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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 4  |  Page : 119-124

Sofosbuvir and daclatasvir in the treatment of chronic hepatitis c virus infection at benghazi medical center: Our experience


1 Department of Medicine, Infectious Disease Unit, Benghazi Medical Centre; Department of Medicine, Faculty of Medicine, University of Benghazi, Benghazi, Libya
2 Department of Medicine, Infectious Disease Unit, Benghazi Medical Centre; Department of Pharmaceutical, Faculty of Pharmacy, University of Benghazi, Benghazi, Libya
3 Department of Medicine, Infectious Disease Unit, Benghazi Medical Centre, University of Benghazi, Benghazi, Libya

Date of Submission05-Nov-2019
Date of Acceptance02-Dec-2019
Date of Web Publication26-Dec-2019

Correspondence Address:
Dr. Ahmed Elhaddad
Infectious Disease Unit, Benghazi Medical Center, Faculty of Medicine, University of Benghazi, Benghazi
Libya
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/LJMS.LJMS_61_19

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  Abstract 


Background: The treatment of hepatitis C virus (HCV) has changed dramatically with the rapid advent of numerous new antiviral agents, including direct-acting antivirals which become the standard of care for HCV infection. Our aim was to investigate the safety and efficacy of combined sofosbuvir (SOF)/daclatasvir (DCV) for HCV in our patients. Patients and Methods: The cohort comprises 157 HCV-infected patients followed from October 2016 to May 2018. The inclusion criteria were treatment experienced or naïve and 18 years or older. Cirrhotic patients included were Child-Turcotte-Pugh A (CTP-A) whereas CTP-B-C patients were excluded. All patients had been treated with SOF/DCV 400/60 mg with or without ribavirin. The primary endpoint was sustained virological response at week 12 (SVR12) and significant adverse events. Results: A total of 157 patients were enrolled in the study with a mean age of 47.74 ± 18.2 years including 48.2% males. Ninety percent of patients were Libyan. One hundred and fifteen (72.9%) patients were treatment naïve. Fifty-eight (36.9%) patients were cirrhotic. The adverse effects of the drug were reported in 25/157 (15.9%); the most commonly reported side effects were gastrointestinal upset and dizziness, whereas hepatic decompensation occurred in five patients and all were cirrhotic and none required drug cessation. Undetectable viremia at the end of treatment was observed in 156 patients (99.3%), and one patient had been labeled as nonresponder. Undetectable viremia 12 weeks after the end of treatment was achieved in 155 patients (98.8%), and only one relapsed. Conclusion: SOF and DCV are safe and efficacious with an SVR12 of about 99.0% among our cohorts. The next step is to improve screening and access to these therapies for eradication of hepatitis C infection from the world and Libya as well in the near future.

Keywords: Hepatitis C virus, sofosbuvir/daclatasvir, Libya


How to cite this article:
Elhaddad A, Elhassi A, Hadiia GM, Taher S, Badr Z. Sofosbuvir and daclatasvir in the treatment of chronic hepatitis c virus infection at benghazi medical center: Our experience. Libyan J Med Sci 2019;3:119-24

How to cite this URL:
Elhaddad A, Elhassi A, Hadiia GM, Taher S, Badr Z. Sofosbuvir and daclatasvir in the treatment of chronic hepatitis c virus infection at benghazi medical center: Our experience. Libyan J Med Sci [serial online] 2019 [cited 2020 Feb 25];3:119-24. Available from: http://www.ljmsonline.com/text.asp?2019/3/4/119/274104




