الفهرس 
Size and main function of HCV proteins. MW, molecular weight in kd (kilodalton)Only 14 pages are availabe for public view
Abstract
he increasingly widespread use of direct-acting antiviral (DAAs) has constituted a major breakthrough in the treatment of hepatitis C virus (HCV) infection, because of the high rates of sustained virological response (SVR) achieved and an excellent safety profile (Pawlotsky , 2014).
The eradication of HCV in patients with cirrhosis is associated with a reduced occurrence of life-threatening complications, whether liver-related or even extrahepatic, and subsequently improved survival (Nahon et al., 2018).
These conclusions have so far been restricted to patients with cirrhosis who achieved SVR following an interferon (IFN)-based regimen, in whom hepatocellular carcinoma (HCC) screening is, however, still recommended considering the persistence of an annual incidence of liver cancer ranging from 0.4% to 2% in these patients. The observation of such clinical outcomes indeed necessitates the long-term follow-up of large patient cohorts to accurately assess the potential benefits of viral eradication in the longer term and to perform accurate analyses that take account of competing risks of death (Trinchet et al., 2015).
The purpose of this study was to clarify the possible effect of DAAs treatment on development of HCC in HCV cirrhotic patients.
In order to achieve this goal, this study was conducted on 400 chronic hepatitis C cirrhotic patients divided into two groups according to treatment with DAAs, group I including (200 Patients with chronic HCV cirrhosis treated with DAAs),and group II including (200 patients with chronic HCV cirrhosis without DAAs treatment), all patients were recruited from the gastroenterology and hepatology department Kobry Elkobba military hospital, all patients were males of age group between 18 & 70 years old with no previous history of HCC, HIV or HBV infection or history of liver transplantation.
After one year of follow up . all patients were devided into further two subgroups according HCC development, group III ( 11 HCV cirrhotic patients treated with DAAs (sofosbuvir and daclatasvir) and developed HCC) and group IV (22 HCV cirrhotic patients not treated and developed HCC).
In this study, there is no significant difference between the baseline characteristics to exclude confounding factors, similar results were detected by Bourcier et al., (2018) who documented that there is no significant difference between the baseline characteristics for the study groups, considering time of enrollment for non-treated patients group and time at initiation of treatment for DAA groups.
In this study, no statistical significant difference between treated and non treated groups as regards age, similar results were detected by Ioannou et al., (2017), Nahon et al., (2018) and Calvaruso et al., (2019) who reported the same results and concluded that there is no significant difference between the baseline characteristics for the study groups as regards age.
In this study, no statistical significant difference between studied patients as regards clinical picture (ascites, lower limb edema, splenomegaly and jaundice), similar results were detected by Innes et al., (2017) who documented that there is no significant difference between study groups at the baseline characteristics as regards clinical picture.
In the present study, no statistical significant difference between studied patients as regards complete blood count, similar results were detected by Kanwal et al., (2017) who documented that there is no significant difference between study groups as regards complete blood count, also, Innes et al., (2017) and Calvaruso et al., (2018) documented that there is no significant difference between study groups at the baseline characteristics as regards platelets.
In this study, no statistical significant difference between studied patients as regards liver and kidney function tests (ALT, AST, total bilirubin, direct bilirubin , INR, Albumin, creatinine), similar results were detected by Layese et al., (2018) who documented that there is no significant difference between study groups as regards ALT, AST , total Bilirubin and direct bilirubin, also, Ioannou et al., (2017) and Bourcier et al., (2018) documented that there is no significant difference between treatment and control groups as regards INR, prothrombin time and Albumin, in addition to Ioannou, et al., (2017) and Cagnot et al., (2018) who documented that there is no significant difference between treatment and control groups as regards Creatinine (P = 0.68).
In this study, no statistical significant difference between studied patients as regards alpha-fetoprotein (AFP), similar results were detected by Layese et al., (2018) who documented that there is no significant difference between study groups as regards alpha-fetoprotein.
In this study, no statistical significant difference between studied patients as regards Ultrasonograhic findings (hepatomegaly, splenomegaly, PV diameter and ascites), this goes in agreement with Bourcier et al., (2018) who documented the same results.
In this study, no statistical significant difference between studied patients as regards Child classification, similar results were detected by Bourcier et al., (2018) who documented that there is no significant difference between the baseline characteristics for the study groups, considering Child classification.
In this study, no statistical significant difference between studied patients as regards osophageal varices (OV) and Portal hypertensive gastropathy (PHG), similar results were detected by Singer et al., (2018) who documented the same results.
