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Adherence to hepatitis C virus (HCV) therapy has been incompletely examined among HIV-infected patients. We assessed changes in interferon and ribavirin adherence and evaluated the relationship between adherence and early (EVR) and sustained virologic response (SVR). We performed a cohort study among 333 HIV/HCV-coinfected patients who received pegylated interferon and ribavirin between 2001 and 2006 and had HCV RNA before and after treatment. Adherence was calculated over 12-week intervals using pharmacy refills. Mean interferon and ribavirin adherence declined 2.5 and 4.1 percentage points per 12-week interval, respectively. Among genotype 1/4 patients, EVR increased with higher ribavirin adherence, but this association was less strong for interferon. SVR among these patients was higher with increasing interferon and ribavirin adherence over the first, second, and third, but not fourth, 12-week intervals. Among HIV/HCV patients, EVR and SVR increased with higher interferon and ribavirin adherence. Adherence to both antivirals declined over time, but more so for ribavirin.
Combination therapy with pegylated interferon alfa-2a or -2b plus ribavirin remains the current standard of care for the treatment of chronic hepatitis C virus (HCV) infection among HIV-infected patients [1-3]. Successful therapy can eradicate chronic HCV infection [4-6] and reduces the risks of cirrhosis, hepatic decompensation, and hepatocellular carcinoma . However, this combination therapy is challenging for patients, requiring weekly subcutaneous injections of interferon, twice-daily oral ribavirin, and frequent monitoring of laboratory results and adverse effects. As with antiretroviral therapy for HIV infection, suboptimal adherence to HCV therapy could reduce the likelihood of treatment response [8, 9].
Despite its importance, few studies have examined adherence to HCV therapy among HIV-infected patients in real-world settings [10, 11]. In particular, since medication adherence can decline over time, as has been observed with antiretroviral therapy [12, 13], it is important to determine how HCV treatment adherence changes over the course of therapy. Such information could identify time points when adherence declines, during which interventions to improve adherence should be tested and implemented. Further, understanding the relation between adherence and response is important because it can determine if a threshold level of adherence exists and can identify the adherence range within which maximal virologic response can be achieved. Therefore, the first objective of this study was to assess the changes in HCV treatment adherence over the course of HCV treatment among HIV/HCV-coinfected patients. Our hypothesis was that adherence to each HCV antiviral would decline over time. Our second objective was to evaluate the relationship between adherence to HCV therapy and early and sustained virologic response among coinfected patients. We hypothesized that increasing levels of adherence to HCV antiviral medications would be associated with correspondingly higher virologic response.
Finally, barriers to HCV treatment have not been thoroughly examined, particularly among HIV/HCV-coinfected patients. No conceptual model of the factors that affect HCV treatment adherence have been formally developed and tested, but psychosocial (e.g., psychiatric disease, lifestyle, social support) and regimen (e.g., pill burden, dosing frequency, toxicities) factors might be important, as they have in antiretroviral adherence . We previously conducted an initial evaluation of possible barriers to adherence to pegylated interferon and ribavirin over the initial 12 weeks of HCV therapy and found no differences in adherence to either drug according to employment status, number of medications concomitantly prescribed, or history of posttraumatic stress disorder or alcohol abuse . In this study, we conducted exploratory analyses to evaluate more thoroughly psychosocial and regimen factors, particularly HCV treatment toxicities requiring medication interventions. In particular, we evaluated depression/bipolar disorder, schizophrenia, methadone use, and new initiation of a growth factor during HCV therapy as potential barriers to adherence. Our rationale for evaluating depression/bipolar disorder and schizophrenia was based on prior research in non-HIV-infected patients that showed that these psychiatric conditions might adversely affect medication adherence . We evaluated methadone use because use of this medication might be associated with other factors (e.g., cognitive impairment) that might predispose to decreased adherence [15, 16]. Our rationale for examining use of growth factors was because initiation of these drugs indicates severe hematologic toxicities that could compromise antiviral adherence and because the addition of these drugs to the treatment regimen would further add to the complexity of HCV therapy.