  Introduction Top


Hepatitis C virus (HCV) infection is the main cause of progressive liver diseases and a public health problem, worldwide.[1] The majority of infected patients develop chronic infection, which may lead to liver cirrhosis, hepatocellular cancer, and death.[2] Approximately 350,000–500,000 people die each year from hepatitis C-related complications around the world. Chronic HCV infection is the main cause of chronic liver disease in Libya, where although the exact number of infected subjects is unknown, a prevalence of approximately 1.3% is estimated in the general population.[3] HCV genotype 4 (HCV-G4) is the most frequent genotypes among patients attending the virology clinic in our center. A previous study conducted in Libya had shown that HCV-G1 was more prevalent in the western region and HCV-G4 was the most prevalent genotype in the eastern region of the country.[4] Direct-acting antiviral (DAAs) agents have revolutionized the treatment of HCV infection over the last 5 years. As a result of our better understanding of the HCV life cycle, specific DAAs have been developed for HCV that are able to target the viral proteins implicated in replication of the virus, i.e., the NS3/4A protease, NS5B polymerase, and multifunctional NS5A replication complex. Oral IFN-free combinations containing at least two DAAs enabled less complex dosing, tolerable side effects, and fewer drug–drug interactions.[5] Daclatasvir (DCV) is an NS5A inhibitor with pan-genotypic activity that is effective against the six major HCV genotypes, with a pharmacokinetic profile permitting once-daily dosing. DCV is well tolerated. Headache is the most frequently encountered adverse event (AE). DCV is a weak inducer of cytochrome P450, and thus, it has minimal drug interactions. In addition, its metabolism is mainly hepatic, which permits its use without dose adjustments in patients with chronic kidney disease. For prevention of emergence of resistant infections, an appropriate dose of DCV in combination with other suitable DAAs is recommended.[6] Sofosbuvir (SOF) is an orally administered HCV nucleotide polymerase NS5B inhibitor. It is given once daily and has a good safety profile. It has a high barrier to resistance, a pan-genotypic antiviral effect, and few drug–drug interactions.[7],[8] Combination of SOF and DCV with or without ribavirin (RBV) has been well tolerated in previously treated or untreated HCV patients and associated with a high rate of sustained virological response (SVR) in genotype 1 or 4 patients who are assumed to be difficult to treat.[5],[9],[10] Hence, in our study, we aim to assess the efficacy and safety of this combination in Libyan population.

Based on published data about the use of newer DAAs and their efficacy, we aimed to assess the efficacy of 12 weeks of SOF 400 mg plus DCV 60 mg, with or without RBV (800–1000 mg) in treating chronic HCV infection in our patients.


  Patients and Methods Top


Study design

In this retrospective study, 157 patients HCV-positive treated at viral hepatitis clinic – Benghazi Medical Centre – were enrolled. HCV patients were selected for exploratory study to use their data.

Inclusion criteria

Eligible patients had been treated between October 2016 and May 2018 who were 18 years or older having chronic hepatitis C infection with HCV-RNA-positive polymerase chain reaction (PCR), regardless of whether they were treatment naïve or have experienced interferon in the past were enrolled in the study.

Exclusion criteria

Patients who were pregnant, breastfeeding mothers, Child-Turcotte-Pugh B, C (CTP-B-C) cirrhotic, or having active renal disease with Glomerular filtration rate (GFR) <30 were excluded from the study as well as patients coinfected with HBV or HIV.

Setting of the study

The data were collected from medical records of patients attending viral hepatitis clinic of infectious disease department at Benghazi Medical Centre. Benghazi Medical Centre is one of the largest tertiary care hospitals that drain not only Benghazi area but also patients from eastern and southern part of Libya.

