Enhanced Adherence to HCV Therapy with Higher Dose Ribavirin Formulation: Final Analyses from the ADHERE Registry

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Enhanced Adherence to HCV Therapy with Higher Dose Ribavirin Formulation: Final Analyses from the ADHERE Registry

Abstract

Background Poor adherence to Hepatitis C virus (HCV) treatment is an important cause of treatment failure. Traditional ribavirin 200 mg (RBV) treatment is associated with a significant daily pill burden. RibaPak (RBP), available as 400 mg and 600 mg ribavirin tablets, offers simplified dosing at two pills daily.Aim To examine whether improved adherence was associated with RBP vs. RBV.Methods Accurate Dosing in Hepatitis C: Examining the RibaPak Experience (ADHERE) was a U.S., multi-centre, prospective registry capturing data on adherence with RBP vs. RBV in adults with HCV. Adherence was measured by the proportion of subjects remaining on treatment at weeks 4, 12 and 24; by pill counts; and by the proportion of subjects who took ≥80% of their prescribed dose.Results A total of 503 patients (RBP = 346, RBV = 157) from 33 sites were included. A greater proportion of RBV vs. RBP subjects prematurely

discontinued treatment. At 12 and 24 weeks, a greater proportion of RBP vs. RBV subjects took ≥80% of their prescribed doses (P < 0.05). For patients who remained on treatment, the mean milligrams missed per day was significantly greater for RBV vs. RBP at 24 weeks.Conclusions First line treatment with RBP may offer the best prospect for less discontinuation and improved treatment adherence.

Introduction

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States (U.S.). It is estimated that over four million people in the U.S. and more than 170 million worldwide have been infected with Hepatitis C.[1, 2] Up to 85% of infected subjects progress to chronic hepatitis. Chronic HCV is associated with significant morbidity and healthcare costs; it can lead to cirrhosis and hepatocellular carcinoma. Hepatitis C virus is the leading cause of liver transplantation in the U.S.[3]

The current standard of care treatment for HCV is combination therapy using pegylated interferon (Peg-IFN) and ribavirin. Adherence to HCV therapy is recognized as being crucial to the suppression and potential eradication of the virus, which is associated with a decrease in hepatocellular carcinoma, disease-related complications and mortality.[4–7] Poor adherence to the prescribed HCV regimen anytime during therapy is associated with lack of an on-treatment response and sustained virological response.[8–11] Physical and psychological side effects of HCV therapy have been found to negatively affect adherence to HCV treatment. Significant treatment-related adverse events occur in 20–40% of patients. Consequently, up to 40% of patients necessitate dose reductions in their HCV medications, while

14–22% discontinue treatment entirely.[3, 12–14]

Adherence to ribavirin has been shown to be lower than adherence to Peg-IFN.[15–17] In addition to the physical and psychological side effects of treatment, another reason patients may discontinue ribavirin, or fail to take prescribed amounts of ribavirin, may be pill burden. Pill burden has been found to be a factor negatively affecting adherence in other chronic conditions (e.g. cardiovascular disease,[18, 19] kidney disease,[20] ulcerative colitis).[21] In HIV treatment, a relationship between pill burden and lower adherence, early treatment discontinuation, and incomplete viral load suppression has been well demonstrated.[22–24] With HCV treatment, patients are commonly taking 5–6 ribavirin tablets a day in divided doses.

We hypothesized that RibaPak [(ribavirin) Tablets, Three Rivers Pharmaceuticals, LLC, Warrendale, PA, USA], which is available as 400 mg and 600 mg ribavirin tablets would be associated with improved adherence compared with traditional ribavirin given the reduced pill burden. The primary objective of this study was to evaluate treatment adherence of subjects who were prescribed weight-based RibaPak compared with subjects prescribed 200 mg weight-based ribavirin tablets, capsules or pills.

