An estimated 185 million people are infected with chronic hepatitis C virus (HCV) infection worldwide . Among HIV-infected patients, coinfection with HCV is associated with a faster progression to liver fibrosis and remains a leading cause of morbidity and mortality [2–6]. In the United States, approximately one-third of all HIV-1 infected patients are coinfected with HCV, with prevalence rates as high as 75–90% in high-risk populations such as patients with intravenous drug use [3,7].
In 2014, a fixed-dose combination of the NS5A inhibitor, ledipasvir (LDV), and the NS5B polymerase inhibitor, sofosbuvir (SOF), was approved by the Food and Drug Administration for treatment of patients infected with HCV genotype 1 . Several studies have shown that 12 weeks of treatment with this regimen results in sustained virologic response (SVR) rates – and therefore functional cure – of 91–100% in both HCV monoinfected and HIV/HCV coinfected patients [9–16]. The impact of HIV coinfection on the adherence threshold for directly acting antiviral-only therapy, however, is presently unknown [17,18].
In this study, adherence rates to the Food and Drug Administration-approved regimen of LDV/SOF were evaluated in HCV monoinfected and HIV/HCV coinfected participants.
Study design and participants
Participants were enrolled in one of two single-center, open-label, phase 2 trials conducted at the National Institutes of Health-Clinical Center, Bethesda, Maryland, from January 2013 to September 2014: SYNERGY, a phase 2a trial for HCV monoinfected individuals (ClinicalTrials.gov number NCT01805882) ; and ERADICATE, a phase 2b trial for HIV/HCV coinfected individuals (ClinicalTrials.gov number NCT01878799) . Full inclusion and exclusion criteria, as well as methods of liver disease staging, have been previously published [11,19]. All participants were infected with HCV genotype 1 and had no prior history of HCV treatment. In the current analysis, three groups of participants were compared: HCV monoinfected, HIV/HCV coinfected antiretroviral naïve, and HIV/HCV coinfected antiretroviral treated. All participants included in this analysis received the fixed-dose combination of LDV/SOF (90 mg/400 mg) once daily for 12 weeks.
Written or oral informed consent was obtained from all participants. At each adherence visit, three tools were used to measure adherence: electronic medication event monitoring system (MEMS)Caps (MWV, Richmond Virginia, USA), pill counts, and written questionnaires (patient reports). On day 0, participants met with a member of the adherence team and were provided seven standardized points describing adherence tools, but were assured that nonadherence would not affect study participation (Supplemental Table 1, http://links.lww.com/QAD/A785). Adherence follow-up visits were scheduled for day 7, week 4, week 8, and end of treatment (week 12). Medication refills occurred at weeks 4 and 8. Twenty-eight tablets were dispensed at day 0 and week 4, and 21 tablets were dispensed at week 8. At these time points, MEMSCaps, as well as remaining tablets, were transferred to the new medication bottles.
The study was approved by the National Institute of Allergy and Infectious Diseases Institutional Review Board and was conducted in compliance with the Good Clinical Practice guidelines, the Declaration of Helsinki, and regulatory requirements. The Regulatory Compliance and Human Subjects Protection Branch of National Institute of Allergy and Infectious Diseases served as the study sponsor and medical monitor. Data collection, review, analysis, and writing were performed by National Institutes of Health investigators.
The primary efficacy outcome for this study was adherence rates as measured by MEMSCaps, pill counts, and patient questionnaires (patient report). The primary efficacy outcome of the two phase 2 clinical trials, which the participants were enrolled in, was SVR12 (undetectable HCV RNA 12 weeks after completion of treatment) measured with COBAS TaqMan HCV test version 2.0 (TaqMan HCV; Roche Molecular Systems, Inc., Branchburg, New Jersey, USA).
Medication event monitoring systems
Each time the medication bottle was opened, the MEMSCap recorded the current date and time, the number of openings within the past 24 h, and the number of hours elapsed since last removal. At each adherence visit, a MEMSCap reader wirelessly transferred this data using the online software MedAmigo by MWV Healthcare, Sion, Switzerland.
At each adherence visit, the number of remaining tablets in each patient's bottle were counted and used to calculate missed doses since the previous visit. Remaining tablets did not necessarily mean missed doses as medication refills would occur at weeks 4 and 8 within a 7-day window. Adherence was defined in terms of missed doses of LDV/SOF over the 12 weeks of treatment.
Baseline and follow-up AIDS Clinical Trials Group antiretroviral adherence questionnaires were used for this study (Supplemental Text 1 and 2, http://links.lww.com/QAD/A785), modified appropriately to be applicable for patients infected with HCV . Adherence team members read questionnaires to participants with low literacy and were available to answer any questions.
Adherence tools were compared using Pearson correlations. Adherence across and within treatment arms was compared using ANOVA and t tests. Demographics between participants on different treatment arms were compared using ANOVA or χ2 tests as appropriate. Significance was defined as a P value less than 0.05.
A total of 70 participants were evaluated in this study. Demographics and patient characteristics are shown in Table 1. The majority of patients were African American (83%), male (73%), with high baseline HCV viral loads more than 800 000 IU/ml (60%), a median age of 59 years, and a median BMI of 26. Sixty-nine out of 70 (99%) participants achieved SVR12[11,19].
