الفهرس 
? HCV and Protocol of TreatmentOnly 14 pages are availabe for public view
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Abstract
What is already known on this subject? AND
What does this study add?
Therapy of hepatitis C has been revolutionized by Direct Antiviral Agents. These drugs are safe and efficacious in infected patients, and are currently largely used in clinical practice worldwide.
It was therefore cause of great concern the publication of two reports suggesting that treatment with DAAs could increase the risk of hepatocellular carcinoma in cirrhotic patients, particularly in those receiving antiviral therapy after having been cured form HCV.
1. INTRODUCTION/ REVIEW
Incidence of Hepatocellular carcinoma (HCC) has rapidly increased world wide. HCC is the sixth most common malignancy and the third most common cause of cancer related death (Kadalayil et al;2013). In Egypt, liver cancer forms 23.81% of the total malignancies. HCC constitutes 70.48% of all liver tumors among Egyptians (Forner et al;2012).Recent investigations in Egypt have shown the increasing importance of HCV infection in the etiology of liver cancer, estimated to account for 40–50% of cases (Shaker et al., 2013)
Chronic infection with HCV is the leading cause of end-stage liver disease, HCC and liver-related death in Egypt. HCV causes chronic hepatitis in 60%–80% of the patients, and 10%–20% of those patients develop cirrhosis over 20–30 years of HCV infection. About 1%–5% of the patients with liver cirrhosis may develop HCC and 3%–6% may decompensate during the following 20–30 years. The risk of death in the following year after an episode of decompensation is between 15% and 20%(Westbrook et al; 2015).
Direct-acting antiviral agents for chronic hepatitis C have initiated a revolution in the management and control of this important liver disease with cure rates over 90%(AASLD/IDSA Hepatitis C guidance,2015 ) &(Conti et al; 2016).
The easy of administration, short duration of treatment, excellent tolerance and absence of severe side effects have made therapy of hepatitis C appropriate to all patients with chronic hepatitis C with different stages of disease severity(Hoofnagle et al;2016).Highly effective DAAs were expected to dramatically decrease HCV related liver disease progression to end-stage liver disease and HCC(Fosteret al;2016.
In fact, the risk of developing HCC continues to persist in those patients with HCV cirrhosis even after they have achieved SVR.(Brown etal; 2016).However, it has been suggested that HCC may occur or recur in patients with chronic HCV infection who received DAAs therapy. Because this phenomenon was not seen in patients treated with interferon or ribavirin, some experts speculate that these novel DAAs may in fact play a significant role in tumor development.(Fosteret al; 2016) However, data on HCC risk following DAAs are still sparse and conflicting.(El-serag et al;2016).
For decades of years, there were a lot of studies explored the relationship of polymorphisms of candidate gene and HCC. Single Nucleotide Polymorphism (SNP) a genetic polymorphism between two genomes that is based on deletion, insertion, or exchange of a single nucleotide.
It is assumed that a decreased ability to eliminate cells with DNA damage may facilitate the accumulation of somatic mutations, and thereby contribute to tumor initiation, progression, and metastasis (Kountouras et al; 2003). There are considerable inter-individual variations in apoptotic capacity, which are largely attributed to an individual’s genetic constitution (Camplejohn et al ;2006) .
Many studies have demonstrated that several polymorphisms in apoptosis-related genes affect either the expression or the activities of enzymes, and thus associated with the risk of various human cancers, including HCC (Deng et al; 2013) Accordingly, it is reasonable to suggest that alterations in apoptotic capacity related polymorphisms of apoptosis-related genes could affect prognosis of patients with HCC. However, evidence is still limited to the demonstration of the effects of apoptotic gene-related polymorphisms on the prognosis of HCC.