Methods

Subjects

Accurate Dosing in Hepatitis C: Examining the RibaPak Experience (ADHERE) was a 24-week, United States, multi-centre, prospective, observational registry. Inclusion criteria were

adults (≥ 18 years);

with chronic HCV disease who had been prescribed RibaPak or 200 mg ribavirin in conjunction with a weekly Peg-IFN injection;

who did not meet any of the exclusion criteria and who provided written informed consent to participate.

Individuals meeting any of the following criteria were excluded:

a known hypersensitivity to ribavirin;

currently prescribed Consensus Interferon (Infergen, Three Rivers Pharmaceuticals, LLC Warrendale, PA, USA) or any non-pegylated interferon;

HIV, HBV or HDV co-infection or autoimmune hepatitis; pregnant or lactating women; men whose female partners were pregnant; and individuals with haemoglobinopathies.

Subjects were identified by their treating physician and invited to participate in the study. Subjects were enrolled at a 3:1 (RibaPak:ribavirin) ratio. The study protocol was approved by all participating centre IRBs.

Adherence

Data were collected at the following discreet time points: 4 weeks, 12 weeks and 24 weeks from start of treatment. Data collected at each follow-up time point were specific to the 4 weeks prior to the follow-up visit. Accordingly, adherence to therapy was evaluated exclusively for patients who remained on therapy during the respective 4-week period under evaluation. Adherence was evaluated in three ways (Table 1). First, the proportion of subjects remaining on treatment at each follow-up time point was compared between the RibaPak and ribavirin groups. Second, within the subset of subjects who remained on treatment, the proportion of prescribed doses taken at each follow-up time point was calculated. The proportion of prescribed doses taken was assessed both objectively and by subject self-report. The objective assessment was calculated in the following manner: at

each visit, site personnel counted the number of pills the subject brought in to the visit. That number represented the number of pills 'left over' and was compared with how many pills should have been left over based on the individual subject's prescribed daily dose and the number of days in the treatment period (determined by subtracting the treatment start date from the visit date). From these calculations, both the number of doses missed and the milligrams of drug missed were determined. Finally, adherence was measured as the proportion of subjects who took at least 80% of their prescribed dose of RibaPak or ribavirin. This metric was used as an approximation of the 80/80/80 rule that is frequently used as an indicator of adherence in HCV treatment. The 80/80/80 rule refers to the greater likelihood of successful treatment outcome that is associated with taking 80% of interferon and 80% of ribavirin for 80% of the planned treatment duration. This

indicator has been shown to be associated with an increase in sustained viral response.[25] In determining whether subjects took 80% of their prescribed dose, the objective measure of doses missed was used.

Data Analysis

Data were summarized using descriptive statistics (mean, standard deviation, median for continuous data, and frequencies and percents for categorical data). A student's t-test (continuous data) or Chi Square test (categorical data) was used to make comparisons between the RibaPak and ribavirin groups. Data were analysed using sas V 9.2 (SAS Institute, Cary, NC, USA; Windows XP). Statistical significance was determined by P < 0.05.

Results

Subjects' Disposition

Five hundred and fifty-eight (558) subjects from 33 sites were initially enrolled in the ADHERE registry. Of the 558 subjects, 55 were subsequently excluded from the analysis for the following reasons: 27 were screen failures, 25 had incomplete data and/or were not validated by the site, two had unresolved treatment discrepancies and one subject did not continue in the study due to denial of coverage by his insurance provider. Of the 503 subjects enrolled in the ADHERE registry with validated data, 68.8% (346/503) were taking RibaPak and 31.2% (157/503) were taking ribavirin at study enrolment. Eighty-seven percent (87%) of subjects had data available at the 4-week time point; 73% had data available at the 12-week time point; and 58% of subjects had data available at the 24-week time point. Thirty-one percent (31%) of subjects discontinued the study prior to 24 weeks (Figure 1).

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Figure 1.

Participants disposition.

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Figure 1.

Participants disposition.

