Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients ( )

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1 ORIGINAL ARTICLE Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): Jnury-Februry, Vol. 11 No.1, 2012: Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in rndomized tril of heptitis C genotype 1 ptients ( ) Dvid R. Nelson,* Stefn Zeuzem, Pietro Andreone, Peter Ferenci, Robert Herring, Donld M. Jensen, Ptrick Mrcellin,** Pul J. Pockros, Mribel Rodríguez-Torres, Lorenzo Rossro, Vinod K. Rustgi, Thoms Sepe, Mrk Sulkowski,*** Isc R. Thomson, Eric M. Yoshid, Ann Chn, George Hill * Division of Gstroenterology, Heptology, nd Nutrition, University of Florid, Ginsville, USA. Deprtment of Medicine, J.W. Goethe University Hospitl, Frnkfurt, Germny. Diprtimento di Medicin Clinic, Università di Bologn, Bologn, Itly. Deprtment of Internl Medicine III, Medicl University of Vienn, Vienn, Austri. Nshville Gstrointestinl Specilists Inc, Nshville, USA. Center for Liver Diseses, Chicgo, Section of Gstroenterology, Heptology nd Nutrition, University of Chicgo Medicl Center, USA. ** Hôpitl Beujon, Clinchy, Frnce. Division of Gstroenterology nd Heptology, The Scripps Clinic, Torrey Pines, USA. Fundcion de Investigcion De Diego Snturce, Puerto Rico nd Ponce School of Medicine, Puerto Rico, USA. Division of Gstroenterology nd Heptology, University of Cliforni, Dvis Medicl Center, Scrmento, USA. Georgetown University Medicl Center, Firfx, VA, USA. University Gstroenterology, Providence, USA. *** Virl Heptitis Center in the Divisions of Infectious Diseses nd Gstroenterology/Heptology, Johns Hopkins University School of Medicine, Bltimore, USA. Mountin West Gstroenterology, Trnsplnt Deprtment, Intermountin Medicl Center, Slt Lke City, USA. Division of Gstroenterology, University of British Columbi, Vncouver, BC, Cnd. Roche, Nutley, NJ, USA. Roche, Plo Alto, CA, USA ABSTRACT Introduction. Blpirvir (R1626, RG1626) is the prodrug of nucleoside nlogue inhibitor of the heptitis C virus (HCV) RNA-dependent RNA polymerse (R1479, RG1479). This phse 2, double-blind interntionl tril evluted the optiml tretment regimen of blpirvir plus peginterferon lf-2 (40KD)/ribvirin. Mteril nd methods. Tretment-nive genotype 1 ptients (N = 516) were rndomized to one of seven tretment groups in which they received blpirvir 500, 1,000, or 1,500 mg twice dily, peginterferon lf- 2 (40KD) 180 or 90 µg/week nd ribvirin 1,000/1,200 mg/dy or peginterferon lf-2 (40KD)/ribvirin. The plnned tretment durtion with blpirvir ws reduced from 24 to 12 weeks due to sfety concerns. Results. The percentge of ptients with undetectble HCV RNA ws consistently higher in ll blpirvir groups from week 2 to 12. However, high rtes of dose modifictions nd discontinutions of one/ll study drugs compromised the efficcy ssessment nd resulted in similr sustined virologicl response rtes in the blpirvir groups (rnge 32-50%) nd the peginterferon lf-2 (40KD)/ribvirin group (43%). Blpirvir ws discontinued for sfety resons in 28-36% of ptients (most often for lymphopeni) nd the percentge of ptients with serious dverse events (especilly hemtologicl, infection, oculr events) ws dose relted. Serious hemtologicl dverse events (prticulrly neutropeni, lymphopeni) were more common in blpirvir recipients. Two deths in the blpirvir/peginterferon lf-2/ribvirin combintion groups were considered possibly relted to study mediction. Conclusion. Further development of blpirvir for the tretment of chronic heptitis C hs been hlted becuse of the uncceptble benefit to risk rtio reveled in this study ( NCT ). Key words. Chronic heptitis C. SVR. Sfety. ( ) Grnt Support: This study ws funded by Roche. The sponsor contributed to study design s well s dt collection, nlysis, nd interprettion with input from the investigtors. Writing support ws provided by Blir Jrvis of Helth Interctions nd funded by Hoffmn L-Roche Ltd. CliniclTrils.gov Identifier: NCT Correspondence nd reprint request: Dr. Dvid R Nelson Division of Heptology nd Liver Trnsplnttion. Shnds Hospitl. University of Florid 1600 SW Archer Rod M440 Ginsville, Florid, USA Tel.: Fx: E-mil: nelsodr@medicine.ufl.edu Mnuscript received: September 09, Mnuscript ccepted: October 10, 2011.

2 16 Nelson DR, et l., 2012; 11 (1): INTRODUCTION Heptitis C virus (HCV) infection is the leding cuse of liver disese worldwide with n estimted prevlence of more thn 170 million individuls. 1 Most infected persons develop chronic disese tht cn progress to cirrhosis, heptocellulr crcinom, nd liver filure. As result, chronic heptitis C is the leding cuse of liver trnsplnttion in the US. 2 Tretments re vilble for chronic heptitis C; however, the current stndrd of cre, pegylted interferon plus ribvirin, is most effective ginst HCV genotype 2 or 3 infection nd less effective ginst the more prevlent genotype 1 infection. 3 Severl clsses of direct-cting ntivirl gents hve been discovered nd re being evluted in humn clinicl trils with the gol of incresing cure rtes for chronic heptitis C. Blpirvir (RG1626) is n orlly dministered tri-isobutyl ester prodrug of potent nucleoside nlogue inhibitor of the RNA-dependent RNA polymerse (RdRp) of HCV (RG1479). 4,5 When dministered lone for 14 dys t dosges rnging from 1,000 mg/dy to 9,000 mg/dy, blpirvir produced men reductions in serum HCV RNA levels up to 3.7 log 10 with n cceptble sfety profile. 6 When dministered for 28 dys t dosge of 3 g/dy in combintion with peginterferon lf- 2 (40 KD) plus ribvirin, the rpid virologicl response (RVR) rte (HCV RNA <15 IU/mL t week 4) ws 74%. 7 Importntly, blpirvir-resistnt HCV vrints were not detected during these short-term clinicl trils. 6,7 Dose-dependent hemtologicl bnormlities were observed with the triple therpy regimen; however, these events were effectively mnged with dose reductions nd were reversible upon discontinution of blpirvir. As result of these promising results phse 2 clinicl tril ws initited to identify the optiml tretment regimen of blpirvir in combintion with peginterferon lf-2 (40KD) nd ribvirin in tretment-nive genotype 1-infected individuls. MATERIALS AND METHODS Ptients Adult ptients ged 18 to 65 yers with HCV genotype 1 infection who hd never received tretment for chronic heptitis C were eligible for the tril. Chronic heptitis C ws defined s the presence of nti-hcv ntibodies nd n HCV RNA titer 50,000 IU/mL in serum (COBAS Ampliprep/CO- BAS TqMn HCV test; detection limit 15 IU/mL, Roche Dignostics, Indinpolis, USA) with liver biopsy obtined within the previous 24 months (36 months in ptients with cirrhosis or incomplete/ trnsition to cirrhosis) consistent with chronic heptitis C. HCV genotype 1 infection ws confirmed by moleculr ssy (Versnt HCV Genotyping 2.0 Assy [LiPA], Byer Dignostics And Innogenetics, NY, USA). Ptients with dvnced fibrosis ccording to biopsy obtined within the previous 36 months were required to hve compensted liver disese (Child Pugh grde A), serum α-fetoprotein level < 100 ng/ml, nd no evidence of heptocellulr crcinom on n ultrsound, computerized tomogrphy, or mgnetic resonnce imging scn performed within the previous 2 months. Ptients were not eligible if they were infected with ny HCV genotype other thn genotype 1 or hd serologicl evidence of infection with heptitis B virus or humn immunodeficiency virus. Ptients were lso excluded if they hd body mss index < 18 kg/m 2 or 36 kg/m 2, n bsolute neutrophil count < 2 x 10 9 cells/l, pltelet count < 90 x 10 9 cells/l, hemoglobin concentrtion < 120 g/l in women or < 130 g/l in men (or in ptients with risk fctors for nemi or in whom nemi would be mediclly problemtic), or serum cretinine level > 1.5 times the upper limit of norml. Use of erythropoietin-stimulting gents or colony stimulting fctors to elevte hemtology prmeters to fcilitte entry into the study ws prohibited. Ptients who hd previously received ny interferon preprtion, ribvirin (or ribvirin nlog), or ny investigtionl HCV protese or polymerse inhibitor were excluded, s were those with history or evidence of chronic liver disese other thn chronic heptitis C, current or pst history of chronic disese (including severe psychitric or pulmonry disese), or history or evidence of cliniclly relevnt ophthlmologicl disorder (e.g. cytomeglovirus infection or mculr degenertion). Pregnnt or brest-feeding femles nd mle prtners of pregnnt femles were ineligible for the tril. Femle ptients of childbering potentil nd mle ptients with prtners of childbering potentil were required to use two forms of effective contrception during tretment nd fter the lst dose of ribvirin in ccordnce with the loclly pproved lbel for ribvirin.

