|Year : 2020 | Volume
| Issue : 2 | Page : 159-167
Efficacy and safety of daclatasvir-containing regimens in the treatment of chronic hepatitis C patients in Damietta
Alaa Eldeen M Hashim1, Samy Zaky2, Magdy Z Alghannam3, Sabry A Ibraheem4, Fathiya M El-Raey5, Ahmed Abdelaziz6
1 Professor and Head of Hepatogastroenterology and Infectious Diseases Department, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
2 Professor of Hepatogastroenterology and Infectious Diseases Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
3 Professor of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
4 Professor of Hepatogastroenterology and Infectious Diseases Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
5 Lecturer of Hepatogastroenterology and Infectious Diseases Medicine, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
6 Assistant Lecturer of Hepatogastroenterology and Infectious Diseases Medicine, Al-Azhar University, Damietta, Egypt
|Date of Submission||06-Aug-2018|
|Date of Decision||24-Aug-2018|
|Date of Acceptance||05-Feb-2020|
|Date of Web Publication||24-Jul-2020|
MD Ahmed Abdelaziz
Assistant Lecturer of Hepatogastroenterology and Infectious Diseases Medicine, Al-Azhar University, Damietta, 34511
Source of Support: None, Conflict of Interest: None
Background Chronic hepatitis C virus infection is one of the most important health problems in Egypt. Since November 2015, generic sofosbuvir (SOF) with daclatasvir (DCV)±ribavirin (RBV) became the standard treatment in all National Committee for Control of Viral Hepatitis centers. Yet, the long-term efficacy, safety, and late complications of generic direct-acting antiviral drugs have not been studied.
Aims Evaluation of the efficacy and safety of generic DCV-containing regimens in the treatment of chronic hepatitis C patients after 72 weeks of close follow-up.
Patients and methods A total of 150 chronic hepatitis C virus patients were classified into easy-to-treat group (naïve patients with no evidence of cirrhosis) and difficult-to-treat group (treatment experienced or have any evidence of cirrhosis) and treated for 12 weeks with generic medications: DCV 60 mg and SOF 400 mg±RBV in easy and difficult-to-treat groups, respectively. A close follow-up of up to 72 weeks was done to assess the efficacy and safety of the generic drugs.
Results Overall sustained virologic response (SVR12) was 94.0%, while the end of treatment response rate was 94.7%. SVR12 rates in easy-to-treat and difficult-to-treat groups were 97.06 and 91.46%, respectively. Multivariate analysis revealed that absence of cirrhosis, higher baseline albumin, lower baseline international normalized ratio, higher baseline platelet count, lower baseline alpha-fetoprotein, normal splenic size, and naivety to previous antiviral therapy were associated with SVR12. PCR after 72 weeks for those who achieve SVR12 is still undetectable. Three cases died during the follow-up period and were related to their advanced liver disease. No serious adverse events were reported.
Conclusion Generic DCV, SOF±RBV regimen is safe and effective for treatment of chronic hepatitis C with minimal adverse events and SVR12 is efficient to predict persistent viral clearance.
Keywords: daclatasvir, direct acting antivirals, HCV, hepatitis C virus, treatment safety
|How to cite this article:|
Hashim AM, Zaky S, Alghannam MZ, Ibraheem SA, El-Raey FM, Abdelaziz A. Efficacy and safety of daclatasvir-containing regimens in the treatment of chronic hepatitis C patients in Damietta. Al-Azhar Assiut Med J 2020;18:159-67
|How to cite this URL:|
Hashim AM, Zaky S, Alghannam MZ, Ibraheem SA, El-Raey FM, Abdelaziz A. Efficacy and safety of daclatasvir-containing regimens in the treatment of chronic hepatitis C patients in Damietta. Al-Azhar Assiut Med J [serial online] 2020 [cited 2020 Aug 9];18:159-67. Available from: http://www.azmj.eg.net/text.asp?2020/18/2/159/290608
| Introduction|| |
Hepatitis C is a disease with significant global impact that infects more than 185-million individuals worldwide corresponding to 2–2.5% of the world’s total population . Egypt is known to be among the countries with the highest hepatitis C virus (HCV) prevalence .
On the basis of the National Egyptian Health Issue Survey (EHIS) in 2015, the prevalence of HCV antibody was 10.0% and that of HCV-RNA was 7.0% of Egyptian adults (15–59-year age groups) . HCV genotype 4 accounts for more than 90% of infections . In 2010, Egypt had the highest age-standardized cirrhosis mortality rate (72.7 deaths per 100 000) .
