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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 474-481

Efficacy of 24-week treatment with sofosbuvir/daclatasvir/ribavirin in chronic hepatitis C virus-infected Egyptian patients with previous sofosbuvir-based treatment failure


1 Department of Hepatology, National Hepatology and Tropical Medicine Research Institute, Egypt
2 Department of Hepato-gastroenterology and Infectious Diseases, Faculty of Medicine, Al Azhar University for Girls, Cairo, Egypt
3 Department of Endemic Diseases, Faculty of Medicine, Helwan University, Helwan, Egypt

Date of Submission24-Jun-2020
Date of Decision10-Jul-2020
Date of Acceptance14-Jul-2020
Date of Web Publication2-Oct-2020

Correspondence Address:
MSc Aisha A Sabal
Department of Hepatology, National Hepatology and Tropical Medicine Research Institute
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_73_20

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  Abstract 


Background Hepatitis C virus (HCV) is a globally prevalent pathogen and a common leading cause of morbidity and mortality. Egypt has the highest HCV prevalence worldwide, with more than 14.7% of the Egyptian adults having been exposed to the virus.
Aim To evaluate the efficacy of 24-week treatment with sofosbuvir (SOF)/daclatasvir/ribavirin in chronic HCV-infected Egyptian patients with previous SOF-based treatment failure.
Patients and methods This cohort study was conducted on 247 patients with chronic hepatitis C infection. They all relapsed on SOF-based treatment regimens. Their ages ranged between 22 and 72 years. They were divided according to FIB-4 results into two groups: group I included 132 cirrhotic patients, and group II included 115 noncirrhotic patients. All patients were followed for 24 weeks with liver function tests, complete blood count, and international normalized ratio, and then along with PCR at 4 and 12 weeks after treatment, with recording of adverse events.
Results Sustained virologic response (SVR) was achieved in 96% of patients. There was a significant improvement of platelet counts, alanine aminotransferase, and aspartate aminotransferase, causing significant improvement in FIB-4 (points from <1.45 to 3.25), APRI score (points from <0.5 to >2), and LOK index (fractions from <0.2 to >0.5), where all significantly declined at SVR 4 and 12. Anemia and hyperbilirubinemia were the most commonly reported adverse events.
Conclusion The combination of SOF plus daclatasvir with ribavirin for 24 weeks has favorable outcomes with high SVR rates and safety profile in treatment of chronic HCV-infected Egyptian patients who relapsed on SOF-based regimens.

Keywords: daclatasvir, Egyptian patients, hepatitis C virus, relapsers, ribavirin, sofosbuvir


How to cite this article:
Sabal AA, Omar HM, El-Taher SM, El-Deen NM, El Kassas M. Efficacy of 24-week treatment with sofosbuvir/daclatasvir/ribavirin in chronic hepatitis C virus-infected Egyptian patients with previous sofosbuvir-based treatment failure. Sci J Al-Azhar Med Fac Girls 2020;4:474-81

How to cite this URL:
Sabal AA, Omar HM, El-Taher SM, El-Deen NM, El Kassas M. Efficacy of 24-week treatment with sofosbuvir/daclatasvir/ribavirin in chronic hepatitis C virus-infected Egyptian patients with previous sofosbuvir-based treatment failure. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Oct 28];4:474-81. Available from: http://www.sjamf.eg.net/text.asp?2020/4/3/474/296960




  Introduction Top


Egypt has the highest hepatitis C virus (HCV) prevalence in the world, with more than 14.7% of the Egyptian adults having been exposed to the virus [1].

With the development of direct-acting antivirals (DAAs), they became the ideal choice for the treatment of chronic HCV (CHC)-infected patients owing to their proven efficacy [sustained virologic response (SVR)>90%] and minimal adverse effects. Egypt launched a large treatment program aimed at providing treatment coverage for Egyptian HCV-infected patients [2].

Treatment with sofosbuvir (SOF) started in Egypt in 2014 with two regimens, SOF, interferon, and ribavirin (RBV) for 12 weeks and SOF/RBV for 24 weeks [3].

After 6 months, simeprevir was added to treatment regimens with SOF for 12 weeks in patients with or without Child-Pugh A cirrhosis [4].

