- Email: [email protected]
sofosbuvir in hepatitis C genotype 4–infected patients with advanced liver fibrosis and decompensated cirrhosis
Accepted Manuscript
Real Life Efficacy of Ledipasvir/Sofosbuvir in Hepatitis C Genotype 4–infected Patients with Advanced Liver Fibrosis and Decompensated Cirrhosis,,✯✯✯ Faisal M. Sanai , Ibrahim H. Altraif , Khalid Alswat , Adnan AlZanbagi , Mohamed A. Babatin , Abdallah AlMousa , Nawaf H Almutairi , Mohammed S. Aljawad , Abdullah S. Alghamdi , Abdulrahman A. Aljumah , Abduljaleel M. Alalwan , Waleed K. Al-Hamoudi , Abdullah M. Assiri , Yaser Dahlan , Ashwaq Alsahafi , Hammad S. Alothmani , Mohammed S. AlSaleemi , Waleed A. Mousa , Ali Albenmousa , Abdelrahman Awny , Haziz Albiladi , Ayman A. Abdo , Hamdan AlGhamdi PII: DOI: Reference:
S0163-4453(18)30104-X 10.1016/j.jinf.2018.04.001 YJINF 4068
To appear in:
Journal of Infection
Received date: Revised date: Accepted date:
24 June 2017 31 March 2018 26 April 2018
Please cite this article as: Faisal M. Sanai , Ibrahim H. Altraif , Khalid Alswat , Adnan AlZanbagi , Mohamed A. Babatin , Abdallah AlMousa , Nawaf H Almutairi , Mohammed S. Aljawad , Abdullah S. Alghamdi , Abdulrahman A. Aljumah , Abduljaleel M. Alalwan , Waleed K. Al-Hamoudi , Abdullah M. Assiri , Yaser Dahlan , Ashwaq Alsahafi , Hammad S. Alothmani , Mohammed S. AlSaleemi , Waleed A. Mousa , Ali Albenmousa , Abdelrahman Awny , Haziz Albiladi , Ayman A. Abdo , Hamdan AlGhamdi , Real Life Efficacy of Ledipasvir/Sofosbuvir in Hepatitis C Genotype 4–infected Patients with Advanced Liver Fibrosis and Decompensated Cirrhosis,,✯✯✯ , Journal of Infection (2018), doi: 10.1016/j.jinf.2018.04.001
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Real Life Efficacy of Ledipasvir/Sofosbuvir in Hepatitis C Genotype 4–infected Patients with Advanced Liver Fibrosis and Decompensated Cirrhosis Faisal M. Sanai1, Ibrahim H. Altraif2,3, Khalid Alswat4, Adnan AlZanbagi5, Mohamed A. Babatin6, Abdallah AlMousa7, Nawaf H Almutairi8, Mohammed S Aljawad9, Abdullah S.
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Alghamdi6, Abdulrahman A. Aljumah2,3, Abduljaleel M. Alalwan2,3, Waleed K. Al-Hamoudi4, Abdullah M Assiri10, Yaser Dahlan1,3, Ashwaq Alsahafi6, Hammad S. Alothmani6, Mohammed S. AlSaleemi7, Waleed A. Mousa8, Ali Albenmousa11, Abdelrahman Awny2, Haziz Albiladi6, Ayman A. Abdo4 Hamdan AlGhamdi2,3
1
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Affiliations:
Gastroenterology Unit, Dept. of Medicine, King Abdulaziz Medical City, Jeddah; 2Hepatobiliary
Sciences & Liver Transplantation, King Abdulaziz Medical City & 3King Saud bin Abdulaziz University for Health Sciences, Riyadh; 4Gastroenterology Unit, Dept. of Medicine & Liver Disease Research Center, College of Medicine, King Saud University, Riyadh; 5Gastroenterology Unit, Department of
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Medicine, King Abdallah Medical City, Makkah; 6Gastroenterology Unit, Dept. of Medicine, King Fahad Hospital, Jeddah; 7Hepatology Dept., King Fahad Specialist Hospital, Buraidah; 8Gastroenterology
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Section, Dept. of Medicine, King Saud Hospital, Unaizah; 9Multi-organ Transplant Center, King Fahad Specialist Hospital, Dammam, 11
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Infectious Disease Dept., King Fahd Medical City, Riyadh;
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Gastroenterology Dept., Prince Sultan Military Medical City, Riyadh; Saudi Arabia.
Corresponding Address:
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Dr. Faisal Sanai
Gastroenterology Unit, Dept. of Medicine,
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King Abdulaziz Medical City, PO Box 9515 (IMB 1440), Jeddah 21423 Saudi Arabia
Fax: 966 12 2266666 ext 28428 Email: [email protected]
Working Title: Hepatitis C virus genotype 4 treatment
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Abbreviations: GT, genotype; SAE, serious adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; SD, standard deviation; HCV, hepatitis C virus; eGFR, estimated glomerular filtration rate; PegIFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; DAA, direct acting antiviral agents; LDV,
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ledipasvir; SOF, sofosbuvir; HCC, hepatocellular carcinoma; ITT, intention-to-treat; LT, liver transplantation
Potential conflict of interest: Dr. Sanai advises, is on the speakers' bureau of, and received grants from Bristol-Myers Squibb and AbbVie pharmaceuticals. He is a consultant for and on the
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speakers' bureau of Merck Sharp Dohme, Gilead Sciences, Roche Pharmaceuticals and Janssen Pharmaceuticals. Drs. AlTraif and Alalwan have received grants from, are on the speakers' bureau of Roche Pharmaceuticals. Drs. Abdo, Babatin, Alghamdi, Aljumah, Altraif advise, and
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are on the speakers' bureau of Merck Sharpe Dohme, Gilead Sciences and Bristol-Myers Squibb. Other authors have nothing to disclose.
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Authors Role: Drs. Sanai, Babatin, Alghamdi, Altraif, Abdo, Albenmousa, Alzanbagi helped in study concept and design; Sanai, Babatin, Al-Hamoudi, Almutairi, Almousa, Dahlan, Mousa,
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Alghamdi, Aljawad, Aljumah, Alalwan, Albiladi, AlTraif, Alsahafi, Alothmani were responsible
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for acquisition of data; Babatin, Alghamdi, Sanai analyzed and interpreted data; Sanai drafted the manuscript; All authors contributed to the critical revision of the manuscript for important
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intellectual content; Sanai, Almousa performed the statistical analysis. Manuscript word count: 2824 Number of figures and tables: 4 tables & 2 figures Financial support: None
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ABSTRACT Limited clinical trial data has shown high efficacy of co-formulated ledipasvir/sofosbuvir (LDV/SOF) in the treatment of hepatitis C virus (HCV) genotype (GT)-4 infected cirrhotic patients. We assessed real-world safety and efficacy of LDV/SOF with or without ribavirin
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(RBV) in GT4-infected patients with compensated and decompensated cirrhosis. Patients & Methods: This observational cohort (n=213) included GT4 treatment-naïve (59.6%) and experienced (40.4%) patients with advanced fibrosis (F3, Metavir; n=30), compensated (F4, n=135) and decompensated cirrhosis (n=48) treated for 12 (n=202) or 24 weeks (n=11) with
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LDV/SOF. RBV was dosed by physician discretion between 600–1200 mg daily. Patients with prior DAA failure were excluded from the analysis. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12) on an intention-to-treat analysis, and
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occurrence of serious adverse events (SAEs). Results: The mean age of the overall cohort was 59.6±12.1 years and 125 (58.7) were female. Overall, 197 (92.5%) of the patients achieved
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SVR12, including 93.3% of F3 fibrosis, 93.3% of compensated cirrhotics and 89.6% of the decompensated cirrhotics (P=0.686). Addition of RBV (68.5%) did not enhance efficacy (91.8%
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vs. 94.0% without RBV, P=0.563), including in F3 fibrosis, compensated and decompensated
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cirrhosis (P>0.05, for all). There was no difference in SVR12 rates with 24 and 12 weeks therapy (90.9% and 92.6%, respectively; P=0.586). Treatment failure (n=16) was mostly related to
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relapse (n=11), while on-treatment death (n=3) and breakthrough (n=2) comprised a minority. SAEs occurred in 9 (4.2%) patients requiring early treatment discontinuation in 4 (3 on-treatment deaths and 1 pregnancy). Conclusion: LDV/SOF therapy yielded high SVR12 rates in both compensated and decompensated cirrhotic GT4 patients. The addition of RBV to this regimen
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did not improve efficacy. The safety profile of this regimen was comparable with that reported for other HCV genotypes.
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Keywords: hepatitis C virus, genotype 4, treatment, sofosbuvir, cirrhosis, efficacy.
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INTRODUCTION Chronic hepatitis C virus (HCV) infection is a major health problem worldwide and is a leading cause of liver-related morbidity and mortality, and the most common indication for liver transplantation (LT) in most parts of the world [1,2]. Worldwide genotype (GT) 4 accounts for
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about 15 million infections and is the commonest type in the Middle-Eastern region [3-5].