After one year of follow up HCC developed more in not treated group with a significant difference between treated and not treated groups , as 11% of not treated group developed HCC compared to 5.5% only of treated group, similar results were detected by Ioannou et al., (2017) who documented that HCC incidence was lower in the treated group who achieved SVR (0.43 per 100 patient-years) than in control group (1.15 per 100 patient-years), also, Kanwal et al., (2017) documented that HCC developed in 183 patients with treatment during follow up at an annual incidence of 0.90 (or 0.90%, 95% CI, 0.77-1.03%), this rate was considerably lower than the 3.45 incidence rate in patients without treatment (3.45%, 95% CI, 2.73-4.18), in addition to Nahon et al., (2018) who documented that there is a significant difference between treatment and control groups as regards HCC occurrence as number of patients with HCC at treatment group was 15 patients (4.5%) while number of patients with HCC at not treated group was 154 patients (35.1%) (P<.001), also, Buonomo et al., (2020) documented that direct acting antivirals treatment for hepatitis C virus infection does not increase the incidence of de novo hepatocellular carcinoma occurrence.
In this study, non treated group alpha-fetoprotein (AFP) is higher than treated group with a statistical significant difference, similar results were detected by Nahon et al., (2018) who documented that there is a significant difference between treatment and control groups as regards after treatment alpha-fetoprotein as mean AFP level in HCC cases at treatment group is 9.0 [4.4–35.1] ng/mL and in non treated group is 19.6 [8.2–102.0] ng/mL with (P <.001).
In this study, treated group with HCC (group III) hemoglobin is higher than non treated group with HCC (group IV) with statistical significant difference, this can be explained as patients treated with DAAs were followed up with complete blood count monthly to follow the possibility of drug induced hemolysis and they received medical treatment to guard against anemia, also non treated patients showed higher rates of decompensation and bleeding tendency, similar results were detected by Kanwal et al., (2017) who documented that there is a significant difference between study groups as regards after treatment Hemoglobin.
In this study, no statistical significant difference detected between treated group with HCC (group III) and non treated group with HCC (group IV) as regards white blood cells count and Platelets, Kanwal et al., (2017) detected similar results that there is no significant difference between treated group with HCC and nontreated group with HCC as regards white blood cells, also, Innes et al., (2017) documented that there is no significant difference between study groups as regards platelets.
In this study, non treated group with HCC (group IV) total bilirubin is higher than treated group with HCC (group III) with statistical significant difference, this can be explained by improvement in progression of cirrhosis after DAAs treatment, Reddy et al., (2018) documented that there is statistical significant difference regarding bilirubin as treated patients with HCC group total bilirubin was lower than untreated patients with HCC group (P <. 001), also, Pereira et al., (2020) documented that DAA-induced SVR remains durable and is associated with an excellent clinical prognosis in patients with compensated advanced liver disease and with improvement or disease stabilization in decompensated patients. SVR is associated with a low risk of HCC occurrence or disease progression, especially in the presence of other causes of liver injury, in addition to Buonomo et al., (2020) DAAs have a great efficacy in the eradication of HCV infection, these treatments were also effective in reducing the incidence of several complications of cirrhosis, such as ascites, jaundice and encephalopathy.
Also, non treated group with HCC (group IV) creatinine is higher than treated group with HCC (group III) with statistical significant difference. Similar results were detected by Reddy et al., (2018) who documented that there is statistical significant difference regarding creatinine as treated patients with HCC group creatinine was lower than untreated patients with HCC group (P < 001). Also Ana et al., (2020) documented that DAA treatment in patients with HCV improves kidney survival and reduces creatinine.
Although there is no statistical significant difference between treated group with HCC (group III) and non treated group with HCC (group IV) as regards ALT, AST, direct bilirubin, albumin and INR, similar results were detected by Osinusi1 et al., (2018) who documented that there is no statistical significant difference in ALT , AST and albumin between study groups and Buti et al., (2018) who documented that there is no statistical significant difference regarding prothrombin time and INR between the studied groups.