In mid-2015, daclatasvir (DCV) was added to treatment regimens in combination with SOF for 12 weeks and then became exclusively the regimen for all patients in the program either naïve or relapsed [5]. The reported results of using SOF/DCV with HCV GT4 patients were very satisfying [6].


  Aim Top


The aim was to evaluate the efficacy of 24-week treatment with SOF/DCV/RBV in CHC-infected Egyptian patients with previous SOF-based treatment failure.


  Patients and methods Top


Written informed consent was taken from all participants after proper explanation of the study.

This cohort study was conducted on 247 patients with chronic hepatitis C infection at the outpatient clinic of New Cairo Viral Hepatitis Treatment Unit between June 2016 and October 2017. They comprised 150 males and 97 females, and their ages ranged between 22 and 72 years.

The study protocol was performed according to treatment failure guidelines of the National Committee for Control of Viral Hepatitis (NCCVH), 2015–2016.

Patients were categorized into two groups: cirrhotic and noncirrhotic groups according to FIB-4 calculation, where FIB-4 more than 3.25 denote advanced fibrosis (cirrhosis), whereas FIB-4 less than 3.25 denote less incidence of fibrosis (no cirrhosis) [7].

All patients were subjected to the following:
  1. Clinical part: detailed history with clinical examination.
  2. Laboratory part: PCR quantitative for HCV RNA; complete blood count; liver function tests; random blood sugar; glycated hemoglobin for diabetic patients; HBsAg; alpha-fetoprotein; pregnancy test for females in childbearing period; calculation of Child-Turcotte-Pugh (CTP) score; and LOK ratio, APRI score, and FIB-4 as indirect serological markers of fibrosis [8] before and after treatment.
  3. Radiological part of the work: abdominal ultrasonography; ECG; and echocardiography for patients more than 65 years with cardiological consultation.


Treatment regimens: all patients were treated with the following:
  1. SOF (Soflanork; Mash Company, Cairo, Egypt; 400 mg, orally, once daily).
  2. DCV (Daklanork; Mash Company; 60 mg, orally, once daily).
  3. RBV: weight-based RBV (Ribovinol; Mash Company) 1200 or 1000 mg/day if more than or equal to 75 or less than 75 kg, respectively, in noncirrhotic patients, whereas in cirrhotic patients, we started with 600 mg which was adjusted according to patient tolerability.


Follow-up visits were scheduled at weeks 4, 8, 12, 16, 20, and 24 during treatment and at 4 and 12 weeks after completing treatment.

Statistical analysis

We used the SPSS statistical, version 22 IBM SPSS statistics (Statistical Package for Social Sciences) software version 22.0, IBM Corp., Chicago, USA, 2013. Qualitative data were presented in the form of numbers and percentages and quantitative variables as mean and SD. A comparison between quantitative variables was carried out by the Student t test of two independent samples. χ2 test was used to compare qualitative variables. P value less than 0.05 is significant, and P value more than 0.05 is nonsignificant.


  Results Top


[Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] and [Figure 1] [Figure 2] [Figure 3] [Figure 4] [Figure 5] [Figure 6] [Figure 7] [Figure 8] [Figure 9].
Table 1 Comparison between both groups regarding demographic characteristics and history

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Table 2 Comparison between both groups regarding basal ultrasonographic findings

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Table 3 Comparison between both groups regarding basal laboratory findings

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Table 4 Comparison between both groups regarding fibrosis scores: LOK, FIB-4, and APRI scores

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Table 5 Comparison between both groups regarding Child-Turcotte-Pugh score before and after treatment

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Table 6 Comparison between cirrhotic and noncirrhotic patients regarding PCR results at weeks 4 and 12 after treatment (sustained virologic response 4 and 12)

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Figure 1 ALT follow-up in both groups. ALT, alanine aminotransferase.

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Figure 2 AST follow-up in both groups. AST, aspartate aminotransferase.

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Figure 3 Albumin follow-up in both groups.

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Figure 4 Bilirubin follow-up in both groups.

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Figure 5 Hemoglobin follow-up in both groups.

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Figure 6 Platelet follow-up in both groups.

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Figure 7 Total patients dropped out: 7 timing of treatment dropout of the studied patients.

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Figure 8 Total patients dropped out: 7 timing of treatment dropout of the studied patients.

