FormalPara Key Summary Points

Why carry out the study?

Chronic hepatitis C virus (HCV) infection has been a human health threat globally.

The World Health Organization (WHO) advocates treatment simplification to patients with HCV infection to facilitating HCV elimination globally.

This study aimed to evaluate the treatment efficacy and safety of a pan-genotypic simplified regimen, 8-weeks glecaprevir/pibretasivir (GLE/PIB), for patients with treatment-naïve HCV with and without liver cirrhosis by using a large real-world cohort from the nationwide Taiwan HCV Registry Program (TACR).

What was learned from the study?

The strategy demonstrated excellent tolerability and achieved a treatment efficacy with a sustained viral response throughout 12 weeks of posttreatment follow-up period (SVR12) rate exceeding 98% in the largest cohort of patients with chronic hepatitis C treated with an 8-week GLE/PIB regimen.

The easily administered, shortened-duration regimen can be applied universally across all subpopulations, regardless of cirrhotic status. This approach would help facilitating HCV elimination through task shifting and treatment simplification.

Introduction

Hepatitis C virus (HCV) infection is one of the major burdensome liver-related outcomes worldwide. It is estimated that 50 million people are infected with HCV. The World Health Organization (WHO) has committed to the goal of viral control by 2030, and many countries have made progress toward HCV management since 2016. Nevertheless, the majority of countries are still not on track for HCV elimination [1]. To facilitate HCV treatment uptake, the WHO further advocates decentralized testing, task shifting, and treatment simplification with direct-acting antivirals (DAAs) at the primary care level [2].

Glecaprevir/pibrentasvir (GLE/PIB) is now recommended as the standard of care for chronic hepatitis C (CHC). We previously reported that GLE/PIB demonstrates high efficacy in the treatment of Taiwanese patients with CHC, with variable treatment durations [3]. An identical finding was observed in a German registry of people who received either 8- or 12-week GLE/PIB [4]. With solid evidence from clinical trials and the real-world data, an 8-week treatment duration is now approved and applied for both treatment-naïve (TN) patients without and with cirrhosis [5,6,7]. Therefore, regional guidelines have recommended a universal 8-week treatment duration for TN patients, eliminating concerns about testing for difficult-to-cure genotypes (GT), such as HCV GT3, or resistance-associated substitutions [8, 9]. Uniform and short-duration therapy for HCV may help strengthen patient adherence [10] and attenuate health care burdens, aligning with the WHO’s strategy of treatment simplification.

According to the label at the time of registration of Taiwan HCV Registry (TACR), we initially adopted GLE/PIB for 8 to 16 weeks on the basis of the cirrhotic status, treatment experience, and HCV genotypes of the patients with CHC, which was published in 2020 [3]. With the updated indication of the US Food and Drug Administration (FDA), we subsequently demonstrated the real-world evidence of 8-week GLE/PIB regimen in a subset of TN patients with cirrhosis, which was published in 2021 [6]. In response to and alignment with the WHO’s new policy of treatment simplification, the current study has further expanded the patient sample, encompassing various patient and viral characteristics.

To this end, the current study aimed to explore the real-world treatment efficacy and tolerability of the 8-week regimen of GLE/PIB in both patients with and without cirrhosis. This study represents the largest CHC cohort to date, utilizing the largest HCV registry worldwide.

Methods

Patients

Patients were recruited from the TACR, which is a prospective, observational, nationwide DAA-treated CHC cohort organized by the Taiwan Association for the Study of the Liver (TASL) [3, 6, 11,12,13,14]. As of October 31, 2023, a total of 43,685 patients with CHC have been registered in the TACR across 53 hospitals, constituting nearly one-third of DAA-treated patients in Taiwan. DAAs TN patients aged > 18 years who have received at least one dose of GLE/PIB were included in the current analysis. Patients were excluded if they received either the 12- or 16-week GLE/PIB regimen, had a history of liver decompensation, or lacked available liver biochemistry data at baseline or at the end of follow-up. The study protocol was approved by the institutional review boards (IRB) of the participating hospitals and conformed to the guidelines of the International Conference on Harmonization for Good Clinical Practice. Ethics approval was granted by Kaohsiung Medical University Chung-Ho Memorial Hospital (IRB number KMUHIRB-F(I)-20170053). This study was conducted in accordance with the principles outlined in the Helsinki Declaration of 1964 and its later amendments. All patients provided written informed consent before being enrolled in the registry. Full details regarding consent to participate and consent for publication are available upon request.