The treatment of HCV has undergone a paradigm shift with the introduction of direct-acting antiviral agents (DAAs). This modality has brought about exceptional cure rates with sustained
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virologic response (SVR) exceeding 90%, with better tolerability, minimized side effects and short duration of treatment [6]. Further, these medications have made it possible for patients previously excluded in the interferon (IFN) therapy era such as decompensated cirrhosis to be treated. The achievement of SVR can bring reversal of decompensation, improved survival rates
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and reduced need for liver transplantation [7].
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Sofosbuvir is a potent pan-genotypic inhibitor of the HCV NS5B polymerase while ledipasvir is an NS5A inhibitor. Limited clinical trial data has shown high efficacy of co-formulated
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ledipasvir/sofosbuvir (LDV/SOF) in the treatment of HCV GT4 infected patients, although the
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data is limited in cirrhotic patients [8,9].
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Evaluation of drugs in the real-world setting is critical, particularly in patients such as those with HCV GT4 infection where clinical trial data is limited. Therefore, we evaluated the clinical effectiveness and safety of LDV/SOF in a cohort of HCV GT4 patients treated in routine clinical practice across Saudi Arabia.
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PATIENTS AND METHODS Study Population This observational cohort study evaluated patients treated with LDV/SOF for chronic HCV for 12 or 24 weeks at nine centers in Saudi Arabia. Consecutive patients were included by a search
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of clinical records from the Systematic Observatory Liver Disease (SOLID) registry, which is a prospective, multicenter observational registry, for the period up to October 2016. Patients were eligible for inclusion in this study if they were treated with LDV/SOF and were infected with
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chronic HCV (positive anti-HCV antibody >6 months with detectable HCV RNA) GT4. Data was collected prospectively according to a pre-outlined management protocol. The institutional review boards (IRB) of each contributing center approved this study. Written informed consent was not obtained from the patients. All consecutive patients ≥18 years of age with ≥F3 fibrosis
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(Metavir) including those with decompensated cirrhosis were included. The study group included both treatment-naïve and treatment-experienced (PegIFN/RBV) patients. Patients with the
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following criteria were excluded: F0-2, fibrosis, HIV co-infection, renal impairment with estimated glomerular filtration rate (eGFR, using the Modification of Diet in Renal Disease
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[MDRD] formula) <30 ml/hour, and prior treatment with DAAs.
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Treatment Allocation
Treatment was administered for 12–24 weeks as determined by individual patient clinical
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characteristics and entirely at the discretion of the physician. All patients were treated with one tablet of the fixed dose combination of LDV 90 mg/SOF 400 mg (Harvoni®, Gilead Sciences, USA) with or without RBV. RBV was dosed at 600 mg (in decompensated cirrhosis) and 10001200 mg based on patient body weight. The inclusion of RBV in the treatment regimen was
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individualized by physician preference. Administration of erythropoietin (EPO) or blood transfusion was allowed upon the discretion of the treating physician. Measurements The following clinical data were obtained at the time of enrollment: age, sex, body mass index
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(BMI), comorbidities, fibrosis stage, HCV genotype (Abbott RealTime HCV Genotype II M2000rt platform [Abbott Molecular Inc., Des Plaines, IL, USA], and prior treatment history. Patients with prior HCV treatment were categorized based on their virologic response during prior PegIFN/RBV-based treatment: virologic relapse was defined as undetectable HCV RNA at
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the end of treatment, but subsequent detectable HCV RNA after treatment discontinuation while null response was defined as failure to achieve a 1 log10 reduction in HCV RNA after 12 weeks of treatment. Virologic breakthrough was defined as detectable HCV RNA after a period of
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initial response while still on therapy. HCV RNA (Abbott RealTime, Abbott Molecular Inc., Abbott Park, IL, USA) was measured as quantitative (Log10 HCV RNA, IU/mL) and/or
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qualitative (detectable/undetectable) as applicable.
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Baseline laboratory values within 3 months prior to commencement of treatment were collected
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for all patients. Follow up tests included total bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatinine, hemoglobin
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(Hb) and platelets at week 4, end of treatment (EOT) and week 12 post-treatment. FibroScan was used to determine the degree of fibrosis and was performed within 6 months prior to treatment commencement. For fibrosis stage, patients were classified as having advanced fibrosis (defined by a FibroScan score of 9.5 – 12.5 kPa) and compensated cirrhosis (≥14.5 kPa). Decompensated
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cirrhosis was defined by a combination of clinical, haematological, biochemical and radiological criteria and classified according to the Child’s Turcotte Pugh (CTP, ≥7) classification.
Outcome Analysis
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Efficacy of the treatment was assessed at weeks 4, EOT and after 12 weeks of treatment discontinuation. SVR (HCV RNA <15 IU/ml) at 12 weeks after the EOT (SVR12), was the primary efficacy endpoint. SVR12 was evaluated by an intent-to-treat (ITT) analysis (including patients who died or lost to follow-up as treatment failures) and by a modified ITT (mITT)
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analysis (excluding patients who died prior to collecting all clinical data or lost to follow-up). Patient records were reviewed for any adverse events, both the clinical as well as any abnormal findings on laboratory tests. Safety data were determined during treatment and at each clinic
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visit. Statistical Analysis
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The outcome for continuous variables is presented as mean ± standard deviation or as median and range, whichever is applicable, and as percentage for categorical data. Baseline clinical and
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demographic characteristics were compared statistically across disease stage and SVR using
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Fisher’s exact test or Chi Square test in case of categorical scale and t-test in case of continuous scale (or log means of the variable). Means of quantitative variables were compared using one-
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way analysis of variance (ANOVA) with Post-Hoc test (Turkey’s) as needed. All patients who took at least one dose of the study medication were included in the efficacy analysis on an ITT principle. A mITT analysis was also used to assess efficacy in all patients who completed the pre-defined treatment duration and had at least 12 weeks of post treatment follow up. All
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statistical tests were considered significant at α level less than 0.05. Statistical analysis was
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performed using SPSS (SPSS Inc., SPSS for Windows, version 16.0. Chicago, IL, SPSS Inc.).
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RESULTS Characteristics of Patients:
During the period between November 2014 and October 2016, 213 patients commenced
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treatment with the fixed-dose combination of LDV/SOF daily. In total, 3 (1.4%) patients had HBV co-infection, 6 (2.8%) were LT and 3 (1.4%) had controlled co-existing hepatocellular carcinoma (HCC). Baseline clinical, biochemical, hematological and virologic characteristics of the patients are shown in Table 1. The mean age of the study group was 59.6 ± 12.1 years and
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125 (58.7%) were females. Eighty-six (40.4%) patients had failed prior IFN-based treatment. Advanced fibrosis (F3) was present in 30 (14.1%), compensated cirrhosis (F4, CTP A) in 135 (63.4%) and decompensated cirrhosis (CTP B/C) in 48 (22.5%) patients. Overall, 202 (94.8%)
146 (68.5%) patients (Table 1).
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patients received 12 weeks, and 11 (5.2%) received 24 weeks of therapy. RBV was prescribed in
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Amongst the patients with F3 fibrosis, compensated CTP ‘A’ cirrhosis and decompensated cirrhosis, 11 (36.7%), 64 (47.4%) and 11 (22.9%) were treatment experienced, respectively
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(P=0.011); 9 (30.0%), 102 (75.6%) and 35 (72.9%) were prescribed concomitant RBV,
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respectively (P<0.001). All patients with F3 fibrosis were treated for 12 weeks while 5 (3.7%) of those with compensated cirrhosis and 6 (12.5%) of those with decompensated cirrhosis were
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treated for 24 weeks (P=0.024, Table 1).
Patients with decompensated cirrhosis had higher total bilirubin (33.7 ± 33.4, P< 0.001) and lower levels of albumin (27.6 ± 4.0, P< 0.001), Hb (121.5 ± 25.2, P=0.019), platelets (118.9 ± 67.1, P< 0.001) and Log10 HCV RNA (5.4 ± 0.9, P=0.005) in comparison to those with other disease stages (Table 1).
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Efficacy of Treatment:
On an ITT analysis, 197 (92.5%) of the patients achieved SVR12, accounting for 28/30 (93.3%) of F3 fibrosis patients, 126/135 (93.3%) compensated cirrhotics and 43/48 (89.6%) of the
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decompensated cirrhotics (Figure 1, P=0.686). On a mITT analysis of patients who completed therapy and had 12 weeks of follow-up (n=209) SVR12 was 94.3% (data not shown). Of the patients not completing therapy, three died on therapy (from sequelae of cirrhosis) and one discontinued therapy due to pregnancy after 4 weeks therapy (and relapsed). Of the baseline
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characteristics and treatment disposition, only female gender (P=0.020) and lower bilirubin levels (P=0.006) identified patients more likely to achieve SVR12. Age, BMI, liver enzymes, albumin, platelets, Hb, Log10 HCV RNA levels, prior treatment experience, concomitant RBV use, treatment duration and disease stage were not different between patients who achieved
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SVR12 and those who did not (P>0.05 for all, Table 2). In patients with cirrhosis (Figure 2),
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SVR12 rates were similar in those with compensated (93.3%) and decompensated disease (89.6%, P=0.601). Basic characteristics of patients who failed therapy (n=16) and their causes of
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failure are highlighted in Supplementary Table 1.
