Direct-acting antivirals for chronic hepatitis C

750 Pages·2017·5.1 MB·English

CochraneDatabaseofSystematicReviews
Direct-acting antivirals for chronic hepatitis C (Review)
JakobsenJC,NielsenEE,FeinbergJ,KatakamKK,FobianK,HauserG,PoropatG,DjurisicS,
WeissKH,BjelakovicM,BjelakovicG,KlingenbergSL,LiuJP,NikolovaD,KoretzRL,GluudC
JakobsenJC,NielsenEE,FeinbergJ,KatakamKK,FobianK,HauserG,PoropatG,DjurisicS,WeissKH,BjelakovicM,BjelakovicG,Klingenberg
SL,LiuJP,NikolovaD,KoretzRL,GluudC.
Direct-actingantiviralsforchronichepatitisC.
CochraneDatabaseofSystematicReviews2017,Issue6.Art.No.:CD012143.
DOI:10.1002/14651858.CD012143.pub2.
www.cochranelibrary.com
Direct-actingantiviralsforchronichepatitisC(Review)
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 25
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Analysis1.1.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome1HepatitisC-
relatedmorbidityorall-causemortality. . . . . . . . . . . . . . . . . . . . . . . . . . 357
Analysis1.2.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome2HepatitisC-
relatedmorbidityorall-causemortality-biasrisk. . . . . . . . . . . . . . . . . . . . . . 360
Analysis1.3.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome3HepatitisC-
relatedmorbidityorall-causemortality-accordingtotypeofDAA. . . . . . . . . . . . . . . . 363
Analysis1.4.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome4HepatitisC-
relatedmorbidityorall-causemortality-accordingtogroupofDAA. . . . . . . . . . . . . . . 367
Analysis1.5.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome5HepatitisC-
relatedmorbidityorall-causemortality-accordingtoHIV-infection. . . . . . . . . . . . . . . 370
Analysis1.6.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome6HepatitisC-
relatedmorbidityorall-causemortality-accordingtocomorbidity. . . . . . . . . . . . . . . . 373
Analysis1.7.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome7HepatitisC-
relatedmorbidityorall-causemortality-accordingtoviralgenotype. . . . . . . . . . . . . . . . 376
Analysis1.8.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome8HepatitisC-
relatedmorbidityorall-causemortality-accordingtohumangenotype(IL28b). . . . . . . . . . . . 379
Analysis1.9.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome9HepatitisC-
relatedmorbidityorall-causemortality-accordingtoAsian-region. . . . . . . . . . . . . . . . 382
Analysis1.10.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome10Hepatitis
C-relatedmorbidityorall-causemortality-accordingtospecificethnicities. . . . . . . . . . . . . 385
Analysis1.11.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome11Hepatitis
C-relatedmorbidityorall-causemortality-accordingtoreachingplannedsamplesize. . . . . . . . . 388
Analysis1.12.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome12Hepatitis
C-relatedmorbidityorall-causemortality-accordingtopriortreatment. . . . . . . . . . . . . . 391
Analysis1.13.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome13Hepatitis
C-relatedmorbidityorall-causemortality-accordingtointerferon. . . . . . . . . . . . . . . . 394
Analysis1.14.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome14Hepatitis
C-relatedmorbidityorall-causemortality-accordingtoribavirin. . . . . . . . . . . . . . . . . 397
Analysis1.15.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome15Hepatitis
C-relatedmorbidityorall-causemortality-accordingtochronickidneydisease. . . . . . . . . . . . 400
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Analysis1.16.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome16Hepatitis
C-relatedmorbidityorall-causemortality-accordingtocryoglobulinaemia. . . . . . . . . . . . . 403
Analysis1.17.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome17Hepatitis
C-relatedmorbidityorall-causemortality-accordingtoDAAgroupasco-intervention. . . . . . . . . 406
Analysis1.18.Comparison1DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome18Hepatitis
C-relatedmorbidityorall-causemortality-accordingtomediandose. . . . . . . . . . . . . . . 409
Analysis2.1.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome1Serious
adverseevents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Analysis2.2.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome2Serious
adverseevents-biasrisk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
Analysis2.3.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome3Serious
adverseevents-accordingtotypeofDAA. . . . . . . . . . . . . . . . . . . . . . . . . 420
Analysis2.4.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome4Serious
adverseevents-accordingtogroupofDAA. . . . . . . . . . . . . . . . . . . . . . . . 425
Analysis2.5.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome5Serious
