Comparative Study between Triple Therapy ( Peginterferon / Ribavirin / Sofosbuvir ) and Dual Therapy ( Simeprevir / Sofosbuvir ) in Treatment of Chronic HCV Patients

Background and study aim: Major changes have emerged during the last few years in the treatment of chronic HCV infection. Several direct acting antiviral agents (DAAs) have been developed showing potent activity with higher rates of sustained virological response. This study shows comparison between triple therapy regimen (Peginterferon/ Ribavirin/ Sofosbuvir) and dual therapy regimen (Simprevir/Sofosbuvir) concerning efficacy and safety for Egyptian patients with chronic HCV infection. Patients and Methods: This retrospective comparative study included 500 Egyptian patients with chronic HCV infection, randomly selected from Beni-Suef centre of treatment of viral hepatitis affiliated to the National committee for control of viral hepatitis (NCCVH). They were classified into two groups; triple therapy group included 250 patients had received pegylated interferon alpha, ribavirin and sofosbuvir for 12 weeks and dual therapy group included 250 patients had received sofosbuvir and simeprevir for 12 weeks. All patients were monitored for treatment safety and efficacy. Results: In the triple therapy group, mostly observed clinical side effects were; flu like illness (40% of patients), GI manifestations (20.8% of patients) and psychological manifestations (10.4% of patients) while photosensitivity (22% of patients), flu like illness (18.8% of patients) and GI manifestations (4.8% of patients) were the most frequently occurring clinical adverse effects in dual therapy group. Anemia (62.4% of patients) and leucopenia (49.6% of patients) were the mostly observed hematological abnormalities in triple therapy group while hyperbilirubinemia (38% of patients) was the mainly observed biochemical abnormality in dual therapy group. In the triple therapy group, the end of treatment response (ETR) rate was 95.6% while sustained virological response (SVR) rate was 91.2%. In dual therapy group, ETR rate was 95.6 % while SVR rate was 93.6 %. Conclusion: The dual therapy (Simeprevir and Sofosbuvir) regimen is more tolerated than triple therapy (Peginterferon, Ribavirin and Sofosbuvir) regimen for Egyptian patients with chronic HCV infection. There was no statistically significant difference as regard sustained virological response between both triple therapy and dual therapy regimens.


INTRODUCTION
The hepatitis C virus (HCV) was discovered in 1989 which affects approximately 3% of the world population, corresponding to about 170 million individuals worldwide, and accounts for about 500000 deaths per year [1].Egypt is the country which has the highest prevalence of HCV infection in the world.It is considered the leading cause of chronic liver disease and Hepatocellular carcinoma (HCC) [2].
Pegylated-interferon (Peg-IFN) with Ribavirin (RBV) was the standard therapy for hepatitis C until 2011, but new regimens have evolved.In 2011, the first generation protease inhibitors (Boceprevir and Telaprevir) were approved [3].In recent years, IFN-based strategies combining direct-acting antivirals (DAAs) with Peg-IFN and RBV were approved.Eventually, as an understanding of the HCV life cycle increases, IFN-free combinations of DAAs have evolved to affect all steps of the HCV life cycle and cure most chronically infected patients [4].
This study evaluates the efficacy and safety of both regimens in treatment of Egyptian patients with chronic HCV infection.

PATIENTS AND METHODS
This non-interventional, retrospective comparative study includes 500 Egyptian patients with chronic HCV infection randomly selected from Beni-Suef centre of treatment of viral hepatitis which is affiliated to the National committee for control of viral hepatitis (NCCVH) from October 2014 till November 2015.

Inclusion criteria
 Patients with chronic HCV infection. Age between 18 -70 years old.

Exclusion criteria
 Patients with other causes of chronic liver disease were excluded (e.g.chronic HBV, confirmed autoimmune hepatitis, non alcoholic fatty liver disease, metabolic liver diseases).
 Patients with history of HCC or other malignancies.
 Alcohol consumption (>50 gm/day in men and 40 gm/day in women).

