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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 38-41

Efficacy and tolerability of ledipasvir/sofosbuvir on chronic hepatitis C virus patients attending viral hepatitis clinic at Benghazi medical center, Libya


Benghazi Medical Center, Infectious Disease Unit, Benghazi, Libya

Date of Web Publication24-Jun-2019

Correspondence Address:
Prof. Ahmed B Elhaddad
Benghazi Medical Center, Infectious Disease Unit, Benghazi
Libya
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/LJMS.LJMS_8_19

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  Abstract 


Background: The prevalence of hepatitis C virus (HCV) infection in Libya is 1.3%. It is considered now a curable disease due to the availability of effective DAAs which open a new horizon for HCV elimination. The aim of this study was to evaluate the efficacy and tolerability of ledipasvir/sofosbuvir (LDV/SOF) (Harvoni) on patients with chronic hepatitis C infection. Patients and Methods: The cohort comprises 266 HCV-infected patients followed from May 2016 to October 2017. The inclusion criteria were treatment experienced or naïve and 18 years or older. Cirrhotic patients included were Child–Pugh A and B whereas Child–Pugh C patients were excluded. All patients had been treated with LDV/SOF 90/400 mg. The primary endpoint was sustained virological response (SVR) at week 12 and significant adverse events. Results: Of 266 patients who participated in the study, it's found that 126 were males(47.3%) and 140 were female (52.7%). The average age of the patients was 45 years for both genders. Ninety percent of patients were Libyan. The predominate genotype was 4 (81.3. %), genotype 1 (15.3%), and genotype 2 (3.2%). One hundred and seventy-eight (66.9%) patients were treatment naïve and 88 (33.1%) patients were treatment experienced. Alanine aminotransferase elevated in 37% of patients at baseline. HCV RNA >5 log at the start of treatment was found in 67.2% of patients. Eighty-eight patients were cirrhotic. The adverse effects of the drug were reported in 38/266 (14.2%); the most commonly reported side effects were headache, gastrointestinal upset, and dizziness, whereas hepatic decompensation occurred in 5 patients and all were cirrhotic. Undetectable viremia at the end of treatment (week 12) was observed in 263 patients (98.5%) and 3 patients have been labeled as nonresponders. SVR at week 12 was available in 263 patients and achieved in 261 patients (98.1%), and only two relapsed. Conclusion: Excellent treatment outcomes among our cohort of HCV-infected patients were achieved with LDV/SOF. Testing for chronic HCV patients and availability of care will help in cure and a step toward eradication of HCV in near future.

Keywords: Hepatitis C virus, ledipasvir/sofosbuvir, Libya


How to cite this article:
Elhaddad AB, Nouh FA, Elhassi A, Taher S, Daw E. Efficacy and tolerability of ledipasvir/sofosbuvir on chronic hepatitis C virus patients attending viral hepatitis clinic at Benghazi medical center, Libya. Libyan J Med Sci 2019;3:38-41

How to cite this URL:
Elhaddad AB, Nouh FA, Elhassi A, Taher S, Daw E. Efficacy and tolerability of ledipasvir/sofosbuvir on chronic hepatitis C virus patients attending viral hepatitis clinic at Benghazi medical center, Libya. Libyan J Med Sci [serial online] 2019 [cited 2019 Nov 18];3:38-41. Available from: http://www.ljmsonline.com/text.asp?2019/3/2/38/261136




  Introduction Top


Hepatitis C infection is a blood-borne virus; the most common modes of infection transmission are through exposure to blood. This may happen through injection drug use, unsafe injection practices, and the transfusion of unscreened blood and blood products.[1],[2],[3] Globally, an estimated 71 million people have chronic hepatitis C infection.[4],[5] A significant number of those who are chronically infected will develop cirrhosis or liver cancer.[6] The most affected regions are the WHO Eastern Mediterranean and European regions, with a prevalence of 2.3% and 1.5%, respectively. The prevalence of hepatitis C virus (HCV) infection in other WHO regions varies from 0.5% to 1.0%.[7],[8] In Libya, the prevalence of HCV among the general population was found to be 1.3%,[9] and HCV genotype 4 was the predominant genotype, followed by genotype 1.[10] In those people who go on to develop chronic HCV infection, the infection is also often undiagnosed because the infection remains asymptomatic until decades after infection when symptoms develop secondary to serious liver damage.[11] When treatment is necessary, the goal of hepatitis C treatment is cure. The cure rate depends on several factors including virus genotypes and the type of treatment given.[12] The standard of care for hepatitis C is changing rapidly. Sofosbuvir (SOF), daclatasvir, and SOF and ledipasvir (LDV) combination are part of the preferred regimens in the most used guidelines and can achieve cure rates above 95%. These medicines are much more effective, safer, and better tolerated than the older therapies. Therapy with Direct Acting Antivirals (DAAs) can cure most persons with HCV infection and treatment is shorter (usually 12 weeks).[13] Although the production cost of DAAs is low, these medicines remain very expensive in many high- and upper-middle-income countries. Prices have dropped dramatically in some countries (primarily low income) due to the introduction of generic versions of these medicines.[14] In October 2014, the US Food and Drug Administration approved the combination of LDV and SOF, brand name Harvoni) which described as one of the best options for treatment of patients with HCV GT 4, and genotype 1, irrespective of treatment history or the presence of compensated cirrhosis.[15] This study is aimed to evaluate the efficacy, safety, and tolerability of LDV/SOF fixed-dose combination (FDC) in participants with chronic HCV infection as measured by the proportion of subjects with Sustained Virological Response (SVR12).


