FormalPara Key Summary Points

Why carry out this study?

The EXPEDITION-8 clinical trial has demonstrated that treatment-naïve patients with compensated cirrhosis (TN/CC) of HCV genotypes 1–6 achieve a 98% intent-to-treat sustained virologic response rate 12 weeks post-treatment with an 8-week glecaprevir/pibrentasvir (G/P) regimen, including HCV genotype 3 and patients with a recent diagnosis of illicit drug use or abuse

This study presents real-world evidence for the effectiveness of 8-week G/P in TN/CC patients with HCV

What was learned from the study?

Overall, 8-week G/P treatment in TN/CC HCV patients was highly effective, with an overall cure rate of 95.5%, including in patients with genotype 3 (95.6%) and patients with a recent diagnosis of illicit drug use or abuse (93%)

Results from this real-world analysis provide further evidence for the 8-week G/P regimen as an efficacious and short-duration treatment in TN/CC patients with all HCV genotypes in this real-world setting

This study redefines the historical length of treatment for TN/CC HCV patients, supporting efforts towards the World Health Organization’s goal of eliminating HCV as a major public health threat by 2030

Introduction

Globally, an estimated 71 million people have chronic hepatitis C virus (HCV) infection [1]. In the United States (US), it was estimated that 2.4 million people had active HCV between 2013 and 2016 [2]. In 2018, an estimated 50,300 new acute and 137,713 new chronic cases of HCV were identified in a noninstitutionalized civilian population in the US [3]. Chronic HCV is associated with progressive liver disease [4], extrahepatic manifestations [5], and an increase in all-cause mortality [6]. The introduction of oral, pangenotypic, ribavirin-free, direct-acting antiviral (DAAs) drugs has improved the efficacy and safety of HCV treatment. DAAs are generally well tolerated and are associated with high cure rates [7]. Specifically, glecaprevir/pibrentasvir (G/P) has been approved for the treatment of patients with chronic HCV without cirrhosis or with compensated cirrhosis (CC) [8, 9], where up to 98% of patients can achieve a sustained virologic response at post-treatment week 12 (SVR12) by G/P treatment in only 8 weeks [10]. By curing HCV infection, health-related quality of life can be improved, and extrahepatic manifestations [11] and onward transmission can be prevented [8].

Previously, only treatment-naïve (TN) patients without cirrhosis and with HCV genotypes 1–6 were eligible for an 8-week regimen of G/P [12]. The results of the EXPEDITION-8 trial [10] demonstrated the efficacy and safety of 8-week G/P in TN patients with HCV genotypes 1–6 and CC, including those with genotype 3, leading to approval and label updates for an 8-week treatment duration in these patients in September 2019 in the US [13, 14] and March 2020 in the EU [15, 16]. HCV genotype 3 is more difficult to treat and has been associated with significantly lower SVR rates than other genotypes [17]. Prior to the EXPEDITION-8 trial outcomes, a highly effective 12-week regimen of G/P for TN/CC patients with genotype 3 yielded high rates of SVR [18, 19]. Both the American Association of the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) guidelines previously recommended a 12-week regimen of G/P for TN/CC patients with genotype 3; currently, AASLD recommends 8 weeks of G/P treatment for TN/CC patients with genotype 3, and EASL recommends 8 to 12 weeks of treatment for these patients [8, 9]. Therefore, the new guidelines and label update for a shorter-duration treatment are especially promising for patients infected with more difficult-to-treat HCV infections, such as genotype 3, and for populations that are more difficult to engage and retain in therapy, such as people who inject drugs (PWID) [20, 21].

Evidence from clinical trials demonstrates that TN/CC patients with genotypes 1–6 who received treatment for G/P for 8 weeks achieved high rates of SVR12 [10, 22, 23]. However, the most-recently published EASL guidelines state that real-world data are needed to consolidate the shortened treatment recommendation of an 8-week regimen [8]. Real-world effectiveness data are promising [24, 25], but data from the US are limited. The first real-world evidence from the US demonstrated a high SVR12 rate (≥ 95%) following an 8-week regimen of G/P for TN/CC patients with genotype 1–6 chronic HCV infection [26]. The aim of this study is to assess the real-world effectiveness of 8-week G/P in TN/CC patients with chronic HCV infection using information from a large US claims database.

