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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 62-68

Study the efficacy of sofosbuvir/daclatasvir in treatment of hepatitis C virus in Egypt


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Tropical Medicine, Center of Cardiac and Digestive System, Sohag, Egypt

Date of Submission04-Mar-2019
Date of Decision10-Apr-2019
Date of Acceptance14-Apr-2019
Date of Web Publication25-Mar-2020

Correspondence Address:
Ayman A. E Ahmed Ali
El-Gomhoria Street, Sohag 82511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_95_19

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  Abstract 

Objectives
To evaluate the efficacy of combination therapy of sofosbuvir and daclatasvir with or without ribavirin as a treatment of chronic hepatitis C virus (HCV), estimated by the rate of achievement of sustained viral response 12 weeks.
Background
Direct-acting antiviral agents opened the gate to a new era for the management of HCV. These agents have shown high sustained viral response rates of ~90% in clinical trials, shorter therapies, less toxicity, and interferon-free regimens.
Patients and methods
This prospective, population-based study included 401 HCV-infected patients, 18–75 years of age, attending the Viral Hepatitis Unit of the National Committee for Control of Viral Hepatitis at Center of Cardiac and Digestive System, Sohag, who were divided into two groups: group I (easy to treat) was treated by sofosbuvir + daclatasvir for 3 months, and group II (difficult to treat) was treated by sofosbuvir + daclatasvir + ribavirin for 3 months.
Results
There was a high statistically significant difference between the studied groups regarding liver echo pattern, splenic size, fibrosis index based on the 4 factors, blood glucose, international normalized ratio, total bilirubin, serum albumin, aspartate transaminase, and platelet count (P < 0.001). Moreover there was a statistically significant difference regarding diabetes prevalence, alanine transaminase, and hemoglobin (P < 0.05). There was a statistically insignificant difference regarding total leukocytic count and serum creatinine levels (P > 0.05).
Conclusion
The treatment regimen of sofosbuvir + daclatasvir with/without ribavirin for chronic HCV patients was of high efficacy.

Keywords: daclatasvir, hepatitis C virus, response, ribavirin, sofosbuvir


How to cite this article:
Nouh MA, Ahmed Ali AA, El-Gazzarah AR. Study the efficacy of sofosbuvir/daclatasvir in treatment of hepatitis C virus in Egypt. Menoufia Med J 2020;33:62-8

How to cite this URL:
Nouh MA, Ahmed Ali AA, El-Gazzarah AR. Study the efficacy of sofosbuvir/daclatasvir in treatment of hepatitis C virus in Egypt. Menoufia Med J [serial online] 2020 [cited 2020 Aug 15];33:62-8. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/62/281322




  Introduction Top


Egypt has the highest prevalence of hepatitis C virus (HCV) infections[1]. HCV-related morbidity and mortality are increasing owing to the aging of persons who were infected decades ago. Because liver disease progresses slowly with few or no symptoms, infected persons are often unaware of it and therefore do not seek prevention, care, or treatment. As this population ages, studies project (past part) that the incidence of cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma (HCC) will markedly increase over the next 10–20 years[2],[3].

Successful treatment will improve fibrosis and cirrhosis of the liver, help prevent development of HCC, and even clear the virus. Treatment can also contribute to disease prevention by reducing the reservoir of infected people who can be responsible for the transmission of the virus[4].

Over the past 30 years, outstanding advances have been achieved in the management of chronic hepatitis C infection, first with a PEG interferon and ribavirin combination[4],[5],[6].

This study aimed at evaluating the efficacy of the combination therapy of sofosbuvir and daclatasvir with or without ribavirin as a treatment of chronic HCV.


  Patients and Methods Top


This study was approved by the Local Ethics Committee of faculty of medicine in Menoufia University, Egypt. All study participants, or their legal guardians, provided informed written consent before study enrollment.

This prospective, population-based study included 401 HCV-infected patients of both sexes (18–75 years of age), attending the viral hepatitis unit of the National Committee for Control of Viral Hepatitis at Center of Cardiac and Digestive System, Sohag.

Patients whose total serum bilirubin more than 3 mg/dl, serum albumin less than 2.8 g/dl, international normalized ratio (INR) more than or equal to 1.7, platelet count less than 50 000/mm, patients who are coinfected with HIV, patients who are less than 18 or more than 75 years old, pregnant women or cannot use appropriate contraceptive method, and those with HCC or other extrahepatic malignancies were excluded from the study.

