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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 1  |  Page : 162-169

Response and safety of treatment of chronic hepatitis C by direct-acting antiviral drugs in patients with Child B-related cirrhosis


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Heptology and Gastroenterology, Shibin El-Kom Fever Hospital, Shibin El-Kom, Egypt

Date of Submission26-Sep-2019
Date of Decision04-Nov-2019
Date of Acceptance11-Nov-2019
Date of Web Publication27-Mar-2021

Correspondence Address:
Mohamed R Moussa
Shibin El-Kom, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_270_19

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  Abstract 


Objectives
To evaluate the response and safety of treatment of chronic hepatitis C virus (HCV) by direct-acting antiviral (DAAs) drugs in patients with Child B-related cirrhosis.
Background
Chronic HCV infection is considered to be one of the major public health diseases that affect most Egyptian population. The appearance of DAAs with its safety and high successful eradication rates has replaced the old treatment protocols, which used interferon.
Patients and methods
This was a cross-sectional study to collect data and outcome of chronic HCV-infected patients who were treated with DAAs. Treatment-naive patients without cirrhosis were treated without ribavirin, and those who had cirrhosis or were treatment experienced (interferon experienced or sofosbuvir experienced) received ribavirin. Efficacy and safety were assessed, and baseline factors associated with sustained virological response at post-treatment week 12 (SVR12) were explored.
Results
SVR at 12 weeks was more seen in Child grade A patients (98.5%) when compared with Child grade B patients (86.7%) and non-SVR was more seen in Child grade B patients (13.1%) when compared with Child grade A patients (1.5%).
Conclusion
Treatment of chronic HCV-infected patients with DAA drugs in patients has proved to be safe and associated with a high SVR12 rate, in patients with different stages of fibrosis.

Keywords: chronic hepatitis, complications, direct-acting antiviral drugs, hepatitis C virus treatment, investigations, symptoms, treatment


How to cite this article:
Ibrahim HM, Moussa MR, Sakr AA. Response and safety of treatment of chronic hepatitis C by direct-acting antiviral drugs in patients with Child B-related cirrhosis. Menoufia Med J 2021;34:162-9

How to cite this URL:
Ibrahim HM, Moussa MR, Sakr AA. Response and safety of treatment of chronic hepatitis C by direct-acting antiviral drugs in patients with Child B-related cirrhosis. Menoufia Med J [serial online] 2021 [cited 2021 May 8];34:162-9. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/162/312046




  Introduction Top


Hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, single-stranded RNA virus of the family Flaviviridae, which takes the liver as the primary organ for infection. The infection is often asymptomatic, but chronic infection can lead to destruction of liver cells and leads to cirrhosis, which is generally apparent after many years. Infection is associated with liver cirrhosis and, in some cases, hepatocellular carcinoma following HCV infection [1]. HCV is a self-limiting infection in only 15–25% of patients in whom HCV RNA in the serum becomes undetectable and alanine aminotransferase (ALT) levels return to normal. Approximately 75–85% of infected patients do not clear the virus by 6 months, and chronic hepatitis develops persistence of HCV RNA in the blood for at least 6 months after onset of acute infection. The rate of chronic HCV infection is affected by many factors, including the age at time of infection, sex, ethnicity, and the development of jaundice during the acute infection [2]. The WHO recently estimated that 170 million people all over the world are infected with the virus. Egypt has the highest epidemic of HCV worldwide, with an overall prevalence of HCV antibodies among the Egyptian population, being around 10–15%, and is highly prevalent among blood donors [3], with ~2.9% infected in Africa and 1.3% in Americas, with a global viremic rate of 67% (118.9 million of HCV RNA positive cases), varying from 64.4% in Asia to 74.8% in Australia. HCV genotype 1 (GT-1) is the most prevalent worldwide (49.1%), followed by GT-3 (17.9%), GT-4 (16.8%), and GT-2 (11.0%). GT-5 and GT-6 are responsible for the remaining less than 5%. Although GT-1 and GT-3 are common worldwide, the largest proportion of GT-4 and GT-5 is in lower income countries. The highest prevalence of HCV infection is present in Egypt, with 92.5% of patients infected with GT-4 [4]. Although HCV GT-1 and GT-3 infections are the most prevalent globally (67.0% if considered together), other GTs are found more commonly in lower income countries, which still account for a significant proportion of HCV cases [5].