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A sub-group analysis for virologic response at week 4 of therapy showed no difference in SVR12 in patients with quantifiable HCV RNA at week 4 of therapy (89.5%) as compared to
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those with undetectable, or detectable but unquantifiable HCV RNA (93.8%, P=0.298). Similarly, no difference in SVR12 was seen in patients with quantifiable HCV RNA compared to those with undetectable HCV RNA (93.7%, P=0.296) at week 4 of therapy (Supplementary Table 2). Finally, 8 patients had detectable HCV RNA at EOT of whom 2 had virologic breakthrough and failed to achieve SVR12. Of the remaining 6 patients, 2 had no documented
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virologic negativity throughout the treatment course and failed therapy, while 4 had unquantifiable HCV RNA at EOT and went on to achieve SVR12 (Supplementary Table 2). Efficacy in Relation to Prior Treatment Experience, RBV Addition and Treatment
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Duration: Patients who were treatment-naïve (n=127, 59.6%) were similar in baseline characteristics, RBV use (P=0.359) and treatment duration (P=0.724) compared to those who were treatmentexperienced (Supplementary Table 3). SVR12 rates did not differ between patients who were
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treatment naïve (89.8%) and treatment experienced (96.5%, P=0.109).
Patients who received RBV (n=146, 68.5%) were more likely to have lower albumin, Hb and platelet levels and were more likely to be cirrhotic (P<0.05 for all) in comparison to those who
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did not receive RBV (Table 3). However, the use of RBV did not result in higher SVR12 rates in the overall cohort (91.8% vs. 94.0%, P=0.563). This trend was also seen in the sub-analysis of
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patients with F3 fibrosis (88.9 vs. 95.2%, P=0.517), compensated cirrhosis (93.1% vs. 93.9%,
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P=0.872) and decompensated cirrhosis (88.6% vs. 92.3%, P=1.000, Figure 1).
Treatment extension to 24 weeks (n=11, 5.2%) was more frequent in decompensated cirrhosis
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(Table 4), and these patients reflected higher CTP and MELD scores, and lower albumin,
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platelets and HCV RNA levels (P<0.05 for all). SVR12 rates in patients receiving 24 weeks treatment duration (90.9%) were similar to those who received 12 weeks treatment (92.6%, P=0.586). A trend towards higher SVR12 rate was seen in compensated cirrhosis receiving 24 weeks of therapy (100%) in comparison to those receiving 12 weeks (93.1%) but this did not achieve statistical significance (P=1.000). Additionally, efficacy was similar in decompensated cirrhotics receiving 24 weeks (83.3%) and 12 weeks (90.5%, P=0.503) therapy.
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Safety and Tolerability:
Overall, serious adverse events (SAEs) occurred in 9 (4.2%) patients and are presented in Supplementary Table 4. In total, 4 patients discontinued treatment early (3 due to on-treatment
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death and 1 due to pregnancy after 4 weeks of therapy). Two of the deaths were liver-related in patients with decompensated cirrhosis, and 1 died from complications of pre-existing dilated cardiomyopathy. Five (3.0%) developed hepatic decompensation and another 4 (8.3%) CTP B/C patients developed additional hepatic decompensation. RBV dose reductions were required in 26
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(17.8%) and one discontinued RBV due to severe anemia.
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DISCUSSION Our study is the largest to date to investigate the real-world effectiveness and safety of LDV/SOF therapy in HCV GT4 patients, including those with decompensated cirrhosis. In our cohort of patients who were managed in routine clinical practice LDV/SOF resulted in rapid
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virologic responses and high rates of SVR12 (overall, 92.5%). In addition, patients with advanced fibrosis (93.3%) responded similarly to those with compensated cirrhosis (93.3%). Although patients with decompensated cirrhosis had numerically lower SVR12 than those with
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compensated disease, this difference was not statistically significant. Our study included the highest number of decompensated GT4 cirrhosis reported to date. The SOLAR-2 trial included a total of 14 GT4 decompensated cirrhotics of whom 71% responded to 12-24 weeks of LDV/SOF plus RBV-based therapy [10]. Our cohort included a sufficiently greater number of patients
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(n=48), with an overall SVR12 of 89.6% and a similar efficacy with 12 or 24 weeks of therapy (P=0.503). However, it is to be noted that the vast majority of patients were treated for 12 weeks
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(87.5%) with an SVR12 rate of 90.5%, while only 6 were treated for 24 weeks. On a mITT analysis (excluding one patient who died on therapy), SVR12 was achieved in all patients
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(100%) who received 24 weeks of therapy. These results were substantially better than the
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SOLAR-2 trial that demonstrated SVR12 of 57% and 86% treated for 12 and 24 weeks, respectively [10]. Although a 24-week regimen of LDV/SOF ± RBV appears more appropriate in
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GT4 patients with decompensated cirrhosis, inferences towards extending treatment duration must be tempered in view of the small sample sizes of either study. Virologic response at week 4 had no impact on SVR12 in our GT4 patients. Similar results have been reported in other genotypes where response-guided therapy did not influence treatment outcome [11,12]. These results suggest that frequent on-treatment HCV RNA testing or
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treatment extension beyond 12 weeks based on viral kinetics is unlikely to be of clinical value. On the other hand, detectable HCV RNA at EOT revealed mixed results in our cohort. Of the 8 such patients with virologic positivity, 4 achieved SVR12. Although EOT virologic positivity with IFN-based therapy was an obvious indicator of treatment failure, recent reports document
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that some patients treated with all-oral DAA regimens achieve cure despite having detectable viremia at EOT [11,13]. This phenomenon has been attributed, potentially, to a small amount of non-infectious HCV RNA being remnant at EOT [13].
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Despite the exclusion of RBV from LDV/SOF-based clinical trials in HCV GT4 patients with compensated disease, including non-cirrhotics, clinical practice guidelines frequently recommend the addition of RBV in treatment-experienced compensated cirrhotic and noncirrhotic patient populations [5,14,15]. Such recommendations potentially stem from the
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anticipated gain in efficacy beyond the 93 - 99% demonstrated in clinical trials [8,9] or limited observational studies [16], by the addition of RBV as seen in certain GT1 categories [17]. In our
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study, patients who were prescribed RBV were generally similar in most aspects of their baseline
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characteristics to the RBV-free cohort, including viral load, treatment-experience, CTP status and duration of treatment. RBV was used in two-thirds of the overall cohort and more frequently
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in those with cirrhosis. Despite its liberal usage, efficacy was not enhanced beyond what has been demonstrated in clinical trials, and the RBV-containing cohorts of compensated and
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decompensated cirrhotics responded similarly to the RBV-free ones (Figure 1). These results are in concordance with a recent Egyptian trial where treatment-naïve and -experienced subjects were stratified by the presence or absence of cirrhosis to 12 weeks of LDV/SOF with or without RBV. The results showed that SVR12 was achieved in 96.2% of the RBV-free arm compared to 97.5% of the RBV-containing regimen [18].
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Furthermore, prior treatment experience and duration of treatment also did not impact SVR12 in our cohort. Patients with prior treatment experience were similar to those who were treatmentnaïve in respect to fibrosis stage (except for a higher number treatment-naïve being decompensated), duration of therapy and RBV allocation. Our findings are once again aligned
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with those of the afore-mentioned Egyptian trial [18] that also showed no difference in efficacy on the basis of prior treatment exposure. Although patients with compensated cirrhosis that extended treatment duration to 24 weeks showed a numerically greater response, the small number of patients in this category limits the generalization of this observation. Hence, based on
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these findings, it appears that a 12-week RBV-free regimen of LDV/SOF is appropriate and sufficient for GT4 patients, regardless of prior treatment experience or underlying histological stage.
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Overall, reported rates of SAEs of this large real-world cohort were only slightly higher or similar to those reported in the pivotal clinical trials or real-life data (3.8 – 4.6%) [19,20]. The
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few SAEs were vastly limited to patients with advanced cirrhosis, and were related to the
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underlying disease rather than the treatment. Despite a longer therapy duration and addition of RBV in most of our patients, the SAE rate was remarkably low (4.2%). There were only three
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deaths while on treatment. CPT ‘B’ or ‘C’ patients were more likely to present SAEs (8.3%), most of them as clinical decompensation. In general, the favorable safety findings in the current
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study are important because of the small number of studies in GT4 patients, particularly those with cirrhosis. Since safety is expected to be poorer in real-world cohorts, which is related to factors such as the presence of significant comorbidities and polypharmacy, these observations are clearly encouraging. This study has the usual limitations related to its observational, real-world design, including the
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potential for bias because of prescribing and patient selection by physicians. However, our study does provide insights into clinician prescribing practice for GT4 patients. Clearly, this study does not aim to address finer details of extended treatment duration in select sub-populations, or the role of RBV in treatment-experienced cirrhotics or decompensated cirrhotics. These issues must
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be evaluated in large-scale, randomized-controlled clinical trials designed specifically to address each aspect individually. Nevertheless, because of the current paucity of data with DAAs in HCV GT4 patients, the relatively large number of patients included in the current study gives an important insight into the effectiveness and safety of LDV/SOF therapy. Finally, information on
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compliance with therapy or development of drug resistance as potential causes of relapse or virologic breakthrough was not available to the investigators. The lack of data on viral kinetics or the time to virologic negativity due to the infrequent testing of HCV RNA serves as another
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limitation in our ability to understand the causes of treatment failure. These, however, are natural
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shortcomings of real-world cohorts and could otherwise be assessed in prospective clinical trials. In summary, LDV/SOF-based therapy yielded high rates of SVR12, comparable with the limited
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results from clinical trials, in both compensated and decompensated cirrhotic HCV GT4 patients managed in a real-world setting. The addition of RBV to this regimen does not offer potential
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gain in efficacy. The safety profile of this regimen was good and comparable with that reported
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for other HCV genotypes.
