Our study demonstrates that in a real-world setting, higher levels of adherence to pegylated interferon and ribavirin are associated with higher rates of early and sustained virologic response. Interferon adherence was higher than that of ribavirin for all adherence intervals. Moreover, adherence to both antiviral medications declined during HCV therapy, but more so for ribavirin. Current methadone use was associated with reduced adherence.
These results support the concept that adherence should be a focus of clinical care teams prior to and throughout HCV treatment to help achieve virologic response. Identifying suboptimal adherence using pharmacy refill records might allow clinicians to counsel patients to improve their adherence during therapy. Although interventions to increase adherence to HCV therapy have not been tested, providers could ask patients about barriers to adherence and help them identify potential solutions. Linking pegylated interferon and ribavirin prescriptions might facilitate increased antiviral adherence, but this strategy has not been tested. Further, a policy of linked prescriptions would result in added costs for unnecessary additional pegylated interferon refills if clinicians rewrite the ribavirin prescription when changing dosage due to treatment-induced anemia.
Our results extend findings from retrospective analyses of clinical trials data (13
). In two studies, receipt of less than 80% of total interferon or ribavirin doses for at least 80% of the duration of therapy resulted in reduced SVR rates among genotype 1, but not genotype 2 or 3, patients (13
). Two other analyses showed that receipt of less than 60% cumulative ribavirin dose (15
) and premature ribavirin discontinuation (16
) adversely affect SVR. However, these studies focused on decreased drug exposure due to interferon and ribavirin dosage reductions and discontinuations rather than due to missed antiviral doses.
Within individuals, adherence to ribavirin was lower than to interferon over each 12-week interval. These adherence differences might be due to ribavirin’s twice daily dosing frequency compared to the once-weekly administration of pegylated interferon. Additionally, prior to the start of therapy, patients may select a day of the week on which they administer their interferon injection, and this weekly routine might facilitate higher levels of adherence for interferon than ribavirin.
Adherence to both medications declined during treatment, but more so for ribavirin. The higher frequency of ribavirin administration may make it more burdensome to remember and more vulnerable to drop-offs in adherence over time. Declines in medication adherence over time have been reported for other chronic diseases, such as antiretroviral therapy for HIV infection (25
), antihypertensive therapy (26
), and lipid-lowering therapy (26
), so this observation is not surprising. It is therefore imperative that clinicians emphasize antiviral adherence throughout the course of HCV therapy and not only at treatment initiation.
Our study also examined risk factors for low adherence to anti-HCV medications. Patients prescribed growth factors in response to leukopenia or anemia as well as either thyroid hormone replacement or anti-thyroid medications due to on-treatment thyroid dysfunction had slightly higher mean adherence to interferon and ribavirin. Use of these therapies during HCV therapy might require more frequent follow-up visits and laboratory monitoring that could promote antiviral adherence. Although patients with a history of bipolar disorder/depression and schizophrenia might be expected to be at risk for non-adherence, our results show that antiviral adherence is not lower among these subgroups. Clinicians should therefore not be reluctant to initiate treatment in these patients because of a perceived risk of non-adherence, particularly since evidence suggests that clinicians’ predictions are poor measures of their patients’ likely adherence (28
). Additional risk factors for non-adherence to HCV therapy should be examined to determine the subgroups that might be at increased risk for poor adherence and in whom interventions to improve adherence should be targeted.
Our results emphasize the need to evaluate adherence to the new direct acting antiviral therapies for HCV (e.g., telaprevir and bocepravir). These drugs may require more frequent dosing (e.g., three times daily) and are expected to be used with pegylated interferon and ribavirin (29
), further increasing the complexity of HCV therapy. Additionally, reduced adherence to these antivirals could select for drug-resistant mutations that could result in virological breakthrough (32
). As new antiviral regimens for chronic HCV are introduced, antiviral adherence will need to be emphasized to achieve viral suppression and prevent antiviral resistance.
This study has several limitations. First, it provides no evidence that pharmacy refill data reflect the actual number of pills taken correctly by a patient. Pharmacy refills might underestimate adherence if patients acquire their medications from non-VA sources. However, the majority of VA patients receive their medications from VA pharmacies (34
). Refills might overstate adherence if patients fill prescriptions but do not take the medication. Yet, numerous studies have shown the validity of VA refill data as a surrogate of adherence (20
). An additional limitation of refill data is that patients who had their ribavirin dosage reduced but who had no prescription rewritten to decrease the quantity dispensed might have been misclassified as having reduced ribavirin adherence. However, subanalyses among patients prescribed recommended dosages of antivirals and not “at risk” for ribavirin dosage reduction showed results that were similar to the overall cohort.
Second, by including only persons who had a follow-up viral load, we might have selected individuals who were more likely to be adherent to antiviral therapy. However, the characteristics of patients excluded from the study were similar to those included, so we do not believe that these exclusions alter our conclusions.
Third, the retrospective study design did not permit HCV RNA testing to be performed at the same time during treatment for all patients. However, we used standard definitions for early and sustained virologic response and required week 12 viral loads to be obtained in a narrow window to reduce early virologic response misclassification.
Fourth, the small sample of genotype 2 and 3 patients receiving antiviral therapy from 12–24 weeks of treatment may have limited our ability to find an association between antiviral adherence during this interval and sustained response.
Finally, our study sample was predominantly male and excluded patients with HIV co-infection, potentially limiting the generalizability of our results.
In summary, this analysis demonstrated that higher levels of adherence to pegylated interferon and ribavirin were associated with higher rates of early and sustained virologic response. Adherence to both antiviral medications declined over time, but more so for ribavirin. Future studies should evaluate interventions to maximize adherence to HCV therapy.