Marie-Paule Schneider

Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions.

Objective Incomplete compliance is one of several possible causes of uncontrolled hypertension. Yet, non-compliance remains largely unrecognized and is falsely interpreted as treatment resistance, because it is difficult to confirm or exclude objectively. The goal of this study was to evaluate the potential benefits of electronic monitoring of drug compliance in the management of patients with resistant hypertension. Methods Forty-one hypertensive patients resistant to a three-drug regimen (average blood pressure 156/106 ± 23/11 mmHg, mean ± SD) were studied prospectively. They were informed that for the next 2 months, their presently prescribed drugs would be provided in electronic monitors, without any change in treatment, so as to provide the treating physician with a measure of their compliance. Thereafter, patients were offered the possibility of prolonging the monitoring of compliance for another 2 month period, during which treatment was adapted if necessary. Results Monitoring of compliance alone was associated with a significant improvement of blood pressure at 2 months (145/97 ± 20/15 mmHg, P < 0.01). During monitoring, blood pressure was normalized (systolic < 140 mmHg or diastolic < 90 mmHg) in one-third of the patients and insufficient compliance was unmasked in another 20%. When analysed according to tertiles of compliance, patients with the lowest compliance exhibited significantly higher achieved diastolic blood pressures (P = 0.04). In 30 patients, compliance was monitored up to 4 months and drug therapy was adapted whenever necessary. In these patients, a further significant decrease in blood pressure was obtained (from 150/100 ± 18/15 to 143/94 ± 22/11 mmHg, P = 0.04/0.02). Conclusions These results suggest that objective monitoring of compliance using electronic devices may be a useful step in the management of patients with refractory hypertension, as it enables physicians to take rational decisions based on reliable and objective data of drug compliance and hence to improve blood pressure control.

Successful efavirenz dose reduction guided by therapeutic drug monitoring.

BACKGROUND There are potential benefits to individualizing dosage in patients treated with efavirenz (EFV). We tested a simplified algorithm based on a Bayesian pharmacokinetic approach for guiding dose reduction in patients with EFV concentrations above the 75th percentile (P75) with documented virological efficacy. METHODS We designed a prospective, open-label, multicentre study. All consenting participants with EFV concentrations above P75 on standard dosage were included in a dose-reduction cycle. Primary end point was the number of patients who reached plasma concentrations within target (1,000-4,000 ng/ml) after, at most, two cycles of dose reduction at 3 and 6 months. CYP2B6 genetic characterization was performed. RESULTS Seventy-two patients were screened and 13 fulfilled selection criteria. These patients, with undetectable viraemia on a stable 600 mg EFV-based regimen, had a median (interquartile range) EFV plasma level of 8,112 ng/ml (5,993-10,278) at baseline; 38% (between P75 and P95) qualified for a 400 mg EFV dose, and 62% (above P95) qualified for a 200 mg EFV dose. After one to two dose-reduction cycles, all patients reached targets for EFV plasma concentration at 24 weeks. The predictive dose reduction based on genetic profile differed from dose reduction according to therapeutic drug monitoring (TDM) in three patients. All patients maintained viral suppression at 6 months. CONCLUSIONS A standardized TDM-guided EFV dose-reduction strategy over a 24-week period was successful, safe and yielded EFV plasma concentrations within the recommended therapeutic range. In addition to improving neuropsychiatric tolerability, EFV dose reduction has the potential to substantially decrease treatment cost.

Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality

Objective:To determine the effect of nonadherence to antiretroviral therapy (ART) on virologic failure and mortality in naive individuals starting ART. Design:Prospective observational cohort study. Methods:Eligible individuals enrolled in the Swiss HIV Cohort Study, started ART between 2003 and 2012, and provided adherence data on at least one biannual clinical visit. Adherence was defined as missed doses (none, one, two, or more than two) and percentage adherence (>95, 90–95, and <90) in the previous 4 weeks. Inverse probability weighting of marginal structural models was used to estimate the effect of nonadherence on viral failure (HIV-1 viral load >500 copies/ml) and mortality. Results:Of 3150 individuals followed for a median 4.7 years, 480 (15.2%) experienced viral failure and 104 (3.3%) died, 1155 (36.6%) reported missing one dose, 414 (13.1%) two doses and, 333 (10.6%) more than two doses of ART. The risk of viral failure increased with each missed dose (one dose: hazard ratio [HR] 1.15, 95% confidence interval 0.79–1.67; two doses: 2.15, 1.31–3.53; more than two doses: 5.21, 2.96–9.18). The risk of death increased with more than two missed doses (HR 4.87, 2.21–10.73). Missing one to two doses of ART increased the risk of viral failure in those starting once-daily (HR 1.67, 1.11–2.50) compared with those starting twice-daily regimens (HR 0.99, 0.64–1.54, interaction P = 0.09). Consistent results were found for percentage adherence. Conclusion:Self-report of two or more missed doses of ART is associated with an increased risk of both viral failure and death. A simple adherence question helps identify patients at risk for negative clinical outcomes and offers opportunities for intervention.

Electronic monitoring of long-term use of the nicotine nasal spray and predictors of success in a smoking cessation program

This study evaluated the efficacy of prolonged administration (18 months) of a nicotine nasal spray in smoking cessation and attempted to characterize the pattern of use of the nasal spray with a specially developed electronic monitor in an effort to assess the factors associated with cessation success or failure. Study participants were 92 patients in a smoking cessation unit of a medical outpatient clinic in Switzerland. Participants were daily smokers who had smoked for more than 5 years and were highly motivated to quit. The main outcome measure was the number of abstainers at 12 and 24 months. Their use of the spray was monitored using a microchip (MDILog) that recorded the date and time of every actuation. Success rates were 17.4% at 12 months and 9.8% at 24 months. During the first month of study, median use was 12 puffs/day in abstainers and 6 puffs/day in failures (p=.049). Abstainers used the spray less in the morning compared with failures (26.6% vs. 32.8% of the total median daily dose; p=.028). By contrast, abstainers used the spray more in the evening/night compared with failures (35.3% vs. 26.7% of the total median daily dose; p=.007). Abstinence during the first two weeks was associated significantly with cessation success at 6 months (OR=17.10) and 24 months (OR=11.09). Although the pattern of use of the nasal spray differed between successful quitters and failures (used in higher doses by the successful quitters), mean daily consumption during the first month was not predictive of success. Mean daily consumption of the nicotine nasal spray remained lower than expected in most participants, particularly in failures.

Patterns of adherence to raltegravir-based regimens and the risk of virological failure among HIV-infected patients: the RALTECAPS cohort study.

Abstract:Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)–based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Adherence to Antiretroviral Treatment Decreases During Postpartum Compared to Pregnancy: A Longitudinal Electronic Monitoring Study