adverseevents-accordingtoHIV-infection. . . . . . . . . . . . . . . . . . . . . . . . 429
Analysis2.6.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome6Serious
adverseevents-accordingtocomorbidity. . . . . . . . . . . . . . . . . . . . . . . . . 433
Analysis2.7.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome7Serious
adverseevents-accordingtoviralgenotype. . . . . . . . . . . . . . . . . . . . . . . . 437
Analysis2.8.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome8Serious
adverseevents-accordingtohumangenotype(IL28b). . . . . . . . . . . . . . . . . . . . 441
Analysis2.9.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome9Serious
adverseevents-accordingtoAsian-region. . . . . . . . . . . . . . . . . . . . . . . . . 445
Analysis2.10.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome10Serious
adverseevents-accordingtospecificethnicities. . . . . . . . . . . . . . . . . . . . . . . 449
Analysis2.11.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome11Serious
adverseevents-accordingtoreachingplannedsamplesize. . . . . . . . . . . . . . . . . . . 453
Analysis2.12.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome12Serious
adverseevents-accordingtopriortreatment. . . . . . . . . . . . . . . . . . . . . . . . 457
Analysis2.13.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome13Serious
adverseevents-accordingtointerferon. . . . . . . . . . . . . . . . . . . . . . . . . . 461
Analysis2.14.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome14Serious
adverseevents-accordingtoribavirin. . . . . . . . . . . . . . . . . . . . . . . . . . 465
Analysis2.15.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome15Serious
adverseevents-accordingtochronickidneydisease. . . . . . . . . . . . . . . . . . . . . 469
Analysis2.16.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome16Serious
adverseevents-accordingtocryoglobulinaemia. . . . . . . . . . . . . . . . . . . . . . . 473
Analysis2.17.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome17Serious
adverseevents-accordingtoDAAgroupasco-intervention. . . . . . . . . . . . . . . . . . . 477
Analysis2.18.Comparison2DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome18Serious
adverseevents-accordingtomediandose. . . . . . . . . . . . . . . . . . . . . . . . . 481
Analysis3.1.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome1Without
sustainedvirologicalresponse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Analysis3.2.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome2Without
sustainedvirologicalresponse-biasrisk. . . . . . . . . . . . . . . . . . . . . . . . . . 488
Analysis3.3.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome3Without
sustainedvirologicalresponse-accordingtotypeofDAA. . . . . . . . . . . . . . . . . . . 491
Analysis3.4.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome4Without
sustainedvirologicalresponse-accordingtogroupofDAA. . . . . . . . . . . . . . . . . . . 500
Analysis3.5.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome5Without
sustainedvirologicalresponse-accordingtoHIV-infection. . . . . . . . . . . . . . . . . . . 503
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Analysis3.6.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome6Without
sustainedvirologicalresponse-accordingtocomorbidity. . . . . . . . . . . . . . . . . . . . 506
Analysis3.7.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome7Without
sustainedvirologicalresponse-accordingtoviralgenotype. . . . . . . . . . . . . . . . . . . 509
Analysis3.8.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome8Without
sustainedvirologicalresponse-accordingtohumangenotype(IL28b). . . . . . . . . . . . . . . 513
Analysis3.9.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome9Without
sustainedvirologicalresponse-accordingtoAsian-region. . . . . . . . . . . . . . . . . . . 517
Analysis3.10.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome10Without
sustainedvirologicalresponse-accordingtospecificethnicities. . . . . . . . . . . . . . . . . . 520
Analysis3.11.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome11Without
sustainedvirologicalresponse-accordingtoreachingplannedsamplesize. . . . . . . . . . . . . . 523
Analysis3.12.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome12Without
sustainedvirologicalresponse-accordingtopriortreatment. . . . . . . . . . . . . . . . . . 526
Analysis3.13.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome13Without
sustainedvirologicalresponse-accordingtointerferon. . . . . . . . . . . . . . . . . . . . 529
Analysis3.14.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome14Without
sustainedvirologicalresponse-accordingtoribavirin. . . . . . . . . . . . . . . . . . . . . 532
Analysis3.15.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome15Without
