[url=http://health.elsevier.ru/journals/med-rus/gastro/issues/41/?id=3429]Результаты клинических исследований III фазы телапревира и боцепревира, представленные на конференции гепатологов в 2010 г.: новый стандарт лечения гепатита C, вызванного вирусом генотипа 1, и вопросы, оставшиеся нерешенными[/url]
С 29 октября по 2 ноября 2010 г. в Бостоне (США) прошла очередная конференция гепатологов. На конференции широкой аудитории были представлены результаты исследований III фазы, посвященных применению двух ингибиторов протеазы вируса гепатита C (HCV), телапревира и боцепревира, в комбинации с пегилированным интерфероном альфа (ПЭГ-ИФН-а) и рибавирином как у больных, не получавших ранее лечения, так и у пациентов, не достигших ответа на первый курс ПЭГ-ИФН-а и рибавирина. Эти результаты были широко освещены в средствах массовой информации. Боцепревиру было посвящено 2 исследования III фазы, включая SPRINT-2 у больных, не получавших ранее лечения, и RESPOND-2 у пациентов, ранее уже получавших терапию.1,2 С телапревиром проведено 3 исследования III фазы, включая ADVANCE и ILLUMINATE у больных, не получавших ранее лечения,3,4 и REALIZE у пациентов, не достигших ответа на первый курс терапии. Результаты последнего исследования не были представлены на конференции, однако информация для СМИ была подготовлена за несколько недель до того, как был проведен отбор материалов для конференции (информация по исследованию доступна на сайте: investors.vrtx.com/releasedetail.cfm?ReleaseID=505239). Результаты этих 5 исследований дают надежду на повышение частоты излечения у больных, инфицированных HCV генотипа 1 (HCV-1), когда эти комбинации препаратов поступят на рынок. Они также вызывают ряд вопросов и сомнений. В настоящем обзоре обобщаются результаты исследований III фазы, представленные на конференции, а также обсуждается внедрение новых схем лечения в современную клиническую практику наряду с некоторыми нерешенными вопросами, возникшими на фоне полученных результатов.
Список литературы:
Poordad F, McCone J, Bacon BR, et al. Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-na?ve patients with hepatitis C virus (HCV) genotype 1: SPRINT-2 final results. Hepatology 2010;52(suppl):402A.
Bacon BR, Gordon SC, Lawitz E, et al. HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin. Hepatology 2010;52(suppl):430A.
Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-na?ve patients: final results of Phase 3 ADVANCE study. Hepatology 2010;52(suppl):427A.
Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study. Hepatology 2010;52(suppl):401A.
Kieffer TL, Bartels DJ, Sullivan J, et al. Clinical virology results from telaprevir Phase 3 study ADVANCE. Hepatology 2010; 52(suppl):879A.
Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010;376:705–716.
Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology 2010 Oct 26 [Epub ahead of print].
Montaudie H, Passeron T, Cardot-Leccia N, et al. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology 2010;221:303–305.
Benhamou Y, Moussali J, Ratziu V, et al. Results of a proof of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 4 HCV patients. J Hepatol 2009;50(suppl 1):S6.
Foster GR, Hezode C, Bronowicki JP, et al. Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-na?ve genotype 2 and 3 hepatitis C patients: interim results of study C209. J Hepatol 2009;50(suppl 1):S22.
Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–1850.
Zeuzem S, Sulkowski MS, Zoulim F, et al. Long-term follow-up of patients with chronic hepatitis C treated with telaprevir in combination with peginterferon alfa-2a and ribavirin: interim analysis of the EXTEND study. Hepatology 2010;52(suppl):436A.
Chevaliez S, Soulier A, Hezode C, et al. The IL28B genotype is a major determinant in the induction of a virological response by high-dose peginterferon and ribavirin in null-responders to standard-of-care therapy. Hepatology 2010;52(suppl):383A.
Lok AS, Gardiner DF, Lawitz E, et al. Combination therapy with BMS-790052 and BMS-650032 alone or with PegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. Hepatology 2010;52(suppl):877A.
Zeuzem S, Buggisch P, Agarwal K, et al. Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment-na?ve, genotype 1 HCV subjects. Hepatology 2010;52(suppl):400A.
Overview of SVR Results
The primary endpoint of the study was SVR in each of the two telaprevir arms compared to the control arm, as well as across the three subgroups of people included in the study. One of the telaprevir treatment arms was designed to evaluate, for the first time, whether there was any further improvement in viral cure rates when delaying the start of telaprevir by four weeks, during which time patients received four weeks of pegylated-interferon and ribavirin alone, compared to a simultaneous start. The SVR rates between these two arms were similar and there was no clinical benefit to the telaprevir delayed start treatment arm in any of the subgroups of patients. The table below combines the two telaprevir arms compared to the control.
Telaprevir- based Treatment Arms+
Relapsers (n=354) 86%* (n=245/286)
Partial Responders (n=124) 57%*(n=55/97)
Null Responders (n=184) 31%*(n=46/147)
Overall (ITT) (n=662) 65%*(n=346/530)
*Combined endpoint analysis: The SVR rates observed in the overall combined telaprevir-based arms were statistically significant when compared with the control arm (p < 0.0001). Additionally, the SVR rates observed in each of the three groups of patients evaluated were statistically significant when compared with the control arm (relapsers and partial responders (p<0.0001) and null responders (p<0.001)).
+Reflects SVR rates from the combined telaprevir-based treatment groups. There were two telaprevir-based treatment groups:
1. 12 weeks of telaprevir (750 mg, q8h), pegylated-interferon (Peg-IFN) & ribavirin (RBV), followed by 36 weeks of Peg-IFN & RBV alone or
2. 4 weeks of Peg-IFN & RBV alone followed by 12 weeks of telaprevir (750 mg, q8h), Peg-IFN & RBV, followed by 32 weeks of Peg-IFN & RBV alone
++12 weeks of placebo, Peg-IFN & RBV, followed by 36 weeks of Peg-IFN and RBV alone
**Supplemental analysis
Null Responder: Defined as a person who achieved a less than 2 log10 reduction in HCV RNA at week 12 of a prior course of therapy.
Relapser: Defined as a person whose hepatitis C virus was undetectable at the completion of at least 42 weeks of a prior course of therapy but whose virus became detectable during the follow-up period.
Partial Responder: Defined as a person who achieved at least a 2 log10 reduction at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy.
Backgrounders on hepatitis C treatment response and the REALIZE study (including trial design diagram) can be found at http://investors.vrtx.com/press.cfm
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