Dear Editor: As recently published in your Journal, the LILAC prospective cohort study showed a decrease in self-reported adherence between pregnancy and postpartum in South America.1 Interestingly, our smaller study with a longitudinal measure and analysis of adherence to antiretroviral treatment confirms these findings. Antiretroviral therapy (ART) during pregnancy and postpartum involves two issues: prophylaxis of perinatal transmission and treatment of maternal infection.2 Adherence, defined as “the process by which patients take their medications as prescribed,” is crucial to address these concerns.3,4 Pregnancy and the first months of motherhood cause important changes in a womens life, which might impact ART adherence. Most frequently cited barriers to adherence were competition with other issues including family obligation and hectic lifestyle. Conversely, the babys health was cited as a motivator for adherence.5 During postpartum, women tend to miss more medical visits, and adherence tends to be lower than during pregnancy.1,6–10 Between 10% and 50% of the women stopped their ART after childbirth, part of them on their own without physicians approval.7–10 Most of published studies are based on pill count or self-reported adherence. To our knowledge this is the first study assessing electronically the dynamics of adherence in a continuum from pregnancy to postpartum along with clinical data. This exploratory, retrospective study was approved by the Swiss Ethic Commission (Vaud) for clinical research. It aimed at comparing adherence to the entire ART—during pregnancy and postpartum—using continuous electronic drug monitoring data. The community Pharmacy of the Department of ambulatory care and community medicine in Lausanne has been running an adherence-enhancing program since 2004, which combines electronic drug monitoring and semistructured, repeated motivational interviews.4 All pregnant HIV-positive women having taken part in the program between 2004 and 2012 were retrieved. The maximal observation period extended from first adherence visit after last menstruation to 6 months after childbirth. Sociodemographic and clinical data were collected from the Swiss HIV Cohort Study database. Percent of attended visits were compared between pregnancy and postpartum using the McNemar test. Electronic data on medication adherence, extracted from the adherence-enhancing program database, were reconciled with pill count and interview notes in order to include reported pocket doses. For each woman, adherence was described with a binary variable (1=correct number of daily opening(s) of all electronic monitors; 0=less daily openings than prescribed). Data were analyzed via a piecewise logistic mixed effect model. Mixed effect models are methods of choice for analyzing data with repeated measures for each participant. They take into account the interindividual variability of the measures and can deal with unbalanced data due to missing values. In particular, a piecewise logistic mixed effect model allowed us to estimate the probability of taking ART as prescribed, for each day d of pregnancy and postpartum periods.11 Adherence at days 0–3 from childbirth has been replaced by missing values before entering the model, because of the bias due to hospitalization. Analysis of change in CD4 over time was performed using a piecewise polynomial mixed effect model. A qualitative inspection of viral RNA individual trajectories was made only graphically, as the large interindividual variability and the small number of data prevented the application of a mixed effect model. We used the Stata/IC software (v12.0, StataCorp, College Station, TX) for data description and the R system for computation and graphic of mixed effect models (v2.12.1, www.r-project.org/, library “nlme”). Among 400 patients referred to the adherence program, 29 pregnant women (7%) were screened and 25 (86%) were included. Three women who did not use electronic monitors were excluded, and one underwent an early pregnancy interruption. Median age was 29 (interquartile range [IQR]: 26.5, 32.0). Seventeen women (68%) were black and 11 (44%) were ART naive. ART included protease and nucleoside reverse transcriptase inhibitors (n=24; 96%). Six women (24%) stopped the program during pregnancy, 3 (12%) at childbirth and 4 (16%) during the postpartum period. Among these 13 women, 8 (62%) were kept on ART, 3 stopped ART after childbirth according to guidelines, and 2 stopped ART without physicians agreement. All these women were considered in the analysis. The percentage of unattended visits increased from 17% during pregnancy to 38% during postpartum (p=0.001). Probability of correct ART intake was continuously high during pregnancy (97% [95% CI: 0.94–0.98]), decreased to 93% (95% CI: 0.87–0.96) at childbirth (p of the difference=0.006), and increased again during postpartum (p of the slope coefficient=0.009) (Fig. 1A) to reach the same probability than during pregnancy after 164 days. A sensitivity analysis with the 10 women who were continuously monitored during pregnancy and postpartum confirmed the decrease in ART intake after childbirth. FIG. 1. Change in drug intake, viral load, and CD4 count over time. (A) Percentage of women with correct number of daily opening(s) of the electronic monitors over time. Curves in bold represent the prediction±95% confidence interval, (days 0–3 ... CD4 count increased during pregnancy, decreased around 40 days after childbirth then increased again (p of the linear, quadratic and cubic coefficient <0.005; Fig. 1B). Individual ARN curves decreased during pregnancy. Within the 13 continuing women after childbirth, 4 (31%) had at least one worsening viral load (range, 25–344 copies per milliliter; Fig. 1C). In summary, our data describe adherence during pregnancy and postpartum from a real-life medication adherence clinic. Our model predicts that 97 women of 100 take all doses of ART during pregnancy versus 93 women 3 days after childbirth. Our results also mean that missing doses increased from 1 per month (i.e., 3 per 100 days) during pregnancy to 2 per month (i.e., 7 per 100 days) at beginning of postpartum. We could show a lag time during postpartum before women were able to reach the same probability of adherence than during pregnancy. Strength of our analysis results from: (1) a day-by-day adherence monitoring to entire ART, (2) reconciliation of electronic data with pill count and interview to reflect actual drug intake, and (3) the use of advanced statistics. Our main limitation is due to the fact that 9 women stopped the program before or at childbirth. Fortunately, it did not impact the adherence level during pregnancy as confirmed by a sensitivity analysis. External validity is limited by the fact that women were included in an adherence-enhancing program. Drop in adherence during standard care might be more significant. Our data show that a major event such as childbirth impacts adherence transiently, which may result in viral rebound. Of note, 4 women of 13 had at least one worsening viral load. These preliminary results need to be confirmed by larger studies. Although much attention in clinical care is devoted to pregnant women, emphasis should be put on postpartum care as well.

