HepatitisC virus HCV Direct Acting Antivirals

M.Farouk .. HCV DAAs 2015

M.Farouk .. HCV DAAs 2015

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By

Mohammad Farouk

M.Sc., Specialist of Tropical medicine and Gastroenterology

Assiut Center for Control of Viral Hepatitis

Direct Acting Antivirals

2015

HCV

Dr.mfarouk.git@hotmail.com

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

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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

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)

M.Farouk .. HCV DAAs 2015

RestIn

Peace

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.

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Such newly approved DAAs allow for* efficacious,* convenient,* and safe treatment

(Schinazi et al., 2014; Kayali and Shmidt, 2014; Webster et al., 2015).

M.Farouk .. HCV DAAs 2015

M.Farouk .. HCV DAAs 2015

M.Farouk .. HCV DAAs 2015

M.Farouk .. HCV DAAs 2015

HCV structure and site for DAAs

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”

M.Farouk .. HCV DAAs 2015

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Cure rates can be optimized by

* combining drugs with synergistic antiviral effects,* and modifying treatment duration.

(Pawlotsky, 2014).

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

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

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

M.Farouk .. HCV DAAs 2015

www.hep-druginteractions.org

M.Farouk .. HCV DAAs 2015

Hep iChart

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)

M.Farouk .. HCV DAAs 2015

103 patients:SVR12:

Cirrhosis ………. 78%without cirrhosis ………. 93%

(Doss et al., 2015)

Sofosbuvir and Ribavirin 24w

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.

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%

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)

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)

M.Farouk .. HCV DAAs 2015