Simeprevir, daclatasvir, and sofosbuvir for hepatitis C virus‐infected patients: Long‐term follow‐up results from the open‐label, Phase II IMPACT study

Abstract Background and aims Direct‐acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection have resulted in high rates of sustained virologic response (SVR) following 8 to 24 weeks of treatment. However, difficult‐to‐cure/cirrhotic patients typically require a longer treatment duration and less is known regarding the long‐term durability of SVR or effect on liver disease progression; to assess this, the IMPACT study followed patients for a 3‐year period after end of treatment. Methods The Phase II, open‐label, nonrandomized IMPACT study assessed the efficacy, safety, and pharmacokinetics of the combination of three DAAs (simeprevir, sofosbuvir, and daclatasvir) in HCV genotype 1/4‐infected, treatment‐naïve/‐experienced cirrhotic patients with portal hypertension or decompensated liver disease. Patients from a single site in the United States were assigned to one of two groups by Child–Pugh (CP) score: CP A, CP score less than 7 and evidence of portal hypertension; CP B, CP score of 7 to 9. All patients received simeprevir 150 mg, daclatasvir 60 mg, and sofosbuvir 400 mg once‐daily for 12 weeks between September 2014 and August 2015. All 40 patients included in the study (male, 63%; median age, 58.5 years) achieved SVR 12 and 24 weeks after end of treatment, and the combination was well tolerated. Results All patients who reached the 3‐year follow‐up timepoint maintained SVR (CP A, 15/15; CP B, 18/18). CP scores and Model for End‐stage Liver Disease scores remained relatively stable, and mean FibroScan and FibroTest scores declined. No new safety signals were identified. Conclusions In the IMPACT study, virologic response to simeprevir, sofosbuvir, and daclatasvir was durable over 3 years (http://ClinicalTrials.gov number: NCT02262728).


| INTRODUCTION
In 2015, it was estimated that 71 million individuals worldwide had chronic hepatitis C virus (HCV) infection. 1 HCV infection is a leading cause of chronic liver disease, 2,3 with many patients developing liver cirrhosis or hepatocellular carcinoma. 4 Furthermore, patients who develop decompensated liver disease have decreased survival rates compared with those patients with compensated cirrhosis. 5 Current guidelines recommend the use of interferon-free combinations of direct-acting antiviral agents (DAAs) for the treatment of HCV infection. 6,7 Favorable efficacy and tolerability have been demonstrated with these regimens following treatment durations of 8 to 24 weeks (dependent on HCV genotype [GT] and patient characteristics). 6 However, difficult-to-cure patients, including those with cirrhosis, typically require a longer treatment duration. 6 In addition, the presence of decompensated liver disease may result in impaired hepatic metabolism, affecting the plasma concentrations of the DAAs used. 8 Simeprevir, sofosbuvir, and daclatasvir are DAAs with nonoverlapping resistance profiles, different mechanisms of action, and different metabolic pathways that target chronic HCV infection. 9,10 Simeprevir is an HCV NS3/4A protease inhibitor with antiviral activity against GTs 1, 2, 4, 5, and 6 11,12 ; sofosbuvir is a pangenotypic nucleotide HCV NS5B polymerase inhibitor 13 ; and daclatasvir is a pangenotypic HCV NS5A replication complex inhibitor. 10,14 The Phase II IMPACT study (ClinicalTrials.gov number: NCT02262728) was the first to assess the combination of simeprevir, sofosbuvir, and daclatasvir for 12 weeks in HCV GT1-or 4-infected treatment-naïve or -experienced patients with Child-Pugh (CP A) cirrhosis with portal hypertension, or decompensated liver disease (CP B), with a planned 5-year follow-up period. 10 As published previously, all 40 patients (100%) achieved sustained virologic response (SVR)12 and SVR24, and the 3-DAA combination was well tolerated. During the long-term follow-up phase, the study sponsor decided to cease their HCV clinical development program. 15 Therefore, this manuscript presents the results of the final analysis for the long-term follow-up period of the study (reduced to up to 3 years after the end of treatment [EOT]).

| METHODS
The study design, methodology, key inclusion and exclusion criteria, and procedures of this trial have been reported previously. 10

| Patients and study design
In brief, IMPACT was a Phase II, open-label study carried out at a single site in the United States. The study comprised a screening phase of approximately 4 weeks, a 12-week open-label treatment phase, and a posttreatment long-term follow-up phase. During the treatment phase, patients received simeprevir 150 mg once daily (QD), daclatasvir 60 mg QD, and sofosbuvir 400 mg QD for 12 weeks. For all patients, a posttreatment follow-up phase was scheduled for a total period of 5 years, during which patients attended follow-up visits every 6 months. As mentioned previously, the follow-up period was subsequently shortened to 3 years.
The study included both treatment-naïve and interferon-based (± ribavirin) HCV treatment-experienced patients of at least 18 years of age with chronic HCV GT1-or 4-infection and cirrhosis (defined as a FibroScan ® score >14.5 kPa at screening). Liver disease was classified by CP score; CP A, score less than 7 with documented portal hypertension; CP B, score 7 to 9.