Methods

Study Design and Data Source

This was a retrospective, real-world study that examined SVR12 rates among TN/CC patients with HCV in the US who were treated with 8-week G/P. Real-world, anonymized data from across the US between August 2017 and December 2020 were collated from the Symphony Health Solutions (SHS) administrative claims database, a large and geographically diverse set of commercial and government (Medicare and Medicaid) electronic claims processors. Anonymized data were linked to patient-level laboratory results from laboratory testing companies in the US.

Patients

Patients were included in the study if they were over the age of 12, had a diagnosis of chronic HCV within 6 months prior to the initial G/P prescription dispensed, and received a diagnosis of cirrhosis (see Fig. 1). Patients were treated with 8-week G/P, defined as a G/P prescription filled for a total days-of-supply of 56 days, with no more than a 7-day gap between fills allowed. A previous publication found that patients with a gap of less than 7 days between fills of G/P can still achieve SVR [27].

Fig. 1
figure 1

Sample identification of eligible patients. G/P glecaprevir/pibrentasvir, HCV hepatitis C virus, RNA ribonucleic acid, SHA Symphony Health Solutions

Full size image

For all patients, G/P was prescribed to be taken orally, once daily, at a fixed dose of 300 mg/120 mg, for 8 weeks [15]. Given that SHS is an open-system claims database, patients were required to have medical or pharmacy claims recorded in the 6 months before the first G/P fill date (as a pre-index proxy for 6 months enrollment), where the index date is defined as the date for the first fill of 8-week G/P. Additionally, patients were required to have a claim recorded any time post the 6-month baseline period as a proxy for continuous enrollment.

Patients were excluded if they received HCV treatment any time before their G/P initiation, had decompensated cirrhosis (excluding those with a prior history of codes associated with hepatic decompensation or hepatic failure any time before their index date; see Table S1 in the Supplementary Information), or had a liver or kidney transplant (excluding those with a prior history of codes for liver or kidney failure any time before their index date; see Table S2 in the Supplementary Information). Patients were required to have a follow-up HCV ribonucleic acid (RNA) level at least 8 weeks or more after the end of treatment. Inconclusive results were excluded.

Data Collection

Demographic and clinical characteristics were collected at baseline, including age, gender, payer type, ethnicity, geographic location, and comorbidities (liver-related diseases, HBV infection, extrahepatic manifestations [see Table S3 in the Supplementary Information], illicit drug use [see Table S4 in the Supplementary Information], and portal hypertension). Laboratory values were also collected at baseline, and included HCV genotype, alanine aminotransferase, HCV RNA viral load, platelet, serum albumin, total bilirubin, and ICD-10 for cirrhosis.

Outcome

The primary outcome in this study is the SVR rate, calculated in patients who have an HCV RNA level observed at least 8 weeks after the end of G/P treatment. Where the HCV RNA value is undetectable or unquantifiable, it means that SVR was achieved, while a quantifiable HCV RNA means that SVR was not achieved.

Statistical Analysis

Descriptive statistics were performed to assess patient characteristics at baseline. The number and percentage of eligible patients with each baseline clinical characteristic and the number and percentage of patients with a diagnosis of a disease among the comorbidities was calculated. The percentage of patients who achieved SVR was calculated among all patients who had an HCV RNA value at least 8 weeks after the end of treatment. Subgroup analyses were explored to repeat the SVR rates based on individual patient’s baseline viral load, HCV genotype, and comorbidities. Univariate comparisons of patient characteristics between patients who achieved SVR and patients who failed to achieve SVR were made using t-tests for continuous variables and chi-square tests for categorical variables. All statistical tests were two-sided and P < 0.05 was considered to be statistically significant. Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc.).

Ethics

Data provided for the study were de-identified and Health Insurance Portability and Accountability Act (HIPAA) compliant; therefore, review board approval was not required.

Results

Patient Attrition

The overall sample size was 123,942 patients treated with G/P (see Fig. 1). Of these, 4139 patients were HCV treatment-naïve, had compensated cirrhosis, and did not receive a liver or kidney transplant. Of these, 494 patients met the inclusion and exclusion criteria and had a follow-up HCV RNA level assessed at least 8 weeks or more after the end of treatment, of whom 45 patients were identified as genotype 3.

