Role of Pharmacy Channel in Adherence to Hepatitis C Regimens

AJPB® Translating Evidence-Based Research Into Value-Based Decisions®January/February 2013
Volume 5
Issue 1

Researchers found that patients who used specialty pharmacy had significantly higher adherence to hepatitis C drug regimens than patients who used retail pharmacy.

Hepatitis C virus (HCV) infection affects between 1.3% and 1.9% of Americans and an estimated 3.2 million suffer from chronic HCV infection.1 Hepatitis C virus is a common cause of cirrhosis and hepatocellular carcinoma as well as the most common cause for liver transplantation in the United States.2

The economic burden of HCV infection is considerable. Recent studies have found the presence of HCV was associated with significantly more hospital admissions, emergency department visits, and liver transplantations.3,4 A 2009 study found that patients with HCV infection had an average incremental annual cost of $9681 compared with patients who had no diagnosis of HCV infection. The average incremental cost per patient per year increased to $27,845 for HCV patients with decompensated cirrhosis, $43,671 for HCV patients with hepatocellular carcinoma, and $93,609 for HCV patients with a liver transplant.5 In addition, HCV infection has been shown to result in significant indirect costs in terms of increased presenteeism, absenteeism, and work impairment.6

Compared with interferon monotherapy, combination therapy with interferon and ribavirin in hepatitis C patients has been shown to signifi cantly improve sustained viral response (SVR). Such improvement has been established in multiple subgroups of hepatitis C patients including treatment- naïve patients, relapsers, nonresponders, and patients with cirrhosis.7 Adherence to this regimen has been shown to be critical for treatment success. A study of patients infected with genotype 1 HCV showed that the patients who could be maintained on more than 80% of their interferon and ribavirin dosage for the duration of treatment had enhanced sustained response rates.8 In May 2011, 2 new novel protease inhibitors, telaprevir and boceprevir, entered the market. Recent guidelines have recommended the use of novel protease inhibitors in combination with peginterferon and ribavirin for HCV genotype 1 patients, but not for HCV genotype 2 or 3 patients.9 Whether on the 3-drug regimen or the 2-drug regimen, which remains applicable treatment for genotype 2 or 3, patient medication adherence remains a challenge.

Hepatitis C patients face many challenges in managing their treatment, including complex dosing regimens, coordination with physicians’ offices for injections, and training to use self-injectable medications. In addition, patients often have to cope with unpleasant side effects for extended periods of time. While retail and other pharmacies continue to dispense these medications, specialty pharmacies that employ teams of trained healthcare professionals including pharmacists and nurses who can support the patient and coordinate care with prescribers are beginning to take the lead in dispensing these medications.10 Services offered by specialty pharmacy are aimed toward patient assistance and support; they help patients to better navigate hepatitis C regimens, manage adverse events, liaison with prescribers to better coordinate care, and encourage adherence to therapy. The objective of this study was to compare hepatitis C regimen adherence between patients enrolled in a specialty pharmacy that had integrated hepatitis C care management and patients using retail pharmacy.


A claims-based, retrospective study design was used to evaluate hepatitis C drug regimen adherence between specialty pharmacy and retail patients.

Data Source

Pharmacy claims and eligibility data were extracted from a large, national pharmacy benefi t management (PBM) company database. The PBM also operates an independent specialty pharmacy that serves patients across the entire country. The claims database contains claims for patients from all over the United States for whom the PBM serves as the network claims processor. Thus, patients in the study could obtain their HCV medications from the PBM-operated specialty pharmacy, external specialty pharmacies, or retail pharmacies. Claims for the period from 2007 to 2009 were used in this analysis. Although more recent claims data from 2010 were available, large numbers of patients delaying treatment in 2010 were reported in anticipation of the approval of novel protease inhibitors.11

The channel used to dispense each claim was identified by the source of origin of the claim that was populated by the PBM at the time of claim adjudication. For the purposes of this analysis, nonspecialty pharmacies were classifi ed as retail or mail-order. Specialty pharmacies were classifi ed into the PBM’s in-house specialty pharmacy and other specialty pharmacies.