The primary objective was to achieve a sustained virologic response (SVR) at 12 weeks, defined as maintaining an undetectable level of HCV ribonucleic acid (RNA) (< 12 IU/mL or < 25 IU/mL depending on individual laboratory testing) throughout the 12 weeks of posttreatment follow-up (SVR12). Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or > 60 mL/min/1.73 m2 with proteinuria for more than 3 months. Liver cirrhosis was defined as previously described, which included any of the following: liver histology, transient elastography (FibroScan®; Echosens, Paris, France, > 12 kPa), acoustic radiation force impulse (> 1.98 m/s), Fibrosis-4 index (> 6.5), or the presence of clinical, radiological, endoscopic, or laboratory evidence of cirrhosis and/or portal hypertension [3, 6]. Health care resource utilization (HCRU) was determined by counting the number of clinic visits from the initiation of GLE/PIB to the SVR12 survey visit. Drug adherence, defined as the percentage of actual dosages of GLE/PIB taken divided by the anticipated 8-week regimen throughout the treatment course (168 pills of GLE/PIB) for each patient, was evaluated. Changes in laboratory parameters were evaluated in patients who achieved an SVR before treatment and at the time of SVR12.

Statistical Analysis

Frequencies were compared between groups using χ2 tests with Yates’ correction or Fisher’s exact test. The group means, presented as the means and standard deviations, were compared using analysis of variance, Student’s t test or the Mann‒Whitney U test. A paired t test was used to compare the changes in laboratory data before and after DAAs therapy. Serum HCV RNA levels were expressed after the logarithmic transformation of the original values. The efficacy of GLE/PIB was evaluated in an intention-to-treat (ITT) population, defined as all enrolled patients who received ≥ 1 dose of GLE/PIB, and a modified intention-to-treat (mITT) population, defined as subjects who received ≥ 1 dose of DAAs and with HCV RNA data available at posttreatment week 12. Safety assessments were reported as adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities in the ITT population. The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation [11, 15]. The Fibrosis-4 score (FIB-4) was calculated as age (years) × aspartate transaminase (AST) [U/L]/{platelets [109/L] × (alanine transaminase [ALT] [U/L])}1/2. Stepwise logistic regression analysis was performed to determine factors associated with treatment failure by analyzing the covariates with a p value < 0.1 in the univariate analysis. All the statistical analyses were conducted with SPSS 14.0 statistical software (SPSS, Chicago, IL, USA).

Results

Among the 8041 patients treated with GLE/PIB, 728 patients who were allocated to 12- or 16-week regimens were excluded. Sixty-three patients were excluded because of unavailable liver biochemistry data, and four were excluded because they were younger than 18 years. Of the remaining 7246 patients [noncirrhosis (n = 6897); cirrhosis (n = 349)], 7204 patients with available treatment outcomes were included in the mITT analysis (Fig. 1). The mean age was 57.9 years, and men accounted for 52.9% of the population. The dominant viral genotype was HCV GT2 (48.8%), followed by GT1 (32.1%). A total of 288 patients (4.0%) had GT3 infection; 1427 patients (19.7%) had a baseline HCV RNA concentration > 6,000,000 IU/ml. A total of 532 (7.3%) and 261 (3.6%) patients were coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV), respectively; 1506 (20.8%) and 1278 (17.6%) patients had CKD and diabetes, respectively. Regarding high-risk behaviors, 585 patients (8.1%) were documented to have a history of intravenous drug abuse (Table 1). Compared to patients without cirrhosis, those with compensated liver cirrhosis were older and had a greater proportion of hypertension, diabetes, CKD, and GT2 infection. These patients also had higher AST, ALT, and bilirubin levels and FIB-4 scores and lower eGFRs, albumin levels, and platelet counts (Table 1).