Egypt was estimated to have the highest HCV prevalence rate in the world in 2013 and had the fifth highest number of HCV-infected individuals in 2017 [5],[6], with a prevalence rate of 14.7% and treatment costs amounting to around 1.4% of the gross national product. The burden of HCV infection in Egypt is substantial [7],[8]. Between 2001 and 2011, the main treatment for patients with chronic HCV infection was the combination of peg-interferon and ribavirin (RBV). This yielded a sustained virological response (SVR) rate of 40–50% in GT-1 infection and 70–80% in GT-2 and GT-3 infections. The first direct-acting antiviral agent (DAAs) was approved by the US Food and Drug Administration in 2011. Grazoprevir (NS3/4 A protease inhibitor) and elbasvir (NS5A inhibitor) with or without RBV for 12 or 18 weeks in patients with GT-1 and GT-4 were approved in January 2016 [9]. DAAs, which opened the gate to a new era for the management of HCV, have shown highly SVR rates of ~ 90% in clinical trials, shorter therapies, less toxicity, and regimens free of interferon [10]. One of the approved DAAs indicated for the treatment of HCV GT-4 is sofosbuvir (SOF), with a clinical efficacy in patients with HCV GT-1–GT-6 [10],[11]. Daclatasvir (DCV), the first-in-class NS5A inhibitor, has been used in combination with several drugs for the treatment of HCV of different GTs under different conditions [12]. Among the current HCV treatment regimens, clinical studies regarding the combination of SOF and DCV demonstrate that it is one of the most promising antiviral therapies, having good tolerability, limited drug–drug interactions, and high antiviral potency, with 90% SVR rates. Moreover, the combination of SOF and DCV shows promise as it is pan-genotypic and easier to use than other combinations [12]. The aim of this study was to evaluate the response and safety of treatment of chronic hepatitis C by DAA drugs in patients with Child B-related cirrhosis.


  Patients and methods Top


The was a cross-sectional case–control study that was carried out in outpatients and inpatients of Tropical Medicine Department in Menoufia university hospitals, Menoufia Fever Hospital, and referrals from private clinics, Menoufia government, Egypt. It was a clinical observatory and retrospective study. The study was conducted in the context of time frame of 12 months starting from October 1, 2017 to the end of October 2018. The study sample was a systematic cluster random sample that included chronic HCV-infected patients. The total number was 601 participants (381 females and 220 males), and their ages ranged from 20 to 78 years old.

Inclusion criteria

This study included patients with chronic hepatitis C infection with positive PCR-HCV RNA and no contraindications to DAAs.

They were classified into two groups according to Child–Pugh classification: group I included 326 Child B chronic hepatitis C-infected patients (Child scores 7, 8, and 9), and group II included 275 Child A chronic hepatitis C-infected patients (Child scores 5 and 6).

Exclusion criteria

The following groups were excluded from the study: (a) Child C cirrhotic patients; (b) patients with platelet count less than 50 000/mm3; (c) hepatocellular carcinoma, except 6 months after intervention, aiming at cure, with no evidence of activity by dynamic imaging (computed tomography or MRI); (d) extrahepatic malignancy; (e) pregnant females or inability to use effective contraception; (f) inadequately controlled diabetes mellitus (HbA1c >9%) until HbA1c drops; and (g) others, such as cardiac patients and patients with chronic renal failure.

Ethical considerations

All participants of the study were volunteers. Oral consents were granted by all participants in the study after illustration of purposes of this study, and they were encouraged to give full informed consent to participate. It was emphasized that all data collected were strictly confidential, and the data were used for scientific purpose only, and they have the right to withdrawn from the study at any time. The Menoufia Faculty of Medicine Committee for Medical Research Ethics reviewed and formally approved the study before it began.

Frequency data were summarized as percentages. Continuous variables were summarized as median and range of distribution. A two-sided P value less than 0.05 means null hypothesis rejection characteristics. The 95% confidence interval method for odds ratio was based on mid P-method. Written informed consents were taken from every patient, and the project was approved by our university ethical board.

All patients were subjected to the following: (a) a detailed history talking and clinical examination: proper history were taken from all patients, including present history, past history, and drug history. Examination were done including systemic examination and local examination. (b) Laboratory investigations included the following: complete blood count using Erma pee-210N (Tokyo, Japan); liver function tests [ALT and aspartate aminotransferase (AST)] using Human Kits (Berlin, Germany); serum albumin using Elitec Kits (Paris, France); total and direct bilirubin using Diamond Kits International normalized ration (INR) (Cairo, Egypt); renal function tests (serum creatinine–blood urea) using Diamond Kits (Cairo, Egypt); serum α-fetoprotein using Biomed Kits (London, England); international normalized ratio (INR) using Biomed Kits, (London, England); using Erba Kim-7 (Mannheim, Germany); and PCR for HCV was done using QIAamp DSP virus spin kit 50, version 1 and HCV QS-RGQ kits using QUA cube (Mannheim, Germany), and Rotor-Gene Q device (Mannheim, Germany) [13]. (c) Regarding imaging studies, abdominal ultrasonography was done using mindray DP2200 plus (Shenzhen, Guangdong, China). (d) Upper endoscopy was done using Olympus 10*50DSPI Standard Binoculars (Tokyo, Japan). It was done for all patients with liver cirrhosis to assess the presence or absence of esophageal varices and assess the degree of the varices.