3 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): Study design Ptients eligible for this phse 2 double-blind, ctive-controlled, prllel-group, interntionl tril were rndomized eqully (strtified by geogrphic region) to one of seven tretment groups (Figure 1). Ptients in six groups (A to F) were ssigned to receive orl blpirvir (s 500 mg tblets) t dosge of 500 mg, 1,000 mg, or 1,500 mg twice dily (bid) in combintion with subcutneous peginterferon lf-2 (40KD) (PEGASYS, Roche, Bsel, Switzerlnd) t dosge of 180 µg or 90 µg once weekly nd orl ribvirin (COPEGUS s 200 mg tblets, Roche, Bsel, Switzerlnd) t dosge of 1,000 mg/dy (body weight < 75 kg) or 1,200 mg/dy (body weight 75 kg). Ptients in groups A, B, D, E, nd F were to stop blpirvir t week 24 nd continue with peginterferon lf-2 (40KD) 180 µg/ week plus ribvirin 1,000/1,200 mg/dy for further 24 weeks to complete totl tretment durtion of 48 weeks. The durtion of tretment for ptients in group C ws bsed on the week 4 HCV RNA ssy result: those ptients with undetectble HCV RNA in serum (< 15 IU/mL) t week 4 nd who remined HCV RNA undetectble through week 22 were to stop ll tretment t week 24; those ptients who did not meet this criterion were to continue the three-drug combintion for further A n = 76 B n = 73 C n = 75 D n = 74 E n = 70 F n = 75 G n = b Study week Figure 1. Study design including the plnned number of ptients in ech tretment group. Therpy ws stopped t week 24 in ptients with n RVR in group C, provided tht their HCV RNA hd remined undetectble t ll visits through to week 22. b A protocol mendment on My 29, 2008 specified tht tretment with blpirvir ws to be stopped immeditely in ll ptients in group D, nd tht tretment with blpirvir ws to be stopped t week 12 rther thn week 24 in ll other tretment groups with corresponding increse in the length of tretment with peginterferon lf-2 (40KD) plus ribvirin from 24 to 36 weeks. Ptients tht hd completed more thn 12 weeks of tretment with blpirvir were required to stop blpirvir immeditely nd switch to peginterferon lf-2 (40KD) plus ribvirin to complete 48 weeks of tretment. Blpirvir ws given twice dily (bid). Peginterferon lf-2 (40KD) ws given once weekly. Ribvirin ws given t dosge of 1,000 mg/dy to ptients weighing < 75 kg nd 1,200 mg/dy to ptients weighing 75 kg. The dily dosge of ribvirin ws divided into two, ech hlf ws dministered bid with food. RVR: undetectble HCV RNA (< 15 IU/mL) in serum t week 4. P/R: Peginterferon lf-2 (40KD) 180 µg/week + ribvirin 1,000/1,200 mg/dy.