We conducted a retrospective cohort study using data from the National Veterans Affairs (VA) Hepatitis C Clinical Case Registry . This registry contains demographic information, laboratory results, pharmacy data, and diagnoses (recorded using International Classification of Diseases, Ninth Revision diagnostic codes) from HCV-infected U.S. veterans receiving care at VA medical facilities. The pharmacy database includes information on medication fill dates, dosages, quantity dispensed, and dosing frequency. Dispensing of pegylated interferon and ribavirin in the VA healthcare system are not linked (i.e., ribavirin is not automatically filled when requesting a refill for interferon or vice versa), and veterans must contact the pharmacy to obtain refills (i.e., refills are not automatically sent). The study was approved by the Institutional Review Boards of the University of Pennsylvania and Philadelphia VA Medical Center.
Patients were included if they: 1) had a recorded diagnosis of HIV infection; 2) were infected with HCV genotype 1, 2, 3, or 4; 3) received at least one prescription each for pegylated interferon and ribavirin between January 2001 and December 2006; 4) had a quantitative HCV RNA prior to HCV therapy; and 5) had an HCV RNA after treatment initiation. If patients had multiple treatment courses (defined as a >20-week gap between interferon fills), only the first course was included.
The frequency and timing of HCV RNA measurements were performed at the discretion of the treating clinician using the assay available at their site. Early virologic response (EVR) was defined as a ≥2 log10 decrease from pre-treatment baseline in HCV RNA IU/mL at 12 weeks [1-3]. HCV RNA results obtained between weeks 9 and 15 were used to determine EVR. The result closest to week 12 was selected if multiple HCV RNA results were available.
Sustained virologic response (SVR) was defined as an undetectable HCV RNA result in all follow-up measurements 24 weeks after treatment end date [1-3], defined as the final days’ supply of the last recorded interferon prescription. Patients with no HCV RNA result measured at least 24 weeks after treatment end date were classified as not having SVR.
Demographic and clinical data were collected from electronic medical record data from dates prior to or at HCV treatment initiation and included: age; sex; race; site; height; weight; HCV genotype; quantitative plasma HCV RNA; CD4 cell count; plasma HIV RNA; history of depression/bipolar disorder and/or schizophrenia; receipt of combination antiretroviral therapy with at least three medications from two different classes dispensed within 90 days of HCV treatment initiation ); interferon and ribavirin dosages, quantities dispensed, and dosing frequency; and methadone use (dispensed within 90 days of HCV treatment initiation). Depression/bipolar disorder and schizophrenia were defined by recorded diagnoses of these conditions.
Follow-up to ascertain SVR ended on June 30, 2008. Plasma HCV RNA was considered undetectable if it was below the lower limit of detection of the least sensitive quantitative assay used among the sites (Versant HCV RNA 3.0 Quantitative Assay, Bayer; lower limit, 615 IU/mL) or negative on qualitative assay. During the treatment course, hemoglobin values and new prescriptions for growth factors (epoetin, darbepoetin, granulocyte macrophage / granulocyte colony-stimulation factor) were collected to identify on-treatment hematologic toxicities.
At each fill date, interferon and ribavirin dosages, quantities dispensed, and frequency of administration were collected. Pegylated interferon alfa-2a dosages below 180 mcg/week and alfa-2b dosages below 1.4 mcg/kg/wk were classified as suboptimal [1, 3]. Ribavirin dosage was classified as suboptimal if: <1,000 mg/day for genotype 1 and 4 patients weighing ≤75 kg or <1,200 mg/day for genotype 1 and 4 patients weighing >75 kg; or <800 mg/day for genotype 2 and 3 patients . Since some clinicians might have reduced ribavirin dosages due to anemia but not updated prescriptions to reflect the change, we classified patients as “at risk” for ribavirin dosage reduction if during HCV therapy: 1) hemoglobin declined below 10 gm/dL, or 2) they received epoetin or darbepoetin .
Adherence was calculated over 12-week intervals (0-12, 13-24, 25-36, and 37-48 weeks). Evaluating pharmacy refill adherence over periods shorter than 12-week intervals has not been shown to reflect a stable measure of medication-taking behavior . Extensive details on the measurement of HCV therapy adherence have been previously published . Briefly, percent adherence was calculated as the sum of the days’ supply of antiviral dispensed over the 12-week interval divided by the number of days between the first and final fills of that interval [21, 22]. Fills obtained closest to weeks 13, 25, and 37 represented initial fills in the second, third, and fourth adherence intervals. Patients were included in adherence analyses for an interval if they filled a prescription for that antiviral during the interval. For those who did not obtain a full 12 weeks’ supply for an interval, only observed fills were used to calculate adherence. We assessed the robustness of the adherence:outcome relation by using alternative adherence definitions as previously published by our group .