Data collection sheet

A predesigned excel form was used for data collection which includes data about the sociodemographic profile of the patients such as age, gender, residence, nationality, and address and whether they were treatment naïve or interferon experienced in the past. All the patients before enrolment were exposed to the following investigations: complete blood count (CBC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum bilirubin levels, serum albumin, serum creatinine, bleeding profile, and alpha-fetoprotein. Their cirrhosis status was determined using noninvasive measures such as Fibroscan, ultrasound, and child class before starting therapy. A quantitative measurement of HCV-RNA was performed by real-time PCR with a detection limit of 15 IU/ml and it was repeated at the end of treatment and 12 weeks after treatment to detect SVR at week 12 (SVR12). All included patients were assumed to have HCV-G4. Monthly follow-up visits were done containing medical examination, side effects (SEs) reporting, and laboratory investigations such as “CBC, ALT, AST, Total Bilirubin (T. Bil), and creatinine.” Treatment advised according to the current international guidelines.[11] Treatment-naïve or interferon-experienced noncirrhotic patients were offered generic SOF 400 mg and DCV 60 mg once daily for 12 weeks. RBV 1000 mg (in patients <75 kg) or 1200 mg (in patients >75 kg) was added to the regimen for cirrhotic patients. SVR was evaluated by PCR after 12 weeks of the end of the treatment.

Data processing and analysis

All the data were entered and analyzed in SPSS version 22 (International Business Machines Corporation [IBM], New York, USA). Descriptive analytic components were calculated as mean ± standard deviation and summarized to describe the study participants. Tables and graphs were used accordingly and when relevant. Inferential analysis was conducted starting by simple correlation ending up with more sophisticated analysis to find if there was any statistical significance with considering 0.05 as a cutoff significance value for judging statistical important results. T-testing was used to compare continuous variables, and Chi-square testing was used for categorical variables.


  Results Top


Descriptive results

A total of 157 patients were included in the study having chronic HCV among which 74 males (48.2%) and 83 females (51.8%) with a mean age of 47.74 ± 18.2 years. Fifty-eight (36.9%) patients had cirrhosis; all of them were CTP-A whereas CTP-B and C patients had been excluded. Study participants who were naïve to any previous interferon treatment were 115 (72.9%), while among remaining 42 (27.1%) patients who had HCV treatment-experienced previously, 18 (42.9%) were nonresponders while 24 (57.1%) were relapsers. The vast majority of the patients were Libyan and 9% non-Libyan (10 - Egyptian and 4 - other nationalities). 78.9% of the patients (124 cases) were from Benghazi, whereas the remaining 21.1% were from other cities around Benghazi. ALT was elevated in 43% of patients at baseline (mean ALT IU/ml 49.61 ± 29.90), mean AST was 42.97 ± 46.24, mean hemoglobin level was 12.87 ± 2.41, and the mean platelet count was 201.11 ± 72.80. HCV-RNA >log 5 IU/ml at diagnosis (high viral load) was found among 63.4% of patients and the mean PCR HCV-RNA quantitative levels were 5.9 × 106 ± 1.06 IU/ml [Table 1].
Table 1: Demographic characteristics of the patients at baseline (n=157)

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Safety profile

The combination was well tolerated as no treatment SE reported by 132 patients (84.1%) of the sample and the adverse effects of the drug were only noted in 25 patients (25/157, 15.9%). Headache, mild gastrointestinal (GI) upset, and dizziness were the most common side effects, whereas acute hepatic decompensation occurred in five cirrhotic patients. The percentage distribution of different AEs is displayed in [Figure 1].
Figure 1: Adverse events for sofosbuvir/daclatasvir regimen

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Virological response

All patients had follow up PCR at the completion of therapy with an End of Treatment Response (ETR) of about 99.4% (156/157) and one patient (1/157) has been labelled as non- responder. ETR in treatment naïve was 99.2% (114/115), treatment experienced was 100% (42/42), and cirrhotic patients was 100% (58/58), whereas ETR in noncirrhotic patients was 98.9% (98/99). One hundred and fifty-six patients had a follow up of 12 weeks posttreatment with an SVR which is defined as undetectable viral load 12 weeks posttreatment (SVR12) of 99.33% (155/156), among which treatment naïve had a response rate of 100% (114/114), treatment experience 97.6% (41/42), cirrhotic 98.3% (57/58), and noncirrhotic patients of 100% (98/98).