4 18 Nelson DR, et l., 2012; 11 (1): weeks to complete totl tretment durtion of 48 weeks. Ptients ssigned to the control group (G) received orl blpirvir plcebo (up to week 24) in combintion with peginterferon lf-2 (40KD) plus ribvirin for 48 weeks. Double-blinding of the dosge of blpirvir nd peginterferon lf-2 (40KD) ws mintined throughout the experimentl portion of the study (week 0-24). Blinding of the blpirvir dosge ws mintined by providing three bottles of tblets contining blpirvir or plcebo nd hving ptients tke one tblet from ech bottle bid (ptients in group G received only mtching plcebo tblets). Dose reductions were chieved by reducing the number of tblets dministered ccording to predefined lgorithm. Blinding of the dosge of peginterferon lf-2 (40KD) ws mintined by the dministrtion of similr initil volume of solution (1.0 ml) in ll ptients nd by chieving dose reductions through chnges in the volume dministered. Physicins were permitted to reduce the dosge of ny study drug in step-wise mnner in order to mnge lbortory bnormlities or dverse events. The dosge of blpirvir ws reduced in 500 mg/ dy (1 tblet) decrements. The dosge of peginterferon lf-2 (40KD) ws reduced in 0.25 ml/week decrements (i.e. from weekly dose of 180 µg to 135 µg, 90 µg, nd 45 µg weekly in ptients ssigned to 180 µg/week, nd from weekly dose of 90 µg to 68 µg, 45 µg, nd 23 µg weekly in ptients ssigned to 90 µg/week). The dosge of ribvirin ws reduced in 200 mg/dy (1 tblet) decrements. Investigtors were llowed to increse the dosge of study drug fter the resolution or n improvement of the precipitting event; however, in the cse of blpirvir, escltion to the full strting dose ws not recommended. Dose modifiction schedules for blpirvir nd peginterferon lf-2 (40KD) were included in the protocol for reductions in neutrophil counts, pltelet counts nd lymphocyte counts, nd for blpirvir nd ribvirin for reductions in the hemoglobin concentrtion. Tretment with blpirvir nd peginterferon lf-2 (40KD) ws withheld in the event of reduction in the neutrophil count to < 0.5 cells x 10 9 /L, or reduction in the pltelet count to < 25 cells x 10 9 /L. Tretment with blpirvir ws to be permnently discontinued in the event of reduction in the lymphocyte count to < 0.5 cells x 10 9 /L. Tretment with blpirvir nd ribvirin ws withheld in the event of reduction in the hemoglobin concentrtion to < 85g/L. Off-lbel use of erythropoietin-stimulting gents nd grnulocyte colony stimulting fctors to mnge hemtologicl dverse events or lbortory bnormlities ws neither recommended nor prohibited in the protocol. Protocol mendments The protocol ws mended for sfety resons on My 29, 2008 fter 516 ptients (100%) were enrolled. All ptients in group D stopped tretment with blpirvir nd switched to open-lbel tretment with peginterferon lf-2 (40KD) plus ribvirin. The plnned durtion of tretment with blpirvir (or blpirvir plcebo) ws decresed from 24 weeks to 12 weeks in ll other tretment groups. Ptients who hd completed 12 or more weeks of tretment with blpirvir in ny group were required to stop blpirvir nd switch to open-lbel tretment with peginterferon lf-2 (40KD) plus ribvirin. The plnned durtion of tretment (24 or 48 weeks in group C nd 48 weeks in ll other groups) ws unchnged nd ws to be chieved by extending the durtion of tretment with peginterferon lf-2 (40KD) plus ribvirin. The protocol ws subsequently mended on October 29, 2008 becuse of reports of persistent lymphopeni. All ptients were unblinded to their tretment ssignment nd, mong those who received blpirvir nd who hd CD4+ count < 200 cells/mm 3, tretment with peginterferon lf-2 (40KD) nd ribvirin ws permnently discontinued. Among those with CD4+ cell counts < 500 cells/mm 3 frequent monitoring for opportunistic infections ws required nd considertion of prophylctic tretment for opportunistic infections ws recommended. Study conduct The study ws conducted in ccordnce with the Declrtion of Helsinki nd the lws of the countries in which the study ws conducted. The protocol ws reviewed by institutionl review bords t study sites in the US nd by Independent Ethics Committees t study sites in the Europen Union/ Europen Economic Are. Ech ptient provided informed written consent prior to prticipting in the study ( NCT ). A dt monitoring committee conducted three scheduled interim sfety reviews fter pproximtely 175 ptients reched tretment weeks 4, 8, nd 12, nd dditionl d hoc reviews when ll ptients completed study weeks 12 nd 24.

5 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): Tble 1. Bseline chrcteristics of ptients receiving study drug into the seven tretment groups (A-G) in the current study. Blpirvir dose A B C D E F G (twice dily) 1,000 mg 500 mg 500 mg 1,500 mg 1,000 mg 500 mg Plcebo Peginterferon lf-2 dose 180 µg once weekly 90 µg once weekly 180 µg once weekly Ribvirin dose 1,000 or 1,200 mg/dy 1,000 or 1,200 mg/dy Durtion of tretment 48 weeks 48 weeks 24 or 48 weeks 48 weeks 48 weeks 48 weeks 48 weeks Ptients, n Mle sex, n (%) 44 (59) 42 (60) 42 (58) 43 (61) 47 (67) 45 (60) 48 (67) Men ge ± SD, yers 48.0 ± ± ± ± ± ± ± 10.6 Rce, n (%) White 69 (93) 65 (93) 69 (96) 61 (86) 63 (90) 65 (87) 63 (88) Africn rcil descent 3 (4) 1 (1) 1 (1) 6 (8) 2 (3) 7 (9) 5 (7) Other 2 (3) 4 (6) 2 (3) 4 (6) 5 (7) 3 (4) 4 (6) Men weight ± SD, kg 79.0 ± ± ± ± ± ± ± 15.8 Men BMI ± SD, kg/m ± ± ± ± ± ± ± 4.0 BMI 30 kg/m 2, n (%) 18 (24) 13 (19) 17 (24) 18 (25) 10 (14) 18 (24) 10 (14) Men ALT ± SD, U/L 65.5 ± ± ± ± ± ± ± 58.6 ALT quotient 3.0, n (%) 56 (75) 52 (74) 60 (83) 63 (89) 58 (83) 58 (77) 57 (79) HCV subtype,* n (%) 1 55 (74) 45 (64) 48 (67) 47 (66) 42 (61) 45 (60) 43 (60) 1b 18 (24) 25 (36) 21 (29) 24 (34) 26 (38) 28 (37) 29 (40) Men log 10 HCV RNA ± SD, IU/mL 6.3 ± ± ± ± ± ± ± 0.6 HCV RNA 400,000 IU/mL, n (%) 66 (89) 62 (89) 59 (82) 61 (86) 64 (91) 65 (87) 65 (90) Fibrosis score,* n (%) F (75) 58 (84) 51 (72) 57 (81) 56 (80) 62 (86) 59 (86) F (25) 11 (16) 20 (28) 13 (19) 14 (20) 10 (14) 10 (14) BMI: body-mss index. SD: stndrd devition. * Ptients with missing vlues were not included in clcultions of percentges.

6 20 Nelson DR, et l., 2012; 11 (1): Figure 2. Flow of ptients through the tril showing the ctul enrolment in ech tretment group. Twelve ptients were rndomized but did not receive study mediction becuse of violtion of entry criteri (n = 3), withdrwl of consent (n = 7) nd dministrtive or other resons (n = 2). The computerized rndomiztion list ws generted by the sponsor, mintined in centrl repository ccessible only to the rndomiztion list mngers, nd incorported in double-blind lbelling of mediction continers. Study site stff were required to cll n interctive voice response system nd enter ptient number t the time of rndomiztion; t week 24, study sites were to cll the interctive voice response system to receive specific instructions on whether to continue tretment with peginterferon lf-2 (40KD) plus ribvirin or to stop tretment. With the exception of ptients in group C, investigtors nd ptients remined blinded to ech individul ptient s tretment ssignment throughout the study. Endpoints HCV RNA ws determined t bseline nd t weeks 1, 2, 3, 4, 6, 8, 12, 18, 22, 24, 30, 36, 42, nd 48 during tretment nd t weeks 4, 12, nd 24 of untreted follow-up. The primry efficcy outcome of the tril ws sustined virologicl response (SVR), defined s undetectble HCV RNA (< 15 IU/mL) fter 24 weeks of untreted follow-up (study week 48 in ptients with n RVR in group C nd study week 72 in ll other ptients). The number of ptients with n RVR t week 4 nd complete erly virologicl response (complete EVR, undetectble

