ebook img

Direct-acting antivirals for chronic hepatitis C PDF

750 Pages·2017·5.1 MB·English
by  
Save to my drive
Quick download
Download
Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.

Preview Direct-acting antivirals for chronic hepatitis C

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 Direct-actingantiviralsforchronichepatitisC(Review) i Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. 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 Direct-actingantiviralsforchronichepatitisC(Review) ii Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. 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 Direct-actingantiviralsforchronichepatitisC(Review) iii Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. 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 Direct-actingantiviralsforchronichepatitisC(Review) iv Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. 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

Description:
Direct-acting antivirals for chronic hepatitis C (Review) Comparison 1 DAA on or on the way to the market versus placebo/no C-related morbidity or all-cause mortality - according to reaching planned sample size. We included trials irrespective of publication type, publication status, and language
See more

The list of books you might like

Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.