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Table 1: Baseline characteristics and treatment allocation of HCV genotype 4 patients based upon liver disease severity who received co-formulated ledipasvir/sofosbuvir Total F3 Fibrosis Compensated Decompensated (n=213) (n=30) Parameter Cirrhosis* Cirrhosis** P value
Platelets (109/L) Log10 HCV RNA
(n=135)
(n=48)
55.2 ± 16.3 18 (60.0) 26.2 ± 7.1 66.9 ± 65.4 62.0 ± 47.3 15.4 ± 8.8 101.7 ± 48.8
60.1 ± 11.2 77 (57.0) 29.9 ± 5.9 64.4 ± 48.9 61.3 ± 41.1 14.5 ± 7.8 117.3 ± 52.4
61.1 ± 10.9 30 (62.5) 27.8 ± 6.1 60.1 ± 55.9 69.3 ± 56.2 33.7 ± 33.4 142.1 ± 74.6
0.084 0.794 0.008 0.842 0.608 < 0.001 0.015
37.8 ± 4.5 130.1 ± 27.4
35.1 ± 5.8 132.5 ± 21.2
27.6 ± 4.0 121.5 ± 25.2
< 0.001 0.019
271.4 ± 113.5
158.4 ± 80.6
118.9 ± 67.1
< 0.001
6.0 ± 0.7
5.8 ± 0.9
5.4 ± 0.9
0.005
86 (40.4)
11 (36.7)
64 (47.4)
11 (22.9)
0.011
202 (94.8) 11 (5.2) 146 (68.5)
30 (100.0) 0 9 (30.0)
130 (96.3) 5 (3.7) 102 (75.6)
42 (87.5) 6 (12.5) 35 (72.9)
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Treatment experienced Treatment Duration 12 Weeks 24 Weeks Received RBV
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Albumin (g/L) Hemoglobin (mg/dL)
59.6 ± 12.1 125 (58.7) 28.9 ± 6.3 63.8 ± 52.9 63.3 ± 45.7 18.9 ± 19.0 121.0 ± 59.1 33.8 ± 6.3 129.7 ± 23.4 165.4 ± 94.7 5.7 ± 0.9
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Age (yrs) Female gender BMI (kg/m2) ALT (U/L) AST (U/L) Bilirubin (mol/L) ALP (U/L)
< 0.001
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Data represented as n (%), or mean ± standard deviation. *F4 fibrosis/ Child’s A cirrhosis; **Child’s B/C cirrhosis; BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; HCV, hepatitis C virus; RBV, ribavirin
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Table 2: Baseline characteristics of patients in relation to sustained and non-sustained virologic response to co-formulated ledipasvir/sofosbuvir treatment Parameter No SVR12 SVR12 P value (n=16) (n=197) Age (yrs) 64.2 ± 9.6 59.3 ± 12.2 0.116 Female gender 5 (31.2) 120 (60.9) 0.020 2 BMI (kg/m ) 27.8 ± 5.8 29.0 ± 6.3 0.460 ALT (U/L) 61.9 ± 58.4 63.9 ± 52.6 0.880 AST (U/L) 69.2 ± 55.4 62.9 ± 45.1 0.634 Bilirubin (mol/L) 31.5 ± 50.8 17.9 ± 13.3 0.006 >35 (mol/L) 3 (18.8) 15 (7.6) 0.141 ALP (U/L) 115.4 ± 51.5 121.4 ± 59.8 0.724 Albumin (g/L) 32.2 ± 6.3 33.9 ± 6.3 0.298 <35 (g/L) 9 (56.2) 96 (48.7) 0.611 Hemoglobin (mg/dL) 126.2 ± 20.9 130.0 ± 23.6 0.534 9 Platelets (10 /L) 152.5 ± 63.6 166.5 ± 96.8 0.571 < 70 (109/L) 0 22 (11.2) 0.383 Log10 HCV RNA (IU/mL) 5.5 ± 1.0 5.7 ± 0.9 0.412 Treatment Duration 12 Weeks 15 (93.8) 187 (94.9) 0.586 24 Weeks 1 (6.2) 10 (5.1) Treatment experienced 3 (18.8) 83 (42.1) 0.109 Fibrosis stage F3 2 (12.5) 28 (14.2) 1.000 F4 14 (87.5) 168 (85.8) Decompensated cirrhosis 5 (31.2) 43 (24.3) 0.551 Received RBV 12 (75.0) 134 (68.0) 0.781
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Table 3: Baseline characteristics of patients in relation to those who received and did not receive RBV Parameter No RBV RBV P value (n=67) (n=146) Age (yrs) 56.9 ± 13.6 60.9 ± 11.1 0.023 Female gender 40 (59.7) 85 (58.2) 0.838 BMI (kg/m2) 28.2 ± 6.5 29.3 ± 6.2 0.265 ALT (U/L) 56.1 ± 45.2 67.3 ± 55.9 0.150 AST (U/L) 55.5 ± 29.1 66.2 ± 50.3 0.157 Bilirubin (mol/L) 20.3 ± 26.6 18.3 ± 14.2 0.493 ALP (U/L) 119.1 ± 61.9 122.0 ± 57.8 0.761 Albumin (g/L) 35.0 ± 5.8 33.2 ± 6.5 0.053 Hemoglobin (mg/dL) 121.1 ± 28.2 133.6 ± 19.7 < 0.0001 Platelets (109/L) 200.4 ± 115.3 149.4 ± 79.0 < 0.0001 Log10 HCV RNA (IU/mL) 5.6 ± 1.0 5.7 ± 0.8 0.410 Fibrosis stage F3 22 (33.8) 9 (6.2) < 0.001 F4 45 (67.2) 137 (93.8) Decompensated cirrhosis 13 (23.6) 35 (25.4) 0.802 Treatment experienced 24 (35.8) 62 (42.5) 0.359 Treatment Duration 12 Weeks 62 (92.5) 140 (95.9) 0.328 24 Weeks 5 (7.5) 6 (4.1) Achieved SVR12 63 (94.0) 134 (91.8) 0.563
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Table 4: Baseline characteristics of patients in relation to those who received 24 weeks versus those who received 12 weeks of co-formulated ledipasvir/sofosbuvir treatment Parameter 24 weeks 12 weeks P value (n=11) (n=202) Age (yrs) 59.1 ± 9.1 59.7 ± 12.2 0.889 Female gender 9 (81.8) 116 (42.6) 0.129 2 BMI (kg/m ) 29.6 ± 4.9 28.9 ± 6.3 0.706 ALT (U/L) 47.0 ± 23.7 64.7 ± 53.9 0.280 AST (U/L) 66.4 ± 33.8 63.1 ± 46.4 0.827 Bilirubin (mol/L) 44.7 ± 59.7 17.5 ± 12.8 < 0.001 ALP (U/L) 129.9 ± 47.9 120.4 ± 59.8 0.624 Albumin (g/L) 30.0 ± 3.9 34.0 ± 6.3 0.041 Hemoglobin (mg/dL) 102.0 ± 35.6 131.2 ± 21.7 < 0.001 Platelets (109/L) 84.5 ± 26.7 169.8 ± 95.1 0.003 Log10 HCV RNA (IU/mL) 4.8 ± 1.2 5.8 ± 0.8 0.001 Treatment experienced 5 (45.5) 81 (40.1) 0.724 Fibrosis stage F3 F3 0 30 (14.9) 0.370 F4 F4 11 (100.0) 172 (85.1) Decompensated cirrhosis 6 (54.5) 42 (23.1) 0.029 Received RBV 6 (54.5) 140 (69.3) 0.328 Achieved SVR12 10 (90.9) 187 (92.6) 0.586 CTP Score* 7.0 (6.0-8.0) 6.0 (5.0-6.0) < 0.001 MELD Score* 12.0 (9.0-17.0) 8.0 (6.0-10.0) 0.001
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Data represented as n (%), or mean ± standard deviation, or *median (interquantile range). BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response; CTP, Child’s Turcotte Pugh; MELD, model for end-stage liver disease
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FIGURE LEGENDS Figure 1: Sustained virologic response to ledipasvir/sofosbuvir for 12 – 24 weeks in patients with advanced fibrosis (F3), compensated (Child Turcotte Pugh, CTP ‘A’) cirrhosis and decompensated (CTP ‘B/C’) cirrhosis in overall (light grey bars), ribavirin-containing (dark grey
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bars) and ribavirin-free cohorts (black bars).
Figure 2: Sustained virologic response to ledipasvir/sofosbuvir with or without ribavirin in
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patients with compensated (Child Turcotte Pugh, CTP ‘A’) cirrhosis and decompensated (CTP ‘B/C’) cirrhosis in overall (light grey bars), 12-weeks duration (dark grey bars) and 24-weeks
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duration cohorts (black bars).
