The critical role of medication adherence in the success of boceprevir and telaprevir in clinical practice
Authors: Jeffrey J. Weiss, Marlene C. Alcorn, Judith G. Rabkin, Douglas T. Dieterich
Journal: Journal of Hepatology (2011)

The excitement about the new standard of care for the treatment of chronic hepatitis C virus (HCV) infection is warranted given the dramatically increased rates of sustained virologic response achieved with the addition of boceprevir or telaprevir to pegylated interferon and ribavirin in clinical trials. However, the success of these two new direct antiviral agents (DAAs) in the real world will depend on the ability of patients to adhere to them. Higher rates of psychiatric and substance use disorders and cognitive impairment in persons with chronic HCV, as compared to the general population, place them at risk for medication nonadherence. A similar development in the complexity of therapeutics occurred in the treatment of HIV infection in the late 1990s with the introduction of HIV protease inhibitors which led to an intensive focus on treatment adherence. The focus on adherence in HCV treatment to date has largely been on early treatment discontinuation and dose reduction rather than missed doses/injections [[1]Weiss J.J. Brau N. Stivala A. Swan T. Fishbein D. Review article: adherence to medication for chronic hepatitis C – building on the model of human immunodeficiency virus antiretroviral adherence research.Aliment Pharmacol Ther. 2009; 30: 14-27Crossref PubMed Scopus (49) Google Scholar] yet data collected through electronic monitoring indicate that patients do miss a significant number of doses of ribavirin and interferon [[2]Smith S.R. Wahed A.S. Kelley S.S. Conjeevaram H.S. Robuck P.R. Fried M.W. Assessing the validity of self-reported medication adherence in hepatitis C treatment.Ann Pharmacother. 2007; 41: 1116-1123Crossref PubMed Scopus (47) Google Scholar]. The additional pill burden and treatment toxicity that DAAs will add to the considerable existing treatment burden will increase the adherence challenge for patients. Boceprevir and telaprevir must be taken three times daily (TID), 7–9 h apart, with food. We know from research that as dosing frequency increases, dose adherence decreases [[3]Saini S.D. Schoenfeld P. Kaulback K. Dubinsky M.C. Effect of medication dosing frequency on adherence in chronic diseases.Am J Manage Care. 2009; 15: E22-E33PubMed Google Scholar]. Five well-designed studies report on both dose adherence (defined as the correct number of pills taken in an observed time period) as well as dose interval adherence (defined as the correct number of doses taken within 2 h of the scheduled dose time) to TID regimens as assessed by electronic monitoring (Table 1). Mean dose adherence ranges from 66% to 89% in these studies and mean dose interval adherence from 5% to 53%.Table 1Dose adherence rates and dose interval adherence rates in studies examining TID regimens using electronic 4Straka R. Fish J. Benson S. Suh J. 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Adherence to angiotensin-converting enzyme inhibitor therapy for heart failure.Prog Cardiovasc Nurs. 2002; 17: 160-166Crossref PubMed Scopus (52) Google Scholar.aOnly median reported. Open table in a new tab aOnly median reported. Adherence data from clinical trials of telaprevir have not been reported. Clinical trial adherence data of boceprevir [[9]Gordon S.C. Lawitz E.J. Bacon B.R. Sulkowski M.S. Yoshida E.M. Davis M. et al.428 Adherence to assigned dosing regimen and sustained virologic response among hepatitis c genotype 1 treatment-naive and peg/ribavirin treatment-failures treated with boceprevir plus peginterferon alfa-2b/ribavirin.J Hepatol. 2011; 54: S173-S174Abstract Full Text PDF PubMed Google Scholar] suggest that adherence is most crucial for treatment experienced patients; in this group, SVR decreased when patients had less than 60% dose interval adherence, a level that is higher than the mean in all studies in Table 1. In a comparison of telaprevir dosing every 12 h vs. every 8 h, comparable rates of SVR were observed [[10]Marcellin P. Forns X. Goeser T. Ferenci P. Nevens F. Carosi G. et al.Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C.Gastroenterology. 2011; 140: 459-468Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar]. However, it is noteworthy that this sample did not include any treatment experienced patients. Since patients in clinical trials routinely have better adherence than patients in clinical practice, and considering the complexity of the new generation of HCV treatment with DAAs, we propose that the systematic assessment of adherence be incorporated into HCV treatment guidelines. In addition, electronic monitoring of adherence should be standard in DAA clinical trials and the adherence data from these trials, including the relationship between missed dose adherence and resistance development, should be reported. Methods to improve missed dose adherence to TID boceprevir and telaprevir warrants dedicated attention. Since these medications are time-limited, different adherence strategies may be needed than in the case of medications for chronic conditions, such as HIV. To maximize the likelihood of benefit for patients who begin the new HCV treatment regimens, resources should be devoted to patient pre-treatment assessment and preparation, as well as on-treatment adherence monitoring and support. Focus on adherence will not only contribute to treatment efficacy but also serve to minimize the development of resistant strains of HCV. This is important both for the individual and for the general public health, due to the risk of transmission of resistant HCV. Given the considerable cost of these treatments, resources invested in optimizing the psychosocial readiness of patients prior to treatment initiation and providing on-treatment adherence support may prove cost-effective. These assessment and intervention strategies should be evaluated through research which includes a cost-effectiveness component. National Institutes of Health – National Institute of Mental Health (Grant # MH071177). Jeffrey Weiss: Consultant: Vertex. Marlene Alcorn: None. Judith Rabkin: None. Douglas Dieterich: Consultant/Advisor/Research Support: Genentech, Gilead, BMS, Merck. Consulting Fees/Honoraria/Advisory Board: Genentech, Gilead, BMS, Merck.