7 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): Week 2 Week 4 Week Virologic response (%) Group A B C D E F G n = Group A B C D E F G n = Group A B C D E F G n = Virologic response (%) Week 12 Week 24 Week Group A B C D E F G n = Group A B C D E F G n = Group A B C D E F G n = Figure 3. Virologicl response during tretment defined s undetectble HCV RNA (< 15 IU/mL). Percentges re shown t the top of ech br. Verticl brs show the upper limit of the 95% confidence intervl. Anlyses were conducted ccording to the intention-to-tret principle. HCV RNA) t week 12 were secondry outcomes. Ptients were required to stop tretment for insufficient therpeutic response if they did not hve n EVR fter 12 weeks of tretment, defined s undetectble HCV RNA in serum (< 15 IU/mL) or 2 log 10 drop in HCV RNA titer. Sttisticl considertions The plnned enrolment ws 490 ptients (70 per group). Men virologicl response rtes nd their corresponding 95% confidence intervls were clculted for ech visit for ech tretment group. No forml pir-wise sttisticl comprisons were specified in the protocol. All efficcy nlyses were conducted ccording to the intention to tret principle (ll rndomized ptients who received t lest one dose of study drug were included). RESULTS The first ptient ws enrolled on November 11, 2007 nd the lst ptient visit occurred on August 4, A totl of 516 ptients from 64 centers in Austrli, Cnd, Frnce, Germny, Itly, Spin nd the USA were rndomized, nd 504 received t lest one dose of study mediction. The mjority of rndomized ptients were mle (58 to 67%), White (86 to 96%) nd infected with

8 22 Nelson DR, et l., 2012; 11 (1): Sustined virologic response (%) Group A B C D E F G (n = 72) Figure 4. Sustined virologicl response defined s undetectble HCV RNA (< 15 IU/mL) in serum t the end of untreted follow-up. Verticl brs show the upper limit of the 95% confidence intervl. Anlyses were conducted ccording to the intention-to-tret principle. HCV genotype 1 (60 to 74%) (Tble 1). The men ge rnged from 45 to 48 yers, the men weight rnged from 77 kg to 79 kg nd the percentge of ptients with dvnced fibrosis on the pretretment liver biopsy rnged from 14 to 28% (Tble 1). The percentge of ptients of Africn rcil descent ws higher in groups D (8%), F (9%), nd G (7%) nd lower (rnge 1 to 4%) in the other tretment groups, while the percentge of ptients with dvnced fibrosis ws higher in groups A (25%) nd C (28%) nd lower (rnge 14 to 20%) in the other tretment groups (Tble 1). The flow of ptients through the study is shown in figure 2. Following recommendtion from the dt monitoring committee protocol mendment resulted in termintion of blpirvir tretment in ptients who hd received 12 or more weeks of tretment with the drug. Therefore, the most common reson for withdrwl from tretment with blpirvir is listed s dministrtive in figure 2. Efficcy Among ptients rndomized to plcebo plus peginterferon lf-2 (40KD) nd ribvirin, men reductions in serum HCV RNA concentrtion t week 2, 4, nd 12 were 1.4 log 10, 2.4 log 10, nd 3.7 log 10, respectively. Tretment with blpirvir produced dose-dependent reductions in serum HCV RNA levels, with the highest men reductions t week 2 (3.5 log 10 ), week 4 (4.2 log 10 ), nd week 12 (4.9 log 10 ) chieved in group A (blpirvir 1,000 mg bid plus peginterferon lf-2 [40KD] 180 µg/ week in combintion with ribvirin). At week 24 the reduction in HCV RNA level ws similr in ll tretment groups (rnge 4.0 log 10 to 4.7 log 10 ). HCV RNA concentrtion dt were unvilble for substntil proportion of ptients (> 20%) fter week 24. The percentge of ptients with undetectble HCV RNA ws consistently higher in ll blpirvir tretment groups compred with the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group t tretment week 2, 4, 8, nd 12; but ws similr in ll groups t tretment week 24 nd 48 (Figure 3). The SVR rte rnged from 32 to 50% cross the blpirvir tretment groups nd ws 43% in the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group (Figure 4). Sfety The percentge of ptients withdrwn from tretment with study drug for sfety resons ws higher in ptients rndomized to the blpirvir groups thn in the plcebo group. Among those rndomized to groups A F, tretment with blpirvir ws withdrwn for sfety resons in 27 to 36% of ptients, tretment with peginterferon lf-2 (40KD) ws withdrwn for sfety resons in 22 to 43% of p-

9 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): tients, nd tretment with ribvirin ws withdrwn for sfety resons in 22 to 45% of ptients. In contrst, mong those rndomized to group G (plcebo plus peginterferon lf-2 (40KD) nd ribvirin), plcebo ws withdrwn for sfety resons in 5% of ptients, tretment with peginterferon lf-2 (40KD) ws withdrwn for sfety resons in 8% of ptients, nd tretment with ribvirin ws withdrwn for sfety resons in 8% of ptients. Among the blpirvir tretment groups, the number of serious dverse events nd the percentge of ptients with serious dverse events incresed with the dose of blpirvir nd ws highest in groups A (blpirvir 1,000 mg bid plus peginterferon lf-2 [40KD] 180 µg/week in combintion with ribvirin), D (blpirvir 1,500 mg bid plus peginterferon lf-2 [40KD] 90 µg/week in combintion with ribvirin) nd E (blpirvir 1,000 mg bid plus peginterferon lf-2 [40KD] 90 µg/week in combintion with ribvirin) (Tble 2). Serious hemtologicl dverse events nd serious infections were more frequent in group A (5 nd 5%, respectively) nd group D (4 nd 6% respectively) thn in ll other tretment groups in which the incidence of serious hemtologicl dverse events nd infections rnged from 0 to 3% (Tble 2). Neutropeni nd lymphopeni were observed during the study. Lymphopeni resolved in most ptients fter ll study mediction ws stopped, but some ptients remined lymphopenic more thn 1 yer fter the end of tretment. Serious oculr dverse events were reported in five ptients (7%) in group D nd in three ptients (4%) in group E (Tble 2). The nture of these events ws diverse nd included optic neuropthy in two ptients, nd trnsient blindness, mculopthy, toxic optic neuropthy, reduced visul cuity, nd optic neuritis in one ptient ech. All but one of these events ws reported fter more thn 12 weeks of therpy (rnge: dy 36 to 114 of tretment), ll of these ptients discontinued study mediction, nd six of eight events resolved during untreted follow-up. One ptient hs reported improvement nd is still being followed (the remining ptient ws lost to follow-up). Four deths were reported during tretment nd follow-up. Three deths were in blpirvir plus peginterferon lf-2 (40KD) plus ribvirin combintion tretment groups nd were ttributed to fulminnt disseminted vricell possibly relted to study mediction (group D), crdic rrest unrelted to study mediction in ptient with lymphom (group C), nd suicide possibly relted to study mediction (group C). One deth in the peginterferon lf-2 Tble 2. Adverse events, lbortory bnormlities nd discontinutions. A B C D E F G Blpirvir dose (twice dily) 1,000 mg 500 mg 500 mg 1,500 mg 1,000 mg 500 mg Plcebo Peginterferon lf-2 (40KD) dose 180 µg once weekly 90 µg once weekly 180 µg once weekly Ribvirin dose 1,000 or 1,200 mg/dy 1,000 or 1,200 mg/dy Durtion of tretment or weeks weeks weeks weeks weeks weeks weeks Ptients, n Serious dverse events, n Ptients with 1 serious dverse events, n (%) 15 (20) 3 (4) 4 (6) 12 (17) 9 (13) 3 (4) 8 (11)