Percentage adherence to interferon and ribavirin within person over each interval was compared using paired t-tests. Mixed effects models were used to estimate changes in adherence to each medication over time . A subanalysis evaluated the mean change in ribavirin adherence among patients who initiated and maintained the recommended dosage of ribavirin and who were not “at risk” for ribavirin dosage reduction.
A longitudinal mixed effects linear regression model with subject as a random intercept evaluated factors associated with non-adherence to each antiviral over all intervals, adjusting for potential confounding by site . We evaluated depression/bipolar disorder, schizophrenia, methadone use, and new initiation of a growth factor during therapy as possible barriers to HCV treatment adherence.
Finally, the proportions with EVR and SVR were determined within four predefined adherence strata for each antiviral over each 12-week interval: 1)≤70%, 2) 71% to 80%, 3) 81% to 90%, and 4) 91% to 100%. There were three major reasons why we evaluated adherence as a categorical exposure variable. First, it was unclear if there was a linear relationship between adherence and virologic response. As a result, evaluating adherence as a continuous variable would force a linear relationship between HCV treatment adherence and virologic response, which would be inappropriate if a linear relationship was not present. Second, analysis of adherence as a categorical exposure variable enables identification of a threshold level of adherence. Third, categorization of adherence permits identification of the range of adherence for clinicians and patients to target to achieve maximal virologic response. Evaluation of adherence as a categorical exposure variable allows the results to be clinically meaningful to clinicians and capable of being explained to patients. The rationale for categorizing adherence within the four pre-defined adherence strata was based on having sufficient numbers of patients within each adherence level. We used logistic regression to determine the association between adherence over the initial 12-weeks and EVR, adjusting for age and race. For analyses examining the relationship between adherence and SVR, we implemented repeated measures logistic regression models using generalized estimating equations to determine the association between adherence over each interval and SVR, adjusting for age and race . We assessed effects of potential confounders by examining changes in odds ratios as potential confounders (other than age and race) were included in models . Analyses were stratified by HCV genotype (1 and 4; 2 and 3). Since suboptimal dosages and dosage reductions of anti-HCV medications are associated with lower virologic response rates [26-29], subanalyses evaluated virologic outcomes among patients prescribed optimal dosages of anti-HCV antivirals and who were not identified as “at risk” for ribavirin dosage reduction. P-values for testing associations of adherence and response were a priori one-sided, since it is biologically implausible that lower adherence could lead to higher response rates.
Assuming a 20% rate of non-adherence, a sample size of 300 patients provided 80% power to detect 20% point differences in EVR and SVR between good and poor adherers. Data were analyzed using SAS 9.0 (SAS Institute Inc., Cary, NC).
A total of 364 HIV/HCV-coinfected patients were prescribed pegylated interferon plus ribavirin during the observation period. Of these, 31 were excluded because they did not meet eligibility criteria (Figure 1). Excluded subjects more commonly had a higher mean body weight (97.0 [22.8] versus 84.3 [15.1] kg; p<0.001). All other characteristics (listed in Table 1) were similar between excluded and included patients. The final sample included 333 patients. This cohort was predominantly male and African-American, and 30% had a diagnosis of depression (Table 1). Ninety percent of the patients were receiving combination antiretroviral therapy. The majority were infected with HCV genotype 1 and had a high (>400,000 IU/mL) baseline HCV RNA level.
Receipt of pegylated interferon alfa-2a, alfa-2b, and ribavirin; initial dosages of these medications; suboptimal dosing at initiation and during therapy; and new initiation of growth factors are presented in Table 1. A total of 333 patients obtained prescription fills during the first 12-week adherence interval, 239 during the second interval, 150 during the third interval, and 106 during the fourth interval. Ninety-two percent of pegylated interferon prescriptions and 89% of ribavirin prescriptions were for either 28 or 30 days’ supply.