There is a genome wide level of significance in the association of a TLL1 variant and hepatocarcino genesis in CHC patients after eradication of HCV. Therefore, genetic testing of the TLL1 variant would be useful for implementing personalized surveillance of HCC in patients who have achieved SVR. (Matsuura et al., 2017)
2. AIM/ OBJECTIVES
To Evaluate The Role Of Genetic Polymorphism In development Of Hepatocellular Carcinoma In Patients Achieving Sustained Virological Response (SVR) After Direct Acting Antiviral Drugs (DAADs) for HCV.
3. METHODOLOGY:
Patients and Methods/ Subjects and Methods/ Material and Methods
Type of Study: CASE COHORT study
Study Setting: Tropical medicine department in Ain Shams University hospitals.
Study Period: one year from the start of treatment
Study Population: 100 patients who achieved SVR after receiving SOF/DAC± Ribavirin For HCV infection.
group A: patients achieved SVR after DAADs without development of HCC.
group B: patients achieved SVR after DAADs with development of HCC.
- inclusion criteria :-
1. Cirrhotic patients who achieved of SVR Confirmed by negative HCV PCR at 1 and 3 month after end of treatment.
2. Age >18 year
-exclusion criteria:-
1. Patients with other etiology of liver disease except HCV
2. patients with previously treated HCC
3. patients with extra hepatic tumors.
Sample method :- Convenience sampling
Sample Size:- 100 patients
Ethical Considerations :- the patient should be informed that they are included in our study to evaluate the genetic susceptibility for development of HCC after achieving SVR after DAAs
Study Interventions:-
All included patients will be subjected to the following:-
1- Full history taking : with detailed history regarding the used regimen of DAADs including doses and duration and side effects if occur.
2- Full examination:- general including signs of LCF and local abdominal examination including liver, spleen and ascites
3- Laboratory investigations:- CBC, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) , serum total bilirubin , serum albumin and prothrombin time (Pt), serum creatinine, alphafetoprotein
4- HCV PCR at 1 and 3 months after end of treatment
5- Abdominal U/S at 1, 3 and 6 months after end of treatment.
6- Assessment of fibrosis : FIB-4 INDEX and APRI SCORE will be calculated for all patients and transient elastography if available.
7- Triphasic CT abdomen with contrast in suspected cases of HCC.
8- The patients will be tested for Single Nucleotide polymorphism (SNP) rs17047200 in TLL1 gene:-
⮚ Sample collection: whole blood will be collected from all patients and will be centrifuged to separate the buffy coat.
⮚ Genome DNA will be extracted from the buffy coat using a QiA Amp DNA blood mini kit (Qlagen, Germany).
⮚ Extraction of DNA: will take place in biosafety cabinets level II ( lobanco USA ) according to the manufactures instructions .
⮚ DNA sample obtained will be preserved at -80 c until further use .Genetic polymorphism of SNPs will be genotyped using Togman SNP genotyping Assays via a7500 Fast real-time PCR system (Applied biosystems , Foster city CA. USA ).
⮚ All laboratory work will be done at the Molecular and genetic unit of Medical Ain Shams research Inistitute ( MASRI).
Diagnosis of HCC :-
a- Abdominal ultrasound with doppler to detect :- hepatic focal lesions (size ,number, site, echogenecity, relation to surrounding and cystic or solid ), Detection of abdominal lymphadenopathy, vascular invasion by the tumor.
b- CT triphasic pelviabdominal: for diagnosis of HCC through the criteria of enhancement in the early arterial phase and washout in portovenous and delayed phases compared to the rest of the liver ( Ghanaati et al., 2012).also to detect size ,number , site of Hepatic focal lesion and the presence of vascular invasion.
c- Dynamic MRI with heavy T2 diffusion : To diagnose HCC that can’t be assessed or not conclusive in The triphasic PA CT .(Kanematsu et al., 2012).
● Statistical Analysis :- chi-square test will be used to compare between groups with qualitative data
● Statistical Package:- data will be collected, revised, coded and entered to the statistical package for social science SPSS version 23 the data will be presented as number and percentage.