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Real Life Efficacy of Ledipasvir/Sofosbuvir in Hepatitis C Genotype 4–infected Patients with Advanced Liver Fibrosis and Decompensated Cirrhosis,,✯✯✯ Faisal M. Sanai , Ibrahim H. Altraif , Khalid Alswat , Adnan AlZanbagi , Mohamed A. Babatin , Abdallah AlMousa , Nawaf H Almutairi , Mohammed S. Aljawad , Abdullah S. Alghamdi , Abdulrahman A. Aljumah , Abduljaleel M. Alalwan , Waleed K. Al-Hamoudi , Abdullah M. Assiri , Yaser Dahlan , Ashwaq Alsahafi , Hammad S. Alothmani , Mohammed S. AlSaleemi , Waleed A. Mousa , Ali Albenmousa , Abdelrahman Awny , Haziz Albiladi , Ayman A. Abdo , Hamdan AlGhamdi PII: DOI: Reference:
S0163-4453(18)30104-X 10.1016/j.jinf.2018.04.001 YJINF 4068
To appear in:
Journal of Infection
Received date: Revised date: Accepted date:
24 June 2017 31 March 2018 26 April 2018
Please cite this article as: Faisal M. Sanai , Ibrahim H. Altraif , Khalid Alswat , Adnan AlZanbagi , Mohamed A. Babatin , Abdallah AlMousa , Nawaf H Almutairi , Mohammed S. Aljawad , Abdullah S. Alghamdi , Abdulrahman A. Aljumah , Abduljaleel M. Alalwan , Waleed K. Al-Hamoudi , Abdullah M. Assiri , Yaser Dahlan , Ashwaq Alsahafi , Hammad S. Alothmani , Mohammed S. AlSaleemi , Waleed A. Mousa , Ali Albenmousa , Abdelrahman Awny , Haziz Albiladi , Ayman A. Abdo , Hamdan AlGhamdi , Real Life Efficacy of Ledipasvir/Sofosbuvir in Hepatitis C Genotype 4–infected Patients with Advanced Liver Fibrosis and Decompensated Cirrhosis,,✯✯✯ , Journal of Infection (2018), doi: 10.1016/j.jinf.2018.04.001
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Real Life Efficacy of Ledipasvir/Sofosbuvir in Hepatitis C Genotype 4–infected Patients with Advanced Liver Fibrosis and Decompensated Cirrhosis Faisal M. Sanai1, Ibrahim H. Altraif2,3, Khalid Alswat4, Adnan AlZanbagi5, Mohamed A. Babatin6, Abdallah AlMousa7, Nawaf H Almutairi8, Mohammed S Aljawad9, Abdullah S.
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Alghamdi6, Abdulrahman A. Aljumah2,3, Abduljaleel M. Alalwan2,3, Waleed K. Al-Hamoudi4, Abdullah M Assiri10, Yaser Dahlan1,3, Ashwaq Alsahafi6, Hammad S. Alothmani6, Mohammed S. AlSaleemi7, Waleed A. Mousa8, Ali Albenmousa11, Abdelrahman Awny2, Haziz Albiladi6, Ayman A. Abdo4 Hamdan AlGhamdi2,3
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Affiliations:
Gastroenterology Unit, Dept. of Medicine, King Abdulaziz Medical City, Jeddah; 2Hepatobiliary
Sciences & Liver Transplantation, King Abdulaziz Medical City & 3King Saud bin Abdulaziz University for Health Sciences, Riyadh; 4Gastroenterology Unit, Dept. of Medicine & Liver Disease Research Center, College of Medicine, King Saud University, Riyadh; 5Gastroenterology Unit, Department of
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Medicine, King Abdallah Medical City, Makkah; 6Gastroenterology Unit, Dept. of Medicine, King Fahad Hospital, Jeddah; 7Hepatology Dept., King Fahad Specialist Hospital, Buraidah; 8Gastroenterology
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Section, Dept. of Medicine, King Saud Hospital, Unaizah; 9Multi-organ Transplant Center, King Fahad Specialist Hospital, Dammam, 11
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Infectious Disease Dept., King Fahd Medical City, Riyadh;
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Gastroenterology Dept., Prince Sultan Military Medical City, Riyadh; Saudi Arabia.
Corresponding Address:
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Dr. Faisal Sanai
Gastroenterology Unit, Dept. of Medicine,
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King Abdulaziz Medical City, PO Box 9515 (IMB 1440), Jeddah 21423 Saudi Arabia
Fax: 966 12 2266666 ext 28428 Email: [email protected]
Working Title: Hepatitis C virus genotype 4 treatment
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Abbreviations: GT, genotype; SAE, serious adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; SD, standard deviation; HCV, hepatitis C virus; eGFR, estimated glomerular filtration rate; PegIFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; DAA, direct acting antiviral agents; LDV,
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ledipasvir; SOF, sofosbuvir; HCC, hepatocellular carcinoma; ITT, intention-to-treat; LT, liver transplantation
Potential conflict of interest: Dr. Sanai advises, is on the speakers' bureau of, and received grants from Bristol-Myers Squibb and AbbVie pharmaceuticals. He is a consultant for and on the
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speakers' bureau of Merck Sharp Dohme, Gilead Sciences, Roche Pharmaceuticals and Janssen Pharmaceuticals. Drs. AlTraif and Alalwan have received grants from, are on the speakers' bureau of Roche Pharmaceuticals. Drs. Abdo, Babatin, Alghamdi, Aljumah, Altraif advise, and
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are on the speakers' bureau of Merck Sharpe Dohme, Gilead Sciences and Bristol-Myers Squibb. Other authors have nothing to disclose.
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Authors Role: Drs. Sanai, Babatin, Alghamdi, Altraif, Abdo, Albenmousa, Alzanbagi helped in study concept and design; Sanai, Babatin, Al-Hamoudi, Almutairi, Almousa, Dahlan, Mousa,
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Alghamdi, Aljawad, Aljumah, Alalwan, Albiladi, AlTraif, Alsahafi, Alothmani were responsible
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for acquisition of data; Babatin, Alghamdi, Sanai analyzed and interpreted data; Sanai drafted the manuscript; All authors contributed to the critical revision of the manuscript for important
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intellectual content; Sanai, Almousa performed the statistical analysis. Manuscript word count: 2824 Number of figures and tables: 4 tables & 2 figures Financial support: None
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ABSTRACT Limited clinical trial data has shown high efficacy of co-formulated ledipasvir/sofosbuvir (LDV/SOF) in the treatment of hepatitis C virus (HCV) genotype (GT)-4 infected cirrhotic patients. We assessed real-world safety and efficacy of LDV/SOF with or without ribavirin
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(RBV) in GT4-infected patients with compensated and decompensated cirrhosis. Patients & Methods: This observational cohort (n=213) included GT4 treatment-naïve (59.6%) and experienced (40.4%) patients with advanced fibrosis (F3, Metavir; n=30), compensated (F4, n=135) and decompensated cirrhosis (n=48) treated for 12 (n=202) or 24 weeks (n=11) with
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LDV/SOF. RBV was dosed by physician discretion between 600–1200 mg daily. Patients with prior DAA failure were excluded from the analysis. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12) on an intention-to-treat analysis, and
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occurrence of serious adverse events (SAEs). Results: The mean age of the overall cohort was 59.6±12.1 years and 125 (58.7) were female. Overall, 197 (92.5%) of the patients achieved
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SVR12, including 93.3% of F3 fibrosis, 93.3% of compensated cirrhotics and 89.6% of the decompensated cirrhotics (P=0.686). Addition of RBV (68.5%) did not enhance efficacy (91.8%
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vs. 94.0% without RBV, P=0.563), including in F3 fibrosis, compensated and decompensated
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cirrhosis (P>0.05, for all). There was no difference in SVR12 rates with 24 and 12 weeks therapy (90.9% and 92.6%, respectively; P=0.586). Treatment failure (n=16) was mostly related to
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relapse (n=11), while on-treatment death (n=3) and breakthrough (n=2) comprised a minority. SAEs occurred in 9 (4.2%) patients requiring early treatment discontinuation in 4 (3 on-treatment deaths and 1 pregnancy). Conclusion: LDV/SOF therapy yielded high SVR12 rates in both compensated and decompensated cirrhotic GT4 patients. The addition of RBV to this regimen
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did not improve efficacy. The safety profile of this regimen was comparable with that reported for other HCV genotypes.
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Keywords: hepatitis C virus, genotype 4, treatment, sofosbuvir, cirrhosis, efficacy.
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INTRODUCTION Chronic hepatitis C virus (HCV) infection is a major health problem worldwide and is a leading cause of liver-related morbidity and mortality, and the most common indication for liver transplantation (LT) in most parts of the world [1,2]. Worldwide genotype (GT) 4 accounts for
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about 15 million infections and is the commonest type in the Middle-Eastern region [3-5].
The treatment of HCV has undergone a paradigm shift with the introduction of direct-acting antiviral agents (DAAs). This modality has brought about exceptional cure rates with sustained
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virologic response (SVR) exceeding 90%, with better tolerability, minimized side effects and short duration of treatment [6]. Further, these medications have made it possible for patients previously excluded in the interferon (IFN) therapy era such as decompensated cirrhosis to be treated. The achievement of SVR can bring reversal of decompensation, improved survival rates
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and reduced need for liver transplantation [7].
