الفهرس 
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Abstract
HCV infection is a major public health burden in Egypt, where it bears the highest prevalence rate in the world. A revolution in HCV infection treatment was achieved in the last years marked by the introduction of the direct antiviral agents (DAAs). Optimal therapy for patients with HCV genotype 4 infections is changing rapidly; the standard of care for a long time has been a combination of pegylated-interferon-alpha (PEG-IFN-α) and ribavirin (RBV), with modest response rates and considerable adverse events.
Recent advances in drug development have led to a number of DAAs which deliver high rates of sustained virological response (SVR) in treatment-naive and previously treated patients infected with genotype 4 HCV with substantial improvements in the side effect profiles. One of these drugs, sofosbuvir (SOF), a potent inhibitor of the HCV NS5B polymerase, has been approved for the treatment of HCV in Egypt. The introduction of the new DAAs marked the beginning of a new era in HCV therapy in Egypt. More than 900,000 Egyptians have been treated for hepatitis C since January 2016 using the DAAs that have proven efficacy in tackling the disease.
Since the introduction of DAAs in 2014, a huge effort has been made to control HCV in Egypt by implementing a national
mass treatment program. As Egypt has the highest HCV worldwide prevalence rate, a unique mass treatment program was established.
This study included 165 chronic HCV infected adult patients who were recruited from the National Hepatology and Tropical Medicine Research Institute (NHTMRI) and National Committee for Control of Viral Hepatitis, in the period from 2015 to 2016. The present study aimed to assess the clinical effectiveness of SOF- based treatment regimens SOF/RBV (Dual-therapy) for 6 months or SOF/RBV/PEG-IFN-α (Triple-therapy) for 3 months in CHC- naive and -experienced Egyptian patients predominately infected with genotype 4 and to demonstrate the possible predictors of response to treatment. This could ultimately help in treatment strategies for Egyptian patients infected with HCV.
Statistical analysis of the presenting data was done highlighting four major entities:
The treatment responses rates
A total of 146 patients had a SVR (88.6%), 13(7.8%) patients relapsed, and 6 (3.6%) patients relapsed and died. The highest SVR rates were achieved with the Triple-therapy, which was reached 93.4% although, the Dual-therapy showed SVR rates of 79.66%. The Non-SVR rates recorded with Dual- and Triple- regimens were 20.34% and 6.6%, respectively. Also, it was found
that a number of 106 patients (78.5%) had cleared HCV RNA thus achieved a rapid virological response (RVR) after 4 weeks of treatment. The rate of RVR was non-significantly better in the Triple-treated group (82.8%) vs. (70.8%) in the Dual-treated group.
The predictors treatment responses/failure
On analyzing the baseline parameters of patients who failed to treatment (Non-SVR), it was clear that those patients had significantly lower thyroid stimulating hormone (TSH); or higher tumor necrosis factor- alpha (TNF-α) and platelet derived growth factor (PDGF).
By analyzing results in this current study, it was found that patients, who achieved RVR, showed a significant decrease in hemoglobin (Hb), TSH, PDGF, and TNF-α among treated groups. In addition, there was a significant decrease in alpha-fetoprotein (AFP) level in patients who achieved RVR in the Triple-treated group only.
Follow-up changes during treatment
Regarding the complete blood count indices, it was found that the Hb level was significantly changed with transient declining during and after the treatment periods. The white blood cells (WBCs) count was not significantly different in Dual-treatment,
while in Triple-treatment, it shows a significant decline after 12 weeks of treatment. The change in platelets was significantly elevated in the Dual-therapy and declined in the Triple-therapy after treatment periods. And for Prothrombin time (PT), it showed a slight decrease after 12 weeks in Dual-therapy only.
The Impact of different SOF-based treatment regimens on the liver enzymes indices; both ALT and AST levels decline significantly after 12 weeks of treatment in both therapies. While, an elevation in serum total bilirubin level was observed after 12 weeks of treatment in Dual- and Triple-therapy groups. The albumin level was within the normal range in both groups of patients after 12 weeks of treatment. Also, there was a significant declination in AFP level after 12 weeks of treatment in both treated groups.
In addition, the results revealed that Dual-treatment for 12 weeks caused asignificant decrease in APRI and fibrosis-4 score from baseline levels, while, AST/ALT ratio showed a non- significant increase. Triple-treatment for 12 weeks caused a significant decrease in APRI only from baseline values. For thyroid function, both treatments showed a significant increase in their TSH level within the normal range.
The level of lipids was also affected, as it was observed that SOF can induce lipid changes in patients with CHC, within 12 weeks of treatment. These changes include a significant increase in the lipid profile (total cholesterol (TC), triglycerides (TG), and lipoproteins (HDL and LDL)), which was still within the normal range. For obesity, the results revealed that after 12 weeks of treatment patients in the Dual-group showed an increase in their leptin level. Conversely, patients who received the Triple- treatment showed a significant decrease in their leptin level.
And kidney function had a share of the change that was observed a slight non-significant increase in creatinine level was observed after treatment in both groups. The same thing happened to the ferritin level, where it was found that after 12 weeks of treatment, its level increased significantly in both groups. Also, changes in PDGF level after 12 weeks of treatment showed a significant increase in both treatment modalities, and this was reversed for the TNF-α level.
It was found that these drugs has some adverse and favorable effects. Adverse effects included a decrease in Hb and WBCs, together with an increase in creatinine, ferritin, and TSH. The favorable effects besides high SVR included normalization of liver indices, correction of hypolipidemia, together with a decrease in TNF-α.
Molecular studies
The results of IL28B SNP rs12979860 shows the overall frequency of IL28B genotypes was 100% for genotype CT. IL28B CT genotypes are heavily linked to therapy effectiveness in genotype 4 patients of HCV infection. Therefore, IL28B genotyping is helpful to predict the result of DAAs.
from the STRING database, we found that IL28B interacted with ten important neighbor proteins. Among them, five proteins (IL10RB, IFNLR1, TYK2, TYK1, and IFNAR1) are involved in signal transduction pathway activating the antiviral response.
In conclusion, SOF-based therapies in Egypt based on was found to be effective and safe with an advantage of the Triple- treatment compared to the Dual-treatment, where it was found that the Triple-treatment achieved the highest response rate (93.4%), followed by the Dual-treatment with (79.66%). Also, it was also found that the IL28B CT genotype is closely related to the treatment efficacy in hepatitis C patients. We also recommend that the study of the effect of treatment should be based on the study of biochemical differences within individuals and that further studies are required to improve treatment options in cases of severe treatment failures.