Monitoring of treatment safety:
-Patients receiving simeprevir were instructed to use sun protection creams and limiting sun exposure as mild to moderate photosensitivity might occur.-History taking for any adverse events specifically about the commonly reported adverse effects as influenza like illness, GI upset, psychological manifestations, pruritus, and photosensitivity, etc. -Clinical examination was performed for any manifestations suspicious of hepatic decompensation (ascites, jaundice and encephalopathy).
-Liver biochemical profile, complete blood count and serum creatinine were tested every visit.-Ultrasound examination if ascites was suspected.

Monitoring of treatment efficacy:
-HCV quantitative PCR was done before starting the treatment, at week 4 from starting treatment (rapid virological response (RVR)), at the end of treatment (end of treatment response (ETR), and at week 12 after the end of treatment (sustained virological response (SVR).-Virological response was considered when HCV RNA is below the lower limit of detection at the end of treatment and after 12 weeks from end of treatment (SVR).-Treatment failure was defined as: -Viral non response: HCV RNA persistently above lower limit of detection at end of treatment -Viral Relapse was defined as confirmed HCV RNA above lower limit of detection during the follow up period for patients who achieved HCV RNA below lower limit of detection at the end of treatment.
The results were collected, arranged in tables and figures and statistically analyzed.

Statistical analysis:
Data were analyzed using the software, Statistical Package for Social Science (SPSS) version 20, then processed and tabulated.
Frequency distribution with its percentage and descriptive statistics with mean values and standard deviation were calculated.Chi-square and t-test were done whenever needed.Probabilities of value (p value) of less than 0.05 were considered significant.

Age and sex:
The mean age of patients of triple therapy group was 49.2±10.

Laboratory findings:
In triple therapy group, the mean hemoglobin level was 13.67 g/dl before treatment and 11.67 g/dl at the end of treatment with statistically significant decrease (p<0.05), the mean WBCs count was 6138.8 /mcl before treatment and 4149.2 /mcl at the end of treatment with statistically significant decrease (p<0.05) and the mean platelet count (*1000) was 183.8 /mcl before treatment and 164.2/mcl at the end of treatment with statistically significant decrease (p<0.05).In dual therapy group, the mean hemoglobin level was 12.7 g/dl before treatment and 12.74 g/dl at the end of treatment with statistically non significant increase, the mean WBCs count was 5612.2 /mcl before treatment and 5031/mcl at the end of treatment with statistically significant decrease (p<0.05) and the mean platelet count (*1000) was 155.4 /mcl before treatment and 166 /mcl at the end of treatment with statistically significant increase (p<0.05)(Table 1).
In triple therapy group, anemia was observed in 13.2% of cases before treatment and in 62.4% of cases at the end of treatment, leucopenia was observed in 6.8% of cases before treatment and in 49.6% of cases at the end of treatment, but in dual therapy group, anemia was observed in 40.8% of cases before treatment and in 28% of cases at the end of treatment and leucopenia was observed in 16.4% of cases before treatment and in 12% of cases at the end of treatment.
There was significant decrease of mean serum AST and ALT levels among both triple therapy and dual therapy groups (mean serum AST in triple therapy group was 63.6 IU/L before starting treatment and 40.1 IU/L after 12 weeks from starting treatment and in dual therapy group it was 69.8 IU/L before starting treatment and 39.8 IU/L after 12 weeks from starting treatment and mean serum ALT in triple therapy group was 57 IU/L before starting treatment and 36.8IU/L after 12 weeks from starting treatment and in dual therapy group it was 55.4 IU/L before starting treatment and 32.9 IU/L after 12 weeks from starting treatment) (p<0.05)(Table 2).
In triple therapy group, the mean serum bilirubin was 0.8 mg/dl before treatment and 0.95 mg/dl at the end of treatment and in dual therapy group, it was 0.89 mg/dl before treatment and 1.37 mg/dl at the end of treatment with statistically significant increase in both groups (p<0.05)(Table 2).Hyperbilirubinemia in triple therapy group was observed in 3.2% of cases before treatment and in 7.2% of cases at the end of treatment while in dual therapy group, it was observed in 6% of cases before treatment and in 38% of cases at the end of treatment.