10 24 Nelson DR, et l., 2012; 11 (1): Ptients with serious dverse events,* n (%) Hemtologicl 4 (5) 2 (3) 0 3 (4) 1 (1) 0 0 Infections 4 (5) (6) 1 (1) 1 (1) 2 (3) Eye disorders (7) 3 (4) 0 0 Deths (3) 1 (<1) (<1) Ptients with dverse events, n (%) Ftigue 41 (55) 37 (53) 46 (64) 34 (48) 34 (49) 39 (52) 43 (60) Hedche 44 (59) 34 (49) 43 (60) 42 (59) 37 (53) 41 (55) 42 (58) Nuse 27 (36) 26 (37) 35 (49) 28 (39) 23 (33) 23 (31) 25 (35) Insomni 35 (47) 30 (43) 25 (35) 32 (45) 24 (34) 28 (37) 24 (33) Mylgi 28 (38) 28 (40) 22 (31) 23 (32) 26 (37) 29 (39) 33 (46) Lymphopeni 33 (45) 23 (33) 21 (29) 21 (30) 29 (41) 33 (44) 2 (3) Chills 24 (32) 26 (37) 29 (40) 17 (24) 22 (31) 20 (27) 30 (42) Pruritus 10 (14) 12 (17) 20 (28) 17 (24) 26 (37) 23 (31) 15 (21) Pyrexi 20 (27) 20 (29) 25 (35) 17 (24) 15 (21) 20 (27) 19 (26) Dirrhe 22 (30) 20 (29) 15 (21) 24 (34) 16 (23) 18 (24) 16 (22) Arthrlgi 23 (31) 17 (24) 16 (22) 19 (27) 12 (17) 13 (17) 16 (22) Irritbility 13 (18) 12 (17) 19 (26) 12 (17) 12 (17) 18 (24) 21 (29) Dizziness 13 (18) 6 (9) 21 (29) 17 (24) 13 (19) 12 (16) 15 (21) Rsh 11 (15) 13 (19) 21 (29) 15 (21) 14 (20) 16 (21) 13 (18) Alopeci 13 (18) 11 (16) 20 (28) 19 (27) 8 (11) 17 (23) 11 (15) Depression 18 (24) 7 (10) 18 (25) 15 (21) 15 (21) 17 (23) 17 (24) Cough 17 (23) 15 (21) 17 (24) 13 (18) 11 (16) 13 (17) 11 (15) Dry skin 7 (9) 6 (9) 17 (24) 9 (13) 8 (11) 13 (17) 16 (22) Anemi 9 (12) 11 (16) 8 (11) 17 (24) 7 (10) 5 (7) 6 (8) Neutropeni 4 (5) 4 (6) 6 (8) 16 (23) 7 (10) 4 (5) 3 (4) Anorexi 8 (11) 10 (14) 15 (21) 8 (11) 11 (16) 10 (13) 6 (8) Dose modifictions For dverse events, n (%) ) Blpirvir 9 (12) 5 (7) 6 (8) 14 (20) 9 (13) 3 (4) Not pplicble b) Peginterferon lf-2 (40KD) 9 (12) 6 (9) 5 (7) 12 (17) 8 (11) 7 (9) 12 (17) c) Ribvirin 12 (16) 8 (11) 14 (19) 19 (27) 13 (19) 9 (12) 18 (25) For lb bnormlities, n (%) ) Blpirvir 53 (72) 42 (60) 42 (58) 57 (80) 45 (64) 39 (52) Not pplicble b) Peginterferon lf-2 (40KD) 61 (82) 59 (84) 47 (65) 68 (96) 55 (79) 53 (71) 50 (69) c) Ribvirin 31 (42) 24 (34) 20 (28) 39 (55) 27 (39) 30 (40) 15 (21) Withdrwl from tretment For dverse events, n (%) ) Blpirvir 3 (4) 2 (3) 2 (3) 9 (12) 4 (6) 0 0 b) Peginterferon lf-2 (40KD) 8 (11) 3 (4) 10 (13) 9 (12) 10 (14) 2 (3) 5 (7) c) Ribvirin 9 (12) 3 (4) 10 (13) 9 (12) 10 (14) 2 (3) 5 (7)

11 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): For lb bnormlities, n (%) ) Blpirvir 24 (32) 18 (25) 18 (24) 15 (20) 21 (30) 25 (33) 4 (5) b) Peginterferon lf-2 (40KD) 25 (33) 13 (18) 9 (12) 14 (19) 18 (26) 23 (31) 1 (1) c) Ribvirin 25 (33) 13 (18) 6 (8) 14 (19) 18 (26) 23 (31) 1 (1) Mximum men decrese from bseline (week of ndir) White blood cells, x 10 9 cells/l -4.3 (wk 12) -3.8 (wk 12) -4.0 (wk 12) -4.0 (wk 4) -4.3 (wk 4) -3.9 (wk 42) -3.5 (wk 30) Neutrophils, x 10 9 cells/l (wk 4) -2.40(wk 4) (wk 4) (wk 4) (wk 4) (wk 8) (wk 8) Lymphocytes, x 10 9 cells/l (wk 12) (wk 42) (wk 12) (wk 12) (wk 42) (wk 48) (wk 48) Pltelets, x 10 9 cells/l -94 (wk 3) -75 (wk 12) -76 (wk 18) -97 (wk 3) -82 (wk 3) -70 (wk 42) -64 (wk 12) Red blood cells, x cells/l (wk 12) (wk 18) (wk 24) (wk 30) (wk 30) (wk 30) (wk 36) Hemoglobin, g/l -37 (wk 6) -37 (wk 18) -36 (wk 24) -37 (wk 4) -38 (wk 30) -42 (wk 30) -35 (wk 24) Ptients with hemtologicl bnormlities, n (%) White blood cells, x 10 9 cells/l ) 1.0 to < (70) 44 (63) 38 (53) 42 (59) 39 (56) 43 (57) 23 (32) b) < (1) (8) 2 (3) 1 (1) 0 Neutrophils, x 10 9 cells/l ) 0.5 to < (34) 18 (26) 24 (33) 22 (31) 16 (23) 25 (33) 18 (25) b) < (18) 8 (11) 4 (6) 25 (35) 6 (9) 4 (5) 1 (1) Lymphocytes, x 10 9 cells/l ) 0.2 to < (47) 33 (47) 35 (49) 37 (52) 29 (41) 36 (48) 18 (25) b) < (28) 8 (11) 7 (10) 16 (23) 25 (36) 16 (21) 1 (1) Pltelets, x 10 9 cells/l ) 20 to < 50 8 (11) 5 (7) 1 (1) 14 (20) 1 (1) 6 (8) 3 (4) b) < 20 2 (3) (3) 2 (3) 0 0 Hemoglobin, g/l ) 85 to < (14) 19 (27) 14 (19) 21 (30) 18 (26) 19 (25) 16 (22) b) < 85 7 (9) 2 (3) 4 (6) 11 (15) 1 (1) 3 (4) 2 (3) Red blood cells < 3.2 x /L 33 (45) 38 (54) 30 (42) 41 (58) 31 (44) 33 (44) 26 (36) Hemtocrit < (16) 9 (13) 12 (17) 19 (27) 10 (14) 12 (16) 7 (10) Ptients receiving interventions to mnge hemtologicl bnormlities, n (%) Blood trnsfusions 4 (5) 2 (3) 2 (3) 2 (3) 1 (1) 0 1 (1) Erythropoietin-stimulting gents 5 (7) 8 (11) 6 (8) 14 (20) 6 (9) 4 (5) 3 (4) Colony stimulting fctors 4 (5) 4 (6) 5 (7) 16 (23) 8 (11) 4 (5) 3 (4) *Serious dverse events occurring in t lest 5% of ptients in t lest one tretment group. One deth ws ttributed to crdic rrest unrelted to tretment in the opinion of the investigtor in ptient with metsttic lymphom in whom progression of lymphom ws considered to be possibly relted to tretment; the second ptient deth ws ttributed to suicide (possibly relted to tretment). The deth ws ttributed to primry fulminnt disseminted vricell infection (possibly relted to tretment). The deth ws ttributed to rod trffic ccident (unrelted to tretment). Adverse events occurring in t lest 20% of ptients in t lest one tretment group.