Baseline Characteristics

The mean age of all subjects was 48.5 years. Subjects in the RibaPak and ribavirin groups were similar in age, gender, race and body mass index (BMI). Overall, 46.5% of subjects were women and 53.5% were men. A majority of subjects were Caucasian (71%), followed by African-American (14%) and Asian (8%). Mean BMI was 28.7 kg/m2. Viral load at enrolment was available for 58% of RibaPak subjects and 49% of ribavirin subjects and was similar for both groups (Table 2).

Study Drug Administration

A majority (484/503; 96.2%) were treatment naïve subjects. Five-percent (16/346) of RibaPak subjects had crossed-over in treatment (i.e. received prior treatment with ribavirin) and 2% (3/157) of ribavirin subjects had crossed-over in treatment at study enrolment (i.e. received prior treatment with RibaPak). The mean daily prescribed dose, although statistically significantly different (P = 0.03), was clinically similar in both the RibaPak (mean of 1069 mg per day) and ribavirin (mean of 1056 mg per day) groups.

Treatment Adherence

As described in the methods, adherence was assessed in terms of (1) treatment discontinuation over the 24-week study period, (2) missed doses during the 4 weeks prior to the 4-, 12- or 24-week follow-up, and (3) proportion of RibaPak vs. ribavirin subjects who took 80% of prescribed dose during the 4 weeks prior to the 4-, 12- or 24-week follow-up.

Treatment Discontinuation

A greater proportion of ribavirin subjects prematurely discontinued treatment compared with RibaPak subjects. While there was a significantly (P < 0.04) greater proportion of RibaPak subjects remaining on treatment at both weeks 12 and 24, the greatest discrepancy in discontinuation rate was between weeks 5 and 12 where there was a 49% difference in the proportion of ribavirin (15.9%) vs. RibaPak (8.1%) subjects who discontinued (Figure 2). Among those who discontinued, reasons for discontinuation were similar. In the RibaPak group, intolerability to study medication (31.1%), loss to follow-up (30.3%) and inadequate response to treatment (15.2%) were the three most common reasons. In the ribavirin group, discontinuation was due to loss to follow-up (30.5%), intolerability to study medication (25.4%) and inadequate response to treatment (22.0%) (Figure 1).

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Figure 2.

Proportion of subjects remaining on treatment over the study period.

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Figure 2.

Proportion of subjects remaining on treatment over the study period.

In a post hoc analysis, it was found that subjects who discontinued between weeks 5 and 12 of therapy missed a significantly (P = 0.002) greater mean number of doses (8.9 doses) during the 0–4 week treatment period compared with subjects who completed 12 weeks of therapy (2.5 doses), suggesting that early (between start of therapy and 4 weeks) non-adherence is associated with later discontinuation.

Missed Doses by Follow-up Time Point

Proportion of Subjects with Missed Doses. For subjects who remained on treatment for the first 4 weeks of therapy, an equal proportion of RibaPak (9.4%) and ribavirin (9.4%) subjects had missed doses at the 4-week time point. For subjects who remained on therapy up to 24 weeks, at the 12-week and 24-week time points, a greater proportion of ribavirin subjects had missed doses compared with the RibaPak subjects. These differences, however, were not statistically significant [12-week: 13.0% vs. 9.4% of subjects had missed doses for ribavirin and RibaPak respectively, (P = 0.31); 24 week: 13.0% vs. 11.7% of subjects had missed doses for ribavirin and RibaPak respectively, (P = 0.77)].

Mean Number of Doses Missed. At the 4- and 12-week follow-ups, there was no significant difference in the mean number of doses missed, either by objective or self-reported measurement, between the RibaPak and ribavirin groups; however, at the 24-week time point, there was a significantly (P = 0.01) greater mean number of missed doses for ribavirin (1.12) vs. RibaPak (0.36) subjects when assessed by objective measurement.