The previous standard of care treatment with peginterferon (IFN)/ribavirin (RBV) for 48 weeks had been limited by both eligibility and tolerability  with response rates of 40–69% .
In 2014, after direct-acting antiviral (DAAs) drugs became available in Egypt, a mass treatment program was started by the National Committee for Control of Viral Hepatitis (NCCVH) in more than 100 specialized centers that was basically founded on sofosbuvir (SOF)-based regimens and the standard of care in the HCV national protocol was shifted from IFN-based, to SOF-based in 2014 (with pegylated IFN and RBV), to totally IFN-free regimens in May 2015.
Since November 2015, generic SOF with daclatasvir (DCV)±RBV became the standard treatment in all NCCVH centers and the NCCVH modified the local guidelines to be based entirely on generic SOF–DCV or SOF–DCV–RBV combinations .
The aim of this study was to assess the efficacy, safety profiles, and possible predictors of response for SOF/DAC with and without RBV combination in the treatment of chronic hepatitis C in Damietta Governorate after 72 weeks of follow-up.
| Patients and methods|| |
It was a prospective, cross-sectional study conducted on 150 chronic hepatitis C Egyptian patients mostly genotype 4 who attended to the Viral Hepatitis Treatment Unit, Damietta Fever Hospital and were eligible for treatment with DAAs drugs according to the protocol designed by the NCCVH in November 2015 and established by the Egyptian Ministry of Health and Publics.
The study was approved by the Ethics Committee of the NCCVH and Al-Azhar University. All patients treated in the national program signed an informed consent before starting treatment allowing the use of their clinical data and laboratory results for reports and publications.
- Age: 18–75 years.
- HCV-RNA positivity.
- Direct 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/mm3.
- If any of the criteria from 1 to 4 is not caused by liver disease, the patient can be included in the treatment protocol.
- Hepatocellular carcinoma (HCC), except 4 weeks after intervention aiming at cure with no evidence of activity by dynamic imaging (computed tomography or MRI).
- Extrahepatic malignancy except after 2 years of disease-free interval. In cases of lymphomas and chronic lymphocytic leukemia, treatment can be initiated immediately after remission based on the report of the treating oncologist.
- Pregnancy or inability to use effective contraception.
- Inadequately controlled diabetes mellitus (glycated hemoglobin>9%) .
All studied patients were subjected to the following:
- Detailed history taking and thorough clinical evaluation.
- Laboratory investigations including: complete blood count, liver biochemical profile including alanine transaminase (ALT), aspartate transaminase (AST), serum albumin, total bilirubin, prothrombin concentration and INR, serum alpha-fetoprotein (AFP), serum creatinine, fasting blood sugar and glycated hemoglobin if diabetic, hepatitis B surface antigen, pregnancy test for any female in the childbearing period.
- Quantitative HCV-RNA by Abbott real-time HCV (R2000; Abbott Park, Illinois, USA). The Abbott real-time HCV assay results and interpretation are reported as follows:
LLQ, lower limit of quantitation; ULQ, upper limit of quantitation.
Abdominal ultrasonography to detect the liver echo pattern (ultrasonographic features of cirrhosis), presence of signs of portal hypertension, and to exclude HCC or other comorbidities.
Patients were categorized into two groups:
Group I (easy-to-treat): a total of 68 patients who were noncirrhotic (by clinical and ultrasonographic examination), with total serum 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, platelet count more than or equal to 150.000/mm3, and who were naïve for HCV treatment.
Group II (difficult-to-treat): a total of 82 patients who were cirrhotic with total serum bilirubin more than 1.2 mg/dl, serum albumin less than 3.5 g/dl, INR more than 1.2, and platelet count less than 150.000/mm3 with a history of previous anti-HCV treatment.
- Easy-to-treat groups were treated by SOF/DAC for 12 weeks, while difficult-to-treat groups were treated by SOF/DAC/RBV for 12 weeks.
- Generic SOF were supplied to the Egyptian Ministry of Health and Publics Center in Damietta Fever Hospital by Pharco Company (Gratisovir 400 mg oral tablets) and DCV were supplied by Mash Premiere Pharmaceuticals (Daklanork 60 mg oral tablets), while RBV was a locally produced generic Minapharm in 200 mg oral capsules. The starting dose of RBV was 600 mg/day to reach a dose of 1000 mg/day in two divided doses based on patient tolerability .
Monitoring of treatment safety
- History taking for any adverse events especially the commonly reported adverse effects such as fatigue, headache, nausea, etc.
- Clinical examination was performed for any manifestations of hepatic decompensation and ultrasound examination if ascites was suspected.