sustainedvirologicalresponse-accordingtochronickidneydisease. . . . . . . . . . . . . . . . 535
Analysis3.16.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome16Without
sustainedvirologicalresponse-accordingtocryoglobulinaemia. . . . . . . . . . . . . . . . . 538
Analysis3.17.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome17Without
sustainedvirologicalresponse-accordingtoDAAgroupasco-intervention. . . . . . . . . . . . . 541
Analysis3.18.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome18Without
sustainedvirologicalresponse-’Best-worstcase’scenario. . . . . . . . . . . . . . . . . . . . 544
Analysis3.19.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome19Without
sustainedvirologicalresponse-’Worst-bestcase’scenario. . . . . . . . . . . . . . . . . . . . 547
Analysis3.20.Comparison3DAAonoronthewaytothemarketversusplacebo/nointervention,Outcome20Without
sustainedvirologicalresponse-accordingtomediandose. . . . . . . . . . . . . . . . . . . 550
Analysis4.1.Comparison4Danoprevirversusplacebo/nointervention,Outcome1HepatitisC-relatedmorbidityorall-
causemortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
Analysis4.2.Comparison4Danoprevirversusplacebo/nointervention,Outcome2HepatitisC-relatedmorbidityorall-
causemortality-accordingtodose. . . . . . . . . . . . . . . . . . . . . . . . . . . 554
Analysis4.3.Comparison4Danoprevirversusplacebo/nointervention,Outcome3Seriousadverseevents. . . . 555
Analysis4.4.Comparison4Danoprevirversusplacebo/nointervention,Outcome4Seriousadverseevents-accordingto
mediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
Analysis4.5. Comparison4Danoprevir versusplacebo/nointervention, Outcome5Withoutsustainedvirological
response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Analysis4.6.Comparison4Danoprevirversusplacebo/nointervention,Outcome6Withoutsustainedvirologicalresponse
-accordingtomediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
Analysis5.1.Comparison5AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome1HepatitisC-
relatedmorbidityorall-causemortality. . . . . . . . . . . . . . . . . . . . . . . . . . 559
Analysis6.1.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome1Serious
adverseevents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
Analysis6.2.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome2Serious
adverseevents-biasrisk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
Analysis6.3.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome3Serious
adverseevents-accordingtotypeofDAA. . . . . . . . . . . . . . . . . . . . . . . . . 575
Analysis6.4.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome4Serious
adverseevents-accordingtogroupofDAA. . . . . . . . . . . . . . . . . . . . . . . . 582
Analysis6.5.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome5Serious
adverseevents-accordingtoHIV-infection. . . . . . . . . . . . . . . . . . . . . . . . 588
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Analysis6.6.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome6Serious
adverseevents-accordingtocomorbidity. . . . . . . . . . . . . . . . . . . . . . . . . 594
Analysis6.7.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome7Serious
adverseevents-accordingtoviralgenotype. . . . . . . . . . . . . . . . . . . . . . . . 600
Analysis6.8.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome8Serious
adverseevents-accordingtohumangenotype(IL28b). . . . . . . . . . . . . . . . . . . . 606
Analysis6.9.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome9Serious
adverseevents-accordingtoAsian-region. . . . . . . . . . . . . . . . . . . . . . . . . 612
Analysis6.10.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome10Serious
adverseevents-accordingtospecificethnicities. . . . . . . . . . . . . . . . . . . . . . . 618
Analysis6.12.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome12Serious
adverseevents-accordingtopriortreatment. . . . . . . . . . . . . . . . . . . . . . . . 624
Analysis6.13.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome13Serious
adverseevents-accordingtointerferon. . . . . . . . . . . . . . . . . . . . . . . . . . 630
Analysis6.14.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome14Serious
adverseevents-accordingtoribavirin. . . . . . . . . . . . . . . . . . . . . . . . . . 636
Analysis6.15.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome15Serious
adverseevents-accordingtochronickidneydisease. . . . . . . . . . . . . . . . . . . . . 642
Analysis6.16.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome16Serious
adverseevents-accordingtocryoglobulinaemia. . . . . . . . . . . . . . . . . . . . . . . 648
Analysis6.17.Comparison6AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome17Serious