Association of disclosure of HIV status with medication adherence

OBJECTIVE Disclosure may affect adherence to antiretroviral treatment. In a medication adherence program, this cross-sectional study describes disclosure, perceived reaction after disclosure, living situations, and the relationship of disclosure with antiretroviral adherence. METHODS A combination of a questionnaire to measure disclosure and longitudinal electronic monitoring of medication adherence was used. RESULTS A total of 103 out of 159 eligible patients gave informed consent. The characteristics differed between participants and nonparticipants (race, education, sexual orientation, medication adherence). Thirteen participants did not disclose their HIV status. Seventy-three (81%) participants judged the reaction after disclosure positive. Among the 62 participants cohabiting, 52% disclosed to all co-residents. Adherence was high (median 100%). HIV disclosure was negatively associated with adherence, when disclosing to the mother (OR=2.46, p-value=0.086) and to siblings (OR=2.89, p-value=0.029). Living alone was associated to a lower adherence than cohabitation (Rate Ratio=1.42, p-value=0.007). CONCLUSION HIV disclosure and adherence are sensitive issues, which may explain the reason for refusal. Nonparticipants may be those with the most difficulties disclosing. PRACTICE IMPLICATIONS An unbiased collection of sensitive information, as HIV disclosure, is a difficult task. A cohort design, with research data collected systematically by a trusted healthcare provider, may better describe the association between adherence and disclosure.

New roles for community pharmacists in modern health care systems: a challenge for pharmacy education and research.

The academic activities led by the Unit of Community Pharmacy can be classified as translational. Our group is interested in person-centered pharmaceutical services aimed at a more responsible use of drugs (effectiveness, safety, efficiency) in collaboration with physicians and other health care professionals in a primary care setting. The following domains of education and research are high priorities for our group: medication therapy management, medication adherence, integrated care, individualization of therapies, care management for the elderly and e-health.

Adherence: the journey of medication taking, are we there yet?

Patient adherence to medications has been an issue challenging healthcare professionals for decades. Adherence rates, causes of non-adherence, barriers and enablers to medication taking, interventions to promote adherence, and the impact of non-adherence on health outcomes, have been extensively studied. In light of this, the area of adherence research has progressed conceptually and practically. This special issue contains a range of articles which focus on different aspects of adherence, from standardising terminology and methods of measurement, to non-adherence in a broad range of patient populations, and to interventions to promote adherence.

Adherence policy, education and practice: an international perspective

Nonadherence to chronic therapy has become a large burden on the healthcare system of many countries. Community pharmacists are well positioned to address nonadherence as part of their overall patient care activities, and contribute to patients’ quality use of medicines. Between 2008 and 2010, a series of narrative, peer-reviewed articles were published in Pharmacy Practice which focused on community pharmacists’ activities in medication adherence, specifically in the areas of the education they receive, their practice, the research conducted and national or local policies. This editorial aims to summarise the key findings presented in the series, and highlight the pertinent issues and gaps in the literature. There is a need to implement global and long-term objectives focussing on enhancing the quality of education and competencies of community pharmacists and the research conducted in medication adherence, to develop guidelines for pharmacists and enhance the uptake of adherence promoting services in routine care.