Virological response:
End of treatment response (ETR) was the same in both triple therapy and dual therapy groups (95.6%), but there was a non-statistically significant difference between both groups in sustained virological response (SVR) (91.2% of cases in triple therapy group versus 93.6% of cases in dual therapy group) (Figure2).In the present study in triple therapy group; anemia before treatment was detected in 13.2% versus 62.4% of cases at the end of treatment.These data nearly comes in accordance with Steinebrunner and others [6] who demonstrated that anemia was detected in 75% of cases received triple therapy regimen in their study [6].But Lawitz and his colleagues [10] declared different results regarding percent of occurrence of anemia with triple therapy regimen; they figured that anemia had occurred in 23% of cases who received triple therapy regimen in their study.
In triple therapy group, Leucopenia in this study was detected before treatment in 6.8% versus 49.6% of cases at the end of treatment which comes in disagreement with Wehmeyer and other colleagues [11] who revealed that leucopenia was occurred in 12.5% of cases.
This relative disparity between results in this study and that of other studies may be due to difference in the cut off values (The cut off value of anemia in this study was (hemoglobin <11.5 g/dL) while in Lawitz and his colleagues [10] it was (hemoglobin <10 g/dL) and the cut off value of leucopenia in this study was (WBCs <4000 /mcl) but in Wehmeyer other colleagues [11] it was (WBCs <2000 /mcl).
In dual therapy group in the present study; anemia (hemoglobin <11.5 g/dL) before starting treatment was detected in 40.8% versus 28% of cases at the end of treatment leucopenia was detected in 16.4% of cases before starting treatment versus 12% of cases at the end of treatment.This data comes in difference with Modi and others [8] who reported that anemia was recorded in 10% of cases received dual therapy regimen.Pearlman and others [5] also reported different results; they declared that anemia was recorded in 2% of cases in received dual therapy regimen [5,8].This relative disparity between the percent of anemia in this study and other studies may be explained by that in this study 40.8% of patients received dual therapy regimen were anemic before starting treatment.

CONCLUSION
In Egyptian patients with chronic HCV infection who had been included in this study; the dual therapy regimen (Simeprevir/ Sofosbuvir) was more tolerated with less adverse effects than the triple therapy regimen (Pegylated interferon/ Ribavirin/ Sofosbuvir) apart from the occurrence of photosensitivity and mild hyperbilirubinemia in some of patients in dual therapy group.There was no statistical difference as regard sustained virological response between both triple and dual therapy groups with slightly higher sustained virological response rates in dual therapy group than triple therapy group.

Table ( 1
): Comparison between the mean values of hemoglobin level (g/dl), WBCs count (/mcl) and platelet count (/mcl) before and after treatment in triple and dual therapy groups: *p value is considered significant "p<0.05"

Table (
2): Comparison between the mean serum levels of AST, ALT (IU/L) and bilirubin (mg/dl) before and after treatment in triple and dual therapy groups: *p value is considered significant "p<0.05" Figure (1): Comparison between Triple and Dual therapy groups regarding clinical adverse effects (%) Figure (2): Comparison between Triple and Dual therapy groups regarding virological response (%) DISCUSSION This relative difference between the current study and the other study regarding SVR in triple therapy group may be attributed to different HCV genotypes which had infected the patients included in both studies; the main HCV genotype in this study is genotype 4 because it is the main prevalent HCV genotype in Egypt, but all patients included in the other study were infected by HCV genotype 1a.
El-Khayat H, Fouad Y, Maher M, El-Amin H, Muhammed H. Efficacy and safety of sofosbuvir plus simeprevir therapy in Egyptian patients with chronic hepatitis C: a real-world experience.Gut; 2016, 0:1-5.16-El Raziky M, Gamil M, Ashour M.K, Sameea EA, Doss W, Hamada Y, et al.Simeprevir plus sofosbuvir for eight or 12 weeks in treatmentnaïve and treatment-experienced hepatitis C virus genotype 4 patients with or without cirrhosis.J Viral Hepat.; 2017, 1-9.17-Eletreby R, Elakel W, Said M, El Kassas M, Seif S, Elbaz T, et al.Real life Egyptian experience of efficacy and safety of Simeprevir\ Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients, Liver international: official journal of the International Association for the Study of the Liver international; 2017, 1-8.