adverseevents-accordingtoDAAgroupasco-intervention. . . . . . . . . . . . . . . . . . . 654
Analysis7.1.Comparison7AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome1Without
sustainedvirologicalresponse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
Analysis8.1.Comparison8AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome1SF-36
physicalscore. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
Analysis8.2.Comparison8AllDAAversusplacebo/nointervention/othermedicalintervention,Outcome2SF-36mental
score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Analysis9.1.Comparison9Daclatasvirversusplacebo/nointervention,Outcome1HepatitisC-relatedmorbidityorall-
causemortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Analysis9.2.Comparison9Daclatasvirversusplacebo/nointervention,Outcome2HepatitisC-relatedmorbidityorall-
causemortality-accordingtodose. . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Analysis9.3.Comparison9Daclatasvirversusplacebo/nointervention,Outcome3Seriousadverseevents. . . . . 668
Analysis9.4.Comparison9Daclatasvirversusplacebo/nointervention,Outcome4Seriousadverseevents-accordingto
mediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Analysis9.5. Comparison 9Daclatasvir versusplacebo/nointervention, Outcome5Withoutsustained virological
response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
Analysis9.6.Comparison9Daclatasvirversusplacebo/nointervention,Outcome6Withoutsustainedvirologicalresponse
-accordingtomediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Analysis10.1.Comparison10Simeprevirversusplacebo/nointervention,Outcome1HepatitisC-relatedmorbidityorall-
causemortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
Analysis10.2.Comparison10Simeprevirversusplacebo/nointervention,Outcome2HepatitisC-relatedmorbidityorall-
causemortality-accordingtodose. . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Analysis10.3.Comparison10Simeprevirversusplacebo/nointervention,Outcome3Seriousadverseevents. . . . 674
Analysis10.4.Comparison10Simeprevirversusplacebo/nointervention,Outcome4Seriousadverseevents-accordingto
mediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
Analysis10.5.Comparison10Simeprevirversusplacebo/nointervention,Outcome5Withoutsustainedvirological
response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
Analysis10.6.Comparison10Simeprevirversusplacebo/nointervention,Outcome6Withoutsustainedvirological
response-accordingtomediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . 678
Analysis11.1.Comparison11Vaniprevirversusplacebo/nointervention,Outcome1HepatitisC-relatedmorbidityorall-
causemortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
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Analysis11.2.Comparison11Vaniprevirversusplacebo/nointervention,Outcome2HepatitisC-relatedmorbidityorall-
causemortality-accordingtodose. . . . . . . . . . . . . . . . . . . . . . . . . . . 681
Analysis11.3.Comparison11Vaniprevirversusplacebo/nointervention,Outcome3Seriousadverseevents. . . . 682
Analysis11.4.Comparison11Vaniprevirversusplacebo/nointervention,Outcome4Seriousadverseevents-accordingto
mediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Analysis11.5.Comparison11Vaniprevir versusplacebo/nointervention,Outcome5Withoutsustainedvirological
response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
Analysis11.6.Comparison11Vaniprevir versusplacebo/nointervention,Outcome6Withoutsustainedvirological
response-accordingtomediandose. . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Analysis12.1.Comparison12AllDAAversusplacebo/nointervention,Outcome1Withoutsignificantreductionsin
ALT/ASTserumlevels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
Analysis12.2.Comparison12AllDAAversusplacebo/nointervention,Outcome2Withoutsignificantreductionsin
ALT/ASTserumlevels-accordingtoDAAstatus. . . . . . . . . . . . . . . . . . . . . . 687
Analysis12.3.Comparison12AllDAAversusplacebo/nointervention,Outcome3Withoutsignificantreductionsin
ALT/ASTserumlevels-accordingtotypeofdrug. . . . . . . . . . . . . . . . . . . . . . 688
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 744
Direct-actingantiviralsforchronichepatitisC(Review) v
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Direct-acting antivirals for chronic hepatitis C
JanusCJakobsen1,2,EmilEikNielsen3,JoshuaFeinberg3,KiranKumarKatakam4,KristinaFobian3,GoranHauser5,GoranPoropat
5,SnezanaDjurisic4,KarlHeinzWeiss6,MilicaBjelakovic7,GoranBjelakovic8,SarahLouiseKlingenberg1,JianPingLiu9,Dimitrinka
Nikolova1,RonaldLKoretz10,ChristianGluud1
1TheCochraneHepato-BiliaryGroup,CopenhagenTrialUnit,CentreforClinicalInterventionResearch,Department7812,Rigshos-
pitalet,CopenhagenUniversityHospital,Copenhagen,Denmark.2DepartmentofCardiology,HolbaekHospital,Holbaek,Denmark.