In this study, using univariate cox regression, it was shown that no treatment was an independent factor affecting the risk of getting hepatocellular carcinoma (HCC), as cases not receiving the study treatment are at higher risk for developing HCC (HR=3.4, P=0.002), this goes in agreement with Singer et al., (2018) who documented that after implementation of inverse probability of treatment weighting and further adjustment for age, gender, baseline medical conditions (including liver conditions such as cirrhosis, portal hypertension and thrombocytopenia) and baseline medication use, the results were indicative of a reduced risk of liver cancer after DAA treatment (adjusted HR = 0.84, 95% CI: 0.73- 0.96), also, Buonomo et al., (2020) documented that direct acting antivirals treatment for hepatitis C virus infection does not increase the incidence of de novo hepatocellular carcinoma occurrence, in addition to Pereira et al., (2020) who documented that DAA-induced SVR remains durable and is associated with an excellent clinical prognosis in patients with compensated advanced liver disease and with improvement or disease stabilization in decompensated patients. SVR is associated with a low risk of HCC occurrence or disease progression, especially in the presence of other causes of liver injury, also, Shiha et al., (2020) documented that the incidence of HCC is reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA treatment. Study of large prospective cohort of HCV patients treated by DAAs with long follow-up period which showed that the annual incidence of HCC is 2.9/100 per year (PY) in cirrhotic patients who achieved SVR following direct-acting antiviral treatment for hepatitis C. Also showed that treatment with DAAs is associated with reduced risk of HCC (2.72/100 py in patients with cirrhosis) compared with HCC incidence of 3.70/100 py in cirrhotic patients who did not receive DAAs.
SUMMARY
D
irect-acting antivirals (DAAs) against hepatitis C virus (HCV) elicited great enthusiasm worldwide for their effectiveness in eradicating the infection since the first available trials.
In fact, treatment with DAAs leads to sustained virologic response at 12 weeks post-treatment (SVR12) in up to 99% of treated patients with few adverse drug reactions.
Such great enthusiasm has been undermined in the first years of DAAs availability due to the aroused question of possible high risk of hepatocellular carcinoma development during and after treatment administration.
Several studies indeed reported high rates of both HCC occurrence and recurrence, first related to DAAs administration. However, all these studies had significant bias, such as the small sample size and the retrospective design. Moreover, the authors often reported incidence rates of HCC that were actually not different from the known incidence rate of HCC among the whole HCV-infected population, which is estimated to be approximately 2%to 8%.
In fact, in a recent review of these studies the risk of HCC recurrence among patients who received DAAs therapy was evaluated and no significant conclusion can be drawn, due to the above-mentioned bias of the available studies. Large prospective study was advocated for what concerns the risk of de novo HCC occurrence.
In such a doubtful setting, results from prospective real-life cohorts are needed to estimate whether a significant association between DAAs and HCC occurrence really exists.
In order to achieve this goal, this study was conducted on 400 chronic hepatitis C cirrhotic patients selected from 8300 patients according to inclusion and exclusion criteria, divided into two groups according to treatment with DAAs, group I including (200 Patients with chronic HCV cirrhosis treated with DAAs), and group II including (200 patients with chronic HCV cirrhosis without DAAs treatment), all patients were recruited from the gastroenterology and hepatology department Kobry Elkobba military hospital, all patients were males of age group between 18 & 70 years old with no previous history of HCC, HIV or HBV infection or history of liver transplantation.
After one year of follow up all patients were devided into further two subgroups according HCC development, group III ( 11 HCV cirrhotic patients treated with DAAs (sofosbuvir and daclatasvir) and developed HCC) and group IV (22 HCV cirrhotic patients not treated and developed HCC).
In this study, there is no significant difference between the baseline characteristics to exclude confounding factors.
In addition to that there is no statistical significant difference between treated and non-treated groups as regards demographic characteristics, clinical picture (ascites, lower limb edema, splenomegaly and jaundice), complete blood count, liver and kidney function tests (ALT, AST, total bilirubin , direct bilirubin , INR, Albumin, creatinine), alpha-fetoprotein (AFP), ultrasonograhic findings (hepatomegaly , splenomegaly , PV diameter and ascites), Child classification, endoscopic findings of presence of esophageal varices (OV) or Portal hypertensive gastropathy (PHG).
After one year of follow up, this study documented that HCC developed more in not treated group with a significant difference between treated and not treated groups, as 11% of not treated group developed HCC compared to 5.5% only of treated group.
In addition to that this study Also documented that non treated group AFP is higher than treated group with a statistical significant difference.
In this study, treated group with HCC (group III) hemoglobin is higher than non treated group with HCC (group IV) with statistical significant difference.
Also, non treated group with HCC (group IV) creatinine is higher than treated group with HCC (group III) with statistical significant difference.
In this study, using univariate cox regression, it was shown that not treated group was independent risk factor of getting hepatocellular carcinoma (HCC), as cases not receiving the study treatment are at higher risk for developing HCC (HR=3.4, P=0.002).
CONCLUSION
• DAA treatment is not associated with a higher risk of HCC in cirrhotic patients with chronic HCV infection in the short-term.
• The occurrence of HCC is significantly decreased in patients treated with DAAs.
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