PENG Qin, TANG Shao-hui *, SHI Heng

504 2016 6 1 41 6 Meta [ ] (CHC) PubMed EMBASE The Cochrane Central Register of Controlled Trials CNKI CHC (RCTs) 2015 10 1 RevMan 5.3 Meta 6 RCT 1100 Meta(RVR) (cevr) (SVR 24 ) (P 0.0001) (60mg/d) RVR cevr SVR 24 (P 0.0001) (10mg/d) RVR cevr (P 0.05) SVR 24 (P=0.65) (P 0.05) CHC 60mg/d CHC 10mg/d [ ] Meta [ ] R512.63 [ ] A [ ] 0577-7402(2016)06-0504-08 [DOI] 10.11855/j.issn.0577-7402.2016.06.14 PENG Qin, TANG Shao-hui *, SHI Heng Department of Gastroenterology, First Affiliated Hospital of Jinan University, Guangzhou 510630, China * Corresponding author, E-mail: tangshaohui205@163.com [Abstract] Objective To evaluate the efficacy and safety of daclatasvir in treatment of chronic hepatitis C (CHC). Methods Articles regarding treatment and safety of CHC were retrieved from PubMed, EMBASE, The Cochrane Central Register of Controlled Trials, Chinese Journals Full-text Database (CNKI, China National Knowledge Infrastructure), and WanFang Digital Journal Full-text Database to collect clinical RCTs (randomized controlled trials) for CHC treated by daclatasvir. Meta-analysis was performed by using Review Manager 5.3. Results A total of six RCTs including 1100 patients met the inclusion criteria. Metaanalysis results were as follows. 1) The overall RVR (rapid virological response), cevr (complete early virological response) and SVR 24 (sustained virological response at post-treatment week 24) rates were significantly higher in daclatasvir group than in control group. 2) The RVR, cevr, and SVR 24 rates were significantly higher in daclatasvir (60mg/d) group than in control group. 3) The RVR and cevr rates were significantly higher in daclatasvir (10mg/d) group than in control group, but no significant difference existedbetweenthetwogroupsinthesvr 24 rate. 4) No significant differences were found in nonspecific adverse events, liver function, hematologic system or skin between daclatasvir and control groups. Conclusion Daclatasviriseffectiveandsafein treatment of CHC, and daclatasvir 60mg/d is a better choice as compared with daclatasvir 10mg/d. [Key words] hepatitis C, chronic; daclatasvir; randomized controlled trials; Meta-analysis 1.7 (hepatitis C virus HCV) [1] 15% HCV (CHC) 20% CHC 5%~7% [2] CHC [ ] [ ] 510630 ( ) [ ] E-mail: tangshaohui205@163.com HCV [3-4] NS3/4A NS5A NS5B NS3 [5] (daclatasvir DCV) HCV NS5A [5] 2011 Nettles [6] CHC CHC

Med J Chin PLA, Vol. 41, No. 6, June 1, 2016 505 1 1.1 PubMed EMBASE The Cochrane Central Register of Controlled Trials CNKI 2015 10 1 daclatasvir randomized controlled trial chronic hepatitis C 1.2 RCT 18~70 >6 -HCV HCV-RNA 105U/ml ALT> 2 CHC Jadad 3 RCT Jadad <3 RCT 1.3 ( ) ( HCV-RNA ) ( ) 1.4 Jadad [7] ( ) 1 3 <3 1.5 Review Manager 5.3 Meta I 2 50% P 0.05 I 2 50% P 0.05 [8] (relative risk RR) 95% (confidence interval CI) P<0.05 1.6 (funnel plot) 2 2.1 147 6 [9-14] ( 1) Ratziu [14] 419 5 [9-13] 681 ( 1) 2.2 Jadad 4~5 ( 2) Literature databases: PUBMED, COCHRANE, EMBASE, WANFANG and CNKI Search fields: Title, abstract, key words Years: All years Limits: Randomized controlled trial Searching strings: (daclatasvir); (BMS-790052) AND (HCV); (hepatitis C); (hepatitis C virus); (HCV infection) Total number of unique hits: n=147 Article selected based on titles Included: n=12 Excluded: n=135 Reason: Relevant information not reported irrelevant study topic Article selected based on full papers Included: n=6 Excluded: n=6 Reason: Relevant information not reported Total=6 1 Meta Fig.1 Search strategy of information related to meta-analysis

506 2016 6 1 41 6 Trial Hézode, et al [9] 2015 (n=395) Dore, et al [10] 2015 (n=151) Suzuki, et al [11] 2014 (n=45) Izumi, et al [12] 2014 (n=42) Pol, et al [13] 2012 (n=48) Median age (range) Gender (male,%) 1 Tab.1 Basic data of the included studies HCV-RNA (median, log10) Genotype Type of treatment and dose Treatment duration (week) RVR cevr SVR 24 51(22-70) 67.3 6.5 G1a,275/395 D(20mg/d)+P(180 g/w)+r(1.0-1.2g/d) 24 91/159 123/159 95/159 50(18-67) 65.2 6.5 G1b,88/395 D(60mg/d)+P(180 g/w)+r(1.0-1.2g/d) 24 87/158 122/158 99/158 51(25-66) 70.5 6.4 G4,31/395 PBO+P(180 g/w)+r(1.0-1.2g/d) 24 11/78 34/78 30/78 52(28-64) 54.2 6.4 D(60mg/d)+P(180 g/w)+r(0.8g/d) 12 43/50 43/50 38/50 52(25-67) 65.2 6.6 G2,71/151 G3,80/151 D(60mg/d)+P(180 g/w)+r(0.8g/d) 16 35/50 43/50 37/50 55(20-63) 45.8 6.6 PBO+P(180 g/w)+r(0.8g/d) 24 20/51 34/51 31/51 51(21-68) 22.0 6.7 D(10mg/d)+P(60-150 g/w)+r(0.6-1g/d) 24/48 12/18 12/18 8/18 55(36-70) 60.0 6.7 G1(G1a+G1b), 45/45 D(60mg/d)+P(60-150 g/w)+r(0.6-1g/d) 24/48 11/19 15/19 12/19 50(42-66) 50.0 6.9 PBO+P(60-150 g/w)+r(0.6-1g/d) 48 0/8 5/8 5/8 56(26-68) 44.0 6.8 D(10mg/d)+P(180 g/w)+r(0.6-1g/d) 24 12/17 15/17 12/17 57(31-67) 25.0 6.6 G1(G1a+G1b), 42/42 D(60mg/d)+P(180 g/w)+r(0.6-1g/d) 24 13/17 16/17 15/17 54(41-65) 38.0 6.5 PBO+P(180 g/w)+r(0.6-1g/d) 24 1/8 5/8 6/8 52(38-66) 75.0 6.3 D(3mg/d)+P(180 g/w)+r(1.0-1.2g/d) 12 5/12 7/12 5/12 51(37-68) 67.0 6.4 G1a,32/48 D(10mg/d)+P(180 g/w)+r(1.0-1.2g/d) 12 11/12 10/12 10/12 51(43-67) 58.0 6.5 G1b,16/48 D(60mg/d)+P(180 g/w)+r(1.0-1.2g/d) 12 10/12 10/12 10/12 50(28-67) 67.0 6.7 PBO+P(180 g/w)+r(1.0-1.2g/d) 12 1/12 5/12 3/12 D(20mg/d)+P/R 12 47/203 71/203 Ratziu, et al [14] 2012 (n=419) D(60mg/d)+P/R 12 53/199 83/199 PBO+P/R 12 0/17 0/17 Median age, gender, HCV-RNA, treatment duration, RVR, cevr and SVR 24 is respectively divided into different groups according to the type of treatment and dose; Genotype is divided into different groups according to G1a, G1b, G2, G3 and G4. D. Daclatasvir; P. Pegylated interferon- ; R. Ribavirin; PBO. Placebo; RVR. Rapid virological response; cevr. Complete early virological response; SVR 24. Sustained virological response at posttreatment week 24 2 Jadad Tab.2 Jadad scores of the included