A total of 500 patients were enrolled and assessed for eligibility for this study, but 59 did not meet one or more of the inclusion criteria, 19 cases declined to participate, and 21 patients were excluded for other reasons including pregnancy.

The remaining 401 patients were divided into two groups:

Group I (easy to treat group, n = 192): it included patients with total bilirubin less than or equal to 1.2 mg/dl, serum albumin more than or equal to 3.5 g/dl, INR less than or equal to 1.2, and platelet more than or equal to 150 000/mm and were treated by sofosbuvir + daclatasvir for 3 months.

Group II (difficult to treat group, n = 209): it included patients with PEG-interferon treatment experienced, total bilirubin more than or equal to 1.2 mg/dl, serum albumin 2.8–3.5 g/dl, INR 1.2–1.7, and platelet count 50 000–150 000 mm and were treated by sofosbuvir + daclatasvir + ribavirin for 3 months [Figure 1].
Figure 1: CONSORT flow chart.

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The success of treatment was considered when sustained virologic response 12 weeks (SVR12) after end of treatment was achieved, which means that HCV RNA, measured by PCR, was under the detection limit of the test, which is 16 IU/ml.

All patients were subjected to complete history taking with special interest on the previous history of viral hepatitis or exposure to risk factors (such as blood transfusion, or previous surgical operations), history of jaundice, bleeding tendency or abdominal pain. Moreover, a history of previous treatment of hepatitis virus C (as PEG interferon and ribavirin) or any other drug therapy will be taken. Any sensitivity to any drug was mentioned.

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS software package, version 20.0 (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, SD, and median. The significance of the obtained results was judged at the 5% level.


  Results Top


Among the studied cases, male sex was the most predominant, representing 62.5% of group I and 61.7% of group II, with mean age of 52.66 ± 11.59 years in group I and 54.0 ± 11.62 years in group II, with a statistically insignificant difference between both groups regarding sex and age distribution (P = 0.873 and 0.249, respectively). There was a highly statistically significant difference between the studied groups regarding mean platelet count and serum albumin level (P < 0.001 for both) and a statistically insignificant difference regarding mean viral load (P = 0.205).

In this study, only 16 patients in both groups were nonresponders to the treatment. A statistically significant difference between responders and nonresponders was found regarding Child–Turcotte–Pugh class, diabetes prevalence, and fibrosis index based on the 4 factors (FIB4) score (P = 0.009, 0.003, and 0.016, respectively), whereas there was a statistically insignificant difference between the responders and nonresponders regarding the treatment regimen and the hepatic echo pattern (P = 0.396 and 0.785, respectively) [Table 1].
Table 1: Factors that may predict failure to achieve sustained viral response for 12 weeks (n=401)

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Concerning laboratory results, there was a statistically significant difference between the responders and nonresponders regarding mean total bilirubin, viral load, and platelet count (P = 0.001, 0.014, and <0.001, respectively). On the contrary, there was a statistically insignificant difference between responders and nonresponders regarding mean serum creatinine level, hemoglobin (Hb), white blood cells, INR, serum albumin, age, liver echo pattern, and splenic size (P = 0.124, 0.835, 0.504, 0.086, 0.127, 0.331, 0.323, and 0.485, respectively) [Table 2].
Table 2: Relation between sustained viral response with age and baseline biochemical parameter (n=401)

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There was a statistically significant between the studied groups regarding liver echo pattern, spleen bipolar diameter, and FIB4 (P < 0.001 for all) [Table 3].
Table 3: Comparison between the studied groups according to different parameters

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Regarding laboratory data of the studied groups, there was a statistically significant difference regarding mean blood glucose levels as well as INR, total bilirubin, serum albumin, aspartate transaminase (AST), alanine transaminase (ALT), platelet count, and Hb (P < 0.001, P < 0.001, P = 0.001, P < 0.001, P < 0.001, P = 0.003, P < 0.001, and P = 0.031, respectively). Yet, there was a statistically insignificant difference between the studied groups regarding mean serum creatinine, viral load, and total leukocytic counts (P = 0.100, 0.205, and 0.081, respectively). Moreover, there was a statistically insignificant difference between both groups regarding the tobacco smoking, viral load, and diabetes prevalence (P = 0.624, 0.205, and 0.008, respectively) [Table 4].
Table 4: Laboratory results of the studied groups according to investigations

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Regarding group I, univariate analysis revealed that AST, albumin, and creatinine was significantly correlated with nonresponder outcome (P = 0.001, 0.031, and 0.006, respectively). However, only AST and creatinine were significantly correlated with nonresponder outcome by multivariate analysis (P = 0.020 and 0.015, respectively).