- Liver biochemical profile, complete blood count, and creatinine were tested on every visit.
- RBV dose modification or discontinuation was allowed according to the change in hemoglobin (Hb). If significant anemia occurs (Hb<10 g/dl), doses of RBV were adjusted downward by 200 mg at decrements and stopped if Hb level falls below 8.5 g/dl .
- Potential drug–drug interactions with the patients’ medications were checked using the University of Liverpool application on smartphones (Liverpool HEP iChart). Drugs with adverse interaction with SOF or DCV were discontinued or changed if possible, or patients’ treatment was deferred.
- Cirrhotic patients who achieve an sustained virologic response (SVR) were advised to remain under surveillance for HCC every 6 months by ultrasound, and for esophageal varices by endoscopy if varices were present at pretreatment endoscopy .
Monitoring of treatment efficacy
- Quantitative HCV-PCR was assessed prior to treatment, on week 12 [end of treatment response (ETR)], week 24 (SVR12 at week 12 posttreatment and week 72 posttreatment.
- The end of treatment virologic response (ETR) was defined as HCV-RNA below the assay’s LLQ measured at the end of treatment.
- The SVR was defined as HCV-RNA below the assay’s LLQ measured at 12 weeks after the end of treatment (SVR12).
- Virologic nonresponse was defined as HCV-RNA more than or equal to LLQ at end of treatment.
- Virologic relapse was defined as HCV-RNA more than or equal to LLQ during any posttreatment follow-up visit in patients who achieve ETR .
All collected data were analyzed and correlated. Statistical analysis was performed using the Statistical Package for the Social Sciences, version 24 (IBM SPSS Inc., Chicago, USA). Basic descriptive statistics including means and SDs were performed. Comparison of qualitative data between groups was performed using the c2 test. Independent test or Mann–Whitney U test were used to compare quantitative data between groups with parametric distribution or nonparametric distribution, respectively. Continuous variables across time were compared using the paired t test or Wilcoxon signed-rank test. Differences were considered statistically significant if the P value was less than 0.05.
| Results|| |
In this study, the participants were 150 patients with chronic HCV who received treatment with SOF–DCV (n=68) or SOF–DCV–RBV (n=82) at the Viral Hepatitis Treatment Center, Damietta Fever Hospital according to the NCCVH protocol in April 2016. Baseline data of both groups are shown in [Table 1].
Overall SVR12 was 94.0% while the end of treatment response rate was 94.7%. SVR12 rates in easy-to-treat and difficult-to-treat groups were 97.06 and 91.46%, respectively with no statistically significant difference between both groups as regards SVR12 (P=0.24). PCR after 72 weeks for those who achieve SVR12 is still undetectable ([Table 2]).
|Table 2 Comparison between the two studied groups regarding treatment efficacy at end of treatment, week 12 after treatment and after 72 weeks of follow-up|
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In the current study, all patients continued their 12-week treatment without serious adverse events that led to treatment cessation. However, some tolerable side effects were reported as fatigue (25.00 and 54.88% in group I and group II, respectively; P<0.001). Headache, insomnia, somnolence, mild-exertion dyspnea, nausea, and diarrhea were also reported with no statistical significance between the two studied groups ([Table 3]).
|Table 3 Comparison between the two studied groups regarding main clinical adverse events|
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Two cases developed advanced HCC in the difficult-to-treat group and died during the follow-up period. Their death mostly related to their advanced liver disease rather than drug related. one case died in the easy-to-treat group (sudden cardiac arrest) ([Table 2]).
As regards laboratory abnormalities in this study, anemia and hyperbilirubinemia were the most prominent events and were significantly higher in group II (RBV arm) than in group I ([Figure 1] and [Figure 2]). Drop of Hb to levels between 8 and 10 g/dl was seen in 13 (15.85%) patients in group II versus 3three cases in group I (4.41%). In such cases, we reduced the dose of RBV and prescribed hematinic (erythropoietin 4000 IU SC) while the drop of Hb to levels below 8 g/dl necessitated discontinuation of RBV and was seen in only two (2.43%) cases presented by melena due to bleeding esophageal varices.
|Figure 1 Comparison between the studied groups as regard mean Hb level at different follow up time.|
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|Figure 2 Comparison between the studied groups as regard meanT.Bilirubin at different follow up time.|
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Predictors of response
Baseline characteristics of the patients who responded to treatment versus those who did not achieve SVR showed that low serum albumin, low platelet count, high international normalization, high AFP levels, and splenomegaly and treatment experience were significantly associated with treatment failure ([Table 4]).
|Table 4 Baseline characteristics of patients who achieved sustained virologic response versus those who failed treatment (nonresponders and relapsers)|
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Durability of sustained virologic response
After 72 weeks of follow-up PCR-HCV for the examined 129 cases is still undetectable rising the sensitivity of SVR12 to 100% ([Table 2]).