Inclusion and Exclusion Criteria

Patients were included in the study if they started a new 2-drug hepatitis C regimen (ribavirin plus interferon), defined as having index claims for ribavirin and interferon within 14 days of each other between July 1 and December 31, 2008. A new start on the regimen was defined as an index claim for either drug after a gap of at least 6 months since any previous claim for ribavirin or interferon. Hepatitis C medications were selected based on Medi-Span Generic Product Identifi er (GPI) codes. (For a list of codes and medications selected, see the


available at A maximum gap of 14 days between interferon and ribavirin index claims was selected to identify patients on concurrent interferon and ribavirin therapy, after sensitivity analysis revealed that 95% of patients started interferon and ribavirin within 11 days of each other. This ensured that the index claims were reasonable markers for the beginning of a new regimen.

Patients with any observed claims for antiretrovirals (GPI code 12-10-xx) or hepatitis B (GPI code 12-35-20-xx) were excluded because they were at higher risk for treatment discontinuation.12-14 Finally, patients using multiple dispensing channels to obtain their medication were excluded. This was done to capture all channel-related services that could influence medication adherence conducted at each stage ofthe long and complex hepatitis C regimen.


For each patient, the length of therapy for each drug (ribavirin and interferon) was calculated separately and defined as the days between the first fill date in the index period and the last depletion date for that medication.

To avoid the possibility of capturing claims from multiple, successive hepatitis C regimens while still allowing for delayed filling of prescriptions in the regimen under study, patients whose total length of therapy for either HCV drug exceeded 365 days (52 weeks) after the index claim were excluded from the analysis. The observed length of regimen was defined as the average of the length of therapy for interferon and ribavirin. All patients included in the study were continuously eligible for pharmacy benefi ts from 6 months before index claim to end of follow-up period. Based on patient genotype and response-guided dosing protocols, the recommended length for an interferon plus ribavirin regimen for hepatitis C is either 24 or 48 weeks.10,15 In the absence of genotype or rapid viral response information, assumptions were made about the expected length of the regimen based on the observed length of the regimen. It was assumed that patients whose regimen was observed to be more than 36 weeks long (ie, closer to 48 weeks than 24 weeks) had an expected regimen length of 48 weeks. Alternately, if the observed length of the regimen was equal to or less than 36 weeks (ie, closer to 24 weeks than 48 weeks), it was assumed that the expected length of the regimen for these patients was 24 weeks. Thus, a patient whose observed regimen was 28 weeks long would be expected to be on a 24-week regimen, but a patient whose observed regimen was 40 weeks long was expected to be on a 48-week regimen.

Outcome Metric

Regimen adherence was defi ned as the proportion of days covered by both ribavirin and interferon divided by the expected length of the regimen period (24 or 48 weeks). Based on evidence that 80% or better adherence is associated with significantly improved rates of SVR, regimen adherence was dichotomized, with 80% or better adherence considered optimum adherence and less than 80% adherence considered suboptimal. Gap days were defined as the number of days between the earliest fill date and latest depletion date for the regimen for which patients did not have an available supply of both ribavirin and interferon.

Statistical Analysis

Unadjusted differences between the retail and specialty pharmacy were evaluated using t tests for continuous variables and χ2 tests for categorical variables. The alpha was set a priori to .05. Multivariate models were created to estimate multivariate adjusted regimen adherence in each of the comparison groups. To account for the variable expected length of the hepatitis C regimen, a weighted Poisson regression model was created to estimate multivariate adjusted adherence.16 The number of days covered by both ribavirin and interferon was the dependent variable, and pharmacy type (ie, specialty vs retail) was the primary predictor along with other covariates. The expected length of therapy was used as the weighting variable (ie, offset). Least squares mean regimen adherence, holding all other variables at their mean values, was compared between patients using retail and specialty pharmacy for hepatitis C medication. A Poisson regression model was used to estimate multivariate adjusted differences in gap days, with the number of gap days as the dependent variable, pharmacy type (specialty vs retail) as the primary predictor, and other covariates. Finally, a logistic regression model was created with optimal adherence (defi ned as regimen adherence >80%) as the dichotomous dependent variable, pharmacy type as the primary predictor, and other covariates. Statistical analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina).