Patient Characteristics

The majority (58%) of the 494 HCV patients included in this analysis were male, Caucasian (40%), and had a mean age of 58 years (see Table 1). Overall, 74%, 12%, 12%, and 1% of the patients were genotype 1, 2, 3, and 4–6 infected, respectively. Of the 494 patients, 24% had a recent diagnosis of illicit drug use or abuse and 39% had one or more extrahepatic manifestations, which are the diseases defined in Table S3 in the Supplementary Information. The mean HCV RNA viral load for the total population at baseline was 4,634,921 IU/mL, and the mean platelet count was 218.6 × 109/L (see Table 2).

Table 1 Demographics and clinical characteristics of patients who achieved SVR and patients who failed to achieve SVR
Full size table
Table 2 Baseline lab values of patients who achieved SVR and patients who failed to achieve SVR
Full size table

SVR Rates

SVR was achieved in 95.5% (n = 472) of all TN/CC HCV patients (see Fig. 2). Across patient subgroups, SVR was achieved in 95.6% (n = 43) of patients with HCV genotype 3, 95.7% (n = 155) of patients with a recent physician visit with a diagnosis of cirrhosis, 100% (n  = 14) of patients with genotype 3 and a recent diagnosis of cirrhosis, 97% (n = 32) of patients with HCV genotype 3 and a recent chronic HCV diagnosis, 96.9% (n  = 219) of patients showing signs of portal hypertension, and 93% (n  = 107) of patients with a recent diagnosis of illicit drug use or abuse. “Recent” was defined as within 6 months prior to G/P initiation.

Fig. 2
figure 2

SVR efficacy rate for all patients and by patient subgroup. Patients with signs of portal hypertension were those who met one of the following criteria: a prior history of a diagnosis of portal hypertension (in any time period before G/P initiation) (ICD-10 K76.6), platelet count < 100 × 109/L, albumin < 33 G/L, AST to platelet ratio index (APRI) score > 1.09. AST aspartate aminotransferase, G/P glecaprevir/pibrentasvir, GT genotype, SVR12 sustained virologic response at post-treatment week 12

Full size image

There was no statistically significant difference in demographics when comparing patients who achieved SVR with those who did not, including age, gender, and race/ethnicity. Of those who achieved SVR, 23% were recent illicit drug users and 38% had an extrahepatic manifestation, whereas among those who did not achieve SVR (defined as a detectable HCV RNA level), 36% had a diagnosis of illicit drug use or abuse within 6 months prior to their G/P treatment and 50% had an extrahepatic manifestation (see Table 2).

There was no statistically significant difference in patients’ baseline laboratory values, including ALT, bilirubin, serum albumin, and RNA viral load (see Table 2). This is likely due to the small sample size of patients who failed to achieve SVR.

Among the 4139 patients identified as not having had a kidney or liver transplant and who had an HCV RNA test earlier than 8 weeks post-treatment, 275 had an HCV RNA test post-treatment in weeks 0–4, of whom 97.5% (268/275) had undetectable HCV RNA. Of the 129 patients who had an HCV RNA test post-treatment in weeks 4–8, 98.5% (127/129) had undetectable HCV RNA.

Discussion

This real-world study demonstrates the high effectiveness (95.5%) of 8-week G/P in TN/CC patients with HCV genotypes 1–6. These results provide further evidence of real-world data on the 8-week effectiveness of G/P in TN/CC HCV patients. This is the first study to use a large claims-linked laboratory dataset to evaluate the SVR in HCV patients with CC treated with 8-week G/P.

The results of this study are consistent with outcomes of clinical trials [10, 22, 23] and early real-world evidence [26]. In the EXPEDITION-8 trial, 99.7% of TN/CC patients with genotypes 1–6 achieved SVR12 in the per protocol (PP) population, and 97.7% of the corresponding patients in the intention-to-treat (ITT) population achieved SVR12 [10]. When compared to baseline clinical characteristics of the EXPEDITION-8 trial, the median platelet count of patients in this study was higher (212 × 109/L versus 151 × 109/L), though the HCV RNA median viral load (6.3 log10 IU/mL [2,120,000 IU/mL] versus 6.3 log10 IU/mL), the albumin level, and the percentage of patients considered recent illicit drug users were all similar. In the current research and in the EXPEDITION-8 trial, achievement of SVR did not depend on the patient or viral characteristics present before treatment [10]. Minor differences in SVR rates between studies may be attributed to a more heterogenous real-world population, especially since clinical trials have stricter criteria for enrollment compared with real-world studies, as well as potential differences in adherence.