  Patients and Methods Top


The medical records of 266 chronic HCV-infected patients were reviewed. Patients older than 18 years diagnosed as chronic HCV infection either treatment naïve or experienced (previous exposure to pegylated interferon and ribavirin or directly acting antivirals). Patients enrolled were treated with the FDC of LDV/SOF for 12 weeks, and the selected period was from May 2016 to March 2017. Patients with HIV or HBV infection were excluded. The study was conducted in the viral hepatitis clinic of the Department of Infectious Diseases, Benghazi Medical Center. The presence of cirrhosis was determined by liver biopsy with a Metavir score of F4 or a score of >12.5 kPa on transient elastography testing (Fibroscan) or radiological imaging consistent with cirrhosis. Cirrhotic patients included were Child–Pugh A and B whereas Child–Pugh C was excluded. For each patient included in the study, the demographic data were collected through excel chart review, including age, race, sex, body mass index (BMI), nationality, HCV genotype, and medical history. Pretreatment, during treatment, and posttreatment data of the standard laboratory testing (complete blood count, levels of albumin, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine) along with evaluations of adherence were collected. Adverse events and clinical laboratory results were recorded throughout the study. Plasma HCV RNA levels were measured using the real-time HCV assay (Abbott), with the Lower Limit of Quantitation of 15 IU/ml. The primary efficacy endpoint was a sustained virological response of HCV at 12 weeks (SVR12) after the completion of therapy. The primary safety endpoint was the frequency and severity of adverse events.

Statistical analysis

The data were analyzed using SPSS version 22 (International Business Machines Corporation (IBM), New York, USA). Descriptive characteristics of the study participants were calculated as mean ± standard deviation, t-testing was used to compare continuous variables, and Chi-square testing was used for categorical variables.


  Results Top


Out of 266 patients participated in the study, the number and percentage of females was 140 (52.7%). Mean age was 45 years for both genders. The patient's nationality is 90% Libyan, 9% Egyptian, and 1% Palestinian. BMI results were as follows: 63.2% – overweight, 24.9% – normal, 2.6% – obese, and 4.3% – underweight. Genotype 4 constitutes 81.3%, while genotype 1 was 15.3% and genotype 2 was 3.2%. One hundred and seventy-eight patients are treatment naïve (66.9%) and 88 patients were treatment experienced (23.1%). HCV RNA >log 5 at diagnosis (high viral load) was found among 67.2% of patients. A total of 88 patients with cirrhosis were treated; all of them are Child–Pugh A and B, whereas Child–Pugh C patients were excluded [Table 1]. Undetectable viremia at end of treatment (week 12) was observed in 263 patients (263/266, 98.5%) and 3 patients (3/266) have been labeled as nonresponders. Sustained virological response (SVR12) which is defined as undetectable viral load 12 weeks posttreatment has been achieved by 261 patients (261/266, 98.1%) and only two relapsed (2/266) [Table 2]. The adverse effects of the drug were noted in 38 patients (38/266, 14.2%) that headache, mild gastrointestinal upset, and dizziness were the most common side effects, whereas acute hepatic decompensation occurred in 5 patients (7/266) [Figure 1].
Table 1: Demographic characteristics of the patients at baseline n (%)

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Table 2: SVR rate in different patients categories

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Figure 1: Incidence of adverse effects