12 26 Nelson DR, et l., 2012; 11 (1): (40KD) plus ribvirin control group ws ttributed to rod trffic ccident unrelted to study mediction (group G). Of note, the progression of disese in the ptient with lymphom in group C ws clssified s possibly relted to study drug. It ws considered likely tht the lymphom hd been present but undetected prior to study strt, bsed on the dvnced stge of the cncer t dignosis. The most common dverse events were ftigue (rnge 48 to 64%), hedche (49 to 60%), nuse (31 to 49%), insomni (33 to 47%), nd mylgi (31 to 46%), which occurred with similr frequency cross the seven tretment groups (Tble 2). Lymphopeni ws frequently reported dverse event in recipients of blpirvir (rnge 29 to 45%), but not in recipients of plcebo (3%). Ptients in group D lso hd considerbly higher dverse event rtes for nemi (24%) nd neutropeni (23%) compred with ll other tretment groups (Tble 2). Dose modifictions of ll three study drugs were more commonly ttributed to lbortory bnormlities thn dverse events in ll tretment groups (Tble 2). Blpirvir dose modifictions for dverse events nd lbortory bnormlities were most common in the highest dosge groups: A, D, nd E. Peginterferon lf-2 (40KD) nd ribvirin dose modifictions for lbortory bnormlities were lso more common in these three tretment groups. The mximum men decrese from bseline in white blood cell count, lymphocyte count, neutrophil count, pltelet count, red blood cell count, nd hemoglobin concentrtion were generlly greter in ll blpirvir tretment groups thn in the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group (Tble 2). The time course of hemtologicl prmeters is shown in figure 5. The ndir in hemtologicl prmeters generlly occurred erlier nd ws greter in ll blpirvir tretment groups, with the exception of group F, thn in the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group. The ndir in white blood cell count occurred between weeks 4 nd 12 in groups A to E compred with week 30 with the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group, the ndir in neutrophil count occurred t week 4 in groups A to E nd t week 18 with plcebo plus peginterferon lf-2 (40KD) nd ribvirin, nd the ndir in pltelet count occurred t week 3 in groups A to E compred with week 12 with plcebo plus peginterferon lf-2 (40KD) nd ribvirin. The lowest ndir for ech of these prmeters ws observed in group D. Lymphocyte count declined mrkedly during the first 12 weeks of tretment nd reched ndir between weeks 12 nd 24 in ll blpirvir tretment groups. In contrst, the lymphocyte decline ws less mrked with plcebo plus peginterferon lf-2 (40KD) nd ribvirin nd did not rech ndir until week 30. Lymphocyte count hd not returned to bseline by week 60 in ny group, including plcebo plus peginterferon lf- 2 (40KD) nd ribvirin. The red blood cell count nd hemoglobin concentrtion declined rpidly during the first 4 weeks nd then slowly therefter to week 30 in ll tretment groups with the exception of the RVR-guided tretment group C. The highest incidence of specific lbortory bnormlities tended to occur in the highest blpirvir dose, i.e. group D (Tble 2). The percentge of ptients with grde 4 leucopeni (white blood cell count < 1.0 x 10 9 /L), grde 3 or 4 lymphopeni (lymphocyte count < 0.5 x 10 9 /L), grde 4 neutropeni (neutrophil count < 0.5 x 10 9 /L), red blood cell count < 3.2 x /L, nd hemtocrit < 0.3 were higher in ll blpirvir tretment groups thn in the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group. The percentge of ptients with grde 4 thrombocytopeni (pltelet count < 20 x 10 9 /L) nd hemoglobin concentrtion < 85 g/l were higher in group A nd D thn in the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group. Of note, the incidence of grde 4 lymphopeni (lymphocyte count < 0.2 x 10 9 /L) ws higher in ll blpirvir tretment groups (rnge 10 to 36%) thn in the plcebo plus peginterferon lf-2 (40KD) nd ribvirin group (1%). DISCUSSION The results of this tril demonstrte tht the ddition of blpirvir (RG1626) to peginterferon lf-2 (40KD) plus ribvirin increses the rte nd extent of the decrese in HCV RNA levels in ptients with chronic heptitis C genotype 1 infection. The decrese in HCV RNA levels ws dose dependent, nd higher percentge of ptients treted with blpirvir chieved n RVR t week 4 nd complete EVR t week 12 compred with peginterferon lf-2 (40KD) plus ribvirin lone. However, the ssessment of efficcy t lter time points ws hmpered by the high rte of sfety-relted dose modifictions nd discontinutions tht ffected ll three study drugs nd ws generlly ssocited with temporry virl lod rebounds during tretment. Subsequently, the higher rtes of virl clernce observed during tretment were not mintined during untreted follow-up nd there ws no overll difference in SVR rtes in the blpirvir combintion tretment

13 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): Figure 5. Men hemtologicl prmeters during tretment nd follow-up. A. White blood cells. B. Neutrophils. C. Pltelets. D. Lymphocytes. E. Red blood cells. F. Hemoglobin. is somewht lower thn tht chieved with this combintion in genotype 1 ptients enrolled in phse 3 registrtion studies (46 to 52%), 8,9 but flls within the rnge reported in other recent rndomized stugroups compred with plcebo plus peginterferon lf-2 (40KD) plus ribvirin. The finl SVR rte of 43% chieved with peginterferon lf-2 (40KD) plus ribvirin lone in the tril

