Adherence to pan-genotypic glecaprevir/pibrentasvir and efficacy in HCV-infected patients: a pooled analysis of clinical trials.

Abstract Background & Aims Adequate adherence to hepatitis C virus (HCV) treatment is believed to be a key component of treatment success because non‐adherence can potentially result in treatment failure and the emergence of resistant viral variants. This analysis assessed factors associated with non‐adherence to glecaprevir/pibrentasvir (G/P) therapy and the impact of non‐adherence on sustained virological response at post‐treatment week 12 (SVR12) rates in HCV genotype (GT) 1‐6‐infected patients. Methods Adherence was calculated by pill counts at study visits during treatment, and defined as having a lowest treatment adherence of ≥80% and ≤120% at each study visit. Exploratory logistic regression modelling assessed predictors of non‐adherence to G/P therapy. SVR12 rates by treatment adherence were assessed in the intent‐to‐treat (ITT) population and modified ITT (mITT) population, which excludes non‐virological failures. Results Overall, 97% (2024/2091) of patients were adherent to G/P therapy at all consecutive study visits. Alcohol use was the only baseline characteristic independently associated with non‐adherence to G/P therapy (OR: 2.38; 95% CI: 1.13‐5.01; P = .022). In the mITT population, overall SVR12 rates were high both in patients who were adherent to G/P therapy and those who were not (99% [1983/2008] and 95% [58/61] respectively; P = .047). Corresponding SVR12 rates in the ITT population were 98% (1983/2024) and 87% (58/67) respectively. Conclusions Most patients adhered to G/P therapy. SVR12 rates were high both in patients who were adherent to G/P treatment and those who were not. Patient education on treatment adherence should remain an important part of HCV treatment. Clinical trials registration NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, NCT02243293, NCT02446717.


| INTRODUC TI ON
In response to the high burden of chronic hepatitis C virus (HCV) disease, the World Health Organization has set a goal of eliminating chronic HCV infection as a major global public health threat by 2030. 1 Well-tolerated, simple, short-duration, pan-genotypic directacting antiviral (DAA) regimens with high cure rates as measured by sustained virological response at post-treatment week 12 (SVR12) will play an important role in realizing this goal. [2][3][4] Adequate adherence to treatment is believed to be a key component of treatment success because non-adherence can potentially result in treatment failure and the emergence of resistant viral variants. 5 Previous analyses of DAA regimens have demonstrated high adherence to treatment in the overall chronic HCV-infected patient population, [6][7][8] including those who were on opioid substitution therapy (OST) and people who use drugs [9][10][11][12][13][14] (≥95% and ≥90% respectively). Some studies have suggested that adherence to DAA therapy decreases with increased treatment duration. 7,8,15,16 In a pooled analysis of 4825 chronic HCV-infected patients from 13 trials receiving 8-24 weeks of HCV antiviral therapy, a longer treatment duration was associated with a lower likelihood of adherence (odds ratio [OR]: 0.98 for each additional week; P = .002). 8 Another identified risk factor for poor treatment adherence includes alcohol use.
In the PREVAIL study of models of HCV care for people who inject drugs (PWID), alcohol use was a significant predictor (OR: 2.2; 95% confidence interval [CI]: 1.0-4.8; P = .04) of poor adherence (<80%) to HCV treatment. 16 Age has been identified in some studies as a risk factor for poor treatment adherence, with lower treatment adherence reported in both elderly (>55 years old) and young (<40 years old) patients. 5 However, a thorough assessment of risk factors for poor treatment adherence has not been performed for 'next-generation' DAA therapies. Moreover, the impact of poor adherence on SVR12 rates has not been evaluated for short-duration 8-week DAA regimens. In phase 2 studies of the sofosbuvir [SOF]/velpatasvir/ voxilaprevir DAA regimen, ultra-short treatment durations of 4 or 6 weeks resulted in high rates of virological relapse. 17,18 Therefore, it is particularly important to determine how 'forgiving' 8-week DAA regimens are when treatment adherence is poor.
Once-daily, coformulated glecaprevir/pibrentasvir (G/P) 300/120 mg is a next-generation, pan-genotypic DAA regimen given for a short, 8-week duration in treatment-naive patients without cirrhosis, and a 12-week duration in treatment-naive patients with compensated cirrhosis. [19][20][21] In pooled analyses of HCV genotype (GT) 1-6-infected patients in phase 2 and 3 clinical trials, G/P demon- This analysis assessed factors associated with non-adherence to G/P therapy and the impact of non-adherence on SVR12 rates in HCV GT1-6-infected patients who were enrolled in eight phase 3 clinical trials.

| Study design
This was a pooled analysis of G/P in HCV GT1-6-infected patients with compensated liver disease (with or without cirrhosis) across eight phase 3 clinical trials that have been published previously. [24][25][26][27][28] In all eight studies, G/P was orally dosed once daily as three 100/40 mg tablets taken with food, for a total dose of 300/120 mg. 24-28 G/P was administered for 8, 12 or 16 weeks, according to HCV genotype, prior treatment experience and cirrhosis status. [24][25][26][27][28] All patients provided written informed consent. Studies were conducted in accordance with the International Conference on Harmonization guidelines and the principles of the Declaration of Helsinki. Study protocols were approved by the ethics committees or institutional review boards at each of the participating study sites.
All authors had access to study data, reviewed and provided feedback on all versions of the manuscript, and made the decision to submit the manuscript for publication.

| Adherence
Patients were allocated study medication at baseline and at week 4 and 8 visits; for those receiving G/P for 16 weeks, patients were also allocated study medication at week 12 visit.