3CopenhagenTrialUnit,CentreforClinicalInterventionResearch,Department7812,Rigshospitalet,CopenhagenUniversityHos-
pital,Copenhagen,Denmark.4CopenhagenTrialUnit,CentreforClinicalInterventionResearch,Department7812,Rigshospitalet,
CopenhagenUniversityHospital,Copenhagen,Denmark.5DepartmentofGastroenterology,ClinicalHospitalCentreRijeka,Rijeka,
Croatia.6InternalMedicineIV:Gastroenterology,InfectiousDiseases,Toxicology,HeidelbergUniversityHospital,Heidelberg,Ger-
many.7MedicalFaculty,UniversityofNis,Nis,Serbia.8DepartmentofInternalMedicine,MedicalFaculty,UniversityofNis,Nis,
Serbia.9CentreforEvidence-BasedChineseMedicine,BeijingUniversityofChineseMedicine,Beijing,China.10GranadaHills,CA,
USA
Contactaddress:JanusCJakobsen,TheCochraneHepato-BiliaryGroup,CopenhagenTrialUnit,CentreforClinicalIntervention
Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Sjælland, DK-2100,
[email protected],[email protected].
Editorialgroup:CochraneHepato-BiliaryGroup.
Publicationstatusanddate:New,publishedinIssue6,2017.
Citation: JakobsenJC,NielsenEE,FeinbergJ,KatakamKK,FobianK,HauserG,PoropatG,DjurisicS,WeissKH,BjelakovicM,
BjelakovicG,KlingenbergSL,LiuJP,NikolovaD, KoretzRL, GluudC.Direct-acting antiviralsfor chronichepatitisC.Cochrane
DatabaseofSystematicReviews2017,Issue6.Art.No.:CD012143.DOI:10.1002/14651858.CD012143.pub2.
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Millions of people worldwide suffer fromhepatitis C, which can leadto severeliver disease, liver cancer, and death. Direct-acting
antivirals(DAAs)arerelativelynewandexpensiveinterventionsforchronichepatitisC,andpreliminaryresultssuggestthatDAAs
mayeradicatehepatitisCvirus(HCV)fromtheblood(sustainedvirologicalresponse).However,itisstillquestionableiferadication
ofhepatitisCvirusinthebloodeliminateshepatitisCinthebody,andimprovessurvivalandleadstofewercomplications.
Objectives
ToassessthebenefitsandharmsofDAAsinpeoplewithchronicHCV.
Searchmethods
WesearchedforallpublishedandunpublishedtrialsinTheCochraneHepato-BiliaryGroupControlledTrialsRegister,CENTRAL,
MEDLINE,Embase,ScienceCitationIndexExpanded,LILACS,andBIOSIS;theChineseBiomedicalLiteratureDatabase(CBM),
ChinaNetworkKnowledgeInformation(CNKI),theChineseScienceJournalDatabase(VIP),GoogleScholar,TheTurningResearch
intoPractice(TRIP)Database,ClinicalTrials.gov,EuropeanMedicinesAgency(EMA)(www.ema.europa.eu/ema/),WHOInterna-
tionalClinicalTrialsRegistryPlatform(www.who.int/ictrp),theFoodandDrugAdministration(FDA)(www.fda.gov),andpharma-
ceuticalcompanysourcesforongoingorunpublishedtrials.SearcheswerelastruninOctober2016.
