICER Liver complictions Decompensted Heptocellulr Liver Liver-relted ICER cirrhosis, n crcinom, n trnsplnt, n deth, n Cost, SGD b QALY b (SGD/QALY) Tretment-nive SOC 1,451 1, ,306 47, BOC 854 1, ,362 47, Reduction, % Filed prior tretment SOC 1,711 2, ,740 57, BOC 896 1, ,365 54, Cost-sving Reduction, % Dt re n for number of complictions per 10,000 ptients. b Per ptient. BOC, boceprevir; ICER, incrementl cost-effectiveness rtio; QALY, qulity-djusted life-yer; SOC, stndrd-of-cre. Tble 3. Subset nlysis of the projected number of liver complictions, cost nd QALY Liver complictions Decompensted Heptocellulr Liver Liver-relted ICER cirrhosis, n crcinom, n trnsplnt, n deth, n Cost, SGD b QALY b (SGD/QALY) Tretment-nive Non-cirrhotic SOC 1,346 1, ,125 45, BOC ,137 43, Cost-sving Reduction, % Cirrhotic SOC 3,446 4, ,745 95, BOC 3,397 3, , , ,159 Reduction, % Filed prior tretment Non-cirrhotic SOC 1,383 1, ,139 47, BOC , ,291 Reduction, % Cirrhotic SOC 3,887 4, , , BOC 2,557 2, ,795 89, Cost-sving Reduction, % Null responder SOC 2,112 2, ,364 61, BOC 1,473 1, ,321 67, ,357 Reduction, % Dt re n for number of complictions per 10,000 ptients. b Per ptient. BOC, boceprevir; ICER, incrementl cost-effectiveness rtio; QALY, qulity-djusted life-yer; SOC, stndrd-of-cre. simultions (see Additionl file 1 for probbilistic sensitivity nlysis). Adjustment of SVR bsed on IL-28B genotypic distribution in Asi Mny studies hve rgued tht interleukin (IL)-28B is strong positive predictor for SVR in HCV ptients following dul therpy with PEG-IFN plus ribvirin. For Cucsin nd other non-asin ptients, rs CC is the strongest single nucleotide polymorphism upstrem of the IL-28B gene tht is fvourble for chieving n SVR. For Asin ptients, rs TT is the fvourble genotype for chieving n SVR. A metnlysis [8] showed tht mong 8 studies on 2,612 Asin HCV ptients from Jpn, Tiwn nd Kore, 73% of them hd the fvourble IL-28B gene. The overll OR rte of Asin ptients who crry the fvourble gene for chieving n SVR ws 5.66 (95% CI 3.99, 8.02) compred with those without the fvourble gene, while the OR rtes were 3.88 (95% CI 2.75, 5.49) nd 4.63 Antivirl Therpy

6 YY Dn et l. (95% CI 2.52, 8.50) for Cucsin nd Blck ptients, respectively. As Asin ptients hve higher incidence of fvourble IL-28B genotype, proxy SVR rtes were clculted bsed on the reltive popultion distribution of fvourble IL28B genotype s reported by Poordd et l. [9] nd Jiménez-Sous et l. [10]. These proxy rtes re summrized in Tble 4 (see lso Additionl file 1 for derivtion of djusted SVR in Asi). The lifetime prediction of liver complictions with these IL-28B-djusted SVR proxy rtes were simulted nd the results re summrized in Tble 5. Boceprevirbsed triple therpy remins cost-effective even when the higher tendency of SVR of ptients with the fvourble IL28B genotype ws considered (Tble 5). Compred with the ptient profiles from SPRINT-2 (85.5% non- Blck, 14.5% Blck), Asin ptients responded to tretments better, therefore the reported reduction of liver compliction between SOC nd boceprevir ws less thn tht reported in the SPRINT-2 ptient cohort. The higher ICER ws driven by the lower reduction of liver compliction. Nevertheless, the cost-effectiveness of boceprevirbsed triple therpy ws robustly mintined. Discussion The two Phse III clinicl trils, SPRINT-2 nd RESPOND-2, demonstrted tht triple therpy consisting of boceprevir nd PEG-IFN plus ribvirin, ws superior in efficcy nd shortened durtion of tretment compred with the stndrd tretment. This study evluted the cost-effectiveness of boceprevir-bsed tretment, beyond the fvourble efficcy, within the setting of first-world Asi-Pcific country, Singpore. The CHOosing Interventions tht re Cost Effective (CHOICE) guidelines [11] from the WHO suggest using GDP per cpit s reference for cost-effectiveness threshold [12]. Following convention, we used the bsolute Singpore GDP in 2012 (65,000 SGD) s threshold for highly cost-effective tretment strtegy. Although the use of boceprevir-ssocited triple therpy in the US hs been shown to be cost-effective for HCV tretment-nive nd re-tretment ptients [6,13], the cost-effectiveness of triple therpy with boceprevir hs not been estblished in Asin countries. We performed two-stge nlysis in our study. In the first stge, we used ctul clinicl tretment response dt from RESPOND-2 nd SPRINT-2 to confirm tht boceprevir is cost-sving for tretment-experienced ptients nd cn be cost-effective for tretment-nive ptients. In stge two, we djusted the SVR in fvour of SOC, tking into ccount the higher prevlence of the fvourble genotype for IL28B in Asi, nd showed tht BOC is still costeffective. Although boceprevir incresed the combined cost during tretment, the improved tretment response Tble 4. Adjusted SVR proxy rtes of Asin ptients who crry IL-28B nd were previously untreted Bse cse Poordd et l. [9] Jiménez-Sous et l. [10] Response PR, % BOC/RGT, % PR, % BOC/RGT, % PR, % BOC/RGT, % F0 F3 SVR NA Futility rule filure t TW Futility rule filure t TW % ws estimted bsed on reltionship of sustined virologicl response (SVR) between pegylted interferon/ribvirin (PR) nd boceprevir (BOC). NA, not pplicble; RGT, response-guided therpy; TW, tretment week. Tble 5. Projected number of liver complictions, cost nd QALY in non-cirrhotic Asin ptients who crry IL-28B nd were previously untreted Liver compliction Decompensted Heptocellulr Liver Liver-relted ICER cirrhosis, n crcinom, n trnsplnt, n deth, n Cost, SGD b QALY b (SGD/QALY) Poordd et l. [9] SOC ,101 32, BOC , ,916 Reduction, % Jiménez-Sous et l. [10] SOC 842 1, ,330 36, BOC , ,851 Reduction, % Dt re n for number of complictions per 10,000 ptients. b Per ptient. BOC, boceprevir; ICER, incrementl cost-effectiveness rtio; QALY, qulity-djusted life-yer; SOC, stndrd-of-cre Interntionl Medicl Press

7 Cost-effectiveness of boceprevir in HCV G1 ptients in Singpore sved money by voiding further tretment costs needed to re-tret ptients or to mnge complictions due to filed tretment. The reltively smll differences between costs of boceprevir triple therpy versus stndrd therpy in the Singpore context lso helped its cost-effectiveness. In generl, co-dministrtion of boceprevir with PEG- IFN plus ribvirin is potentilly cost-effective tretment option for heptitis C genotype 1 ptients in Singpore, prticulrly those who hve filed previous tretment. However, for untreted cirrhotic ptients, BOC regimen decreses the incidence rte of liver-relted complictions by only 1 2%. Additionlly, it is known tht the Asin ethnicity hs higher incidence of IL28B genotype tht will render them more responsive to stndrd therpy. In the second prt of our nlysis, we djusted the response rte bsed on published met-nlysis on the prevlence of the fvourble IL28B genotype in the Asin popultion nd showed tht ICER ws still well within the costeffectiveness threshold for both tretment-nive nd tretment-experienced ptients. Furthermore, nother dvntge of triple therpy is the potentil for shortened tretment durtion s shown by the results from SPRINT-2: 57% (208/368) of tretment-nive ptients on the boceprevir rm hd undetectble HCV RNA t week 8 compred with 16.5% (60/363) of ptients on the SOC rm. For both rms, t lest 85% of those erly responders reched SVR t the end of SPRINT-2 tril. Since the ptients were more likely to respond to triple therpy erlier thn trditionl tretment, the incresed cost of boceprevir cn be offset by the