Fig. 1
figure 1

Patient flowchart. DAA direct-acting antiviral. GLE/PIB glecaprevir/pibrentasvir, ITT intention-to-treat, mITT modified intention-to-treat, SVR sustained virologic response, SVR12 undetectable HCV RNA concentration throughout 12 weeks of posttreatment follow-up

Full size image
Table 1 Baseline characteristics and clinical features of the patients
Full size table

Treatment Responses

The overall SVR12 rates were 98.3% (7122/7246) and 98.9% (7122/7204) according to the ITT and mITT analyses, respectively. When patients were stratified according to cirrhosis status, the SVR12 rates were 98.3% (6780/6897) and 98.9% (6780/6856) among patients without cirrhosis and 98.0% (342/349) and 98.3% (342/348) among patients with cirrhosis in the ITT and mITT analyses, respectively. Of the 82 patients with virological failure, 81 experienced relapse after the end of treatment, and only one experienced virological breakthrough during treatment (Table 2).

Table 2 Treatment response of 8 week glecaprevir/pibrentasvir regimen
Full size table

Subgroup analysis using mITT analysis revealed that the high SVR12 rates were generalized to all subgroups regardless of cirrhosis status, including viral GT, comorbidity, and special population subgroups. There was a lower SVR12 rate (83.3%; 15/18) among patients whose DAAs compliance was < 80%. Patients with GT3 responded less well than those with other genotypes [95% (274/286) vs. 99% (6850/6918)] (Table 3). Logistic regression analysis of factors associated with SVR12 including HCV non-GT3 [odds ratio (OR)/95% confidence intervals (CI) 4.31/2.33–7.96, P < 0.01], HCV RNA < 6,000,000 IU/mL (OR/CI 2.27/1.42–3.61, P < 0.01), non-HIV (OR/CI 2.45/1.21–4.98, P = 0.01), and drug adherence > 80% (OR/CI 25.45/6.70–96.63, P < 0.01) (Supplementary Table 1).

Table 3 SVR12 (mITT) in subgroups stratified by cirrhotic status
Full size table

Up to 99.7% of patients maintained a drug adherence rate > 80% throughout the 8-week regimen. This high drug adherence rate was observed across diverse populations, including persons who inject drugs (PWID) (99.7%), patients with HIV (99.6%) and patients with liver cirrhosis (98.9%) (Fig. 2).

Fig. 2
figure 2

Proportion of patients with drug compliance > 80% in the overall patients and subpopulations. CKD chronic kidney disease, CVD cardiovascular disease, PWID persons who inject drugs, HIV human immunodeficiency virus

Full size image

Safety

As shown in Table 4, 1021 patients (14.1%) experienced AEs. The most common AEs (≥ 1% of total patients) were fatigue (5.6%), pruritus (5.4%), insomnia (1.7%), and headache (1.7%). Twenty-two patients (0.3%) had documented serious AEs, and only one patient with symptoms of jaundice and pruritus was identified as having a potentially DAA-related event. The proportions of patients with abnormal liver function are also displayed. The causal relationships between adverse events and laboratory abnormalities were not fully addressed as these data are not generally recorded in the TACR database. The mean number (mean ± SD) of outpatient visits during GLE/PIB treatment was 4.9 ± 0.9.

Table 4 Safety profile of 8-week glecaprevir/pibrentasvir regimen
Full size table

Changes in Laboratory Data Before and After Patients Achieved SVR12

A total of 1278 patients had available laboratory data at baseline and at SVR12. Liver-related biochemical parameters, including AST, ALT, and albumin levels, along with platelet counts and the FIB-4 score, showed significant improvement. In addition, hemoglobin A1C levels decreased significantly (5.98% to 5.83%, P < 0.01) (Table 5). Among patients with CKD, there was a significant increase in eGFR from 48.30 to 50.58 mL/min/1.73 m2 (P < 0.001), with a more pronounced improvement observed in those with a baseline eGFR < 60 mL/min/1.73 m2 (from 39.25 to 42.23 mL/min/1.73 m2, P < 0.001). (Supplementary Table 2).

Table 5 Laboratory examinations changes before and after HCV eradication
Full size table

Discussion

To the best of our knowledge, this is the largest CHC cohort to receive a universal 8-week regimen of GLE/PIB for both patients without and with cirrhosis. Our findings demonstrated that the regimen was highly effective and well tolerated among patients with CHC in Taiwan. The high SVR12 rate was generalized across all HCV genotypes and special populations, with a satisfactory safety profile observed in the real-world setting.