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Figure 9 Comparison between both groups regarding adverse events during treatment.

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  Discussion Top


In our study, males were more common (60.7%) than females (39.3%). This is in agreement with many studies, which revealed the high prevalence of HCV in male sex than females, such as in Ghosh and Klein [9].

Cirrhotic patients were significantly older (56.0±7.3) than noncirrhotics (51.3±9.0) and had a significantly lower incidence of hypertension ((16.7%) than noncirrhotics (28.7%).

There was no significant difference between both groups regarding sex, the incidence of diabetes, BMI, or history of ascites.

Relapsers on SOF/RBV represented the higher percent, representing 59.5%, whereas SOF/INF/RBV relapsers represented 30.8%, and the lowest number was of SOF/simeprevir relapsers (9.7%).

These results came in agreement with all studies done in Egypt comparing the efficacy of different DAA regimens, which revealed that SOF/RBV regimen was the least effective with the highest relapse, such as in the studies by Elsharkawy et al. [10] and El Kassas et al. [11]. However, El Kassas et al. [11] added that despite its apparent low rate of virological response, SOF/RBV regimen was an excellent treatment option in cases of interferon ineligibility.

Hepatic focal lesions were seen in three (1.2%) patients with cirrhosis; two patients had history of hepatocellular carcinoma (HCC), which was completely ablated and proved with dynamic study before inclusion into the study, and the third patient had hemangioma; they all completed treatment.

Regarding noninvasive fibrosis indices, they were significantly higher in cirrhotics than noncirrhotics before and after the treatment, and at the same time, they significantly improved in both groups owing to the significant improvement of platelets count, alanine aminotransferase, and aspartate aminotransferase levels.

FIB-4 declined from mean±SD of 4.29±3.09 before treatment to 2.59±1.62 and 2.51±1.68 at weeks 28 and 36, respectively (P<0.001). APRI score declined from 1.51±1.45 before treatment to 0.72±0.39 and 0.59±0.44 at weeks 28 and 36, respectively (P<0.001). LOK index significantly declined from 0.66±0.24 before treatment to 0.63±0.23 and 0.62±0.24, with P=0.035 and 0.002 at weeks 28 and 36, respectively.

Although the current anti-HCV therapies were not designed to be antifibrotic [12], many studies were done to rule out the effect of DAAs on improving liver fibrosis, as Tao et al. [13] found that the reduction of FIB-4 in GT-3 cirrhotic patients treated for 24 weeks with SOF+DCV+RBV (from 5.70 to 3.48, P=0.006) and APRI score (from 3.11 to 1.13, P<0.001) were both significant at week 24 after end of treatment.

In contrary to these theories, Elsharkawy et al. [14] suggested that the first reduction in the fibrosis indices mostly reflects a reduction in necroinflammation rather than fibrosis regression. Hsu et al. [15] also assumed that the cause of the rapid decline in APRI and FIB-4 values is the improvement in necroinflammation.

The Child’s score (CTP) was significantly higher in cirrhotics before and after treatment in comparison with noncirrhotics (P<0.000). Despite this, there was nonsignificant change in the Childs score of total patients and subgroups separately before and after the treatment at week 28 and week 36 (P=0.508 and 0.219), respectively.

In contrary to us, Mohamed et al. [16] used SOF/DCV/RBV for treatment of patients with CHC, where 44% of the patients showed Child’s score improvement, 51% showed no change, and only 5% showed deterioration.

Another study by Elnadry et al. [17] used multiple DAA regimens, and one of them was SOF/DCV/RBV. The results also showed improvement in CTP in comparison with nontreated patients (P=0.015).

At week 36, two (0.8%) Child B patients developed ascites and became Child C; one of them developed de-novo HCC. However, none of the two patients with previously ablated HCC had a recurrence of HCC, and they both completed treatment with SVR 4 and 12. These findings may suggest a relationship between the development of HCC following DAAs, or it could be related to the baseline risk factors and patient selection as it occurred with cirrhotic patient.

El Kassas et al. [18] pointed to a high rate of recurrence after DAA treatment for patients with a history of successfully treated HCC when compared with nontreated patients.

It was suggested that rapid changes to the immune system and/or antitumor response following DAAs treatment could be the reason for the apparent increase in HCC recurrence [19].

