الفهرس 
Introduction, Pathophysiology and Epidemiology of HCVOnly 14 pages are availabe for public view
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Abstract
H
epatitis C virus (HCV) infection is treated with oral drugs termed ”direct-acting antiviral agents” (DAAs). Globally, DAA based regimens have obtained excellent rate of cure (Grebely et al., 2017). Cure of HCV infection is defined as undetectable HCV RNA 12 week after stopping drugs, also referred to as sustained virological response (SVR 12) (Cheung et al., 2016). Despite using these DAA based treatment regimens, a number of people fail to achieve SVR 12, and HCV RNA appear after few weeks of stopping the drugs (Pawlotsky, 2016).
Appearance of resistance to DAAs is disappointing to the clinicians and the patients yet referring to treatment centers again and choosing the proper re-treatment regimen according to the available protocol of treatment may solve this problem (El Kassas et al., 2018).
Velpatasvir is metabolized in vitro by CYP2B6, CYP2C8 and CYP3A4. However, because of the slow turnover, the vast majority of drug in plasma is the parent drug. Importantly, velpatasvir is transported by P-gp and BCRP and, to a limited extent, by organic anion transporting polypeptide (OATP). Biliary excretion of the parent drug is the major route of elimination. The median terminal half-life of velpatasvir following administration of sofosbuvir and velpatasvir is approximately 15 hrs. Velpatasvir plasma exposure (AUC) is similar in subjects with moderate and severe hepatic impairment compared to subjects with normal hepatic function. Cirrhosis (including decompensated cirrhosis) has no clinically relevant effect on velpatasvir exposure in a population pharmacokinetic analysis in HCV - infected individuals (Minutolo et al., 2018).
Voxilaprevir is metabolised in vitro by CYP3A4, with the vast majority of drug in plasma being the parent drug the pharmacokinetics of single dose voxilaprevir were also studied in patients with moderate and severe hepatic impairment (Child – Pugh B and C, respectively). Relative to patients with normal hepatic function, the voxilaprevir AUC was 3-fold and 5-fold higher in patients with moderate and severe hepatic impairment, respectively. Thus, the combination of sofosbuvir, velpatasvir and voxilaprevir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and contraindicated in those with severe hepatic impairment (Child-Pugh C) (Minutolo et al., 2018).
Patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis who failed after a DAA (protease inhibitor and/or NS5A inhibitor) containing regimen should be retreated with the fixed-dose combination of sofosbuvir, velpatasvir and voxilaprevir for 12 weeks (Pearlman and Hinds, 2018).
Patients with decompensated (Child-Pugh B or C) cirrhosis who failed after a DAA (protease inhibitor and / or NS5A inhibitor) - containing regimen have a contraindication for the use of protease inhibitors, and should therefore be retreated with the fixed - dose combination of sofosbuvir and velpatasvir with weight - based ribavirin (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively) for 24 weeks (Pearlman and Hinds, 2018).
Treatment outcome will be categorized as: Success SVR at week 12. Treatment failure (any detectable HCV RNA) after the end of 24 week treatment duration (Cheung et al., 2016).
The goal of therapy is to cure HCV infection in order to: (i) Prevent the complications of HCV-related liver and extra – hepatic diseases, including hepatic necroinflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic manifestations and death. (ii) Improve quality of life and remove stigma. (iii) Prevent onward transmission of HCV (Martinot‐Peignoux et al., 2010).