shortened durtion of tretment. Limittions of this study re ssocited with the ssumptions of model structure nd dt input. First, the efficcy dt were from SPRINT-2 nd RESPOND-2, which excluded HCV-infected ptients with other liver disese comorbidities (such s non-lcoholic stetoheptitis nd heptitis B). In rel-life, these ptients my hve higher risks of liver complictions. Second, the licensing lbel for boceprevir in Singpore is different from the clinicl tril design, the tretment-relted inputs were therefore bsed on post hoc nlysis from the clinicl trils. Third, no further tretment option ws tken into considertion for ptients who filed to rech n SVR fter either stndrd tretment or boceprevir-bsed triple tretment, therefore the ssessment of long-term effect of ntivirl tretment ws bsent. In conclusion, boceprevir is demonstrted to be costsving mong tretment-experienced ptients compred with PEG-IFN plus ribvirin (the current SOC) nd is cost-effective for tretment-nive ptients with 65,000 SGD threshold. The min driving force for this result is the significnt reduction of liver complictions ssocited with HCV genotype 1, prticulrly mong ptients who hve filed prior tretment. Moreover, the subset nlysis showed tht the boceprevir-bsed tretment regimen is cost-sving for non-cirrhotic ptients who re tretment-nive nd lso for cirrhotic ptients who hve filed prior tretment, with 46% nd 42% liver trnsplnt reduction, respectively. For non-cirrhotic ptients who hve filed the prior tretment, boceprevir is cost-effective with 53% reduction in liver compliction. Despite the initil higher cost of boceprevir regimens in heptitis C genotype 1 tretment, our model suggest tht boceprevir-bsed regimens re still highly cost-effective compred with SOC in Asin countries, even fter correcting for expected higher prevlence of the fvourble IL28B genotype. Disclosure sttement This mnuscript is supported by stff nd personnel from Merck & Co., Inc., nd MSD Phrm (Singpore) Pte. Ltd. DYY hs been on the dvisory committee nd hs received honorrium nd/or reserch funding from compnies including MSD, Giled, BMS, Snofi Aventis, GSK nd Novrtis. All other uthors declre no competing interests. Additionl file Additionl file 1: Supplementry informtion on the stndrd-of-cre nd boceprevir tretment strtegies, heptitis C nd liver disese progression, sensitivity nlyses, results of probbilistic sensitivity nlysis, nd the lgorithm of proxy rtes of SVR of ptients who hve IL-28B gene cn be found t com/uplods/documents/3208_dn_additionl_file.pdf References 1. WHO. Heptitis C fct sheet number 164. (Updted July Accessed 5 December 2013.) Avilble from Mohd Hnfih K, Groeger J, Flxmn AD, Wiersm ST. Globl epidemiology of heptitis C virus infection: new estimtes of ge-specific ntibody to heptitis C virus seroprevlence. Heptology 2013; 57: Li SC, Lim SG, Yeoh KG, et l. A cost comprison of mngement of chronic heptitis B nd its ssocited complictions in Hong Kong nd Singpore. J Clin Gstroenterol 2004; 38:S136 S Poordd F, McCone J, Bcon BR, et l. Boceprevir for untreted chronic HCV genotype 1 infection. N Engl J Med 2011; 364: Bcon BR, Gordon SC, Lwitz E, et l. Boceprevir for previously treted chronic HCV genotype 1 infection. N Engl J Med 2011; 364: Ferrnte SA, Chhtwl J, Brss CA, et l. Boceprevir for previously untreted ptients with chronic heptitis C Genotype 1 infection: US-bsed cost-effectiveness modeling study. BMC Infect Dis 2013; 13: Elbsh EH, Chhtwl J, Ferrnte SA, El Khoury AE, Lires PA. Cost-effectiveness nlysis of boceprevir for the tretment of chronic heptitis C virus genotype 1 infection in Portugl. Appl Helth Econ Helth Policy 2013; 11: Antivirl Therpy

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