Study of adherence comes to the treatment of chronic hepatitis B
Authors: Maximilian Lee, Emmet B. Keeffe
Journal: Journal of Hepatology (2010)

Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis BJournal of HepatologyVol. 54Issue 1PreviewLong-term treatment with nucleos(t)ide analogues (NUCs) is associated with increasing rates of antiviral drug resistance. Medication adherence is important in preventing drug resistance. This study aimed to determine, first, the persistence rates and the adherence rates to NUCs in patients with chronic hepatitis B (CHB), and second, the factors associated with adherence. Full-Text PDF The primary goal of antiviral treatment of chronic hepatitis B is to achieve sustained suppression of hepatitis B virus (HBV) replication to an undetectable level, thus preventing or reducing the complications of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and death [[1]Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2380) Google Scholar]. It logically follows that a concomitant and equally important goal of therapy is to achieve a high rate of patient adherence to antiviral treatment when using a nucleos(t)ide (NUC) analogue, which requires long-term and potentially lifelong administration. It is reasonable to assume that non-adherence can result in poor virologic suppression, breakthrough resistance, and progression of disease, although the contribution of non-adherence to these outcomes is uncertain [[2]EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol 2009;50:227–242.Google Scholar]. However, in order to study the association between adherence and the outcomes of antiviral therapy of chronic hepatitis B, it is important to determine first the medication adherence rate that occurs in practice. In this issue, Chotiyaputta et al. [[3]Chotiyaputta W, Peterson C, Ditah FA, Goodwin D, Lok ASF. Persistance and adherence to nucleos(t)ide treatment for chronic hepatitis B. J Hepatol; in press.Google Scholar] have published the first, large-scale evaluation of patient adherence with HBV oral antiviral therapy, as well as some of the factors associated with adherence, from a retrospective population-based study of 11,100 patients with chronic hepatitis B. Adherence (synonymous with compliance, or concordance) with medication usage is defined as the proportion of prescribed doses of medication actually taken by a patient over a specified period of time [[4]Osterberg L. Blaschke T. Adherence to medication.N Engl J Med. 2005; 353: 487-497Crossref PubMed Scopus (5985) Google Scholar], and has been extensively studied in various chronic medical conditions, including hypertension, hyperlipidemia, and human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome (AIDS). Although the preferred terminology remains a matter of debate, the World Health Organization (WHO) and a number of other agencies have selected adherence as the preferred term [[5]World Health Organization. Adherence to long-term therapies: evidence for action. http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Geneva: World Health Organization; 2003.Google Scholar]. Compliance, which was commonly used in the past, implies a passive role and simply following the demands of a prescriber, and non-compliance has been regarded as associated with deviant or irrational behavior. Adherence, on the other hand, implies an active role in collaboration with a prescriber, and non-adherence encompasses the diverse reasons for patients not following a treatment recommendation, including the characteristics of the disease, social and economic factors, the health care team and system, and cost of medications as well as a number of patient-related factors. Medication adherence rates during clinical trials are required to be high, at approximately 90% or more, but patient adherence rates with medication used for chronic conditions in clinical practice are highly variable. The WHO has identified poor adherence to treatment as a worldwide problem, with adherence to therapy of chronic illnesses in developed countries estimated to average only 50%, with lower rates in developing countries [[5]World Health Organization. Adherence to long-term therapies: evidence for action. http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Geneva: World Health Organization; 2003.Google Scholar]. With respect to statin therapy for hyperlipidemia, adherence rates for secondary prevention range between 81% and 94% [6Sacks F.M. Pfeffer M.A. Moye L.A. Rouleau J.L. Rutherford J.D. Cole T.G. et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.N Engl J Med. 1996; 335: 1001-1009Crossref PubMed Scopus (7169) Google Scholar, 7The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349–1357.Google Scholar], with a dramatic drop-off after 6 months [8Jackevicius C.A. Mamdani M. Tu J.V. Adherence with statin therapy in elderly patients with and without acute coronary syndromes.JAMA. 2002; 288: 462-467Crossref PubMed Scopus (926) Google Scholar, 9Cramer J. Rosenheck R. Kirk G. Krol W. Krystal J. Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes.Value Health. 2003; 6: 566-573Abstract Full Text PDF PubMed Scopus (168) Google Scholar, 10Haynes R.B. McDonald H.P. Garg A.X. Helping patients follow prescribed treatment: clinical applications.JAMA. 2002; 288: 2880-2883Crossref PubMed Scopus (669) Google Scholar], whereas antihypertensive therapy adherence rates are even lower between 50% and 75% [11Schroeder K. Fahey T. Ebrahim S. How can we improve adherence to blood pressure lowering medication in ambulatory care? Systematic review of randomized controlled trials.Arch Intern Med. 2004; 164: 722-732Crossref PubMed Scopus (331) Google Scholar, 12Bramley T.J. Gerbino P.P. Nightengale B.S. Frech-Tamas F. Relationship of blood pressure control to adherence with antihypertensive monotherapy in 13 managed care organizations.J Manag Care Pharm. 2006; 12: 239-245Crossref PubMed Scopus (302) Google Scholar, 13Fung V. Huang J. Brand R. Newhouse J.P. Hsu J. Hypertension treatment in a medicare. A population: adherence and systolic blood pressure control.Clin Ther. 2007; 29: 972-984Abstract Full Text PDF PubMed Scopus (107) Google Scholar]. Although the medication regimens for hyperlipidemia and hypertension are relatively uncomplicated, consisting of a single medication dose once daily (at least during the initial stages of disease) as compared to the highly active antiretroviral therapy (HAART) regimen for HIV treatment, these adherence rates are still unfortunately low. Furthermore, in general, adherence rates can only be expected to decrease as additional doses or extra medications are required, with an estimated 10% stepwise decrease in the mean adherence rate for each additional daily dose of medication, such as required with HAART in patients with HIV infection [[14]Claxton A.J. Cramer J. Pierce C. A systematic review of the associations between dose regimens and medication compliance.Clin Ther. 2001; 23: 1296-1310Abstract Full Text PDF PubMed Scopus (1940) Google Scholar]. Finally, non-adherence has significant negative health impacts, such as a stepwise reduction in viral suppression and progression to AIDS and death in HIV infection [15Glass T.R. De Geest S. Weber R. Vernazza P.L. Rickenbach M. Furrer H. et al.Correlates of self-reported nonadherence to anitretroviral therapy in HIV-infected patients: the Swiss HIV cohort study.J Acquir Immune Defic Syndr. 2006; 41: L385-L392Crossref PubMed Scopus (158) Google Scholar, 16Kitahata M.M. Reed S.D. Dillingham P.W. Van Rompaey S.E. Young A.A. Harrington R.D. et al.Pharmacy-based assessment of adherence to HAART predicts virologic and immunologic treatment response and clinical progression to AIDS and death.Int J STD AIDS. 2004; 15: 803-810Crossref PubMed Scopus (91) Google Scholar], and myocardial infarction and stroke in poorly controlled hypertension [4Osterberg L. Blaschke T. Adherence to medication.N Engl J Med. 2005; 353: 487-497Crossref PubMed Scopus (5985) Google Scholar, 5World Health Organization. Adherence to long-term therapies: evidence for action. http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Geneva: World Health Organization; 2003.Google Scholar]. Antiviral therapy for chronic hepatitis B would appear to possess a profile favoring high adherence rates given the once daily dosing of a single NUC analogue, which is usually well tolerated with minimal side effects. However, patients with chronic hepatitis B may face barriers to adherence similar to those found in other chronic medical conditions, such as lack of symptoms during the early stage of disease that may be associated with uncertainty regarding the beneficial impact of the prescribed medication on overall health and, therefore, an equivocal need for treatment. Other common reasons affecting patient adherence, such as forgetfulness, overriding priorities, emotional or cultural factors, may be expected to