Table 2 shows pegylated interferon and ribavirin adherence over each interval. Mean adherence to interferon was higher than for ribavirin over each interval. Mean adherence to both antiviral medications was high during the initial 12 weeks, but declined over the course of treatment. There was a mean decline in interferon adherence of 2.5 percentage points (test for trend, p=0.04) and in ribavirin adherence of 4.1 percentage points (test for trend, p=0.002) per 12-week interval. Subanalyses among patients who maintained the recommended ribavirin dosage and who were not “at risk” for ribavirin dosage reduction demonstrated a mean decline in ribavirin adherence similar to that in primary analyses (5.5% points per 12-week interval; test for trend, p=0.002).
Methadone use during HCV therapy was associated with lower mean adherence to interferon and ribavirin compared to those not taking this medication (Table 3). In contrast and contrary to our hypothesis, patients newly prescribed growth factors had higher mean adherence to both antivirals than those not prescribed them.
Sixty percent (201) of patients had an HCV RNA measured between weeks 9 and 15. These patients more commonly had an HCV RNA level >400,000 IU/mL than those with no HCV RNA results measured between weeks 9 and 15 (118/201 [59%] versus 61/132 [46%]; p=0.02). Among patients with a week 9-15 HCV RNA, 71/159 (45%) of genotype 1 and 4 and 32/42 (76%) of genotype 2 and 3 patients achieved EVR.
Among patients infected with HCV genotype 1 or 4, the proportion with EVR was greater with higher levels of adherence to interferon and ribavirin (Table 4; Figure 2). After adjustment for age and race, this association was significant for ribavirin (p=0.009), but was less strong for pegylated interferon (p=0.1). Subanalyses among patients prescribed optimal ribavirin dosages and not identified as “at risk” for ribavirin dosage reduction demonstrated a stronger association between ribavirin adherence and EVR compared to results from primary analyses (data not shown). Sample sizes for patients with genotypes 2 and 3 were insufficient for EVR analyses. Similar results were obtained with sensitivity analyses using alternative adherence definitions.
A total of 72/267 (27%) patients with genotype 1 or 4 and 33/66 (50%) with genotype 2 or 3 achieved SVR. Among HCV genotype 1 or 4 patients, the proportion with SVR was greater with higher levels of interferon adherence over the first, second, and third, but not the fourth, adherence intervals (Table 5; Figure 3). This association was marginally significant for higher levels of ribavirin adherence over the second and third, but not the first or fourth, intervals. In repeated measures logistic regression models, associations between antiviral adherence over each interval and SVR were not significant after adjustment for age and race. Subanalyses among patients prescribed optimal ribavirin dosages and who were not “at risk” for ribavirin dosage reduction showed stronger associations between ribavirin adherence and SVR compared to primary analyses (data not shown). Sample sizes for patients with genotypes 2 and 3 were insufficient for SVR analyses. Sensitivity analyses using alternative adherence definitions did not change the results.
Our study demonstrated that among HIV/HCV-coinfected patients receiving HCV therapy, adherence to pegylated interferon was higher than that of ribavirin over all 12-week adherence intervals. Moreover, adherence to both antiviral medications declined during HCV therapy, but more so for ribavirin. Among genotype 1 and 4 patients, EVR increased with higher levels of ribavirin adherence over the initial 12 weeks of therapy, but this association was less strong for pegylated interferon. Higher levels of adherence to both pegylated interferon and ribavirin over various adherence intervals were associated with higher rates of SVR.
Our results extend findings from a prior retrospective analysis of data from HIV/HCV-coinfected patients treated in the AIDS Pegasys Ribavirin International Co-Infection Trial . That study demonstrated that receipt of 80% or more of planned pegylated interferon plus ribavirin doses for at least 80% of the treatment duration resulted in increased SVR rates among genotype 1 subjects. However, it focused on decreased drug exposure due to interferon and ribavirin discontinuations and dosage reductions (without assessment of percent adherence). Our study demonstrates that decreased drug exposure due to missed doses of anti-HCV antiviral medications at appropriate dosages also impacts treatment outcomes.
