Global real‐world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts

Abstract Background and aims Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real‐world analysis to date, the effectiveness of pangenotypic, panfibrotic, single‐tablet, sofosbuvir/velpatasvir (SOF/VEL) once‐daily for 12 weeks was assessed in 12 clinical real‐world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. Methods Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post‐treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. Results Overall, 5552 patients were included: 13.3% treatment‐experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non‐virological reasons (67% lost to follow‐up; 26.5% early treatment discontinuation). Conclusions In this large cohort, representative of clinical practice, a simple 12‐week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.


| INTRODUC TI ON
Hepatitis C virus (HCV) is a major medical and public health concern globally. 1 The clinical effectiveness, favourable safety profile and high patient tolerability of direct-acting antivirals (DAAs) have been well reported and cure rates exceed 95% in the DAA treatment era. 2 Owing to the high cure rates and an associated reduction in liver transplantation, hepatocellular carcinoma and death, 3,4 DAAs have revolutionized the management of HCV and are recommended by the World Health Organization (WHO) to ensure over 80% of those affected are cured and achieve HCV elimination by 2030. 1,5 However, despite the availability of these highly effective DAA regimens, approximately 71 million people globally are still waiting to be treated and only 15 countries are currently on track to achieve HCV elimination by 2030. 6 Recommended DAA regimens can vary in duration, dosing frequency and pill burden, and the requirement for coadministration with ribavirin. 2,7 The choice of therapeutic regimen can also depend on HCV genotype, previous treatment history and severity of hepatic impairment. Effective pangenotypic regimens that allow the simplification of HCV management, with respect to minimal monitoring, genotyping and assessment of fibrosis stage, have been identified as being essential in ensuring HCV elimination becomes a reality. 8,9 Sofosbuvir/velpatasvir (SOF/VEL) is the first pangenotypic, panfibrotic, protease inhibitor-free, all-oral single-tablet regimen and can be used as a fixed 12-week treatment duration in all adult patients with chronic hepatitis C. 10 The Phase 3 ASTRAL-1, −2, −3 and −5 trials established the efficacy and safety of SOF/VEL in over 1100 patients with chronic HCV and reported sustained virological response (SVR) rates of 95%-100% in patients infected with HCV genotypes 1-6, with or without compensated cirrhosis and irrespective of human immunodeficiency virus (HIV) status, or previous treatment failure with interferon, ribavirin or protease inhibitors. [11][12][13][14] The expanding use of DAAs in clinical practice in recent years has provided an opportunity to assess their effectiveness and safety in real-world cohorts, outside the controlled settings of clinical trials. Several real-world cohorts have evaluated SOF/VEL effectiveness and safety in varying settings, with the results being similar to those of clinical trials. 10,[15][16][17][18][19][20][21][22][23][24] In this integrated real-world analysis, data from 12 clinical practice cohorts across different real-world settings in Canada, Europe and the USA were pooled to allow the evaluation of the real-world effectiveness of SOF/VEL for 12 weeks without ribavirin (based on the label or physician discretion) in the largest available heterogeneous HCV patient population and to investigate any patient characteristics affecting the risk of not achieving SVR.
( Table 1). Patients treated with the oral, once-daily single-tablet regimen SOF/VEL 400/100 mg for 12 weeks were included. Patients were treated in different clinical settings, including university hospitals, academic centres, community centres, outpatient clinics and private practices. Treatment and patient monitoring were based on local clinical practice and standard of care, at the discretion of the treating physician.

| Data collection
Demographics and treatment characteristics were collected at baseline. Reasons for not achieving SVR 12 or 24 weeks after the end of treatment (SVR12/24), for early treatment discontinuation, for being lost to follow-up (LTFU) and cause of death (if applicable) were evaluated according to local clinical practice standards and documented at the discretion of the treating physician. Patient-level data were available for 10 cohorts and summary level data for the remaining two cohorts.

| Inclusion and exclusion criteria
Adult patients who were treated with SOF/VEL 400/100 mg for 12 weeks with a valid SVR12/24 status or patients who had discontinued treatment early (before the end of February 2019) were included. Inclusion criteria included infection with HCV genotypes 1-6 and the absence or presence of compensated cirrhosis. Patients who were treatment naïve or had previously received interferon-based therapy (pegylated interferon plus ribavirin with or without telaprevir, boceprevir or simeprevir) were also included. The following patients were excluded from the analysis: patients who received SOF/VEL for more than 12 weeks or received ribavirin as part of the treatment regimen; patients with current or prior decompensated cirrhosis or hepatocellular carcinoma; and patients who had previously failed a DAA treatment (patients previously treated with pegylated interferon plus ribavirin with or without boceprevir, telaprevir or simeprevir were included).

| Outcome assessments
Effectiveness was assessed in the overall population, including all patients with a virological, non-virological and unknown reason for not achieving SVR12/24. Effectiveness was also assessed in the effectiveness population, which excluded patients who did not have a valid SVR12/24 status because of non-virological reasons or unknown reasons. Non-virological reasons were defined as early treatment discontinuation, non-adherence, reinfection, LTFU, death before SVR assessment, consent withdrawal.