occur in patients prescribed NUC therapy [[17]Cramer J. Identifying and improving compliance patterns.in: Cramer J.A. Spilker B. Patient compliance in medical practice and clinical trials. Raven Press, New York1991: 387-392Google Scholar]. Provider factors affecting medication adherence, such as properly communicating the intention and benefits of treatment, are also important. In their retrospective population-based study, Chotiyaputta et al. [[3]Chotiyaputta W, Peterson C, Ditah FA, Goodwin D, Lok ASF. Persistance and adherence to nucleos(t)ide treatment for chronic hepatitis B. J Hepatol; in press.Google Scholar] specifically evaluated patient-oriented adherence with antiviral therapy in terms of both actual medication possession by a patient during its prescribed period (the adherence rate) and the rate of continuing to refill prescriptions during its prescribed period (the persistence rate) by studying a large pharmacy claims database, which represented 25% of the American market for hepatitis B treatment. The study population included an overall total population of 11,100 patients with chronic hepatitis B (comprised of three smaller, but similarly sized, annual cohorts), who were receiving one of several NUCs (lamivudine, adefovir, entecavir, tenofovir) between 2007 and 2009. A vast majority (10,582 or 95.3%) of these patients had existing prescriptions prior to their enrollment into an annual cohort, while only a very small minority (518 or 4.7%) of patients was started on a new prescription upon cohort enrollment. Demographic (age and gender) and medical insurance status data were only available for the 2008 and 2009 cohorts, which consisted of 7405 patients (66.7%). The overall adherence rate between 2007 and 2009 was remarkably high, with a mean of 87.8% and median of 93.2% having medications in their possession. Approximately half of all patients (55.3%) had an adherence rate of more than 90%, while 15.9% of all patients had adherence rates ⩽70% and only 5.7% of all patients had adherence rates ⩽50%. Patients who received new prescriptions also had similar adherence rates of 84.6%, with half of new patients having an adherence rate of more than 90% and only 9.2% of new patients with adherence rates ⩽50%. Given the very low number of new patients to compare to, the difference in these rates was not likely to be clinically significant. Nevertheless, it was still promising to see that adherence rates with antiviral therapy compared favorably to, or better than, those reported with treatment of hypertension and hyperlipidemia. From the multivariate analysis of the 2008 and 2009 cohorts, independent predictors of good adherence included patients older than 45 years and those who were prescribed NUCs other than lamivudine. Patients who were already receiving antiviral therapy were also more likely to be adherent than those starting therapy; however, the duration of their existing therapy, which may be an important predictor of adherence, was unknown. Similar to the rates of adherence, the overall persistence rate, or rate of refilling prescriptions, for patients between 2007 and 2009 was almost as high at 81%. As seen with other chronic medical conditions, there was a rapid drop-off in persistence within the first 6 months of cohort enrollment; the persistence rate declined by 9.1% and 22.4% by 6 months in existing and new patients, respectively. The decline in persistence among most NUCs had similar slopes, but interestingly, patients with new prescriptions for either lamivudine or tenofovir experienced the largest drop-off in persistence, declining to 65% after 6 months. A follow-up study from the same unit reported in preliminary fashion a discrepancy between virologic breakthrough and confirmed genotypic resistance in patients with chronic hepatitis B undergoing NUC therapy, suggesting that medication non-adherence was an important cause of virologic breakthrough [[18]Hongthanakorn C, Chotiyaputta W, Oberhelman K, Fontana RJ, Marrero JA, Licari TL, et al. Discrepancy between virological breakthrough and confirmed genotypic resistance in chronic hepatitis B patients receiving nucleos(t)ide analogue therapy in clinical practice. Gastroenterology 2010;138:S-793 [abstract].Google Scholar]. This study was a retrospective review of 112 patients with chronic hepatitis B treated with an NUC analogue for more than one year from January 2001 to October 2009. The index treatment included lamivudine (n = 28), adefovir (n = 18), entecavir (n = 38), tenofovir (n = 13), telbivudine (n = 1), Truvada® (combination tenofovir and emtricitabine) (n = 5), or other combination of NUCs (n = 9). The cumulative incidence of virologic breakthrough at 3 and 5 years was 34% and 58%, and the incidence of confirmed genotypic resistance was 18% and 41%, respectively, at the same time points. Of 24 NUC-naïve patients receiving lamivudine, 13 had virologic breakthrough and seven had genotypic resistance; by contrast, of 26 NUC-naïve patients receiving entecavir, six had virologic breakthrough and none had genotypic resistance. Overall, only 49% of patients with virologic breakthrough were confirmed to have genotypic resistance, suggesting that medication non-adherence is an important cause of breakthrough. The obvious recommendation from this study is that mutation testing should be performed prior to switching treatment with the occurrence of virologic breakthrough, especially for patients receiving an NUC with a high genetic barrier to resistance. In summary, Chotiyaputta et al. [[3]Chotiyaputta W, Peterson C, Ditah FA, Goodwin D, Lok ASF. Persistance and adherence to nucleos(t)ide treatment for chronic hepatitis B. J Hepatol; in press.Google Scholar] have conducted the first large-scale study of patient adherence with antiviral therapy for chronic hepatitis B in a real-world practice setting outside of clinical trials, and they have shown that the overall adherence and persistence rates are both high at 87.8% and 81%, respectively. While it may be argued that possession of medication does not represent its actual utilization, the converse (i.e., failing to possess or continue to refill medications) does represent a failure of adherence. As expected, antiviral therapy was still found to be subject to the same rapid decline in persistence after several months of treatment as reported for medication treatment of other chronic conditions [8Jackevicius C.A. Mamdani M. Tu J.V. Adherence with statin therapy in elderly patients with and without acute coronary syndromes.JAMA. 2002; 288: 462-467Crossref PubMed Scopus (926) Google Scholar, 9Cramer J. Rosenheck R. Kirk G. Krol W. Krystal J. Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes.Value Health. 2003; 6: 566-573Abstract Full Text PDF PubMed Scopus (168) Google Scholar, 10Haynes R.B. McDonald H.P. Garg A.X. Helping patients follow prescribed treatment: clinical applications.JAMA. 2002; 288: 2880-2883Crossref PubMed Scopus (669) Google Scholar, 11Schroeder K. Fahey T. Ebrahim S. How can we improve adherence to blood pressure lowering medication in ambulatory care? Systematic review of randomized controlled trials.Arch Intern Med. 2004; 164: 722-732Crossref PubMed Scopus (331) Google Scholar, 12Bramley T.J. Gerbino P.P. Nightengale B.S. Frech-Tamas F. Relationship of blood pressure control to adherence with antihypertensive monotherapy in 13 managed care organizations.J Manag Care Pharm. 2006; 12: 239-245Crossref PubMed Scopus (302) Google Scholar, 13Fung V. Huang J. Brand R. Newhouse J.P. Hsu J. Hypertension treatment in a medicare. A population: adherence and systolic blood pressure control.Clin Ther. 2007; 29: 972-984Abstract Full Text PDF PubMed Scopus (107) Google Scholar]. It remains unclear whether this decline is a function of generalized medication fatigue, and further study will be needed to determine what additional factors, both patient- and provider or health system-oriented, affect this rapid decline. Adherence with use of NUCs requires study in various patient and practice situations, e.g., in tertiary and primary care practices, among patients with various educational levels and socioeconomic status, in health plans with different out-of-pocket costs to patients, and in specific patient ethnic populations. A number of important questions related to adherence cannot be correlated or explained from studies based upon pharmacy records, but the study of Chotiyaputta and colleagues is an important first step that should be a stimulus for future prospective studies to address the complex patient and provider issues associated with rates of adherence and the sequelae of non-adherence. The results of such future studies should lead to interventions aimed at improving adherence in specific practice settings and enhance the effectiveness of the treatment of chronic hepatitis B with NUC analogues. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.