Both groups were homogeneous as regards age, sex, BMI, medical history of diabetes mellitus, and hypertension with no statistical difference and these factors had no impact on both efficacy and safety outcomes.
| Discussion|| |
HCV genotype 4 which accounts to about 90% in Egypt  was previously considered a difficult-to-treat genotype . Using peg-IFN/RIB as the standard of care for 48 weeks, SVR24 rates were substantially lower than those seen in patients with genotypes 2 and 3. Overall, SVR rates for genotype 4 in Egypt and the Middle East were about 60–69% ,,.
In 2014, after DAAs drugs became available in Egypt, a mass treatment program was started by the NCCVH in more than 100 specialized centers that was basically founded on SOF-based regimen., Since November 2015, generic SOF with DCV±RBV became the standard treatment in all NCCVH centers with significant improvement in SVR rates.
In this prospective, cross-sectional study, SVR12 rate was 97.06 and 91.46% while ETR rate was 98.5 and 91.46% in group I and group II, respectively.
These results were matching with Abdel-Moneim et al.  who found that SVR12 was achieved by 94% in the overall patients, by 95 and 92% in the easy-to-treat group and difficult-to-treat group, respectively.
Omar et al.  found that overall, 95.1% achieved SVR12 (95.4% among patients treated without RBV and 94.7% for patients treated with RBV, P=0.32).
El Kassas et al.  studied the effect of seven different DAA regimens on 7042 chronic hepatitis C Egyptian patients and found that the SVR  was 99.8 and 99.2% for SOF/DAC and SOF/DAC/RBV regimens, respectively.
This also came in agreement with Ahmed et al.  who found that SOF+DCV for 12 weeks resulted in 96% achievement of SVR at week 12.
The same results were obtained by Welzel et al.  who studied the efficacy and safety of DCV, SOF, and RBV on 485 European patients, 359 received DCV+SOF and 126 DCV+SOF+RBV and found that SVR12 was achieved by 91% of patients (419/460); one patient had virological breakthrough and 13 patients relapsed.
Moreover, DCV+SOF, with or without RBV, has demonstrated excellent efficacy and safety in a phase 2 study by Sulkowski et al.  SVR12 was achieved in 98% of both treatment–naïve and treatment-experienced genotype 1, 92% in genotype 2, and 89% in genotype 3 treatment– naïve patients.
Pol et al.  have reported a real-world experience for 768 HCV-G1 patients, and found an overall 95% SVR12 rate (92–99%), and that the SVR rates were not affected by treatment duration or RBV use. The ANRS-CUPILT report of treating liver transplant patients with SOF–DCV in France included 11 patient HCV-G4 patients, and the SVR12 rate was 91% .
In a study by Fontaine et al. , 82 genotype 4 infected patients were treated with SOF+DCV with or without RBV. The 33 patients who received SOF+DCV 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, irrespective of whether because they were treatment experienced or with advanced liver disease.
In this study, all patients continued their 12-week treatment without serious adverse events that led to treatment cessation. However, some tolerable side effects were reported such as fatigue (25.00 and 54.88% in group I and group II, respectively; P<0.001), headache, insomnia, somnolence, mild-exertion dyspnea, nausea, and diarrhea with no statistical significance between the two studied groups.
This came in agreement with the results of phase I studies which demonstrated that DCV was well absorbed and safe over a range of 1–200 mg and could be administered as a once- daily regimen. Similar rates of adverse events were reported among placebo and treatment groups, with headache reported most frequently ,.
This also came in agreement with Ahmed et al.  who found that the SOF/DAC regimen was well tolerated with no notable adverse events. None of their patients stopped treatment due to significant adverse events, with some tolerable side effects such as fatigue (12.4%), headache (11.9%), diarrhea (6.2%), and nausea (5.1%). Babatin et al.  who observed that 42.5% of patients who received the SOF/DAC regimen developed adverse events whereas 27.5% suffered from fatigue, 25% from headache, 10% from insomnia, 3% from nausea, and 4% suffered diarrhea.
The ALLY-3 study concluded that DCV–SOF–RBV was well tolerated. Overall, 94% of patients reported at least one on-treatment AE; the most common adverse events (AEs) occurring in at least 10% of patients were insomnia, fatigue, headache, irritability, asthenia, diarrhea, and dyspnea. There were no AEs leading to discontinuation of treatment .