Similar to our finding in HCV-monoinfected individuals , we found that, adherence to ribavirin was lower than adherence to interferon over each 12-week interval. These adherence differences might have been due to ribavirin's twice daily dosing frequency compared to the once-weekly administration of pegylated interferon. Fatigue and loss of concentration are common side effects reported by patients during interferon-based therapy [4-6]. As a result, the higher frequency of ribavirin administration may make it more burdensome to remember and more vulnerable to drop-offs in adherence over time. Further, patients may select a day of the week on which they administer their interferon injection prior to the start of therapy, and this scheduling routine might facilitate higher levels of adherence for interferon than ribavirin. The increased adherence associated with use of growth factors may have been due to the benefits of additional attention from the care team needed to manage these side effects.
Declines in medication adherence over time have been reported for other chronic diseases, particularly antiretroviral therapy for HIV infection , anti-HCV therapy among HCV-monoinfected individuals , antihypertensive therapy , and lipid-lowering therapy [32, 33]. These results demonstrate the need to emphasize antiviral adherence throughout the course of HCV therapy and not only at treatment initiation. Interestingly, the declines in antiviral adherence observed in this cohort of coinfected veterans were smaller in magnitude than those observed among HCV-monoinfected veterans reported in a recent analysis . Since coinfected patients are often also prescribed antiretroviral therapy, they may be more aware of the importance of adherence on virologic response compared to HCV-monoinfected persons.
Our study also examined risk factors for poor antiviral adherence. Patients receiving methadone for the treatment of narcotic dependence had reduced adherence to interferon and ribavirin. Methadone use might be associated with other factors (e.g., cognitive impairment) that might predispose to decreased adherence or it might be a marker for more severe past narcotic addiction, which may relapse during HCV therapy and result in non-adherence [15, 16]. In contrast, use of growth factors in response to leukopenia or anemia was associated with higher mean antiviral adherence. Administration of these therapies during HCV treatment requires more frequent follow-up visits and laboratory monitoring, which might increase adherence. Additional risk factors for non-adherence to HCV therapy should be examined to facilitate the development of interventions to improve adherence.
These results show that adherence to anti-HCV medications should be a focus of clinical care teams prior to and throughout HCV treatment to help achieve SVR. Indeed, the addition of new direct-acting antiviral agents (e.g., telaprevir and boceprevir) to the existing pegylated interferon and ribavirin regimen will increase the complexity of HCV therapy for HIV/HCV-coinfected patients [34-36]. In particular, these new medications may be dosed more frequently (e.g., every 8 hours), require dietary modifications to ensure absorption, and have new toxicities that will further challenge adherence. 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 might consider tailored approaches, such as asking patients about their barriers to adherence, brainstorming with them to identify potential solutions, and then monitoring antiviral adherence for feedback.
This study has several limitations. First, 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 [37, 38]. Alternatively, refills might overstate actual adherence if patients fill prescriptions but do not take the medication. However, previous studies have demonstrated the validity of VA refill data as a surrogate of medication adherence [20, 22, 39, 40]. In particular, 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 subjects who had a follow-up HCV RNA result, we might have selected individuals who were more likely to be adherent to antiviral therapy. However, the characteristics of subjects 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 subjects. However, we used standard definitions for EVR and SVR and required week 12 HCV RNA results to be obtained in a narrow window to reduce EVR misclassification.
Finally, the small numbers of genotype 1 and 4 patients receiving HCV therapy during some adherence intervals, particularly weeks 37-48, limited our ability to identify associations between pegylated interferon and ribavirin adherence and SVR. Additionally, the overall small sample of genotype 2 and 3 patients who received HCV treatment limited our ability to find associations between HCV antiviral adherence and virologic outcomes in these patients. Future studies will need to examine adherence further in these subgroups.
This analysis demonstrated that among HIV/HCV-coinfected patients higher levels of adherence to interferon and ribavirin were associated with higher rates of EVR and SVR. Adherence to both antiviral medications declined over time, but more so for ribavirin. Future studies should examine additional risk factors for non-adherence and evaluate interventions to maximize adherence to HCV therapy in this population.
This work was supported by the National Institutes of Health [K01-AI070001 to V.L.R.] and a Department of Veterans Affairs Competitive Pilot Project Fund grant [to V.K.A.]. This material is based upon work supported in part by the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.