Mean Milligrams of Drug Missed. For subjects who remained on treatment, at the 4- and 12-week time points, the mean daily milligrams missed of RibaPak and ribavirin did not significantly differ. At the 24-week time point, the mean milligrams missed per day was significantly (P = 0.01) greater in the ribavirin (47.1 mg) vs. RibaPak (14.5 mg) group.

Comparison of Objective vs. Self-report Measurement. For both the RibaPak and ribavirin groups, there was a statistically significant difference observed between the self-reported number of missed doses and the objectively measured number of missed doses for both the 4-week and 12-week time points. Specifically, subjects in both the RibaPak and ribavirin group underreported the number of missed doses when compared with the objective measurement of missed doses. At the 24-week time point, the self-reported missed doses were also less than the objectively measured missed doses; however, the difference was not statistically significant.

Proportion of RibaPak vs. Ribavirin Subjects who Took 80% of Prescribed Dose

At the 12-week and 24-week time points, there was a significantly greater proportion of RibaPak vs. ribavirin subjects who took at least 80% of their prescribed medication. At the 4-week time point, there was a greater proportion of RibaPak subjects who took at least 80% of their prescribed dose (92%) compared with ribavirin subjects (89%), which was not statistically significant (P = 0.30). In contrast, at the 12-week time point, 94% of RibaPak subjects were adherent (i.e. took 80% of their prescribed RibaPak dose) compared with 84% of ribavirin subjects, which was statistically significant (P = 0.02). Additionally, at the 24-week time point, 98% of RibaPak subjects were adherent compared with 89% of ribavirin subjects, which was also statistically significant (P = 0.005).

Discussion

Adherence to treatment is a critical component for successful outcomes in HCV; despite this, treatment adherence is suboptimal.[26] We hypothesized that pill burden is a factor associated with poor adherence to HCV treatment. RibaPak allows for fewer pills to be taken per day compared with 200 mg ribavirin; the potential effect of this lower pill burden on adherence in a large sample of HCV patients had not been previously reported. The results from this study suggest that RibaPak is associated with improved adherence compared with traditional 200 mg ribavirin tablets. Specifically, a greater proportion of RibaPak vs. ribavirin subjects remained on treatment over the course of the 24-week study period. Other indicators of adherence, including a greater proportion of RibaPak vs. ribavirin subjects who took all of their prescribed doses at the 24-week time point, a lower number

of missed doses for RibaPak vs. ribavirin at the 24-week time point and a lower mean milligrams of study drug missed per day at the 24-week time point for RibaPak compared with ribavirin, were also observed.

Importantly, the adherence results in terms of doses and milligrams taken are only representative of the subjects who remained on therapy. Subjects who remained on therapy are those who were presumably doing well on their prescribed treatment. Subjects not doing well for any reason, from lack of response to intolerability, would probably be switched to a different treatment. Thus, even in the 'best of the best' cohort of subjects who remained on treatment, RibaPak subjects missed fewer doses and milligrams of study drug. However, the absolute difference between the groups for the milligrams of drug and doses missed was relatively small.

It remains unknown whether the lower amount of doses and milligrams missed in the RibaPak group is associated with differences in early or sustained virological response, as virological response was not assessed in this study. It has been reported that taking at least 80% of both interferon and ribavirin for at least 80% of the time is associated with a significantly improved sustained virological response,[11, 25, 27] whereas adherence of ≥85% to Peg-IFN and ribavirin treatment was associated with increased HCV suppression and early virological response.[8] Furthermore, Giannini et al. demonstrated that the majority of patients who achieve sustained virological response (negative serum HCV-RNA 24 weeks after the end of Peg-IFN and ribavirin treatment) will continue to have negative viral

load long-term.[28] In their comprehensive review of the literature, Weiss et al. [29] identified five studies that assessed adherence to interferon or ribavirin in terms of missed doses; only two of those five studies included virological response as an outcome. One of the studies found an association between taking at least 85% of both Peg-IFN and ribavirin and achievement of increased HCV suppression and early virological response at treatment week twelve,[8] whereas the other found no association between adherence and virological response.[17] There are important differences between the two studies – the study in which no association between

adherence and virological response was found was cross sectional and relied on self-report of missed doses; the study in which a significant association between adherence and virological response was found was prospective and relied on pharmacy refills for determination of adherence. Both self-reported adherence and adherence based on pharmacy refills have been shown to correlate with objective measures only moderately (i.e. electronic monitoring).[30]