Selectioncriteria
RandomisedclinicaltrialscomparingDAAsversusnointerventionorplacebo,aloneorwithco-interventions,inadultswithchronic
HCV.Weincludedtrialsirrespectiveofpublicationtype,publicationstatus,andlanguage.
Direct-actingantiviralsforchronichepatitisC(Review) 1
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Datacollectionandanalysis
WeusedstandardmethodologicalproceduresexpectedbyCochrane.OurprimaryoutcomeswerehepatitisC-relatedmorbidity,serious
adverseevents,andqualityoflife.Oursecondaryoutcomeswereall-causemortality,ascites,varicealbleeding,hepato-renalsyndrome,
hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological
response.Wesystematicallyassessedrisksofbias,performedTrialSequentialAnalysis,andfollowedaneight-stepproceduretoassess
thresholdsforstatisticalandclinicalsignificance.TheoverallqualityoftheevidencewasevaluatedusingGRADE.
Mainresults
Weincludedatotalof138trialsrandomisingatotalof25,232participants.The138trialsassessedtheeffectsof51differentDAAs.
Ofthese,128trialsemployedmatchingplacebointhecontrolgroup.Allincludedtrialswereathighriskofbias.Eighty-fourtrials
involvedDAAsonthemarketorunderdevelopment(13,466participants).Fifty-seventrialsadministeredwithdrawn(ordiscontinued)
DAAs.Trialparticipantsweretreatment-naive(95trials),treatment-experienced(17trials),orbothtreatment-naiveandtreatment-
experienced(24trials).TheHCVgenotypesweregenotype1(119trials),genotype2(eighttrials),genotype3(sixtrials),genotype4
(ninetrials),andgenotype6(onetrial).Weidentifiedtwoongoingtrials.
Meta-analysisoftheeffectsofallDAAsonthemarketorunderdevelopmentshowednoevidenceofadifferencewhenassessinghepatitis
C-relatedmorbidity orall-causemortality(OR3.72, 95%CI0.53to26.18, P=0.19, I2 =0%,2,996participants,11trials,very
low-qualityevidence).AstherewerenodataonhepatitisC-relatedmorbidityandveryfewdataonmortality(DAA15/2377(0.63%)
versuscontrol1/617(0.16%)),itwasnotpossibletoperformTrialSequentialAnalysisonhepatitisC-relatedmorbidityorall-cause
mortality.
Meta-analysis ofallDAAsonthemarketor underdevelopmentshowednoevidenceof adifferencewhenassessing seriousadverse
events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I2 = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial
Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was
sufficientinformationtoruleoutthatDAAscomparedwithplaceboreducedtherelativeriskofaseriousadverseeventby20%.The
onlyDAAthatshowedasignificant differenceonriskofseriousadverseeventswhenmeta-analysedseparatelywassimeprevir(OR
0.62,95%CI0.45to0.86).However,TrialSequentialAnalysisshowedthattherewasnotenoughinformationtoconfirmorrejecta
relativeriskreductionof20%andwhenonetrialwithanextremeresultwasexcludedthenthemeta-analysisresultshowednoevidence
ofadifference.
WithdrawnDAAshadnoevidenceofadifferencewhenassessinghepatitisC-relatedmorbidityandall-causemortality(OR0.64,95%
CI0.23to1.79,P=0.40,I2=0%;5trials,verylow-qualityevidence).However,withdrawnDAAsseemedtoincreasetheriskof
seriousadverseevents(OR1.45,95%CI1.22to1.73,P=0.001,I2=0%,29trials,verylow-qualityevidence),andTrialSequential
Analysisconfirmedthismeta-analysisresult.