Inferential results

For categorical variables, we applied Chi-square test to explore association between the treatment status (naïve or interferon experienced) and virological response (ETR or SVR), but no statistically significant difference was observed in patients whether attained ETR or SVR12 or not, based on previous treatment status with all P > 0.05. Similarly, no statistically significant association was observed between the baseline viral load (high ≥ log 105 IU or low < log 105 IU) and virological response (ETR or SVR) with all P > 0.05. Furthermore, treatment results for SVR12 according to gender revealed no significant difference between male and female patients; the results are very close to each other. The distribution of virological responses in the study participants is displayed in [Table 2]. Regarding treatment responders, pretreatment ALT showed a median value of 49 IU/L, while posttreatment ALT showed a median of 24 IU/L. Pretreatment AST showed a median value of 42 IU/L, while posttreatment AST showed a median value of 25 IU/L (P < 0.05) [Table 3].
Table 2: The distribution of virological responses in study participants

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Table 3: Comparison of liver biochemical, blood profiles and kidney function tests among the studied groups before and at the end of treatment

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  Discussion Top


The introduction of DAA agents is a dramatic success in HCV treatment, which leads to remarkable change in the projected morbidity and mortality due to the infection complications. There are number of effective regimens and combinations with minimum SE and maximum cure rates even with the most resistant genotypes. The main goal of treatment of HCV patients is to eliminate the viremia, minimize the progression of the liver disease, and decrease the incidence of hepatocellular carcinoma.[7] Before the introduction of the DAAs, the treatment regimen was confined to the interferon with high rates of treatment failure and relapse and a lot of documented SE.[12] With the introduction of the DAAs in 2011, higher SVR rates and good tolerability with minimal SE achieved.[13],[14] A new era of DAAs is now dawning in the entire world and Libya as well. Experience of applying SOF-based therapy in Libyan patients with hepatitis C is evolving. The first DAA drugs introduced in Libya were telaprevir and bocepravir in 2012 and 2014, respectively. SOF and SOF-containing regimens were becoming available in Libya since March 2015. The first published results from Libya on the efficacy and safety of DAA drugs came from Elhaddad et al., who presented results on the efficacy and safety of the brand SOF/ledipasvir (LDV) combination in 266 patients with chronic hepatitis C. The authors concluded that treatment with such DAA drugs achieved a high rate of HCV-RNA undetectability at the end of the treatment and SVR12 in 98% of patients, and no clinically significant treatment emergent AEs were noted.[15]