clinical trials Trial Randomization Double-blinding Withdraw and drop out Jadad score Hézode, et al [9] /2015 Dore, et al [10] /2015 Suzuki, et al [11] /2014 Izumi, et al [12] /2014 Pol, et al [13] /2012 Ratziu, et al [14] /2012 and it was appropriate(2) and it was appropriate(2) and it was appropriate(2) and it was appropriate(2) but not described(1) but not described(1) 5 5 5 5 4 4 2.3 2.3.1 (RVR) 4 HCV-RNA 2 log [15] 6 RCT [9-14] 2.3.1.1 ( ) 4 HCV-RNA 6 (P=0.05) Meta RVR (46.44%) (18.97% RR=3.77 95%CI 1.95~7.28 P 0.0001 2) 2.3.1.2 60mg/d (60mg/d) 4 HCV-RNA 6 (P=0.06) Meta (60mg/d) RVR (49.90%) (18.97% RR=3.20 95%CI 2.35~4.35 P 0.00001 3) 2.3.1.3 10mg/d (10mg/d) 4 HCV-RNA 3 [11-13] (P=0.85) Meta (10mg/d) RVR (74.47%)

Med J Chin PLA, Vol. 41, No. 6, June 1, 2016 507 2 CHC (RVR) Meta Fig.2 Forest plot of RVR rate of DCV+P/R and PBO+P/R for CHC 3 (60mg/d) CHC (RVR) Meta Fig.3 Forest plot of RVR rate of DCV(60mg/d)+P/R and PBO+P/R for CHC (7.14% RR=8.79 95%CI 2.67~28.95 P=0.0003 4) 2.3.2 (cevr) 12 HCV-RNA [15] 6 RCT [9-14] 2.3.2.1 ( ) 12 HCV-RNA 6 (P=0.10) Meta cevr (61.56%) (47.70% RR=1.63 95%CI 1.39~1.92 P 0.00001 5) 4 (10mg/d) CHC (RVR) Meta Fig.4 Forest plot of RVR rate of DCV(10mg/d)+P/R and PBO+P/R for CHC 5 CHC (cevr) Meta Fig.5 Forest plot of cevr rate of DCV+P/R and PBO+P/R for CHC 2.3.2.2 (60mg/d) (60mg/d) 12 HCV-RNA 6 (P=0.10) Meta (60mg/d) cevr (65.74%) (47.70% RR=1.65 95%CI 1.40~1.94

508 2016 6 1 41 6 P 0.00001 6) 2.3.2.3 (10mg/d) (10mg/d) 12 HCV-RNA 3 [11-13] (P=0.43) Meta (10mg/d) cevr (78.72%) (53.57% RR=1.44 95%CI 1.00~2.07 P=0.05 7) 2.3.3 (SVR 24 ) 24 HCV-RNA [15] 5 RCT [9-13] 2.3.3.1 ( ) 24 HCV-RNA 5 (P=0.11) Meta SVR 24 (65.08%) (47.77% RR=1.41 95%CI 1.18~1.68 P=0.0001 8) 2.3.3.2 (60mg/d) (60mg/d) 24 HCV-RNA 5 (P=0.15) Meta (60mg/d) SVR 24 (68.95%) (47.77% RR=1.44 95%CI 1.20~1.71 P 0.0001 9) 2.3.3.3 (10mg/d) (10mg/d) 24 HCV-RNA 6 (60mg/d) CHC (cevr) Meta Fig.6 Forest plot of cevr rate of DCV(60mg/d) +P/R and PBO+P/R for CHC 7 (10mg/d) CHC (cevr) Meta Fig.7 Forest plot of cevr rate of DCV(10mg/d)+P/R and PBO+P/R for CHC 8 CHC (SVR) Meta Fig.8 Forest plot of SVR rate of DCV+P/R and PBO+P/R for CHC 9 (60mg/d) CHC (SVR) Meta Fig.9 Forest plot of SVR rate of DCV(60mg/d)+P/R and PBO+P/R for CHC

Med J Chin PLA, Vol. 41, No. 6, June 1, 2016 509 3 [9-11] (P=0.03) Meta (10mg/d) SVR 24 (P=0.65 10) 10 (10mg/d) CHC (SVR) Meta Fig.10 Forest plot of SVR rate of DCV(10mg/d)+P/R and PBO+P/R for CHC 2.3.4 2.3.4.1 4 [9,11-13] Meta ( ) (P 0.05 3) (RR=0.41 95%CI 0.32~0.52 P 0.00001 3) (RR=0.67 95%CI 0.44~1.01 P=0.05 3) 2.3.4.2 4 [9-12] (ALT) (TBil) Meta (P 0.05 3) 2.3.4.3 5 [9-13] ( ) Meta (P 0.05 3) 2.3.4.4 5 [9-13] Meta (P 0.05 3) 2.4 RR Suzuki [9] RR Dore [10] RR (logrr) ( 11) 3 Tab.3 Adverse events of the included studies Category Concrete forms Events/Total (incidence rate, %) DCV+P/R PBO+P/R RR, 95%CI(P values) Fatigue 211/424(49.76) 