DAAsseemedtoreducetheriskofnosustainedvirologicalresponse(RR0.44,95%CI0.37to0.52,P<0.00001,I2 =77%,6886
participants,32trials,verylow-qualityevidence),andTrialSequentialAnalysisconfirmedthismeta-analysisresult.
Only1/138trialsassessedtheeffectsofDAAsonhealth-relatedqualityoflife(SF-36mentalscoreandSF-36physicalscore).
Themajorityofalloutcomeresultswereshort-termresults,sowecouldneitherconfirmnorrejectanylong-termeffectsofDAAs.None
ofthe138trialsprovidedusefuldatatoassesstheeffectsofDAAsontheremainingsecondaryoutcomes(ascites,varicealbleeding,
hepato-renalsyndrome,hepaticencephalopathy,andhepatocellularcarcinoma).
Authors’conclusions
Overall,DAAsonthemarketorunderdevelopmentdonotseemtohaveanyeffectsonriskofseriousadverseevents.Simeprevirmay
havebeneficialeffectsonriskofseriousadverseevent.InallremaininganalyseswecouldneitherconfirmnorrejectthatDAAshadany
clinicaleffects.DAAsseemedtoreducetheriskofnosustainedvirologicalresponse.TheclinicalrelevanceoftheeffectsofDAAson
nosustainedvirologicalresponseisquestionable,asitisanon-validatedsurrogateoutcome.Alltrialsandoutcomeresultswereathigh
riskofbiassoourresultspresumablyoverestimatebenefitandunderestimateharm.Thequalityoftheevidencewasverylow.
PLAIN LANGUAGE SUMMARY
Reviewquestion
Direct-actingantiviralsforchronichepatitisC(Review) 2
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Toassessthebeneficialandharmfuleffectsofdirect-actingantivirals(DAAs)forchronichepatitisC.
Background
MillionsofpeopleworldwidesufferfromhepatitisC,whichcanleadtosevereliverdisease,livercancer,anddeath.Numerousprevious
interventionshavebeenusedforhepatitisC,butnoneoftheseinterventionshaveproveneffectiveonpatient-centredoutcomes.DAAs
arerelativelynewbutexpensiveinterventionsforhepatitisC,andpreliminaryresultshaveshownthatDAAsseemtoeradicatehepatitis
Cvirusfromtheblood(sustainedvirologicalresponse).However,itisquestionableifaneradicationofhepatitisCvirusintheblood
leadsnohepatitisCinthebodyandimprovedsurvivalandfewercomplications. InthisCochraneReview,theauthorsassessedthe
evidenceontheclinicaleffectsofDAAsforhepatitisC.
Studycharacteristics
Theauthorsincluded351publicationsof138randomisedclinicaltrials.Allincludedtrialswereathighriskofbias.The138trials
used51differentDAAs.Ofthese,84trialsassessedDAAsonthemarketorunderdevelopment;57trialswereonDAAswithdrawn
fromthemarket.Trialswereconductedfrom2004-2016.Thetrialswerefromallovertheworldincluding34differentcountries.We
included17trialswherealltheparticipantshadpreviouslybeentreatedforhepatitisC(treatment-experienced)beforebeingincluded
inthetrial.Therewere95trialsthatincludedonlyparticipantswhohadnotbeenpreviouslytreatedforhepatitisC(treatment-naive).
Theinterventionperiodsrangedfromonedayto48weekswithanaverageof14weeks.Thecombinedinterventionperiodandfollow-
upperiodrangedfromonedayto120weekswithanaverageof34weeks.