In this study, the combination of SOF and DCV was examined for its effectiveness and safety in the treatment of chronic HCV infection in Benghazi. DCV is an approved DAA in Europe and in Japan. It is conventionally used in combination with other DAAs such as SOF with or without RBV. In the USA, DCV is not available on the market; however, in 2015, the American Association for the study of liver disease proposed a DCV-free regimen for treatment-naïve and treatment-experienced patients (prioritized for patients with advanced fibrosis, cirrhosis, liver transplantation, or severe extrahepatic HCV manifestations).[5] Most of the studied patients in this study were naive cases (not previously treated for HCV) who represented 72.9% and the remaining part were treatment experienced cases. Although genotyping was not performed at baseline, more than 85% of patients in eastern part of Libya are infected with HCV-G4 followed by HCV-G1 (10%),[4] this report can thus be taken to represent results of HCV-G4 treatment and to less extend to HCV-G1. Sulkowski et al. recruited HCV-G1–3 patients without cirrhosis who were either treatment naive or experienced. SVR12 ranged between 89% and 98% depending on genotype.[16] However, the findings of our study are reasonably good and quite comparable with the international data. Similar results have been recently reported from Egypt, a neighbor country of Libya with predominant HCV-G4, in adult patients with genotype 4 using SOF/DAC combination with SVR12 of 96%.[17] Omar et al. reported a real-world experience for 18,378 HCV-G4 patients in Egypt and found an overall 95.8% SVR12 rate and that the SVR rates were not affected by treatment duration or RBV use.[18] El Monem et al. reported that SVR12 rate for their HCV4-naive patients who received SOF/DAC regimen was 96.5%.[19] A study from Europe stated a real-world report from compassionate use of SOF-DCV in patients with HCV and advanced liver disease included 19 HCV-G4 patients, and the SVR12 rate was 100%.[20] Both agents have proven effectiveness against HCV-G4 infections in Phase III ALLY-1, ALLY-2, and ALLY-3 studies that evaluate the role of this combination among different HCV genotypes. Phase II IMPACT study evaluates this combination in addition to simeprevir in the treatment of HCV-G1 and HCV-G4 DAA-naïve patients with portal hypertension or decompensated cirrhosis. All patients achieved SVR12 regardless of the presence of baseline detectable resistance associated mutations in 83% of patients[21] Pol et al. reported a real-world experience for 768 HCV-G1 patients and found an overall 95% SVR12 rate (92%–99%) and found that the SVR rates were not affected by treatment duration or RBV use.[21] In the current study, 132 of the as-treated group (84.1%) tolerated SOF plus DCV with no notable AEs, six patients of the as-treated population (4.0%) experienced dizziness, four patients (2.7%) experienced headache, 10 patients (7.9%) experienced mild GI upset, and five patients (3.7%) experienced acute hepatic decompensation which was successively treated medically, and none of our patients died during treatment and none of them stopped treatment due to significant AEs. This came in accordance with Omar et al., who had noted that SOF plus DCV treatment was well tolerated: only 0.3% (n = 54) of their patients reported AEs.[18] Furthermore, all previous studies concluded that SOF-DCV combination is safe with limited AEs. Statistically significant reductions in ALT and AST were observed in responders following 12 weeks of treatment (P < 0.05) which came in accordance with one previous study by Elsharkawy et al. in 2017 who studied impact of different SOF-based treatment regimens on the biochemical profile of chronic hepatitis C genotype 4 patients. Treatment responders showed significant improvement in transaminases compared to pretreatment values after 12 weeks of treatment with all regimens including SOF plus DCV, indicating their role in improving necro-inflammation in patients with chronic HCV.[22] In the current study, SVR12 was high regardless of the severity of the underlying liver disease[23] and the baseline demographic characteristics of the patients. Since hepatitis C is now proven to be a curable disease, such a response is required for this infection in Libya and elsewhere. The number of treatment uptakes, therefore, should increase to 15,000 in 2018–2030 annually to achieve the goal of HCV elimination in Libya by 2030 through the efforts to secure new efficient treatment with DAAs that is pan-genotypic, is well tolerated with minimal adverse effects, has low pill burden, and shows minimal drug interactions.[24] Nowadays, in 2019, with availability of recent DAAs regimens, the fixed-dose combination grazoprevir-elbasvir (zepateir) and SOF-velpatasvir (epclusa) in addition to the first used treatment regimen of fixed-dose combination SOF-LDV and SOF/DCV; furthermore, approximately 2000 HCV patients have received treatment with DAAs; among them, nearly 200 patients on hemodialysis in Benghazi centers in 2015–2019, the treatment strategy of hepatitis C might become more feasible and less complex than before, and more hepatitis C patients can uptake treatment including complex cases such as patients with end-stage renal disease on hemodialysis, decompensated cirrhosis, or failure following interferon-free DAAs regimens.


  Conclusion Top


The introduction of DAA therapy clearly revolutionized the approach to treatment of HCV infection. In summary, DCV + SOF, with or without RBV, achieved high SVR12 rates in our cohort of patients including those with cirrhosis. Treatment was well tolerated and was associated with improvements in liver function. DAAs grant the cure to thousands of patients and give them a new hope to definitively clear HCV infection, not only in newly infected patients but also in who underwent to Interferon (IFN)- and RBV-related SE and failed to be cured. Although we have a long way to eradication of HCV in Libya, the next steps could be including proper planning to patient finding, availability of new treatments with DAAs, and development of HCV prevention strategies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Full text]  
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