In group II, univariate and multivariate analysis revealed that diabetes was significantly correlated with nonresponder outcome (P = 0.001).


  Discussion Top


Direct-acting antiviral agents (DAA) opened the gate to a new era for the management of HCV. These agents have shown highly SVR rates of ~ 90% in clinical trials, shorter therapies, less toxicity, and regimens free of interferon[7].

There was a high statistically significant difference between groups I and II regarding liver echo pattern, spleen size, FIB4, blood glucose, INR, total bilirubin, serum albumin, platelet count, and AST (P < 0.001 for all). Moreover, there was a statistically significant difference between groups I and II regarding ALT, Hb, and incidence of diabetes (P = 0.003, 0.031, and 0.008, respectively). These results indicate a more progressive disease in group II at the three main parameters of liver disease, which are cirrhosis (indicated by coarse hepatic echo pattern, FIB4, ALT, and AST), decompensation (indicated by INR, albumin, and bilirubin), and portal hypertension (roughly indicated by platelet count and splenic size).

In the present study, only 16 patients in both groups were nonresponders to treatment. There was a high statistically significant difference between the nonresponders and responders regarding mean total bilirubin and platelet count (P ≤ 0.001), whereas there was a statistically significant difference between the nonresponders and responders regarding viral load, Child–Turcotte–Pugh score, diabetes prevalence, and FIB4 (P = 0.014, 0.009, 0.003, and 0.016, respectively).

There was a statistically insignificant difference between responders and nonresponders to the treatment regarding the used regimen, creatinine, Hb, white blood cells, INR, serum albumin, age, liver echo pattern, and spleen size (P = 0.396, 0.528, 0.785, 0.124, 0.835, 0.651, 0.086, 0.127, 0.331, 0.323, and 0.485, respectively). These results are in agreement with the study of Abdel-Moneim et al.[8], which stated that baseline characteristics did not significantly affected the virologic outcome; however, the percentage of fibrosis or cirrhosis (in the difficult-to-treat group) was clearly affected.

Moreover, the study by Ahmed et al.[9] concluded that neither age nor any of the pretreatment biochemical markers including Hb, leukocytic count, platelet count, ALT, AST, albumin, INR, bilirubin, and viral load showed significant correlation with treatment response.

In disagreement with our results, Reddy et al.[10] stated that the virological response was not related to pretreatment viral load. The difference may be related to small sample size in their study.

In disagreement with our results, Welzel et al.[11] concluded that SVR12 rates were high regardless of cirrhotic status or liver disease severity. SVR12 was achieved by 90% (331 of 368) of patients with cirrhosis (91% with sofosbuvir + daclatasvir, 88% with sofosbuvir + daclatasvir + ribavirin, and 90% (225 of 250) of patients with platelet counts less than 100 × 109 cells/l. This can be explained by the fact that the study included both HCV genotypes 1 and 4.

In the present study, the SVR12 rate was 96.9% in group I versus 95.2% in group II.

Although high, variable figures have been reported among different studies regarding the rate of achievement of SVR12.

The addition of ribavirin to the sofosbuvir + daclatasvir regimen increased SVR rates to 83 and 89%, respectively, in patients with advanced fibrosis or compensated cirrhosis[12].

El-Khayat et al.[13] in their multicenter study involved 551 patients with liver cirrhosis genotype 4: 432 naïve patients and 119 treatment-experienced patients. All patients received sofosbuvir/daclatasvir daily in addition to weight-based ribavirin for 12 weeks, and when ribavirin is contraindicated, the treatment duration was extended to 24 weeks. The study concluded that the SVR12 rate was 92% in naïve cirrhotic patients and 87% in previously treated patients. Virological failure was infrequent, occurring in 42 (8%) patients overall.