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Sofosbuvir is a potent pan-genotypic inhibitor of the HCV NS5B polymerase while ledipasvir is an NS5A inhibitor. Limited clinical trial data has shown high efficacy of co-formulated
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ledipasvir/sofosbuvir (LDV/SOF) in the treatment of HCV GT4 infected patients, although the
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data is limited in cirrhotic patients [8,9].
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Evaluation of drugs in the real-world setting is critical, particularly in patients such as those with HCV GT4 infection where clinical trial data is limited. Therefore, we evaluated the clinical effectiveness and safety of LDV/SOF in a cohort of HCV GT4 patients treated in routine clinical practice across Saudi Arabia.
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PATIENTS AND METHODS Study Population This observational cohort study evaluated patients treated with LDV/SOF for chronic HCV for 12 or 24 weeks at nine centers in Saudi Arabia. Consecutive patients were included by a search
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of clinical records from the Systematic Observatory Liver Disease (SOLID) registry, which is a prospective, multicenter observational registry, for the period up to October 2016. Patients were eligible for inclusion in this study if they were treated with LDV/SOF and were infected with
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chronic HCV (positive anti-HCV antibody >6 months with detectable HCV RNA) GT4. Data was collected prospectively according to a pre-outlined management protocol. The institutional review boards (IRB) of each contributing center approved this study. Written informed consent was not obtained from the patients. All consecutive patients ≥18 years of age with ≥F3 fibrosis
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(Metavir) including those with decompensated cirrhosis were included. The study group included both treatment-naïve and treatment-experienced (PegIFN/RBV) patients. Patients with the
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following criteria were excluded: F0-2, fibrosis, HIV co-infection, renal impairment with estimated glomerular filtration rate (eGFR, using the Modification of Diet in Renal Disease
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[MDRD] formula) <30 ml/hour, and prior treatment with DAAs.
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Treatment Allocation
Treatment was administered for 12–24 weeks as determined by individual patient clinical
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characteristics and entirely at the discretion of the physician. All patients were treated with one tablet of the fixed dose combination of LDV 90 mg/SOF 400 mg (Harvoni®, Gilead Sciences, USA) with or without RBV. RBV was dosed at 600 mg (in decompensated cirrhosis) and 10001200 mg based on patient body weight. The inclusion of RBV in the treatment regimen was
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individualized by physician preference. Administration of erythropoietin (EPO) or blood transfusion was allowed upon the discretion of the treating physician. Measurements The following clinical data were obtained at the time of enrollment: age, sex, body mass index
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(BMI), comorbidities, fibrosis stage, HCV genotype (Abbott RealTime HCV Genotype II M2000rt platform [Abbott Molecular Inc., Des Plaines, IL, USA], and prior treatment history. Patients with prior HCV treatment were categorized based on their virologic response during prior PegIFN/RBV-based treatment: virologic relapse was defined as undetectable HCV RNA at
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the end of treatment, but subsequent detectable HCV RNA after treatment discontinuation while null response was defined as failure to achieve a 1 log10 reduction in HCV RNA after 12 weeks of treatment. Virologic breakthrough was defined as detectable HCV RNA after a period of
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initial response while still on therapy. HCV RNA (Abbott RealTime, Abbott Molecular Inc., Abbott Park, IL, USA) was measured as quantitative (Log10 HCV RNA, IU/mL) and/or
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qualitative (detectable/undetectable) as applicable.
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Baseline laboratory values within 3 months prior to commencement of treatment were collected
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for all patients. Follow up tests included total bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatinine, hemoglobin
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(Hb) and platelets at week 4, end of treatment (EOT) and week 12 post-treatment. FibroScan was used to determine the degree of fibrosis and was performed within 6 months prior to treatment commencement. For fibrosis stage, patients were classified as having advanced fibrosis (defined by a FibroScan score of 9.5 – 12.5 kPa) and compensated cirrhosis (≥14.5 kPa). Decompensated
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cirrhosis was defined by a combination of clinical, haematological, biochemical and radiological criteria and classified according to the Child’s Turcotte Pugh (CTP, ≥7) classification.
Outcome Analysis
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Efficacy of the treatment was assessed at weeks 4, EOT and after 12 weeks of treatment discontinuation. SVR (HCV RNA <15 IU/ml) at 12 weeks after the EOT (SVR12), was the primary efficacy endpoint. SVR12 was evaluated by an intent-to-treat (ITT) analysis (including patients who died or lost to follow-up as treatment failures) and by a modified ITT (mITT)
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analysis (excluding patients who died prior to collecting all clinical data or lost to follow-up). Patient records were reviewed for any adverse events, both the clinical as well as any abnormal findings on laboratory tests. Safety data were determined during treatment and at each clinic
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visit. Statistical Analysis
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The outcome for continuous variables is presented as mean ± standard deviation or as median and range, whichever is applicable, and as percentage for categorical data. Baseline clinical and
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demographic characteristics were compared statistically across disease stage and SVR using
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Fisher’s exact test or Chi Square test in case of categorical scale and t-test in case of continuous scale (or log means of the variable). Means of quantitative variables were compared using one-
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way analysis of variance (ANOVA) with Post-Hoc test (Turkey’s) as needed. All patients who took at least one dose of the study medication were included in the efficacy analysis on an ITT principle. A mITT analysis was also used to assess efficacy in all patients who completed the pre-defined treatment duration and had at least 12 weeks of post treatment follow up. All
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statistical tests were considered significant at α level less than 0.05. Statistical analysis was
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performed using SPSS (SPSS Inc., SPSS for Windows, version 16.0. Chicago, IL, SPSS Inc.).
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RESULTS Characteristics of Patients:
During the period between November 2014 and October 2016, 213 patients commenced
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treatment with the fixed-dose combination of LDV/SOF daily. In total, 3 (1.4%) patients had HBV co-infection, 6 (2.8%) were LT and 3 (1.4%) had controlled co-existing hepatocellular carcinoma (HCC). Baseline clinical, biochemical, hematological and virologic characteristics of the patients are shown in Table 1. The mean age of the study group was 59.6 ± 12.1 years and
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125 (58.7%) were females. Eighty-six (40.4%) patients had failed prior IFN-based treatment. Advanced fibrosis (F3) was present in 30 (14.1%), compensated cirrhosis (F4, CTP A) in 135 (63.4%) and decompensated cirrhosis (CTP B/C) in 48 (22.5%) patients. Overall, 202 (94.8%)
146 (68.5%) patients (Table 1).
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patients received 12 weeks, and 11 (5.2%) received 24 weeks of therapy. RBV was prescribed in
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Amongst the patients with F3 fibrosis, compensated CTP ‘A’ cirrhosis and decompensated cirrhosis, 11 (36.7%), 64 (47.4%) and 11 (22.9%) were treatment experienced, respectively
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(P=0.011); 9 (30.0%), 102 (75.6%) and 35 (72.9%) were prescribed concomitant RBV,
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respectively (P<0.001). All patients with F3 fibrosis were treated for 12 weeks while 5 (3.7%) of those with compensated cirrhosis and 6 (12.5%) of those with decompensated cirrhosis were
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treated for 24 weeks (P=0.024, Table 1).
Patients with decompensated cirrhosis had higher total bilirubin (33.7 ± 33.4, P< 0.001) and lower levels of albumin (27.6 ± 4.0, P< 0.001), Hb (121.5 ± 25.2, P=0.019), platelets (118.9 ± 67.1, P< 0.001) and Log10 HCV RNA (5.4 ± 0.9, P=0.005) in comparison to those with other disease stages (Table 1).
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Efficacy of Treatment:
On an ITT analysis, 197 (92.5%) of the patients achieved SVR12, accounting for 28/30 (93.3%) of F3 fibrosis patients, 126/135 (93.3%) compensated cirrhotics and 43/48 (89.6%) of the
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decompensated cirrhotics (Figure 1, P=0.686). On a mITT analysis of patients who completed therapy and had 12 weeks of follow-up (n=209) SVR12 was 94.3% (data not shown). Of the patients not completing therapy, three died on therapy (from sequelae of cirrhosis) and one discontinued therapy due to pregnancy after 4 weeks therapy (and relapsed). Of the baseline
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characteristics and treatment disposition, only female gender (P=0.020) and lower bilirubin levels (P=0.006) identified patients more likely to achieve SVR12. Age, BMI, liver enzymes, albumin, platelets, Hb, Log10 HCV RNA levels, prior treatment experience, concomitant RBV use, treatment duration and disease stage were not different between patients who achieved
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SVR12 and those who did not (P>0.05 for all, Table 2). In patients with cirrhosis (Figure 2),
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SVR12 rates were similar in those with compensated (93.3%) and decompensated disease (89.6%, P=0.601). Basic characteristics of patients who failed therapy (n=16) and their causes of
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failure are highlighted in Supplementary Table 1.