The overall SVR 4 and 12 in our study was 96% for all patients. SVR 4 and 12 for noncirrhotics was 98.3% and for cirrhotics 93.9%, respectively, and despite being higher in noncirrhotic group, it was statistically nonsignificant. Overall, 4% (10/247) of patients who did not achieve SVR 12 were treatment nonresponders: seven (2.8%) discontinued treatment, and three (1.2%) relapsed after the end of treatment, and they had cirrhosis.

These results were in agreement with El Kassas et al. [2], who found that the presence of cirrhosis was correlated with a lower SVR.

Osman et al., 2018, also found an insignificant difference in SVR results between cirrhotics (94.8%) and noncirrhotics (97.5%) despite being lower in cirrhotics.

Treatment of 18 378 treatment-naïve and experienced Egyptian patients with different fibrosis stages, with SOF/DCV±RBV for 12 weeks, resulted in 95.1% SVR (95.4% among patients treated without RBV and 94.7% for patients treated with RBV, P=0.32) [20].

Many studies reported that RBV remains an essential drug for HCV therapy, especially in patients with predictors of inadequate response to treatment, as found in cirrhotic patients.

Tao et al. [13] suspected that from 102 studied patients, the cause of relapse of 10 patients might be the short course of therapy (12 weeks) in SOF+DCV+RBV group and absence of RBV in SOF+DCV group.

Muir et al. [21] stated that RBV could still be useful in pretreated patients (93 vs. 87% SVR with and without RBV, respectively). Nevertheless, Pol et al. [22] reported a real-world experience for 768 HCV-G1 patients and found an overall 95% SVR 12 rate (92–99%) and that the SVR rates were not affected by treatment duration or RBV use.

Regarding adverse effects, most of them were mild in severity. The most common adverse effects in both cirrhotic and noncirrhotic groups were anemia (31.8% and 40.9%, respectively) and hyperbilirubinemia (34.1% and 16.5%, respectively), hyperbilirubinemia was significantly higher in cirrhotics than noncirrhotics (P=0.002) while anemia showed non-significant difference.

Only four patients discontinued the treatment in our study owing to serious adverse events including hepatic decompensation (one cirrhotic Childs B patient), ascites (single cirrhotic Childs B patient), severe anemia (one noncirrhotic patient), and one cirrhotic Childs B patient died.Anemia is a known adverse effect related to RBV use, and previous studies indicate that adjustments in RBV doses are necessary in ∼20% of cases [23].

In the study by Shiha et al. [24], the most common adverse events were fatigue, headache, insomnia, and anemia. No treatment-related serious adverse events or death were reported.

In disagreement with us, Attia et al. [25] studied the effect of different DAA regimens and one of them was SOF/DCV±RBV, which had the lowest incidence of adverse effects, which developed in 38 (19%) patients with this regimen. Anemia and hyperbilirubinemia were the most commonly reported adverse events in this study and occurred mainly in the SOF/RBV group.

Attia et al. [25] also reported that HCC and mortality were found in 0.02 and 0.06% of treated patients, respectively and adverse events were more common in patients who were males and with cirrhosis, such as hyperbilirubinemia, and low hemoglobin, platelets, and albumin levels.

El-Khayat et al. [26] studied the effect of SOF/DCV±RBV on 551 genotype 4 cirrhotic patients. The most commonly occurred adverse events were anemia, fatigue, headache, and pruritus, whereas serious adverse events were HCC and hepatic encephalopathy, and they were present in Child B patients.

Osman et al. [27] also concluded that the most common adverse effects in their study were fatigue (15%), hyperbilirubinemia (13.1%), anemia (12.1%), and headache (12%).


  Conclusion Top


The combination of SOF/DCV/RBV for 24 weeks has favorable outcomes with high rates of SVR and safety profile in the treatment of Egyptian patients with CHC infection, with a clinically significant improvement in parameters of liver fibrosis.

Recommendations

Large-scale studies of SOF plus DCV for the treatment of CHC, particularly in the so-called difficult-to-treat’ patients, are recommended.

Enhancing the follow-up of treated patients especially cirrhotic is highly advocated for early detection of decompensation and developing HCC.

Financial support and sponsorship

Nill.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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