| Treatment completion
Completion of treatment was defined as treatment durations of ≥52 days, ≥77 days and ≥105 days for 8-week, 12-week and 16-week G/P regimens respectively.

| Safety
Treatment-emergent adverse events (TEAEs) were collected from study drug initiation until 30 days after study drug discontinuation.
Causality of each adverse event (AE) with respect to study drugs was determined by the study physician. Changes from baseline in laboratory tests and vital sign measurements were also assessed.

| Statistical analyses
SVR12 rates by treatment adherence were assessed in the ITT population (defined as all patients who received at least one dose of study drug) and modified ITT (mITT) population, which excludes non-virological failures. Safety analyses were performed in the ITT population. All CIs were calculated as two-sided 95% CIs using the Wilson score method for binomial proportions.
Reasons for not achieving an SVR12 in patients who were adherent to G/P therapy were compared with those of patients who were

| Baseline predictors of non-adherence to G/P therapy
The exploratory logistic regression analysis demonstrated that alcohol use was the only baseline characteristic independently associated with non-adherence to G/P therapy (OR: 2.38; 95% CI: 1.13-5.01; P = .022; Table 2).

| Virological response
In the ITT population, SVR12 rates were lower in patients who were non-adherent versus those who were adherent to G/P therapy ( Figure 1A). In the mITT population, which excludes patients with non-virological failure, there was a marginally significant difference in overall SVR12 rates between patients who were adherent and those who were non-adherent to G/P therapy ( Figure 1B). Although rates of on-treatment virological failure were low in both patients who were adherent and those who were non-adherent to G/P therapy, the rate was statistically higher in patients who were non-ad-  Table 3. In total, nine patients who were nonadherent to G/P therapy failed to achieve an SVR12. Most non-adherent patients (56% [5/9]) failed to achieve SVR12 as a result of premature discontinuation of study drug; three non-adherent patients (33%) failed to achieve SVR12 as a result of virological failure.
Overall, 78% (7/9) were male, 67% (6/9) were <55 years old, 67% (6/9) were infected with HCV GT3, and all nine reported current or past alcohol use. Characteristics of patients who were non-adherent to G/P therapy and failed to achieve an SVR12 are given in Table 4.

| Safety
TEAEs and laboratory abnormalities are presented in Table 5.
The frequency of TEAEs was numerically higher in patients who were non-adherent to G/P therapy versus those were who adher- were non-adherent to G/P therapy and four among patients who were adherent (all deaths were considered by the study investigator as having no reasonable possibility of being related to study drug). Some numerical differences in the frequencies of TEAEs occurring in ≥10% of patients in either group were observed between patient groups; however, the small number of patients who were non-adherent to G/P therapy should be considered when interpreting the clinical relevance of these findings. Rates of grade ≥3 laboratory abnormalities are presented in Table 5; there were no grade 4 laboratory abnormalities.

| D ISCUSS I ON
In this analysis of 2091 HCV GT1-6-infected patients across eight phase 3 clinical trials, overall adherence to G/P therapy was very high, with only 3% of patients (67/2091) found to be non-adherent TA B L E 3 Treatment outcomes at post-treatment week 12, by adherence to G/P therapy (intent-to-treat population) TA B L E 4 Characteristics of patients who were non-adherent to G/P therapy and did not achieve SVR12 This analysis did not address treatment duration as a predictor of adherence; however, rates of non-adherence were low regardless of treatment duration.
In the ITT population, there was a slight but significant decrease in SVR12 rates among patients who were non-adherent versus those who were adherent to G/P therapy ( non-adherent to the G/P regimen. The high SVR12 rates in non-adherent patients, including those with proposed baseline predictors of non-adherence, support the potency of G/P and suggest that G/P is a 'forgiving' regimen 29 in patients who are not fully adherent to the G/P regimen.
The small number of patients who were non-adherent to G/P across clinical trials is an important limitation of this analysis and should be considered when interpreting predictors of non-adherence and the impact of non-adherence on SVR12 rates. Twenty-one patients had no adherence data at any study visit; these patients were considered non-adherent for the purpose of this analysis, potentially leading to underestimation of treatment adherence.
Treatment adherence is commonly measured by pill counts, which can provide empirical evidence of non-adherence; however, an important limitation of this method is the potential for patients to discard pills before study visits to appear adherent, potentially leading to overestimation of treatment adherence. 29 Another limitation of pill counts is that it does not provide qualitative data on adherence, for example, dose timing or non-adherence on sequential days, both of which can have an important impact on treatment outcome. 29 The results of this study are based on patients in clinical trials who may not be representative of patients in the 'real world' or emerging treatment groups such as adolescents or prisoners. However, recent real-world effectiveness data for G/P have demonstrated very high overall mITT SVR12 rates (≥98%). 30,31 In summary, this analysis indicates high adherence to G/P treatment as well as high SVR12 rates in those who are not fully adherent to the G/P regimen. While adequate treatment adherence is important to avoid treatment failure and the emergence of resistant viral variants, 5 the results of this analysis suggest G/P is a 'forgiving' regimen 29 in patients who are not fully adherent to the G/P regimen and that high SVR12 rates can still be achieved. However, as with all medications, patient education on treatment adherence should remain an important part of HCV treatment.

ACK N OWLED G EM ENTS
Glecaprevir was identified by AbbVie and Enanta Pharmaceuticals.
Medical writing support was provided by Andrew Kerr of Medical Expressions, funded by AbbVie.

CO N FLI C T O F I NTE R E S T
A Brown: Advisor and speaker for, and recipient of research grants from, AbbVie, Bristol-Meyers Squibb, Janssen, Gilead Sciences and MSD. TM Welzel: Consultant or speaker for AbbVie, Boehringer