Keyresults
DAAsdonotseemtohaveanyeffectsontheriskofhepatitisC-relatedmorbidityorall-causemortality.Infact,therewerenodata
onhepatitisC-relatedmorbidityandveryfewdataonmortality(15deaths/2377direct-actingantiviralparticipants(0.63%)versus1
death/617controlparticipants(0.16%)resultinginanoddsratioof3.72,95%CI0.53to26.18,P=0.19,I2=0%,2996participants,
11trials,verylow-qualityevidence).DAAsdonotseemtohaveanyeffectsontheriskofseriousadverseevents(376/13,574(2.77%)
direct-actingantiviralparticipantshadoneormoreseriousadverseeventsversus125/2,243(5.57%)controlparticipantsduringthe
observationperiodresultinginanoddsratioof0.93,95%CI0.75to1.15,P=0.52,I2=0%,15,817participants,66trials,verylow-
qualityevidence).Whenanalysedseparately,simeprevirwastheonlydirect-actingantiviralthatshowedevidenceofabeneficialeffect
whenassessingriskofaseriousadverseevent.Ouranalyses,however,showedthatthevalidityofthisresultisquestionableandthat
’playofchance’mightbethecauseforthedifference.TherewasnotenoughinformationtoconfirmorrejectifDAAshaveclinically
relevanteffectsonotherclinicallyrelevantoutcomes.OurresultsconfirmthatDAAsseemtohaveaneffectontheriskofnosustained
virological response, but all of the trial results were at high risk of systematic error (’bias’), and the clinical relevanceof results on
virologicalresponseisquestionable.Thelackofvalidevidenceandthepossibilityofpotentiallyharmingpeoplewithchronichepatitis
oughttobeconsideredbeforetreatingpeoplewithhepatitisCwithDAAs.
Qualityoftheevidence
Duetoseverallimitations,weassessedthequalityoftheevidenceinthisreviewasverylowquality.First,alltrialsandoutcomeresults
wereathighriskofbias,whichmeansthatourresultspresumablyoverestimatethebeneficialeffectsofDAAsandunderestimateany
potentialharmfuleffects.Second,therewerelimiteddataonmostofourclinicaloutcomes,thatis,therewereonlyrelevantclinical
dataformeta-analysesonall-causemortalityandseriousadverseevents,andforthese,dataweresparse.Third,mosttrialsprimarily
focusedandassessedtheeffectsofDAAsonsustainedvirologicalresponse;however,itisquestionableifsustainedvirologicalresponse
hasanyclinicalrelevancetothepersonwithchronichepatitisC(see‘Background’inthisPlainlanguagesummary).
Direct-actingantiviralsforchronichepatitisC(Review) 3
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CopyrighDirect-ac SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
t©tin
2g
0a Direct-actingantiviralsversuscontrol
1n
7TheCoctiviralsfor PSaettiteinngt:oarnpyospeutltaintigon:adultswithchronichepatitisC
hc
ranhro Intervention:direct-actingantiviralsonthemarketorunderdevelopment
en Comparison:placeboornointervention
Cic
oh
llaep
boratioatitisC Outcomes Anticipatedabsoluteeffects∗(95%CI) R(9e5la%tiCveI)effect (troiaflpsa)rticipants Q(GuRaAlitDyEo)ftheevidence Comments
n.Pu(Rev Riskwithplaceboorno Risk withdirect-acting (TSA-adjustedCI)
blisiew intervention antivirals
h)
e
d
b
y All-cause mortality at 2per1000 7per1000 OR3.72 2996 (cid:13)(cid:13)(cid:13)(cid:13) It was not possible to
Joh maximum follow-up (1to42) (0.53to26.18) (11RCTs) Verylow1 perform Trial Sequen-
n
W (-) tialAnalysisbecauseof
ile limiteddataandtoofew
y
& events
S
o
n
s
,L Proportion of partici- 56per1000 52per1000 OR0.93 15,817 ⊕(cid:13)(cid:13)(cid:13) Trial Sequential Anal-
td. pants withoneormore (49to55) (0.75to1.15) (43RCTs) Verylow2 ysis showed that the
serious adverse event (TSACI0.71to1.33) boundary for futility
atmaximum follow-up was crossed. This
leads us to conclude
that anypossible inter-
ventioneffect,if any,is
lessthan20%
Proportion of partici- 541per1000 238per1000 RR0.44 6886 (cid:13)(cid:13)(cid:13)(cid:13) Trial Sequential Anal-
pantswithnosustained (200to281) (0.37to0.52) (32RCTs) Verylow3 ysis showed that the
virological response at (TSACI0.42to0.55) boundary for benefit
maximum follow-up was crossed.This indi-
cates that DAAs seem
to decrease the risk
of no sustained viro-
logical response by at
4