HepatitisC virus HCV Direct Acting Antivirals
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Transcript of HepatitisC virus HCV Direct Acting Antivirals
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M.Farouk .. HCV DAAs 2015
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M.Farouk .. HCV DAAs 2015
Keep calm and thank you for listening and your attention
By
Mohammad Farouk
M.Sc., Specialist of Tropical medicine and Gastroenterology
Assiut Center for Control of Viral Hepatitis
Direct Acting Antivirals
2015
HCV
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M.Farouk .. HCV DAAs 2015
Hepatitis C virus (HCV) infection is a major health problem worldwide
(Hajarizadeh et al., 2013; Bruggmann et al., 2014).
HCV
Keep calm and thank you for listening and your attention
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with estimated
130-170 millionpeople to have chronic infection; (Hajarizadeh et al., 2013; Bruggmann et al., 2014).
HCV
Keep calm and thank you for listening and your attentionM.Farouk .. HCV DAAs 2015
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M.Farouk .. HCV DAAs 2015
the highest reported prevalence is in
Egypt (>10%)with the largest number of patients in a single
country reported from
China (29.8 millions)(Hajarizadeh et al., 2013; Bruggmann et al., 2014).
HCV
Introduction
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M.Farouk .. HCV DAAs 2015
Consequences includeCirrhosis,
end-stage liver disease,
and hepatocellular carcinoma.
(Fenney and Chung, 2014; Webster et al., 2015.)
Introduction
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M.Farouk .. HCV DAAs 2015
HCV-genotype 4 (HCV-4) is the predominant subtype in Egypt representing >80% of the chronic HCV infection; it is also highly prevalent in sub-Saharan Africa and in the Middle East(Antaki et al., 2010).
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M.Farouk .. HCV DAAs 2015
The epidemiology of HCV-4 has changed, and this genotype has crossed borders to spread in several regions in Europe through immigration and injection drug use.(Kamal, 2011).
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M.Farouk .. HCV DAAs 2015
The standard of care was combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) that resulted in a sustained virologic response (SVR) of approximately 50% meanwhile, associated with significant adverse events.(Yau and Yoshida, 2014; Webster et al., 2015)
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Since the discovery of HCV, there have been several developments in treating HCV patients.(de Kanter et al., 2014)
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M.Farouk .. HCV DAAs 2015
RestIn
Peace
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M.Farouk .. HCV DAAs 2015
Advances in HCV cell culture have enabled an improved understanding of HCV virology, which led to development of many new direct-acting antiviral drugs (DAAs) that target key components of virus replication.
Keep calm and thank you for listening and your attention
Such newly approved DAAs allow for* efficacious,* convenient,* and safe treatment
(Schinazi et al., 2014; Kayali and Shmidt, 2014; Webster et al., 2015).
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M.Farouk .. HCV DAAs 2015
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M.Farouk .. HCV DAAs 2015
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M.Farouk .. HCV DAAs 2015
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M.Farouk .. HCV DAAs 2015
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HCV structure and site for DAAs
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M.Farouk .. HCV DAAs 2015
NS3 /4A Inhibitors (Protease inhibitorI)High potencyLimited genotypic coverage
Low barrier to resistance
NS5A Inhibitors High potencyMulti-genotypic coverageIntermediate barrier to resistance
NS5B Nucleos(t)ide Inhibitors (NI)Intermediate potencyPan genotypic coverageHigh barrier to resistance
NS5B Non Nucleoside Inhibitors (NNI) Intermediate potency
Limited genotypic coverageLow barrier to resistance
Directly Acting Antivirals “DAAs”
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M.Farouk .. HCV DAAs 2015
Keep calm and thank you for listening and your attention
Cure rates can be optimized by
* combining drugs with synergistic antiviral effects,* and modifying treatment duration.
(Pawlotsky, 2014).
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M.Farouk .. HCV DAAs 2015
Sofosbuvir has
low toxicity,high barrier to resistance,and minimal drug interactions with other DAAs
Introduction
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making it the ideal candidate to become backbone for several IFN-free regimens.
(Kayali and Schmidt, 2014; Bourliere el al., 2014
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M.Farouk .. HCV DAAs 2015
Sofo
sbuv
ir
Ribavirin
DaclatasvirLedipasvir
INFSimeprevir
Paritaprevir/ritonavir/
ombitasvir
•Simeprevir•Daclatasvir•Paritaprevir/ritonavir/
ombitasvir/dasabuvir
EASLAASLD
•Daclatasvir
•SMV + INF + RBV
•SOF + SMV + RBV
•SOF + RBV…24w
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M.Farouk .. HCV DAAs 2015
Genotype 4
2015AASLD EASL
sofosbuvir/ledipasvir … 12 w
paritaprevir/ritonavir/ombitasvir+ribavirin … 12 w
sofosbuvir/ribavirin … 24 w
sofosbuvir/ INF & ribavirin … 12 w
sofosbuvir/simeprevir ± ribavirin … 12 w
sofosbuvir/ledipasvir … 12 w
paritaprevir/ritonavir/ombitasvir + ribavirin… 12 w
sofosbuvir/simeprevir … 12 w
Sofosbuvir/daclatasvir … 12 w
sofosbuvir/ INF & ribavirin … 12 w
simeprevir/ INF & ribavirin … 12 w
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M.Farouk .. HCV DAAs 2015
www.hep-druginteractions.org
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M.Farouk .. HCV DAAs 2015
Hep iChart
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M.Farouk .. HCV DAAs 2015
The 12 weeks (wk) regimen of SOF plus Peg-IFN/RBV results in 96% SVR rate in patients infected with HCV-4.(Lawitz et al., 2013)
Introduction
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However, SVR is relatively lower in patients with cirrhosis (80%).
(Papastergiou and Karatapanis, 2015)
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M.Farouk .. HCV DAAs 2015
103 patients:SVR12:
Cirrhosis ………. 78%without cirrhosis ………. 93%
(Doss et al., 2015)
Sofosbuvir and Ribavirin 24w
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M.Farouk .. HCV DAAs 2015
Simeprevir is efficacious and generally well tolerated in patients with chronic HCV infection (genotypes 1 and 4). (Sanford, 2015)
Introduction
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Skin rashes with SMV are mostly mild or moderate; serious photosensitivity reactions occur.
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M.Farouk .. HCV DAAs 2015
HCV-1
Treatment-naïve patientswithout cirrhosis andbaseline viral levels of less than 6 million IU/mL may be considered for
8 weeks of treatment.
Introduction
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(Kowdley et al., 2014).
SVR … 94%
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M.Farouk .. HCV DAAs 2015
Daclatasvir and Sofosbuvir
•14/14 … 100% … 24w, -ribavirin, naiive
•15/15 … 100% … 24w, +ribavirin, naiive
•21/21 … 100% … 24w, -ribavirin, nullresponder
•19/21 … 95% … 24w, +ribavirin, null responder
•40/41 … 98% … 12w, -ribavirin, naiive
(Sulkowski et al., 2014)
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M.Farouk .. HCV DAAs 2015
ritonavir-boosted paritaprevir and ombitasvir with ribavirin
PEARL-I trialgenotype 4 treated for 12 weeks
•treatment-naïveSVR12 in 100% (42/42)
•treatment-experienced.SVR12 in 100% (49/49)
(Pol et al., 2014)
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M.Farouk .. HCV DAAs 2015