| Statistical analyses
Descriptive characteristics were presented as the number (n) and percentage of patients (%) for the categorical variables.
Continuous variables were summarized as mean (standard error; SE

| Patient flowchart and baseline characteristics
A total of 5552 patients infected with HCV from 12 clinical cohorts (Table 1) who started treatment with SOF/VEL for 12 weeks, without ribavirin, were included in this real-world pooled analysis (overall patient population). Patients who did not achieve SVR12/24 due to non-virological (n = 332) or unknown reasons (n = 24) were excluded from the effectiveness population. The patient flowchart including SVR12/24 result is provided in Figure 1. Patient baseline characteristics for the overall patient population and for the effectiveness population are shown in Table 2.
When stratified by intravenous drug use, treatment history and PPI use SVR12/24 ≥ 98.4% was achieved by all subgroups ( Figure 2C).

F I G U R E 1
Flowchart and response of patients included in the real-world effectiveness analysis. † Overall population includes all patients who achieved SVR12/24, and those who did not achieve SVR12/24 due to virological and non-virological reasons and patients for which the reason for achieving SVR12/24 was unknown. ‡ Effectiveness population includes all patients who achieved SVR12/24 and those who did not achieve SVR12/24 due to virological reasons. § Two patients died due to sepsis, one due to cancer (not specified further), one due to haemoptysis secondary to primary lung cancer, cause of death was not specified for 13 patients. ¶ 32 patients relapsed, 11 were non-responders, three were breakthroughs; details of the virological reason were not specified for nine patients, as evaluated and documented by the treating physician. LFTU, lost to follow-up; SVR12/24, sustained virological response 12/24 weeks after end of treatment to non-virological reasons and 1.0% (55/5552) due to virological reasons ( Figure 3). The reason for not achieving SVR12/24 was unknown in 0.4% (24/5552) of patients. Baseline characteristics of patients who did not achieve SVR12/24 are provided in Table 3.

| Patients who did not achieve SVR12/24 due to a non-virological reason
The main non-virological reasons for not achieving SVR12/24 were being LTFU (66.9%; 222/332) and early treatment discontinuation The reasons for discontinuing treatment early were available in 17% (15/88) of patients: three discontinued treatment because they were denied insurance or could not afford treatment; one moved to another country; three were non-adherent; and eight discontinued because of adverse events (not otherwise specified) or fear of adverse events.

| Patients who did not achieve SVR12/24 due to virological reasons
In the overall patient population, 1.0% (55/5552) of patients did not achieve an SVR12/24 due to a virological reason (Figure 3)

| D ISCUSS I ON
In this pooled analysis of real-world clinical practice cohorts, over 5000 patients with HCV infection completed treatment with SOF/ VEL for 12 weeks and achieved an SVR12/24 rate of 98.9%, which is in line with previous clinical trial results. 11,12 This is the largest realworld cohort of patients treated with DAAs to date, which allowed effectiveness to be analysed in multiple patient subgroups. SVR12/24 rates were high despite inclusion of diverse patient types from different geographical regions, treated in different clinical settings with a variety of management protocols for pre-and on-treatment monitoring and testing. The low discontinuation (<2%) and LTFU rates (4%) in this real-world analysis are consistent with previous clinical studies. 11,12 Additionally, where information was available, few of the discontinuations were due to adverse events linked to SOF/VEL therapy, which is The definition of former drug use varied between cohorts with respect to timing and this level of detail was not available for most patients. c Fibrosis score determined by the treating physician.
d No information available on PPI treatment continuation or discontinuation during SOF/VEL treatment.

TA B L E 3 (Continued)
with compensated cirrhosis, and patients with current or former drug use. 11,12,[26][27][28] High SVR12/24 rates were achieved across all genotypes, including genotype 3, which was not associated with a higher risk of not achieving SVR12/24 due to virological reasons. Of note, this cohort includes the largest number of patients infected with genotype 3 reported so far in a real-world data analysis. Of the 1677 patients with genotype 3 infection, 98.3% were cured without ribavirin. These results are in line with the Phase 3 ASTRAL-3 and POLARIS-3 trials which reported SVR12 rates between 93% and 98% in non-cirrhotic and cirrhotic patients. 12,25 As the focus of HCV management moves towards elimination, the need for simplified treatment and patient management -with a reduced need for pretreatment and on-treatment testing -is considered a key step in achieving the WHO goals, by allowing a shorter time between HCV diagnosis and treatment start, thus encouraging a test-and-treat approach. 8,29,30 This is also endorsed in the call to action to work towards HCV elimination launched by  In addition to the low number of patients that did not achieve SVR12/24 due to virological reasons, only 6.7% of patients did not achieve SVR12/24 due to a non-virological reason, which is consistent with previously reported data in the current DAA era. 34 To summarize, this large, multicentre, real-world, diverse, clinical practice cohort emphasizes the strength of SOF/VEL as a simple and effective pangenotypic, panfibrotic DAA regimen, that requires only minimal monitoring and could be applicable in a test-and-treat approach to progress towards the goal of HCV elimination.

ACK N OWLED G EM ENTS
Medical writing assistance was provided by Ridda Jabbar and Liesje Quine from Elements Communications Ltd, funded by Gilead Sciences Ltd.