New direct-active antiviral agents for hepatitis C virus - ESCMID

39 Pages·2013·1.05 MB·English

by  Joop Arends

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New direct-active antivriral agents
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for hepatitis C virues infection in

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previous treatment failure patients
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©
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C Joop Arends
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Dept. of Internal Medicine and Infectious Diseases
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University Medical Center Utrecht
the Netherlands
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Hepatitis C – the facts r
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• single stranded RNA-
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virus
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- quasispecies e h
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• 6 genotypes
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Worldwide presence of HCV r
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Outcome of therapy in pre-DAA era r
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treatment

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Torriani et al. NEJM 2004
Manns Lancet 2001,
Carrat et al. JAMA 2004
Fried N Eng J Med 2002, HCV mono HCV co
Chung et al. NEJM 2004
Hadzyannis Ann Intern Med 2004
Nunez et al. AIDS Res Hum Retroviruses 2007
Definitions of non-response to
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pegIFN/ RBV therapy
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Null response
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R O yP artial response e drop
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Detection limit
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0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Weeks
Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52
Neumann A, et al. Science 1998;282:103–7
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HCV lifecycle and DAA targets r
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Receptor binding t
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Fusion
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uncoating i
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TranNslSa3ti/o4n and LD
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Membranous
pporloytperaostee in NS5B polymerase
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pinrohcibeistosrins g inhibitors
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NS5A* inhibitors
* Role in HCV lifecycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Better knowledge of HCV enzymes
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targeted by specific inhibitors
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non-
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Asselah et al. Liver Int. 2012
Boceprevir and Telaprevir -
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Clinical Trials
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• Phase III trials leading to approval
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- Boceprevir plus pegIFN/ RBV
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• SPRINT-2: treatmente-naive patiehnts[1]
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• RESPOND-2: ntlreatment-eaxperienced patients[2]
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- Telaprevir plus p© egIFN/ RBV
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• ILLUMINATE: treatment-naive patients[4]
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• REALIZE: treatment-experienced patients[5]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 2010 AASLD. Abstract LB2. 5. Zeuzem
S, et al. N Engl J Med. 2011;364:2417-2428.
Addition of new DAA’s leads to heigher y
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SVR and shorter length of therapy
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P / R P / R / protease
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previous non-responders
1. Poordad F, et al. NEJM 2011. 2. Jacobson IM, et al. NEJM 2011. 3. Bacon BR, et al. NEJM 2011. 4. Mchutchison J., et
al. NEJM 2011.
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