On the other side, Welzel and colleagues studied the efficacy and safety of DCV, SOF, and RBV on 485 European patients and found that 28 patients discontinued treatment due to adverse events (n=18) or death (n=10) and 18 died during follow-up. However, deaths and most safety events were associated with advanced liver disease and not considered treatment related and concluded that DCV+SOF with or without RBV was well tolerated in a diverse cohort of patients with severe liver disease .
In his study, anemia and hyperbilirubinemia were the main laboratory abnormalities and were significantly higher in group II (RBV arm) than in group I.
The same results were reported also by Landis et al.  who presented an integrated safety analysis of SOF/DAC±RBV and found that addition of RBV seems to increase the number of serious AEs (2.7 vs. 7.9%) and the rate of discontinuations (0.2 vs. 7.9%, respectively) mainly due to anemia. The presence of cirrhosis and the duration of treatment period did not show to have an effect on AEs.
Nelson et al.  found that increased incidence of anemia is consistent with hemolytic anemia which is known to occur with RBV treatment. Also, Lawitz et al.  found that anemia was reported more frequently in the groups receiving RBV than in those not receiving RBV, but did not lead to premature discontinuation of therapy. Moreover, Sulkowski et al.  found that Hb did not significantly decrease in patients not receiving RBV with no treatment discontinuation.
In this study, there was chemical improvement of necroinflammatory changes in the liver as seen by the statistically significant reduction in ALT and AST levels posttreatment.
This is in agreement with Elsharkawy et al.  who studied the impact of different SOF-based treatment regimens on the biochemical profile of chronic hepatitis C genotype 4 patients and concluded that DAAs improve liver necroinflammatory markers in cirrhotic and noncirrhotic patients.
This is also in accordance with Ahmed et al.  who found that treatment of HCV with SOF/DAC and SOF/DAC/RBV was associated with a significant reduction in AST and ALT level (P<0.001 for both) after completion of antiviral treatment.
Among all patients, the following characteristics were more likely to predict treatment failure: low serum albumin, low platelet count, high international normalization, high AFP level, splenomegaly, and treatment experience were significantly associated with treatment failure.
This came in agreement with Werner et al. , who studied the predictors of response to new DAAs and found that negative predictors of SVR12 were a platelet count less than 100/nl, MELD score more than or equal to 10 (P<0.0001), and liver cirrhosis (P=0.005) at baseline and the side effects were mild.
Moreover, El Kassas et al.  found that patients with significantly lower albumin, total leukocyte count, platelet count, and prothrombin; higher INR, AFP, AST, bilirubin, and FIB-4 score; Child–Pugh class B; and high liver stiffness as assessed by FibroScan responded less to treatment with DAAs.
In a recent Egyptian study, predictors of nonresponse included male sex, previous IFN therapy, and being in the difficult-to-treat group .
Poordad et al.  have found lower albumin levels associated with nonresponse in Child C patients as a reflection of an impaired hepatic function while Omar et al.  found several factors that could impact SVR12 rates. These include sex, bilirubin, albumin, INR, and platelets count.
Lastly and importantly, all examined 129 cases still have undetectable HCV-RNA after 72 weeks of follow-up, which rises the sensitivity of SVR12 to 100%. The SVR is generally associated with resolution of liver disease in patients without cirrhosis.
Burgess et al.  found that among persons who achieve an SVR12 with DAA therapy, more than 99% go on to achieve an SVR24. Long-term follow-up of patients who achieve an SVR24 has shown that nearly 100% remain HCV-RNA negative years after therapy ,,.
Several large studies have shown a minimal relapse rate, of between 0 and 1% at 5 years ,. Thus, an undetectable HCV-RNA 12 or 24 weeks after antiviral therapy can be considered a virologic cure. It is important to note that persons cured of HCV can become reinfected with HCV ,.
This matched with EASL guidelines 2015 which stated that the infection is cured in more than 99% of patients who achieve an SVR  and AASLD, IDSA recommendations which defined that a SVR is an undetectable HCV-RNA level using a sensitive assay (typically with a lower limit of 25 IU/ml) after at least 12 weeks of completion of HCV therapy .
| Conclusion|| |
In this report, we can conclude that the use of generic SOF/DCV combination with or without RBV was well tolerated with minimal adverse events and is associated with high response rate in patients with different stages of liver disease after long periods of close follow-up.
The authors acknowledge the National Committee for Control of Viral Hepatitis, Egypt, for approving this work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]