Variables that are known covariates of the relationship between adherence and channel were identifi ed on the basis of a literature review, and covariates for these factors or their proxies were generated from the pharmacy claims data and included in multivariate analysis. Demographic confounders included patient age at the time of the first index claim and patient sex. Because urbanicity may impact access to pharmacies as well as adherence, a dichotomous indicator for whether the 3-digit zip code of the patient’s residence was at least in part inside a metropolitan statistical area was created as a proxy for the whether the patient resided in an urban setting.17 Patient out-of-pocket payment was defi ned as the average of the patient-paid amount (sum of copayment, coinsurance, and deductible) per 30 regimen days for hepatitis C medications during follow-up. Patient medication burden was proxied by the number of medications filled by the patient during the 6-month baseline period as defi ned by unique 10-digit GPI codes.18 Patients suffering from depression have great difficulty adhering to any medication regimen.19 We used evidence of treatment for depression as a proxy for depression. An indicator variable was created for the presence of any pharmacy claim for selective serotonin reuptake inhibitors and serotonin—norepinephrine reuptake inhibitors as identified by claims for medications with GPI codes starting with 56-16 or 56-18 in the baseline period.


The patient selection procedure is outlined in the


. A total of 23,798 patients with at least 1 claim for 1 or more hepatitis C drugs from 2007 to 2009 were identified. Of these, 6087 (25.6%) had the first hepatitis C claim between July 1, 2007, and December 31, 2008. However, 167 (2.7%) were excluded because they had claims for antiretrovirals or hepatitis B medications. A further 4997 (84.4%) out of 5920 patients had claims for both interferon and ribavirin, and of those 4774 (80.6%) began interferon and ribavirin within 14 days of each other. An additional 710 (14.9%) patients were excluded from the target sample because they were observed to continue hepatitis C therapy beyond 52 weeks after therapy initiation. Of the remaining 4064 patients, 392 (9.6%) patients were not continuously eligible throughout the expected length of therapy, and 969 (26.4%) additional patients were not continuously eligible throughout the 6-month period before the index claim, leaving a total of 2703 patients eligible for inclusion. Of the remaining patients, 463 (17.1%) used multiple dispensing channels (including patients who may have used multiple specialty pharmacies) and were excluded from the analysis. Ten patients (0.4%) exclusively used mail order pharmacy, a cohort that was too small to use in this analysis. Our comparison of adherence was restricted to 1489 (55.1%) exclusive users of a single specialty pharmacy and 741 (27.4%) exclusive users of retail pharmacy.

The demographic and clinical characteristics of the selected patients are presented in

Table 1

. On average patients in both groups were approximately 49 years old and more than half were male. Most patients in either group resided in a metropolitan statistical area, but therewere significantly more urban patients in the retail group than in the specialty group (87.8% vs 82.6%, P = .002). Out-of-pocket spending per 30-day adjusted hepatitis C prescription was signifi cantly higher in the retail group ($62.10 vs $39.25, P <.001). Retail patients had a signifi - cantly higher medication burden (14 vs 12 medications, P = .002) and more frequent indications for depressive symptoms (24.6% vs 19.7%, P = .009) at baseline compared with specialty patients.

Compared to specialty pharmacy patients, a higher proportion of retail patients had an expected length of therapy of 24 weeks (81.4% vs 73.9%). A significantly higher proportion of specialty patients had 80% or better regimen adherence compared with retail patients (53.9% vs 40.6%).

Unadjusted regimen adherence was 66.8% in the retail group (95% confi dence interval [CI] 64.6%-69.2%) and 76.8% in the specialty group (95% CI 75.2%-78.6%). Multivariate adjusted regimen adherence was estimated to be 69.5% in the retail group (95% CI 66.7%-72.4%) and 78.1% in the specialty group (95% CI 75.7%-80.5%) (

Table 2

). The retail and specialty groups had an average of 76 gap days (95% CI 71-81 days) and 58 gap days (95% CI 55-61 days), respectively. After multivariate adjustment, the retail and specialty groups had an adjusted average of 70 gap days (95% CI 64-77 days) and 55 gap days (95% CI 51-59 days), respectively (

Table 3

). Patients in the specialty group had higher odds of attaining optimum adherence (adjusted odds ratio [AOR] 1.71; 95% CI 1.43-2.04). After adjusting for confounders, patients in the specialty group had a signifi cantly higher likelihood of achieving optimum adherence (AOR 1.59; 95% CI 1.32-1.91).