14 28 Nelson DR, et l., 2012; 11 (1): dies in tretment-nive genotype 1 ptients (41 to 55%) Tretment with blpirvir ws not well tolerted nd unexpected dverse events were observed in the present study. Hemtologicl dverse events were nticipted nd the protocol included severl mesures to mitigte ginst the incidence nd severity of these events. The tril included two reduced dosge levels of peginterferon lf-2 (40KD), nd the highest dosge of blpirvir ws dministered with the lower dosge of peginterferon lf-2 (40KD). Ptients were monitored frequently nd dose reduction protocols were provided for ll study drugs. Despite these precutions high proportion of ptients treted with blpirvir developed nemi, neutropeni, lymphopeni, nd thrombocytopeni, nd study drug tretment ws discontinued in lrge number of these individuls becuse of lbortory bnormlities. In two of the highest blpirvir dosge groups (blpirvir 1,000 mg bid plus peginterferon lf-2 [40KD] 180 µg/week nd ribvirin; blpirvir 1,500 mg bid plus peginterferon lf-2 [40KD] 90 µg/week nd ribvirin), serious infections were reported in 5 to 6% of ptients nd one ptient died from disseminted vricell infection. The occurrence of lte-onset serious oculr events in smll number of recipients of blpirvir ws unexpected. The nture of these oculr events ws diverse, nd vilble dt suggest tht they re reversible. The mechnism tht led to these events is under investigtion. Previous humn studies of blpirvir include dose escltion tril in which single doses s high s 12,000 mg were well tolerted in helthy volunteers, dy tril of blpirvir monotherpy in ptients with chronic heptitis C t dosges of 500 mg to 4,500 mg bid, 6 nd 28-dy tril in which blpirvir ws dministered to ptients with chronic heptitis C t dosge of 1,500 mg bid or 3,000 mg bid in combintion with peginterferon lf-2 (40KD) 180 µg/week or t dosge of 1,500 mg bid in combintion with peginterferon lf-2 (40KD) plus ribvirin. 7 In the 14-dy monotherpy study no ptients were withdrwn due to dverse events, nd lthough dose-relted hemtologicl bnormlities were detected, they were described s being mild to moderte in severity. 6 Hemtologicl bnormlities were reported when blpirvir ws dministered in combintion with peginterferon lf-2 (40KD) with or without ribvirin in the 28-dy study. 7 The most common lbortory bnormlities in the tril were neutropeni nd nemi, while lymphopeni ws comprtively rre. Lbortory bnormlities were dose relted nd resolved fter the end of tretment with blpirvir, nd the rte of infections ws similr in ptients with mild or severe neutropeni. On the bsis of preclinicl toxicity testing, the severity of hemtologicl toxicity ssocited with longer-term dministrtion of blpirvir in combintion with peginterferon lf-2 (40KD) nd ribvirin in ptients with chronic heptitis C ws unexpected. Blpirvir ws well tolerted t doses up to 3,000 mg/kg/dy (highest dose tested) for 3 months in mice, up to 2,000 mg/kg/dy (highest dose tested) in rts for 6 months nd up to 1,500 mg/kg/dy (highest dose tested) for 9 months in femle dogs. These studies hd not identified ny trget orgn toxicity. 16 In vitro studies in humn primry cells demonstrted mesurble inhibition of bone mrrow stem cell differentition with low intrinsic cytotoxicity. Bone mrrow stem cell differentition into erythroid precursor cells ws more sensitive to inhibition by blpirvir thn ws differentition into myeloid or megkryocytic lineges. Inhibition of erythroid differentition by blpirvir ws more thn 80-fold less potent thn tht occurring with the comprtor nucleoside nlogue zidovudine. 16 Consistent with the in vitro nlysis, the most obvious dose-dependent hemtologicl effect of blpirvir in ptients treted with monotherpy ws reduction in hemoglobin concentrtion nd erythrocyte counts tht ws reversible upon discontinution, consistent with inhibition of precursor differentition. 6 The mechnism responsible for the hemtologicl toxicity ssocited with blpirvir when dministered in combintion with peginterferon lf-2 (40KD) nd ribvirin is currently unknown, lthough it ppers tht this combintion my hve excerbted direct nd brod-bsed suppressive effect of blpirvir on bone mrrow nd lso resulted in n uncompensted reduction in lymphocytes. The hemtologicl toxicity of blpirvir does not pper to be clss effect of HCV nucleoside polymerse inhibitors. Vlopicitbine (NM283) ws not ssocited with mrked hemtologicl dverse events when combined with peginterferon plus ribvirin; however, clinicl development of this gent ws hlted becuse of severe gstrointestinl dverse events. 17 Mericitbine (RG7128) is nother nucleoside polymerse inhibitor currently being investigted in phse 2b study to evlute its sfety nd efficcy in triple combintion therpy (500 mg or 1,000 mg bid with peginterferon lf-2 [40KD] plus ribvirin) in HCV genotype 1 nd 4 tretment-nive p-

15 Blpirvir plus peginterferon lf-2 (40KD)/ribvirin in heptitis C., 2012; 11 (1): tients. A preliminry nlysis of 12 weeks sfety dt from 408 ptients enrolled in this study hs confirmed tht mericitbine hs promising sfety profile with no significnt unexpected toxicities. 18 To dte no hemtologicl, renl, gstrointestinl, dermtologicl, or other orgn system events different thn those expected with peginterferon lf-2 (40KD) plus ribvirin hve been detected. Mericitbine hs lso been investigted in combintion with n HCV protese inhibitor (dnoprevir) in the proof of concept study of dul interferonfree regimen for chronic heptitis C (INFORM-1). 19 The ll orl direct cting ntivirl regimen ws effective nd well tolerted in this study, in which 88 ptients were treted for up to 13 dys with mericitbine/dnoprevir. No ptient discontinued therpy becuse of dverse events, no tretment-relted serious or severe dverse effects were reported nd no grde 3 or 4 lbortory bnormlities were detected. 19 Further development of blpirvir in combintion with peginterferon lf-2 (40KD) nd ribvirin for the tretment of chronic heptitis C hs been hlted becuse of the uncceptble sfety profile reveled in this study. However, non-clinicl studies re ongoing in n effort to identify the mechnism responsible for the hemtologicl nd oculr toxicities ssocited with the dministrtion of blpirvir. Longer-term experience with other investigtionl nucleoside polymerse inhibitors is currently lcking nd close monitoring of sfety in ongoing studies is wrrnted. ABBREVIATIONS bid. Twice dily. HCV. Heptitis C. RVR. Rpid virologicl response. SVR. Sustined virologicl response. ACKNOWLEDGEMENTS This work ws supported in prt by the NIH/ NCRR Clinicl nd Trnsltionl Science Awrd to the University of Florid UL1 RR The institutions nd principl investigtors who prticipted in this study re s follows: Austrli: D. Crwford: Greenslopes Privte Hospitl, Greenslopes. J. George: Westmed Hospitl, Westmed. S. Roberts: The Alfred Hospitl, Melbourne. D. Shw: Royl Adelide Hospitl, Adelide. S. Strsser: Westmed Hospitl, Westmed. Austri: P. Ferenci: AKH Wien Innere Medizin III, Wein. Cnd: F. Anderson: Liver nd Intestinl Reserch Centre, Vncouver. C. Cooper: The Ottw Hospitl, Ottw. J. Hethcote: Toronto Western Hospitl, Toronto. S. Lee: Heritge Medicl Reserch Clinic, Clgry. M. Shermn: Toronto Generl Hospitl, Toronto. E. Yoshid: The Gordon nd Leslie Dimond Centre, Vncouver. Frnce: M. Bourlière: Hôpitl Sint-Joseph, Mrseille. N. Boyer: Hôpitl Beujon, Clichy. J. Bronowicki: Hôpitl de Brbois Adultes, Nncy. C. Hezode: Hôpitl Henri Mondor, Créteil. V. Ledinghen: Hôpitl Hut-Lévêque, Pessc. P. Mrcellin: Hôpitl Beujon, Clichy. S. Pol.: Hôpitl Cochin, Pris. Germny: T. Berg: Universitätsmedizin Berlin, Berlin. P. Buggisch: I. Medizinische Klinik und Poliklinik, Hmburg. A. Lohse: I. Medizinische Klinik und Poliklinik, Hmburg. T. Goeser: Klinikum der Universität zu Köln, Köln. M. Mnns: Medizinische Hochschule, Hnnover. J. Rsenck: Medizinische Universitätsklinik Freiburg, Freiburg. S. Zeuzem: Klinikum der Johnn Wolfgng Goethe Universität, Frnkfurt. Itly: P. Andreone: Diprtimento Mlttie Apprto Digerente e Medicin Intern, Bologn. A. Ascione: Struttur Compless di Gstroenterologi ed Eptologi, Milno. F. Lmpsi: Struttur Compless di Gstroenterologi ed Eptologi, Milno. M. Rizzetto: Università di Torino, Torino.