While addressing the characteristics of DAA-treated patients in recent years, there has been a notable rise in the proportion of TN and noncirrhotic individuals reported in both Eastern [3, 13, 14] and Western populations [16]. In Taiwan, more than 90% of patients with CHC were TN according to recent nationwide studies [3, 13]. As a consequence, an 8-week regimen of GLE/PIB or 12-week regimen of sofosbuvir/velpatasvir is currently the preferred treatment choice in the real-world setting [8, 9]. As demonstrated in the present study, the SVR12 rates were as high as 98.3% and 98.9% according to the ITT and mITT analyses, respectively. A short course of 8 weeks regimen of GLE/PIB in TN patients with cirrhosis was first approved by the US FDA in 2019 and by the Taiwan FDA (TFDA) in 2020, on the basis of the 99.7% SVR12 rate in the EXPEDITION-8 study [5]. Along these lines, certain small-scale and collaborative studies have proven the applicability of the regimen in clinical practice [3, 6, 17,18,19,20,21,22]. The present study recruited a large number of patients from the nationwide registry, enabling a more extensive and detailed subgroup analysis. The results align with previous studies and demonstrate that 8 weeks of GLE/PIB treatment is highly effective in TN patients with cirrhosis, regardless of patient characteristics such as HCV-GT3 infection, PWID status, and HIV coinfection (SVR12 rates were all 100% in the present study).

A relatively low SVR12 rate of 83.3% was noted among patients whose drug adherence was < 80%. Poor drug compliance is a predictive factor of treatment failure in the DAAs era [14, 23]. A prolonged treatment duration of GLE/PIB of 16 weeks has been reported to lead to an increased proportion of nonadherent patients [23]. Similarly, a pooled analysis of 10 clinical trials of GLE/PIB demonstrated that drug adherence decreased substantially with increasing treatment duration from week 4 to week 12 [24]. In the real world, a study assessing 7203 PWID revealed that, in comparison to patients who received the 12-week regimen of GLE/PIB, those who received an 8-week regimen had greater pill refill persistence [25]. Owing to the truncated 8-week treatment course in the registry, only 18 (0.2%) patients exhibited a drug adherence rate less than 80%. A short-course treatment regimen was selected on the basis of patient preference [26]. Imperatively, this approach helps to ensure drug adherence and facilitate the decentralization or outreach HCV care [27].

The most common AEs were fatigue and pruritus in the present study, which were predictable and manageable. A recent cohort study demonstrated that protease inhibitor (PI)-containing DAAs were as well tolerated as non-PI DAAs in terms of patient safety, even among patient with advanced cirrhosis [28]. Another study indicated the absence of specific safety signals in patients with compensated cirrhosis receiving GLE/PIB, even in cases where patients presented with overt thrombocytopenia or a Child‒Pugh score of A6 [29]. A pooled analysis of nine clinical trials revealed only three liver decompensation events among patients with portal hypertension, which were judged as non-investigational drug-related events [30]. According to the current registry of the present study, only one SAE, jaundice and pruritus, was considered DAA related. We did not address drug‒drug interactions in the large registry, which could be a potential concern issue, especially for PI-containing DAAs. However, this should not pose a critical concern provided that pretreatment assessments are conducted by experienced or trained care providers. Studies have demonstrated that GLE/PIB could be safely used for patients with multiple comorbidities and complex comedications, such as those with severe mental illness [27] and hemodialysis [31]. According to the current database, only one patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, who took Paxlovid (nirmatrelvir/ritonavir), had transiently discontinued GLE/PIB for 5 days, but the outcomes still resulted in treatment success. This result may reinforce the strategy of simplifying treatment by shifting tasks toward other marginalized populations, such as underserved drug users [32] and incarcerated individuals [33, 34].

The present study has several limitations. Despite the sizable cohort in the present study, the very low prevalence rates of GT 3, 4, and 5 infections in Taiwan restricted the exploration of the real-world efficacy of GLE/PIB in our study to other populations in Western countries. Since these were registry-based data rather than clinical trial data, it is possible that the incidence of adverse events may have been underreported. We tried our best to overcome reporting bias by adopting, utilizing, and cross-verifying the results on a uniform database platform. Finally, we also failed to explore the long-term outcome in the post-SVR era in the cohort.

Conclusion

This Taiwanese cohort study stands as the largest real-world report, demonstrating that an 8-week regimen of GLE/PIB was highly effective and well tolerated in TN patients with HCV, irrespective of cirrhosis status.