| Procedures
During the long-term follow-up period of the study, efficacy

| Detection of HCV RNA
Blood samples were collected at predefined time points during the long-term follow-up period, at the 1-, 1.5-, 2-, 2.5-, and 3-year followup visits, and plasma was subsequently isolated. RNA extraction and quantification of HCV RNA was performed in a central laboratory using the COBAS ® AmpliPrep/COBAS ® TaqMan ® HCV Quantitative Test v2.0 (Roche; lower limit of quantification: 15 IU/mL). Further details of this methodology have been reported previously 10 (see appendix S1 of the previous IMPACT article).

| Assessment of liver disease status
Liver disease status was monitored by the assessment of CP, MELD, FibroTest, and FibroScan scores, which were assessed at screening or baseline and during follow-up.

| Safety
During the long-term follow-up phase, reporting of adverse events (AEs) was limited to all serious AEs (SAEs) only.

| Objectives
The objectives of the long-term follow-up phase were to assess the durability of SVR in the IMPACT study and the effect of treatment on liver disease progression.

| Statistics
Since this was an exploratory analysis within an exploratory study, no formal sample size calculation was performed; however, it was considered that a total sample size of 40 patients would be sufficient to explore the primary and secondary objectives, as reported previously. 10 All efficacy analyses were performed on the intentto-treat (ITT) population (all enrolled patients who had taken at least one dose of any study drug). The endpoints were analyzed overall and by CP class using descriptive statistics, using SAS version 9.4.

| Ethics
The study was approved by IntegReview IRB, a regional Institutional Review Board in Austin, Texas, and met the principles of the Declaration of Helsinki. All patients provided written informed consent.

| Patient disposition
In total, 74 patients were screened for the IMPACT study. All of the 40 patients enrolled in the treatment phase (19 patients

| Efficacy
All patients remaining in the study at the 3-year follow-up visit (

| Safety
During the treatment phase, there were no deaths or AEs that led to treatment discontinuation. 10  Other SAEs reported in two patients or more within the CP B group included: abdominal pain (n = 2) and ascites (n = 2). One patient in the CP B group died during the 3-year follow-up period (due to an upper GI bleed). However, no SAEs or deaths were considered to be related to study treatment (Table 1).

| DISCUSSION
The During the long-term follow-up phase of this study, the sponsor decided not to continue their HCV clinical development program. This decision was not driven by a safety concern. Irrespective of this decision, the 3-year follow-up data analyzed here, provides insight into durability of response in patients with decompensated liver disease and, therefore, it was considered to be of significant relevance to the field.  months, late relapse in patients who achieved SVR with daclatasvir and asunaprevir was rare (4 of 413 patients) and comparable with that seen following interferon therapy. 17 The results of the IMPACT study also provide insight into the long-term effects of such treatment regimens on liver function. The CP scores for the majority of patients in the CP A and CP B groups stiffness were most pronounced in those patients with the highest stiffness scores at baseline. This may be due to the regression of liver fibrosis or reductions in inflammation associated with SVR. 18 No new safety signals for this combination treatment were identified during long-term follow-up in this study and, overall, this DAA regimen was well tolerated. While liver-related SAEs were rare among patients in the CP A group, several patients in the CP B group experienced liverrelated SAEs, including ascites, hepatic encephalopathy, and de novo HCC. In the CP B group, one patient died due to an upper GI bleed, which was not considered to be related to the study treatment.
In this study, four patients developed de novo HCC following SVR. A recent review article summarizing the results of 11 studies examining the incidence of HCC following DAA treatment reported a de novo incidence rate of 0% to 7.4%, with the authors commenting that their review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy. 19 Furthermore, it has also been suggested that SVR is associated with a significant decrease in de novo or recurrent HCC, 20 dissipating concerns of DAA treatment being associated with subsequent occurrence of HCC.
When compared with interferon-based regimens, evidence has indicated that there may be a mild increased risk of de novo HCC with DAA treatment. 21 However, interferon-based regimens can only be given with caution to patients with cirrhosis and only if they have sufficient liver function and minimal portal hypertension. 21 This was an exploratory study, and as such, there were several limitations, including the open-label design and that the study was conducted at a single center. There was also a relatively small sample size, which only included patients with CP A and B stage of liver disease. In addition, the posttreatment follow-up was shortened to 3 years, following the discontinuation of the sponsor's HCV clinical development program. At the time this study was conducted, the MELD score was used as a measure of change in liver function as it was the most suitable measurement for patients with CP A and B. The recently reported Albumin-Bilirubin grades 22 for the assessment of liver disease in those with mild deterioration of liver function have since been proven to be a more sensitive marker of liver function in the setting of mild dysfunction and in HCC.
In conclusion, HCV eradication by triple DAA therapy provided durable SVR and a good clinical prognosis in HCV-infected patients.
To further assess the long-term clinical benefit of achieving SVR in patients with advanced liver disease, studies involving greater patient numbers and longer durations of follow-up would be required.