hepatitisc virus hcv direct acting antivirals

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

[email protected]


Hepatitis C virus (HCV) infection is a major health problem worldwide

(Hajarizadeh et al., 2013; Bruggmann et al., 2014).

HCV


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


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



Consequences includeCirrhosis,

end-stage liver disease,

and hepatocellular carcinoma.

(Fenney and Chung, 2014; Webster et al., 2015.)

Introduction



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).



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).



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)


Since the discovery of HCV, there have been several developments in treating HCV patients.(de Kanter et al., 2014)


RestIn

Peace


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.


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

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

HCV structure and site for DAAs


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”



Cure rates can be optimized by

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

(Pawlotsky, 2014).


Sofosbuvir has

low toxicity,high barrier to resistance,and minimal drug interactions with other DAAs

Introduction


making it the ideal candidate to become backbone for several IFN-free regimens.

(Kayali and Schmidt, 2014; Bourliere el al., 2014


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


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


www.hep-druginteractions.org


Hep iChart


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


However, SVR is relatively lower in patients with cirrhosis (80%).

(Papastergiou and Karatapanis, 2015)


103 patients:SVR12:

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

(Doss et al., 2015)

Sofosbuvir and Ribavirin 24w


Simeprevir is efficacious and generally well tolerated in patients with chronic HCV infection (genotypes 1 and 4). (Sanford, 2015)

Introduction


Skin rashes with SMV are mostly mild or moderate; serious photosensitivity reactions occur.


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


(Kowdley et al., 2014).

SVR … 94%


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)


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)

hepatitisc virus hcv direct acting antivirals

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hcv daas

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hcv structure

epidemiology of hcv

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mohammad farouk