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A sub-group analysis for virologic response at week 4 of therapy showed no difference in SVR12 in patients with quantifiable HCV RNA at week 4 of therapy (89.5%) as compared to
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those with undetectable, or detectable but unquantifiable HCV RNA (93.8%, P=0.298). Similarly, no difference in SVR12 was seen in patients with quantifiable HCV RNA compared to those with undetectable HCV RNA (93.7%, P=0.296) at week 4 of therapy (Supplementary Table 2). Finally, 8 patients had detectable HCV RNA at EOT of whom 2 had virologic breakthrough and failed to achieve SVR12. Of the remaining 6 patients, 2 had no documented
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virologic negativity throughout the treatment course and failed therapy, while 4 had unquantifiable HCV RNA at EOT and went on to achieve SVR12 (Supplementary Table 2). Efficacy in Relation to Prior Treatment Experience, RBV Addition and Treatment
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Duration: Patients who were treatment-naïve (n=127, 59.6%) were similar in baseline characteristics, RBV use (P=0.359) and treatment duration (P=0.724) compared to those who were treatmentexperienced (Supplementary Table 3). SVR12 rates did not differ between patients who were
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treatment naïve (89.8%) and treatment experienced (96.5%, P=0.109).
Patients who received RBV (n=146, 68.5%) were more likely to have lower albumin, Hb and platelet levels and were more likely to be cirrhotic (P<0.05 for all) in comparison to those who
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did not receive RBV (Table 3). However, the use of RBV did not result in higher SVR12 rates in the overall cohort (91.8% vs. 94.0%, P=0.563). This trend was also seen in the sub-analysis of
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patients with F3 fibrosis (88.9 vs. 95.2%, P=0.517), compensated cirrhosis (93.1% vs. 93.9%,
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P=0.872) and decompensated cirrhosis (88.6% vs. 92.3%, P=1.000, Figure 1).
Treatment extension to 24 weeks (n=11, 5.2%) was more frequent in decompensated cirrhosis
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(Table 4), and these patients reflected higher CTP and MELD scores, and lower albumin,
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platelets and HCV RNA levels (P<0.05 for all). SVR12 rates in patients receiving 24 weeks treatment duration (90.9%) were similar to those who received 12 weeks treatment (92.6%, P=0.586). A trend towards higher SVR12 rate was seen in compensated cirrhosis receiving 24 weeks of therapy (100%) in comparison to those receiving 12 weeks (93.1%) but this did not achieve statistical significance (P=1.000). Additionally, efficacy was similar in decompensated cirrhotics receiving 24 weeks (83.3%) and 12 weeks (90.5%, P=0.503) therapy.
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Safety and Tolerability:
Overall, serious adverse events (SAEs) occurred in 9 (4.2%) patients and are presented in Supplementary Table 4. In total, 4 patients discontinued treatment early (3 due to on-treatment
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death and 1 due to pregnancy after 4 weeks of therapy). Two of the deaths were liver-related in patients with decompensated cirrhosis, and 1 died from complications of pre-existing dilated cardiomyopathy. Five (3.0%) developed hepatic decompensation and another 4 (8.3%) CTP B/C patients developed additional hepatic decompensation. RBV dose reductions were required in 26
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(17.8%) and one discontinued RBV due to severe anemia.
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DISCUSSION Our study is the largest to date to investigate the real-world effectiveness and safety of LDV/SOF therapy in HCV GT4 patients, including those with decompensated cirrhosis. In our cohort of patients who were managed in routine clinical practice LDV/SOF resulted in rapid
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virologic responses and high rates of SVR12 (overall, 92.5%). In addition, patients with advanced fibrosis (93.3%) responded similarly to those with compensated cirrhosis (93.3%). Although patients with decompensated cirrhosis had numerically lower SVR12 than those with
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compensated disease, this difference was not statistically significant. Our study included the highest number of decompensated GT4 cirrhosis reported to date. The SOLAR-2 trial included a total of 14 GT4 decompensated cirrhotics of whom 71% responded to 12-24 weeks of LDV/SOF plus RBV-based therapy [10]. Our cohort included a sufficiently greater number of patients
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(n=48), with an overall SVR12 of 89.6% and a similar efficacy with 12 or 24 weeks of therapy (P=0.503). However, it is to be noted that the vast majority of patients were treated for 12 weeks
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(87.5%) with an SVR12 rate of 90.5%, while only 6 were treated for 24 weeks. On a mITT analysis (excluding one patient who died on therapy), SVR12 was achieved in all patients
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(100%) who received 24 weeks of therapy. These results were substantially better than the
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SOLAR-2 trial that demonstrated SVR12 of 57% and 86% treated for 12 and 24 weeks, respectively [10]. Although a 24-week regimen of LDV/SOF ± RBV appears more appropriate in
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GT4 patients with decompensated cirrhosis, inferences towards extending treatment duration must be tempered in view of the small sample sizes of either study. Virologic response at week 4 had no impact on SVR12 in our GT4 patients. Similar results have been reported in other genotypes where response-guided therapy did not influence treatment outcome [11,12]. These results suggest that frequent on-treatment HCV RNA testing or
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treatment extension beyond 12 weeks based on viral kinetics is unlikely to be of clinical value. On the other hand, detectable HCV RNA at EOT revealed mixed results in our cohort. Of the 8 such patients with virologic positivity, 4 achieved SVR12. Although EOT virologic positivity with IFN-based therapy was an obvious indicator of treatment failure, recent reports document
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that some patients treated with all-oral DAA regimens achieve cure despite having detectable viremia at EOT [11,13]. This phenomenon has been attributed, potentially, to a small amount of non-infectious HCV RNA being remnant at EOT [13].
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Despite the exclusion of RBV from LDV/SOF-based clinical trials in HCV GT4 patients with compensated disease, including non-cirrhotics, clinical practice guidelines frequently recommend the addition of RBV in treatment-experienced compensated cirrhotic and noncirrhotic patient populations [5,14,15]. Such recommendations potentially stem from the
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anticipated gain in efficacy beyond the 93 - 99% demonstrated in clinical trials [8,9] or limited observational studies [16], by the addition of RBV as seen in certain GT1 categories [17]. In our
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study, patients who were prescribed RBV were generally similar in most aspects of their baseline
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characteristics to the RBV-free cohort, including viral load, treatment-experience, CTP status and duration of treatment. RBV was used in two-thirds of the overall cohort and more frequently
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in those with cirrhosis. Despite its liberal usage, efficacy was not enhanced beyond what has been demonstrated in clinical trials, and the RBV-containing cohorts of compensated and
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decompensated cirrhotics responded similarly to the RBV-free ones (Figure 1). These results are in concordance with a recent Egyptian trial where treatment-naïve and -experienced subjects were stratified by the presence or absence of cirrhosis to 12 weeks of LDV/SOF with or without RBV. The results showed that SVR12 was achieved in 96.2% of the RBV-free arm compared to 97.5% of the RBV-containing regimen [18].
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Furthermore, prior treatment experience and duration of treatment also did not impact SVR12 in our cohort. Patients with prior treatment experience were similar to those who were treatmentnaïve in respect to fibrosis stage (except for a higher number treatment-naïve being decompensated), duration of therapy and RBV allocation. Our findings are once again aligned
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with those of the afore-mentioned Egyptian trial [18] that also showed no difference in efficacy on the basis of prior treatment exposure. Although patients with compensated cirrhosis that extended treatment duration to 24 weeks showed a numerically greater response, the small number of patients in this category limits the generalization of this observation. Hence, based on
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these findings, it appears that a 12-week RBV-free regimen of LDV/SOF is appropriate and sufficient for GT4 patients, regardless of prior treatment experience or underlying histological stage.