All 70 participants were included in the pill count adherence analysis (Supplemental Table 2, http://links.lww.com/QAD/A785). However, two patients were excluded from the MEMSCap adherence analysis: one patient did not return the medication bottle at the end of treatment, whereas the other did not comply with MEMSCap usage and instead used a pill box.
High adherence to medications by medication event monitoring system Cap, pill count, and patient report
In all three participant groups, adherence to LDV/SOF was high as measured by MEMSCap, pill count, and patient report and did not fall below 96% for all three modalities (Fig. 1a). There were no significant differences in adherence among the three participants groups as measured by MEMSCap (P = 0.65), pill count (P
= 0.82), and patient report (P
= 0.62). However, in all the three groups, adherence measured by MEMSCap was significantly less than that by patient report (Fig. 1a).
According to adherence as measured by pill count, 50% (35/70) of all participants displayed full (100%) adherence over 12 weeks and 90% (63/70) of all participants had greater than 95% adherence over the 12-week treatment course (Supplemental Table 2, http://links.lww.com/QAD/A785). All seven participants whose adherence was less than 95% achieved SVR12.
Adherence declines over the course of treatment
Adherence as measured by MEMSCap declined significantly from the beginning of treatment (measured between baseline and week 4) to the end of treatment (measured between weeks 8 and 12). Adherence decreased from 98 ± 0.9% to 95 ± 1.2% (P
= 0.01) in the HCV monoinfected cohort, from 99 ± 0.5% to 96 ± 1.3% (P
= 0.02) in the HIV/HCV antiretroviral untreated cohort, and from 97 ± 0.9% to 95 ± 1.2% in the HIV/HCV antiretroviral treated cohort (P
= 0.01) (Fig. 1b).
A comparison of adherence using three measures (MEMSCap, pill count, and patient report) in an inner-city patient population reflective of the HCV epidemic in the United States revealed high rates of adherence to LDV/SOF among HCV monoinfected and HIV/HCV coinfected participants, regardless of antiretroviral treatment.
In all three patient groups, there was a significant difference between adherence as measured by MEMSCap and adherence as measured by patient report. This supports the findings of others: when prompted to report adherence rates to antiretrovirals, patients tend to overestimate their adherence and underestimate their number of missed doses . Therefore, evaluating adherence by MEMSCap or pill count may be a more accurate measure of adherence compared with patient report. Given the cost of MEMSCaps, pill count provides a reasonable measure of adherence in the clinical setting.
Our study found no difference in adherence to HCV therapy between HIV participants taking antiretrovirals and those not taking antiretrovirals, suggesting that the higher pill burden of concurrent antiretrovirals does not negatively impact adherence to HCV therapy nor does prior experience with daily medications positively impact adherence to HCV therapy .
Our study participants, who were demographically representative of the current HCV epidemic in the United States , were highly adherent to treatment, with the vast majority of patients taking over 90% of their tablets. Although it is possible that adherence rates may be lower outside the setting of a study protocol, given the high tolerability and efficacy of LDV/SOF, it is likely that adherence will remain high in a real-world population. Of particular interest would be the existence of an adherence threshold, defined as a limit of adherence below which SVR12 rates can be expected to diminish. As we noted, there was a significant drop-off of adherence from the 0 to 4 weeks compared with the 8 to 12 weeks periods. This phenomenon may reflect ‘pill fatigue’ and may have important implications for maintaining drug levels. As more patients undergo HCV treatment, it will be important to monitor real-world findings regarding the degree of adherence, SVR12 rates, and the development of viral mutations.
Adherence to LDV/SOF was high in our group of HCV-infected participants, regardless of HIV coinfection or concurrent antiretroviral treatment. All three methods of adherence measurement (MEMSCap, pill count, and patient report) provided consistently high adherence rates and appeared to correlate with SVR12.
The authors would like to acknowledge the contributions of Rachel Silk, RN, Colleen Kotb, NP, Angie Price, NP, and Senora Mitchell for their clinic support.
Author contributions: K.T. and A.K. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. T.P., L.A.G., A.K., M.A.P., H.M., and S.K. contributed to the study design. K.T., T.P., L.A.G., and C.G. collected data. K.T., T.P., A.K., and S.K. analyzed data. K.T., T.P., L.A.G., M.A.P., H.M., A.O., A.K., and S.K. interpreted data. K.T. and A.K. contributed to figure design. K.T. wrote the first draft of the manuscript and all authors participated in the review and critique of the manuscript.
Disclaimer: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Funding/Support: the Regulatory Compliance and Human Subjects Protection Branch of the National Institute of Allergy and Infectious Diseases (NIAID) served as the study sponsor. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported in part by the National Institute of Allergy and Infectious Diseases. The study was partially funded by a Collaborative Research and Development Agreement between NIH and Gilead Sciences.
Role of the Sponsors: Gilead provided the study drug. The Regulatory Compliance and Human Subjects Protection Branch was involved in the review and approval of the study via the usual peer-review process as well as the study management but did not play a role in the design of the study, data collection and analysis, interpretation of the data, preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Conflicts of interest
A.O. is an employee of Gilead Sciences, Inc. There are no other conflicts of interest.
Previous presentations: presented in part as a poster at the Conference on Retroviruses and Opportunistic Infections (CROI); 23–26 February 2015; Seattle, Washington, USA.
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