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  Discussion Top


A new era of direct-acting antivirals 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. LDV and SOF are both direct-acting antiviral agents.[16] SOF is a liver-targeted nucleotide prodrug of the active triphosphate GS-461203, which has been approved for use in HCV genotypes 1–4. It works as an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which acts as a chain terminator.[17],[18] LDV is an NS5A inhibitor that is effective against genotypes 1a, 1b, 4a, and 5a and (with lower activity) against genotypes 2a and 3a. Its exact mechanism of action is unknown, but one suggested mechanism is its inhibition of hyperphosphorylation of NS5A, which seems to be required for viral production. NS5A inhibitors may also cause faulty viral assembly by redistributing the subcellular localization of the protein.[19] The NS5A and NS5B inhibitors demonstrate an additive or synergistic effect when used in combination.[15] HCV genotype 4 is the most frequent genotypes among patients attending the virology clinic in our center. A previous study conducted in Libya had shown that HCV infection with genotype 1 was more prevalent in the western region and genotype 4 was the most prevalent genotype in the eastern region of the country.[20] Over the two third of our patients had a high baseline viral load and one third were treatment experienced and/or had advanced stages of liver disease (F3 or F4), factors previously associated with treatment failure in HCV patients. The study shows that the treatment with SOF and LDV for 12 weeks resulted in an SVR12 rate of 98% in treatment naïve and those who failed previous therapy including cirrhotic patients. In contrast, pegylated interferon plus ribavirin was associated with a poorer response rate with less than 50% of patients achieving SVR which indicate the big difference in effectiveness between the old and the new regimens.[13],[21],[22] The use of LDV and SOF in our cohorts, HCV treatment naïve and experienced, resulted in high cure rates exceeding those seen with the previous standard of care, and our data have been supported with recently published data from a study in Egypt conducted by Shiha et al. who stated that patients with hepatitis C genotype 4 had high SVR rates with Harvoni over 12 weeks regardless of cirrhosis or treatment experience with 98% SVR12 and negligible side effects.[23] El-Khayat et al. in a recent real-world study done on adolescents with HCV GT 4 with SOF/LDV regimen also showed SVR12 of 99% which was also similar to our study.[24] Our result was also compared to another trial (the SYNERGY trial), the overall SVR in SOF/LDV for 12 weeks was well tolerated, and SVR achieved was 100% regardless of previous treatment status and underlying liver cirrhosis.[25] Abergel et al. reported data from an open-label single-arm study including 22 HCV genotype 4-infected, treatment-naïve patients (only 1 with cirrhosis) with an SVR12 rate of 95%.[26] These two pilot studies support the use of this regimen in patients with HCV genotype 4 infection. In recent years, many direct-acting antiviral agents (DAAs) have been developed, and their efficacy and safety have been tested in many clinical trials as our study which reveals no clinically significant treatment-emergent adverse events where the adverse effects of the drug were noted in 38 patients (14.2%), hepatic decomposition occurred in 5 patients, and all were cirrhotic. None of the patients receiving LDV/SOF for 12 weeks needed to have the drug discontinued. Across the ION-1, ION-2, and ION-3 studies, treatment with oral LDV/SOF was well-tolerated.[27],[28],[29],[30] Fewer adverse events were observed in groups who received LDV/SOF alone compared with their counterparts who received Ribavirin (RBV). In the RBV-free groups, the most common adverse events were headache and fatigue, while in the RBV-regimen groups, the most common adverse events were fatigue, headache, nausea, insomnia, and anemia. Unlike interferon-based regimen, the safety of LDV/SOF has allowed treatment of patients in special situations such as cirrhotic, organ transplantation, inherited hemolytic anemias, neuropsychiatric disorders and who are suffering from autoimmune diseases, as well as no drug–drug interactions were reported with LDV/SOF and concomitant medications of the previous medical conditions. The achievement of SVR is highly associated with improvement in clinical events. Once SVR is achieved, additional liver damage caused by HCV was stopped. Liver enzyme tests often return to normal, and liver function improves[31] a similar result which was noted in our study.


  Conclusion Top


Excellent treatment outcomes among our cohort of HCV-infected patients were achieved with the FDA approved a combination of LDV/SOF for HCV. This study suggests, with agreement of larger trials, that the use of 12-week LDV and SOF is effective for the treatment of HCV GT 4. A safe and simple, single-pill regimen will be ideal to treat large number of patients and impact the global hepatitis GT 4 epidemic. This simple, well-tolerated therapy for HCV GT 4 holds promises to dramatically improve and simplify the treatment of HCV in the resource-limited countries and open a new horizon for viral eradication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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