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Overall, reported rates of SAEs of this large real-world cohort were only slightly higher or similar to those reported in the pivotal clinical trials or real-life data (3.8 – 4.6%) [19,20]. The
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few SAEs were vastly limited to patients with advanced cirrhosis, and were related to the
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underlying disease rather than the treatment. Despite a longer therapy duration and addition of RBV in most of our patients, the SAE rate was remarkably low (4.2%). There were only three
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deaths while on treatment. CPT ‘B’ or ‘C’ patients were more likely to present SAEs (8.3%), most of them as clinical decompensation. In general, the favorable safety findings in the current
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study are important because of the small number of studies in GT4 patients, particularly those with cirrhosis. Since safety is expected to be poorer in real-world cohorts, which is related to factors such as the presence of significant comorbidities and polypharmacy, these observations are clearly encouraging. This study has the usual limitations related to its observational, real-world design, including the
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potential for bias because of prescribing and patient selection by physicians. However, our study does provide insights into clinician prescribing practice for GT4 patients. Clearly, this study does not aim to address finer details of extended treatment duration in select sub-populations, or the role of RBV in treatment-experienced cirrhotics or decompensated cirrhotics. These issues must
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be evaluated in large-scale, randomized-controlled clinical trials designed specifically to address each aspect individually. Nevertheless, because of the current paucity of data with DAAs in HCV GT4 patients, the relatively large number of patients included in the current study gives an important insight into the effectiveness and safety of LDV/SOF therapy. Finally, information on
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compliance with therapy or development of drug resistance as potential causes of relapse or virologic breakthrough was not available to the investigators. The lack of data on viral kinetics or the time to virologic negativity due to the infrequent testing of HCV RNA serves as another
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limitation in our ability to understand the causes of treatment failure. These, however, are natural
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shortcomings of real-world cohorts and could otherwise be assessed in prospective clinical trials. In summary, LDV/SOF-based therapy yielded high rates of SVR12, comparable with the limited
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results from clinical trials, in both compensated and decompensated cirrhotic HCV GT4 patients managed in a real-world setting. The addition of RBV to this regimen does not offer potential
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gain in efficacy. The safety profile of this regimen was good and comparable with that reported
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Table 1: Baseline characteristics and treatment allocation of HCV genotype 4 patients based upon liver disease severity who received co-formulated ledipasvir/sofosbuvir Total F3 Fibrosis Compensated Decompensated (n=213) (n=30) Parameter Cirrhosis* Cirrhosis** P value
Platelets (109/L) Log10 HCV RNA
(n=135)
(n=48)
55.2 ± 16.3 18 (60.0) 26.2 ± 7.1 66.9 ± 65.4 62.0 ± 47.3 15.4 ± 8.8 101.7 ± 48.8
60.1 ± 11.2 77 (57.0) 29.9 ± 5.9 64.4 ± 48.9 61.3 ± 41.1 14.5 ± 7.8 117.3 ± 52.4
61.1 ± 10.9 30 (62.5) 27.8 ± 6.1 60.1 ± 55.9 69.3 ± 56.2 33.7 ± 33.4 142.1 ± 74.6
0.084 0.794 0.008 0.842 0.608 < 0.001 0.015
37.8 ± 4.5 130.1 ± 27.4
35.1 ± 5.8 132.5 ± 21.2
27.6 ± 4.0 121.5 ± 25.2
< 0.001 0.019
271.4 ± 113.5
158.4 ± 80.6
118.9 ± 67.1
< 0.001
6.0 ± 0.7
5.8 ± 0.9
5.4 ± 0.9
0.005
86 (40.4)
11 (36.7)
64 (47.4)
11 (22.9)
0.011
202 (94.8) 11 (5.2) 146 (68.5)
30 (100.0) 0 9 (30.0)
130 (96.3) 5 (3.7) 102 (75.6)
42 (87.5) 6 (12.5) 35 (72.9)
0.024
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(IU/mL)
Treatment experienced Treatment Duration 12 Weeks 24 Weeks Received RBV
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Albumin (g/L) Hemoglobin (mg/dL)
59.6 ± 12.1 125 (58.7) 28.9 ± 6.3 63.8 ± 52.9 63.3 ± 45.7 18.9 ± 19.0 121.0 ± 59.1 33.8 ± 6.3 129.7 ± 23.4 165.4 ± 94.7 5.7 ± 0.9
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Age (yrs) Female gender BMI (kg/m2) ALT (U/L) AST (U/L) Bilirubin (mol/L) ALP (U/L)
< 0.001
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Data represented as n (%), or mean ± standard deviation. *F4 fibrosis/ Child’s A cirrhosis; **Child’s B/C cirrhosis; BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; HCV, hepatitis C virus; RBV, ribavirin
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Table 2: Baseline characteristics of patients in relation to sustained and non-sustained virologic response to co-formulated ledipasvir/sofosbuvir treatment Parameter No SVR12 SVR12 P value (n=16) (n=197) Age (yrs) 64.2 ± 9.6 59.3 ± 12.2 0.116 Female gender 5 (31.2) 120 (60.9) 0.020 2 BMI (kg/m ) 27.8 ± 5.8 29.0 ± 6.3 0.460 ALT (U/L) 61.9 ± 58.4 63.9 ± 52.6 0.880 AST (U/L) 69.2 ± 55.4 62.9 ± 45.1 0.634 Bilirubin (mol/L) 31.5 ± 50.8 17.9 ± 13.3 0.006 >35 (mol/L) 3 (18.8) 15 (7.6) 0.141 ALP (U/L) 115.4 ± 51.5 121.4 ± 59.8 0.724 Albumin (g/L) 32.2 ± 6.3 33.9 ± 6.3 0.298 <35 (g/L) 9 (56.2) 96 (48.7) 0.611 Hemoglobin (mg/dL) 126.2 ± 20.9 130.0 ± 23.6 0.534 9 Platelets (10 /L) 152.5 ± 63.6 166.5 ± 96.8 0.571 < 70 (109/L) 0 22 (11.2) 0.383 Log10 HCV RNA (IU/mL) 5.5 ± 1.0 5.7 ± 0.9 0.412 Treatment Duration 12 Weeks 15 (93.8) 187 (94.9) 0.586 24 Weeks 1 (6.2) 10 (5.1) Treatment experienced 3 (18.8) 83 (42.1) 0.109 Fibrosis stage F3 2 (12.5) 28 (14.2) 1.000 F4 14 (87.5) 168 (85.8) Decompensated cirrhosis 5 (31.2) 43 (24.3) 0.551 Received RBV 12 (75.0) 134 (68.0) 0.781
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Data represented as n (%), or mean ± standard deviation. BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response
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Table 3: Baseline characteristics of patients in relation to those who received and did not receive RBV Parameter No RBV RBV P value (n=67) (n=146) Age (yrs) 56.9 ± 13.6 60.9 ± 11.1 0.023 Female gender 40 (59.7) 85 (58.2) 0.838 BMI (kg/m2) 28.2 ± 6.5 29.3 ± 6.2 0.265 ALT (U/L) 56.1 ± 45.2 67.3 ± 55.9 0.150 AST (U/L) 55.5 ± 29.1 66.2 ± 50.3 0.157 Bilirubin (mol/L) 20.3 ± 26.6 18.3 ± 14.2 0.493 ALP (U/L) 119.1 ± 61.9 122.0 ± 57.8 0.761 Albumin (g/L) 35.0 ± 5.8 33.2 ± 6.5 0.053 Hemoglobin (mg/dL) 121.1 ± 28.2 133.6 ± 19.7 < 0.0001 Platelets (109/L) 200.4 ± 115.3 149.4 ± 79.0 < 0.0001 Log10 HCV RNA (IU/mL) 5.6 ± 1.0 5.7 ± 0.8 0.410 Fibrosis stage F3 22 (33.8) 9 (6.2) < 0.001 F4 45 (67.2) 137 (93.8) Decompensated cirrhosis 13 (23.6) 35 (25.4) 0.802 Treatment experienced 24 (35.8) 62 (42.5) 0.359 Treatment Duration 12 Weeks 62 (92.5) 140 (95.9) 0.328 24 Weeks 5 (7.5) 6 (4.1) Achieved SVR12 63 (94.0) 134 (91.8) 0.563
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Table 4: Baseline characteristics of patients in relation to those who received 24 weeks versus those who received 12 weeks of co-formulated ledipasvir/sofosbuvir treatment Parameter 24 weeks 12 weeks P value (n=11) (n=202) Age (yrs) 59.1 ± 9.1 59.7 ± 12.2 0.889 Female gender 9 (81.8) 116 (42.6) 0.129 2 BMI (kg/m ) 29.6 ± 4.9 28.9 ± 6.3 0.706 ALT (U/L) 47.0 ± 23.7 64.7 ± 53.9 0.280 AST (U/L) 66.4 ± 33.8 63.1 ± 46.4 0.827 Bilirubin (mol/L) 44.7 ± 59.7 17.5 ± 12.8 < 0.001 ALP (U/L) 129.9 ± 47.9 120.4 ± 59.8 0.624 Albumin (g/L) 30.0 ± 3.9 34.0 ± 6.3 0.041 Hemoglobin (mg/dL) 102.0 ± 35.6 131.2 ± 21.7 < 0.001 Platelets (109/L) 84.5 ± 26.7 169.8 ± 95.1 0.003 Log10 HCV RNA (IU/mL) 4.8 ± 1.2 5.8 ± 0.8 0.001 Treatment experienced 5 (45.5) 81 (40.1) 0.724 Fibrosis stage F3 F3 0 30 (14.9) 0.370 F4 F4 11 (100.0) 172 (85.1) Decompensated cirrhosis 6 (54.5) 42 (23.1) 0.029 Received RBV 6 (54.5) 140 (69.3) 0.328 Achieved SVR12 10 (90.9) 187 (92.6) 0.586 CTP Score* 7.0 (6.0-8.0) 6.0 (5.0-6.0) < 0.001 MELD Score* 12.0 (9.0-17.0) 8.0 (6.0-10.0) 0.001
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Data represented as n (%), or mean ± standard deviation, or *median (interquantile range). BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response; CTP, Child’s Turcotte Pugh; MELD, model for end-stage liver disease
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FIGURE LEGENDS Figure 1: Sustained virologic response to ledipasvir/sofosbuvir for 12 – 24 weeks in patients with advanced fibrosis (F3), compensated (Child Turcotte Pugh, CTP ‘A’) cirrhosis and decompensated (CTP ‘B/C’) cirrhosis in overall (light grey bars), ribavirin-containing (dark grey
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bars) and ribavirin-free cohorts (black bars).
Figure 2: Sustained virologic response to ledipasvir/sofosbuvir with or without ribavirin in
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patients with compensated (Child Turcotte Pugh, CTP ‘A’) cirrhosis and decompensated (CTP ‘B/C’) cirrhosis in overall (light grey bars), 12-weeks duration (dark grey bars) and 24-weeks
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duration cohorts (black bars).
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