Evaluation of efficacy of treatment: (a) virological response

Virological follow-up was done to determine the response and SVR using quantitative PCR for HCV RNA at 12 weeks for Child grade B and comparing it with the results of Child grade A patients.

Evaluation of safety and adverse effects of drug therapy

It was done by detection of any complications that occurred during treatment and comparing the results between Child grade A patients and Child grade B patients.

Statistical analysis

Data were collected, tabulated, and statistically analyzed using an IBM personal computer with Statistical Package of Social Science, version 20 (SPSS Inc., New York, New York, USA), where the following statistics were applied.

Descriptive statistics

Descriptive statistics are used to give summary about the sample data. Mean, SD, and range are used for quantitative variables, whereas frequencies and percentages are used for qualitative ones. To generalize sample results on the target population, statistical tests are used to test the significance of the relations in the sample.

Analytical statistics

  1. Independent t tests were used for difference of means in two independent groups (group A and group B)
  2. Paired t test for paired groups is used for testing equality of two means in two dependent groups (before and after groups)
  3. c2 test is used to test relation between two qualitative variables.


P value of less than 0.05 was considered statistically significant.


  Results Top


There was a trend toward association between female sex and abnormal pathology, although this did not meet statistical significance (P = 0.052). Three hundred patients in Child's grade B were average body built. There were 74 patients with hypotension, 11 patients with lower limb edema, 180 patients with shrunken liver, 272 patients with splenomegaly, and 260 patients with ascites. Regarding treatment history, 275 patients in Child's grade A patients were naïve, whereas in Child's grade B, there were 269 naïve patients and 58 patients experienced previous treatment: 39 patients received interferon/RBV therapy (24 weeks), five patients received SOF/simeprevir therapy (12 weeks), and 14 patients received SOF/Daclatasvir (DAC) therapy (12 weeks), and this was highly significant (P ≤ 0.001) [Table 1].
Table 1: Sociodemographic characteristics of the nurses among the studied sample

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In this study, low viremia was highly significant in Child's grade A patients, whereas moderate and high viremia was highly significant in Child's grade B patients. Moreover, there was a highly significant decrease in mean hemoglobin concentration, serum albumin level, and prothrombin activity (increase INR); significant decrease in mean platelet count; significant increase in mean serum bilirubin and serum creatinine levels; and nonsignificant difference in studied groups regarding white blood cells, ALT, AST and α-fetoprotein in Child's grade B patients in comparison with Child's grade A patients (P ≤ 0.001) [Table 2].
Table 2: Pretreatment laboratory finding of the studied groups

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There was a highly significance increase in mean serum albumin and platelet count and highly significant decrease in AST and ALT level in post-treated Child's grade A patients (P ≤ 0.001) [Table 3].
Table 3: Posttreatment versus pretreatment laboratory findings in Child's grade A

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There was a highly significance decrease in mean hemoglobin concentration, platelet count, AST, ALT, INR, and α-fetoprotein and highly significance increase in serum total bilirubin in post-treated Child's grade B patients (P ≤ 0.001) [Table 4].
Table 4: Posttreatment laboratory changes in comparison with pretreatment basal finding of Child's grade B (12 weeks)

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This study shows highly significant SVR12 in Child's grade A patients (98.5%) when compared with Child's grade B patients (86.7%), whereas non-SVR12 was highly significant in Child's grade B patients (13.1%) when compared with Child's grade A patients (1.5%) (P ≤ 0.001) [Table 5].
Table 5: Sustained virological response at 12 weeks in the studied groups