In this study, the data were collected with regard to ribavirin at discreet time points and therefore we were unable to determine percent of interferon taken or the duration of time ribavirin was taken for subjects who discontinued; however, we were able to approximate the proportion who took at least 80% of their RibaPak vs. ribavirin doses for specific follow-up time points. In that modified analysis, we found that a greater proportion of RibaPak subjects took at least 80% of their prescribed doses at the 12- and 24-week time points. This would suggest that improved virological response may be associated with RibaPak vs. ribavirin in the real world setting. In a study by McHutchison et al. that included patients from three clinical trials, 72–80% were found to be adherent, meeting the 80/80/80 rule, when considering both interferon and ribavirin (i.e. received ≥80% of both their interferon α-2b and ribavirin doses ≥80% of the

time).[25] When only considering interferon α-2b (patients on monotherapy), 91–98% were found to be adherent. Data on adherence specifically to ribavirin were not reported in that study. Thus, the proportion of subjects found to meet the 80% definition for RibaPak or ribavirin in the present study was somewhat greater than the 72–80% reported for interferon and ribavirin and similar to that reported for interferon monotherapy. A recently published observational study did compare RibaPak to ribavirin and found trends of better adherence and greater sustained virological response for subjects taking RibaPak vs. ribavirin.[31]

The data for this study were from an observational registry; therefore, we are unable to make causal interpretations. The increased discontinuation rate for ribavirin vs. RibaPak may have been due to reasons other than pill burden; however, the most frequent reason for early discontinuation (as reported by the sites) in the RibaPak group was intolerability to study medication (31.1%), while the most frequently reported reason for early discontinuation in the ribavirin group was loss to follow-up (30.5%). Inadequate response to treatment was the reason reported for 15.2% of RibaPak subjects vs. 22.0% of ribavirin subjects. Loss to follow-up and inadequate response to treatment, both greater in the ribavirin group, are two potential consequences of high pill burden.

While adherence to medical treatment is recognized as a significant determinant of treatment success for a variety of chronic conditions,[32] measurement of adherence has not been standardized.[29, 33, 34] In particular, an operational definition of adherence to HCV treatment has not been established, nor are there guidelines for assessing adherence in HCV treatment.[29] We found that subjects over-reported adherence when we compared self-reported missed doses vs. the calculation of missed doses based on pill counts. Likewise, et al. found that subjects tended to underreport missed doses in comparison with the objective measurement (electronic monitor placed inside the cap of prescription bottles) used in that

study.[16] Future studies of adherence should take special care in the consideration of how adherence is assessed.

In summary, these data suggest that in the HCV population, RibaPak is associated with improved adherence to treatment compared with traditional 200 mg ribavirin tablets. In this study, the indicators of adherence regarding dosing (missed doses and milligrams of drug taken) were specific to subjects who remained on treatment for the particular follow-up period being assessed, and the data captured reflected the 4 weeks prior to that specific follow-up period. We were able to detect important differences in adherence even in this cohort of subjects who presumably represent those most successful with their treatment. Medication adherence is crucial to obtaining virological response to treatment. Moreover, sustained virological response is associated with improvements in quality of life and thus is an important consideration in maximizing treatment adherence. Unsuccessful treatment increases the potential for progression to severe liver disease, which

is associated with significant healthcare costs.[35] Thus, the cumulative impact of treatment adherence has the potential to impact virological response, quality of life and healthcare costs.

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