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Study of adherence comes to the treatment of chronic hepatitis B
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Jnl of Hepatology Jan 2011
Maximilian Lee1, Emmet B. Keeffe2
1Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA; 2Division of Gastroenterology and Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509, USA
"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%.....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%.....In this study, patients older than 45years of age, existing patients, and those receiving ADV, ETV or TDF were more likely to have good adherence.....younger patients and new patients who had lower rates of adherence and persistence rates dropped rapidly during the first 6months."
"A lower adherence rate among younger patients and newly diagnosed patients had also been observed in studies of other medical conditions [20], [26], [29]. Young persons are generally less concerned about their health and many consider themselves invincible. Lower adherence among new patients might be related to inadequate understanding of their illness or insufficient reinforcement of medication adherence by the treating physicians. It is not clear why patients receiving LAM had a lower adherence. One possible explanation is that LAM was the first NUC available for hepatitis B, and most patients receiving LAM will have been on treatment a few years longer than those receiving ADV, ETV or TDF. Studies in hypercholesterolemia also found that adherence declined in patients who had been on the same treatment for a long time, possibly related to complacency particularly if the patients were aware that their condition had improved."
"In summary, Chotiyaputta et al. [3] 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 [8], [9], [10], [11], [12], [13]. 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."
"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%.....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 6months of cohort enrollment; the persistence rate declined by 9.1% and 22.4% by 6months 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 6months."
"Among the 2008 and 2009 cohorts, the factors associated with good adherence are: age older than 45years, existing patients, and receipt of NUCs other than LAM (Table 3). There was no difference in adherence rates between men and women and among patients with commercial insurance, Medicare, Medicaid or other payors. Multivariate analysis showed that age >45years (p=0.001), receipt of HBV medication other than LAM (p<0.001) and existing patients (p=0.002) were independent predictors of good adherence."
Refers to article:
Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis B, 31 August 2010
Watcharasak Chotiyaputta, Carolyn Peterson, Fausta A. Ditah, Diane Goodwin, Anna S.F. Lok
Journal of Hepatology
January 2011 (Vol. 54, Issue 1, Pages 12-18)
See Article
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]. 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]. 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] 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], 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]. 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]. With respect to statin therapy for hyperlipidemia, adherence rates for secondary prevention range between 81% and 94% [6], [7], with a dramatic drop-off after 6months [8], [9], [10], whereas antihypertensive therapy adherence rates are even lower between 50% and 75% [11], [12], [13]. 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]. 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 [15], [16], and myocardial infarction and stroke in poorly controlled hypertension [4], [5].
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]. 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] 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 45years 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 6months of cohort enrollment; the persistence rate declined by 9.1% and 22.4% by 6months 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 6months.
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]. This study was a retrospective review of 112 patients with chronic hepatitis B treated with an NUC analogue for more than oneyear 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 5years 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] 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 [8], [9], [10], [11], [12], [13]. 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.
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