62/106(58.49) 0.86[0.72,1.03](P=0.11) Headache 184/424(43.40) 48/106(45.28) 0.96[0.76,1.21](P=0.73) Insomnia 132/424(31.13) 36/106(33.96) 0.86[0.64,1.14](P=0.29) Nonspecific AEs Nausea 126/390(32.31) 29/98(29.59) 0.79[0.37,1.68](P=0.53) Diarrhea 90/388(23.20) 54/94(57.45) 0.41[0.32,0.52](P 0.00001) Decreased appetite 104/424(24.53) 26/106(24.53) 0.99[0.69,1.44](P=0.98) Cough 72/387(18.60) 53/98(54.08) 0.66[0.18,2.37](P=0.52) Arthralgia 66/388(17.01) 24/94(25.53) 0.67[0.44,1.01](P=0.05) Liver dysfunction Elevated ALT 9/488(1.84) 1/145(0.69) 1.51[0.34,6.68](P=0.59) Elevated bilirubin 4/488(0.82) 1/145(0.69) 0.87[0.19,4.07](P=0.86) Anemia 45/524(8.59) 14/157(8.92) 0.90[0.53,1.54](P=0.70) Hematologic abnormalities Thrombocytopenia 12/488(2.46) 6/145(4.14) 0.62[0.24,1.65](P=0.34) Neutropenia 139/524(26.53) 46/157(29.30) 0.87[0.65,1.15](P=0.32) Rash 147/524(28.05) 46/157(29.30) 0.93[0.71,1.23](P=0.63) Skin abnormalities Pruritus 179/524(34.16) 49/157(31.21) 1.06[0.81,1.38](P=0.67) Alopecia 116/424(27.36) 23/106(21.70) 1.06[0.50,2.24](P=0.88) DCV. Daclatasvir; P. Pegylated interferon- ; R.Ribavirin;PBO.Placebo

510 2016 6 1 41 6 0 SE(log[RR]) 0.5 1 1.5 RR 2 0.01 0.1 1 10 100 11 6 Fig.11 Funnel plot of the included studies 3 CHC 6 70 1-3 [16] [17] HCV 1 CHC NS3/4A ( ) NS5A ( ) NS5B ( ) NS3 ( ) [16] 2014 [18] (Peg IFN)/ RBV (telaprevir TVR) (boceprevir BOC) 1 TVR BOC (1 /8h) ( ) [19] (daclatasvir DCV) TVR BOC CHC DCV HCV NS5A DCV NS3 DCV NS5A NS5A [20-22] DCV ( 1 ) 1-4 [23] [9-14] Peg IFN/RBV CHC Meta CHC ( Jadad 3 ) Meta RVR cevr SVR 24 (60mg/d) RVR cevr SVR 24 (10mg/d) RVR cevr SVR 24 ( ) CHC ( 6 RCTs 1100 ) (12~48 ) CHC [1] Gower E, Estes C, Blach S,et al. Global epidemiology and genotype distribution of the hepatitis C virus infection[ J]. J Hepatol, 2014, 61(1 Suppl): S45-S57. [2] Chen PY, Ma AX. Meta-analysis of the effectiveness on peginterferon for chronic hepatitis C[ J]. J Evid Based Med, 2014, 31(6): 345-355. [,. Meta [J]., 2014, 31(6): 345-355.] [3] Ma LY, Zhang P, Chen Q, et al. Changes in number of peripheral blood cells in patients with chronic hepatitis C after treated with interferon alpha 2b combined with ribavirin and their clinical significances[ J]. J Jilin Univ (Med Ed), 2015, 41(3): 599-605. [,,,. -2b [J]. ( ), 2015, 41(3): 599-605.] [4] Ma YH, Zhou LH. Clinical observation of patients with chronic hepatitis C and diabetes mellitus treated by PEG-interferon and ribavirin[ J]. J Logist Univ PAPF (Med Sci), 2013, 22(3): 207-209. [,. [J]. ( ), 2013, 22(3): 207-209.] [5] Wan JL, He X, Bai M. Research progress on combination therapeutic regimen of direct anti HCV agents[ J]. Drug Clin, 2014, 29(4): 442-446. [,,. [J]., 2014, 29(4): 442-446.] [6] NettelsRE,GaoM,BifanoM,et al. Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus

Med J Chin PLA, Vol. 41, No. 6, June 1, 2016 511 genotype 1[ J]. Hepatology, 2011, 54(6): 1956-1965. [7] JadadAR,MooreRA,CarrollD,et al. Assessing the quality of reports of randomized clinical trails: is blinding necessary?[ J]. Control Clin Trials, 1996, 17(1): 1-12. [8] Tian JH, Li L, Zhao Y, et al. Writing and reporting of network meta-analysis[ J]. Chin J Drug Evaluation, 2013, 30(6): 321-323, 333. [,,,. Meta [J]., 2013, 30(6): 321-323, 333.] [9] Hézode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study[ J]. Gut, 2015, 64(6): 948-956. [10] Dore G J, L aw itz E, Hézode C, et al. Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection[ J]. Gastroenterology, 2015, 148(2): 355-366. [11] Suzuki F, Toyota J, Ikeda K, et al. A randomized trial of daclatasivir with peginterferon alfa-2b and ribavirin for HCV genotype 1 infection[ J]. Antivir Ther, 2014, 19(5): 491-499. [12] Izumi N, Yokosuka O, Kawada N, et al. Daclatasivir combined with peginterferon alfa-2b and ribavirin in Japanese patient infected with hepatitis C genotype 1[ J]. Antivir Ther, 2014, 19(5): 501-510. [13] Pol S, Ghali RH, Rustgi VK, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial[ J]. Lancet Infect Dis, 2012, 12(9): 671-677. [14] Ratziu V, Gadano A, Pol S, et al. Triple therapy with daclatasvir (DCV; BMS-790052), peginterferon alfa/2a and ribaviron in HCV-infected prior null and partial responders: 12 week results of phase 2b command-2 trial[ J]. J Hepatol, 2012, 56(Suppl 2): 478-479. [15] LI GY. Efficiency of different peginterferons and ribaviron for the treatment of chronic hepatitis C[ J]. Anti Infect Pharm, 2014, 11(5): 528-530. [. [J]., 2014, 11(5): 528-530.] [16] Yang XY, Wang JX. Advance in research of anti-hcv drugs and therapies[ J]. Chin J New Drug, 2014, 23(22): 2624-2630. [,. [J]., 2014, 23(22): 2624-2630.] [17] Zhou YM, Dou XG, Zhang L. Research progress of hepatitis C virus genotyping[ J]. Chin J Pract Intern Med, 2014, 34(8): 819-822. [,,. [J]., 2014, 34(8): 819-822.] [18] European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatitis C virus infection[ J]. J Hepatol, 2014, 60(1): 392-420. [19] WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for the screening, care and treatment of persons with hepatitis C infection[m]. Geneva: World Health Organization, 2014. [20] Fridell RA, Qiu D, Valera L, et al. Distinct functions of NS5A in hepatitis C virus RNA replication uncovered by studies with the NS5A inhibitor BMS-790052[ J]. J Virol, 2011, 85(14): 7312-7320. [21] Qiu D, Lemm JA, O'Boyle DR II, et al. The effects of NS5A inhibitors on NS5A phosphorylation, polyprotein processing and localization[ J]. J Gen Virol, 2011, 92(Pt 11): 2502-2511. [22] Lee C, Ma H, Hang JQ, et al. The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein[ J]. Virology, 2011, 414(1): 10-18. [23] Wang C, Jia L, Huang H, et al. In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A[ J]. Antimicrob Agents Chemother, 2012, 56(3): 1588-1590. ( 2015-12-29 2016-03-31) ( )