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  Discussion Top


The demographic characteristic of the studied group showed that females were higher than males (381 vs. 220) in both groups, with a mean age of 48.68 ± 13.02 years in Child's grade A group and a mean age of 50.54 ± 12.82 years in Child's grade B group. In our study, age and sex did not affect the response of DAAs therapy, as 151 (85.8%) females in Child's grade B were negative at SVR12, with a mean age of 50.49 ± 12.78 years. This agreed with the study by Conti et al. [14], which demonstrated that the age did not influence the success of interferon-free treatments in elderly patients with chronic hepatitis C and that all DAA regimens seem well tolerated and safe in patients with advanced liver disease and in those aged older than 75 years. Additionally, Ossama et al. [15], study showed that, neither age nor any of the pretreatment biochemical markers including hemoglobin, leukocyte count, platelet count, ALT, AST, albumin, INR, bilirubin, and PCR for HCV RNA resulted in a significant correlation with treatment outcome. Overall, 27 of 28 females treated with SOF/DAC/RBV regimen achieved SVR12, and the female who did not achieve SVR was younger than 60 years. Moreover, 28 of 29 females treated with Qurevo and RBV regimen achieved SVR12, and the female who did not respond was younger than 60 years. So sex does not affect treatment outcome, and this is similar to the study by Paola et al. [16], which did not identify meaningful association between virological responses and sex. Our study showed that there was a highly significance increase in serum albumin and platelet count and highly significant decrease in AST and ALT level in post-treated Child's grade A patients, and this agreed with the study by Abdel-Moneim et al. [17], which indicated that the combination of SOF/DCV with or without RBV significantly decreased the elevated liver transaminases (ALT and AST). In our study, there was a decreased in hemoglobin concentration, which was mainly owing to RBV administration, and this was agreed by the study by Abdel-Moneim et al. [17]. These findings were previously reported in the study by Wu and colleagues, who suggested that RBV is a triggering factor of hemolytic anemia. RBV in combination with SOF revealed a decrease in hemoglobin concentration (anemia), and this was agreed by the study by Sulkowski et al. [18]. Thus, the adverse effects of RBV were reduced in the current study, as compared with previous studies, owing to modulating the dose according to the patients' tolerability. In our study, the SVR12 in Child's grade A patients was 98.5%, whereas the SVR12 in Child's grade B was 86.7%, and this was agreed by the study by Omar et al. [19], which included more than 18 000 Egyptian patients with HCV infection, and the Child's grade A patients achieved 95.4% SVR12, and the Child's grade B patients including previous treatment failures, patients with cirrhosis, and/or advanced liver disease based on laboratory tests achieved a 94.7% SVR12 rate. They found that using SOF/DCV, with or without RBV, led to a high SVR12 rate among a large group of HCV-G4 patients. It was concluded that SOF plus DAC with or without RBV regimen is safe and effective for the treatment of Egyptian patients with chronic hepatitis C GT-4. Moreover, this was in agreement with the study by Pol et al. [20], which documented the combination of SOF and DAC with or without RBV had high antiviral potency, with more than 90% SVR rate in patients with chronic HCV infection. This was also agreed by a study by Fontaine et al. [21], in 2015, where 82 GT-4-infected patients were treated with SOF plus DAC with or without RBV and with or without simeprevir. A total of 33 patients who received SOF plus DAC only were subjected to statistical analysis. SVR12 was achieved in 88.9% of those patients. However, this could be explained by the fact that the studied group included patients who were difficult to treat, whether because they were treatment experienced or with advanced liver disease. This current study, concerning viral response, SVR12 rate achieved was agreed by Abdel-Moneim et al. [17], as SVR12 was 94% in the overall patients (891/946), was 95% (718/758) in SOF/DCV group, and was 92% (173/188) in SOF/DCV/RBV group. Efficacy outcomes of our study were in parallel with the results of Sulkowski et al. [18] and Nelson et al. [22], for treatment of HCV, and with the finding of El-Khayat et al. [23], and Salama et al. [24], for treatment of Egyptian patients with HCV GT-4 infection. Moreover, Babatin et al. [25] revealed that SOF/DCV with or without RBV was highly effective in HCV GT-4 treatment by achieving SVR12 of 100% in experienced and cirrhotic patients. Moreover, our results concerning SVR12 were parallel to Lacombe et al. [26], which included a large real-world cohort of HIV/HCV coinfected patients with advanced liver disease. Lacombe et al. [26] concluded that SOF ± RBV achieved SVR12 rate of 92% overall, 90% in patients with cirrhosis, and 95% in patients without cirrhosis in patients infected with HCV GT-1, GT-3, and GT-4. Furthermore, Herzer et al. [27] showed that DCV/SOF ± RBV was well tolerated and achieved high SVR12 (94%) in patients with post-transplant HCV recurrence, including patients with the severe liver disease. Moreover, Coilly et al. [28] indicated that the combination of DCV/SOF with or without RBV for 12 or 24 weeks enabled 96% SVR12 rate, with low rates of serious adverse events among liver transplantation recipients.


  Conclusion Top


The use of SOF and DAC combination, with or without RBV, was well tolerated and associated with high response rate in patients with different stages of liver disease. This can be an example for other countries of similar limited resources for managing their patients with HCV.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

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



 

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