The study by Salama and colleagues included 475 patients with chronic HCV infection, who were divided into three groups: group I (193 patients) received sofosbuvir/daclatasvir with weight-adjusted dose of ribavirin, group II (193 patients) received sofosbuvir/daclatasvir with fixed dose of ribavirin, and group III (89 patients) received sofosbuvir/daclatasvir only. The treatment was given for 12 weeks with 12-week follow-up to assess SVR12. The treatment overall response was 92, 95, and 91% in groups I, II, and III, respectively[14].

Abdel-Moneim et al.[8] in a large cohort included 946 patients with chronic HCV genotype 4. The SVR12 was achieved by 94% (891/946) in the overall patients, by 95% (718/758) in the sofosbuvir/daclatasvir group, and by 92% (173/188) in the sofosbuvir/daclatasvir/ribavirin group.

Shiha and colleagues reported a SVR12 rate of 96.6% in patients receiving 12 weeks of sofosbuvir/daclatasvir treatment, 95.7% of the patients receiving sofosbuvir/daclatasvir/ribavirin for 12 weeks, 93.3% of those receiving 24 weeks of sofosbuvir/daclatasvir, and 92.2% of patients receiving 24 weeks of sofosbuvir/daclatasvir/ribavirin[15].

In group II, univariate and multivariate analyses revealed that only diabetes was significantly correlated with nonresponder outcome (P = 0.001 for both). Diabetes or insulin resistance was included in predictors of non-response to DAAs. In disagreement with this result, Elhelbawy et al.[16] reported that age, platelet counts, and liver stiffness are good predictors of response to treatment but insulin resistance does not impair the response of patients with HCV treated with DAAs.


  Conclusion Top


The present finding suggested that treatment of sofosbuvir + daclatasvir with/without ribavirin for chronic HCV-infected patients was generally safe, well tolerated, and of high efficacy, reflecting the antiviral potency and high resistance barrier of the combination regimen.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Jensen DM, O'leary JG, Pockros PJ, Sherman KE, Kwo PY, Mailliard ME, et al. Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort: 45. Hepatol 2014; 60:219A–220A.  Back to cited text no. 6
    
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Abdel-Moneim A, Aboud A, Abdel-Gabaar M, Zanaty MI, Ramadan M. Efficacy and safety of sofosbuvir plus daclatasvir with or without ribavirin: large real-life results of patients with chronic hepatitis C genotype 4. Hepatol Int 2018; 12:348–355.  Back to cited text no. 8
    
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Ahmed OA, Safwat E, Khalifa MO, Elshafie AI, Fouad MHA, Salama MM, et al. Sofosbuvir plus daclatasvir in treatment of chronic hepatitis C genotype 4 infection in a cohort of Egyptian Patients: an experiment the size of Egyptian village. Int J Hepatol 2018; 2018:1–5.  Back to cited text no. 9
    
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Reddy S, Sharma RK, Mehrotra S, Prasad N, Gupta A, Kaul A, et al. Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation. Clin Kid J 2017; 11:429–433.  Back to cited text no. 10
    
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Welzel TM, Petersen J, Herzer K, Ferenci P, Gschwantler M, Wedemeyer H, et al. Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut 2016; 65:1861–1870.  Back to cited text no. 11
    
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Leroy V, Angus P, Bronowicki JP, Dore GJ, Hezode C, Pianko S, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: a randomized phase III study (ALLY-3+). Hepatology 2016; 63:1430–1441.  Back to cited text no. 12
    
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Salama H, Zekri A, Medhat E, Zienab Z, Shousha H. Sofosbuvir plus daclatasvir with fixed versus weight adjusted dose of ribavirin for treatment of HCV, genotype 4 among Egyptian patients. EC Gastroenterol Dig Syst 2016; 1:143–153.  Back to cited text no. 14
    
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Shiha G, Soliman R, ElBasiony M, Hassan A, Mikhail N. Sofosbuvir plus daclatasvir with or without ribavirin for treatment of chronic HCV genotype 4 patients: real-life experience. Hepatol Int 2018; 12:1–9.  Back to cited text no. 15
    
16.
Elhelbawy M, Abdel-Razek W, Alsebaey A, Hashim M, Elshenawy H, Waked I. Insulin resistance does not impair response of chronic hepatitis C virus to direct-acting antivirals, and improves with the treatment. Eur J Gastroenterol Hepatol 2019; 31:16–23.  Back to cited text no. 16
    


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    Tables

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