16 30 Nelson DR, et l., 2012; 11 (1): Spin: M. Digo-Mdrid: Hospitl Generl Universitrio de Vlenci, Vlenci. J. Luis-Cllej: Hospitl Puert de Hierro, Mdrid. R, Plns-Vil: Hospitl Universitrio Germns Tris i Pujol, Brcelon. M. Romero-Gómez: Hospitl Nuestr Señor de Vlme, Seville. R. Sol-Lmogli: Hospitl del Mr, Brcelon. United Sttes: D. Bernstein: North Shore-Long Islnd Helth System, Mnhsset. T. Box: Mountin West Gstroenterology, Uth. N. Bräu: Bronx VA Medicl Center, New York. N. Bzowej: Cliforni Pcific Medicl Center, Cliforni. G. Everson: University of Colordo Denver, Colordo. M. Fried: Univ. of North Crolin t Chpel Hill, North Crolin. R. Ghlib: The Liver Institute t Methodist Hospitl, Texs. E. Godofsky: University Heptitis Center t Bch & Godofsky, Florid. S. Hrrison: Brooke Army Medicl Center, Texs. T. Hssnein: University of Cliforni Sn Diego Medicl Center, Sn Diego. R. Herring: Nshville Gstrointestinl Specilists, Inc., Nshville. I. Jcobson: Weill Medicl College of Cornell University, New York. D. Jensen: University of Chicgo, Chicgo. M. Kugelms: South Denver Gstroenterology, Denver. E. Lwitz: Almo Medicl Reserch, Sn Antonio. T. Morgn: VA Long Bech Helthcre System, Long Bech. D. Nelson: University of Florid Heptology, Florid. L. Nyberg: Kiser Permnente, Sn Diego. C. O Brien: University of Mimi, Mimi. P. Pockros: Scripps Clinic, Sn Diego. M. Rodríguez-Torres: Fundción de Investigción de Diego, Sn Jun. L. Rossro: University of Cliforni, Scrmento. V. Rustgi: Metropolitn Reserch, Firfx. T. Sepe: University Gstroenterology, Rhode Islnd. M. Shiffmn: McGuire DVAMC, Virgini. K. Shermn: University of Cincinnti College of Medicine, Cincinnti. C. Smith: Minesot Gstroenterology, Minesot. J. Smith: Penn Stte Milton S. Hershey Medicl Center, Hershey. M. Sulkowski: Johns Hopkins University, Mrylnd. A. Sunyl: McGuire DVAMC, Virgini. I. Thomson: Mountin West Gstroenterology, Uth. H. Vrgs: Myo Clinic Arizon, Arizon. A. Zmn: Oregn Helth nd Science University, Oregn. REFERENCES 1. Wsley A, Alter MJ. Epidemiology of heptitis C: geogrphic differences nd temporl trends. Semin Liver Dis 2000; 20: Kim WR. The burden of heptitis C in the United Sttes. Heptology 2002; 36: S30-S Ghny MG, Strder DB, Thoms DL, Seeff LB. Dignosis, mngement, nd tretment of heptitis C: n updte. Heptology 2009; 49: Klumpp K, Leveque V, Le Pogm S, M H, Jing W-R, Kng H, Grnycome C, et l. The novel nucleoside nlog R1479 (4 -zidocytidine) is potent inhibitor of NS5B-dependent RNA synthesis nd heptitis C virus repliction in cell culture. J Biol Chem 2006; 281: Brndl M, Wu X, Holper M, Hong L, Ji Z, Birudrj R, Reddy M, et l. Physicochemicl properties of the nucleoside prodrug R1626 leding to high orl biovilbility. J Biol Chem 2008; 48: Roberts SK, Cooksley G, Dore GJ, Robson R, Shw D, Berns H, Hill G, et l. Robust ntivirl ctivity of R1626, novel nucleoside nlog: rndomized, plcebo-controlled study in ptients with chronic heptitis C. Heptology 2008; 48: Pockros PJ, Nelson D, Godofksy E, Rodríguez-Torres M, Everson GT, Fried MW, Ghlib R, et l. R1626 plus peginterferon Alf-2 provides potent suppression of heptitis C virus RNA nd significnt ntivirl synergy in combintion with ribvirin. Heptology 2008; 48: Fried MW, Shiffmn ML, Reddy KR, Smith C, Mrinos G, Goncles FL Jr., Hussinger D, et l. Peginterferon lf-2 plus ribvirin for chronic heptitis C virus infection. N Engl J Med 2002; 347: Hdziynnis SJ, Sette H Jr., Morgn TR, Bln V, Digo M, Mrcellin P, Rmdori G, et l. Peginterferon-lph2 nd ribvirin combintion therpy in chronic heptitis C: rndomized study of tretment durtion nd ribvirin dose. Ann Intern Med 2004; 140: Ascione A, De Luc M, Trtglione MT, Lmpsi F, Di Costnzo GG, Lnz AG, Picciotto FP, et l. Peginterferon lf-2 plus ribvirin is more effective thn peginterferon lf-2b plus ribvirin for treting chronic heptitis C virus infection. Gstroenterology 2010; 138: Ferenci P, Lferl H, Scherzer TM, Mieron A, Hofer H, Stuber R, Gschwntler M, et l. Peginterferon lf-2/ribvirin for 48 or 72 weeks in heptitis C genotypes 1 nd

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