The primary objective of this study was to determine whether there are differences in hepatitis C regimen adherence between specialty and retail pharmacy patients. Our findings show that after adjusting for a number of known confounders, patients who used a single specialty pharmacy exclusively had on average 8.6% higher regimen adherence and 15 fewer gap days than patients who used retail pharmacy exclusively. Our adherence metric takes into account adherence to the complete regimen, rather than measures of adherence for individual medications aggregated across both drugs in the regimen. This approach makes our fi ndings more readily interpretable in the context of fi ndings that regimen adherence is a major modifiable factor governing the effectiveness of hepatitis C treatment.8,20

We found that patients using specialty pharmacy had nearly 60% higher odds of achieving SVR than patients using retail pharmacy. Suboptimal adherence to ribavirininterferon regimens is highly prevalent in US hepatitis C patient populations. Other researchers who used claims data from a US managed care population and similar possession-based adherence metrics also reported adherence to the ribavirin-interferon regimen in the range of 57% to 76%.21 Another study of self-reported adherence from a cross-sectional survey of patients at 7 US urban clinics found that 7% of patients reported missing at least 1 injection of pegylated interferon in the last 4 weeks and 21% reported missing at least 1 dose of ribavirin in the last 7 days.22

The addition of drugs such as novel protease inhibitors to the 2-drug hepatitis C regimen adds complexity, cost, and side effects to an already difficult, lengthy, and complex regimen. Although the newer 3-drug regimens may deliver improved cure rates,23 they also pose an additional barrier to achieving optimum regimen adherence in real-life environments. In addition to adequate therapy adherence, timely follow-up and intermediate viral load testing are required for accurately guiding responsedriven dosing. Patients must feel comfortable in the use of self-injectable medications and manage signifi cant sideeffects such as severe flu-like symptoms and neuropsychiatric effects.10 Given the increasingly complex nature of hepatitis C treatment, higher levels of care including

disease-specific and drug-specific patient counseling, instruction and training on self-injection, and assistance with administrative issues including payment processes and financial aid will be needed. Dispensing channels such as specialty pharmacy that provide such services may be positioned to drive superior outcomes for hepatitis C patients.

This study has several limitations, several of which are derived from the exclusive use of pharmacy claims data. We could not observe any medical claims or diagnosis codes associated with such claims for the primary condition (hepatitis C), confounders, correlates, and measures of comorbidity derived from medical claims data. However, claims for hepatitis C medications are almost exclusively dispensed in the outpatient pharmacy setting. We were able to generate proxies for important confounders such as baseline comorbidity (measured as medication burden) and diagnosis of baseline depressive symptoms (proxied as pharmacy claims for antidepressants). We did not have patient genotype information or any information about the prescribed length of ribavirin and interferon therapy or response-guided changes to such therapy. Our assumptions regarding the expected length of therapy might have miscategorized early discontinuers of 48-week therapy as having an expected length of therapy of 24 weeks. We used a possessionbased measure of regimen adherence, assuming that medication possessed by the patient would be used as prescribed. An earlier retrospective study of adherence to hepatitis C medication defi ned medication adherence as the ratio of the days of supply in the patient’s possession divided by the number of days in a fi xed follow- up period based on assumptions about the length of hepatitis C regimens similar to those in this study.21 We could not distinguish between treatment-naïve and experienced patients except to ensure that no patient had been on an earlier hepatitis C regimen 6 months prior to the study regimen. For experienced patients, we were unable to ascertain the treatment status from previous rounds of treatment. Finally, although patient race has been shown to be a determinant of treatment response and tolerability,24,25 information about patient race was unavailable and thus could not be controlled for as a confounder in multivariate analysis. Owing to issues with a small sample size and heterogeneity in specialty pharmacy interventions, we restricted the specialty pharmacy to only a single specialty pharmacy. Our analysis might also have been confounded by patients with worse prognosis, patients who generally espouse healthy behaviors, or other patients who were more motivated to be adherent and successfully complete treatment, who selected specialty pharmacy over retail to take advantages of the additional services offered in this dispensing channel. Finally, we could not determine what specifi c services offered by specialty pharmacy were used by patients or whether such services were being used by retail pharmacy patients.


Findings from our study suggest that in real-life practice settings, patients exclusively using a specialty pharmacy had about 8.6% higher adherence, 2 fewer weeks of gap days, and a 60% higher likelihood of achieving optimum adherence compared with patients exclusively using retail pharmacy. Given the increasing complexity of hepatitis C regimens, dispensing channels such as specialty pharmacy that offer services to better assist patients and support them through the treatment regimens may drive improved adherence. Future research should not only describe differences in adherence between 2-drug and 3-drug hepatitis C regimens but also evaluate the effect of dispensing channel and specific services and programs for hepatitis C patients on regimen adherence.

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