In the current study, the high rate of SVR achieved was observed across patient subgroups, consistent with other G/P real-world research [28]. SVR rates in patients with genotype 3 are of particular interest due to the difficulty in achieving SVR with other therapies [29, 30]. Of the genotype 3 patients in our study, 95.6% achieved SVR. These results replicate outcomes from the EXPEDITION-8 trial in which the SVR12 rate was 98.4% in the PP population and 95.2% in the ITT population for patients with genotype 3 [10]. In data pooled from phase 2 and 3 trials, 97% of ITT and 100% of modified ITT of genotype 3 TN patients with cirrhosis achieved SVR12 after 12 weeks of G/P [19]. In recent real-world research, there were only 4 TN/CC patients with genotype 3, all of whom achieved SVR12 on 8-week G/P [26]; the efficacy and smaller number of patients with genotype 3 are consistent with the current study. Therefore, 8-week G/P provides an efficacious and shorter-duration treatment for patients diagnosed with the more challenging-to-treat genotype 3.

PWID patients account for a growing number of new cases and are a target population for elimination of the disease [9]. Of patients with a recent diagnosis of illicit drug use or abuse, 93% achieved SVR in this study. By comparison, in phase 2 and 3 trials for G/P, 89% of current/recent PWID patients and 98% of former/non-PWID patients achieved SVR [13]. In those trials, recent/current PWID participants were more likely to be TN (94%) and had higher proportions of HCV genotype 3 infection (44%) and HIV co-infection (24%) when compared to former/non-PWID participants. PWID patients face many barriers to accessing and engaging in healthcare [21, 31], and follow-up appointments after treatment can be a challenge to attend [32]. Therefore, PWID HCV patients may benefit from a shorter HCV treatment duration.

In the current study, 97.5% of patients had undetectable HCV RNA as early as 0–4 weeks after the end of treatment. A recent clinical trial found that achieving SVR4 following 8 weeks of G/P was highly predictive of long-term SVR [33]. This validates the reliability of a shorter-term follow-up and can provide a shorter-duration yet effective therapy for treating and curing patients of HCV, particularly those who face barriers to accessing healthcare. In support of a shorter follow-up period, recent EASL guidelines recommend that SVR testing can be omitted for patients who are adherent and who are not high risk [8].

This study provides real-world evidence for the recommendations outlined in the AASLD and EASL guidelines of 8-week G/P treatment in TN/CC patients [8, 9], especially for those infected with HCV genotype 3 or who have advanced liver diseases. The added benefits of an 8-week therapy for patients with HCV, regardless of genotype and CC status, include simplified treatment and reduced costs [34].

There are limitations on the generalizability of these findings, as this study was conducted using patients in the Symphony Health Analytic Dataset. The population described (n = 494) represent < 1% of both the total population of patients’ data retrieved from SHS and those that met the criteria for this study. While there were only three patients under genotype 4–6, this is consistent with US population estimates [35, 36]. The results for effectiveness represent patients with available HCV RNA data post-treatment, essentially eliminating patients lost to follow-up. In addition to this, patients were required to have a follow-up HCV RNA level at least 8 weeks after the end of treatment, and so no minimum end-of-treatment follow-up was required. Therefore, the post-treatment follow-up time was not assessed. It was confirmed that the prescription for 8-week G/P was dispensed, but we cannot be certain that patients followed the prescription directions which may impact SVR rates. Due the high effectiveness rate of 8-week G/P, there were a limited number of patients available to assess patient characteristics that did not achieve SVR.

Conclusion

In summary, it is evident that the 8-week G/P regimen provides an efficacious and short-duration treatment in TN/CC patients of all HCV genotypes in this real-world setting. Clinical trial results, combined with the growing body of real-world evidence, can instill physicians with confidence when prescribing 8 weeks of G/P for TN/CC HCV patients. This study redefines the historical length of treatment for TN/CC HCV patients, supporting efforts to eliminate HCV as a major public health threat by 2030.