ORIGINALES

 

Influence of pharmacotherapy complexity on compliance with the therapeutic objectives for HIV+ patients on antiretroviral treatment concomitant with therapy for dyslipidemia. INCOFAR Project

Influencia de la complejidad farmacoterapéutica en el cumplimiento de los objetivos terapéuticos en pacientes VIH+ con tratamiento antirretroviral y concomitante para la dislipemia. Proyecto INCOFAR

 

 

Rocío Jiménez Galán¹, Inés María Montes Escalante² and Ramón Morillo Verdugo¹

¹Pharmacy Department. Hospital de Valme.
²Unit of Pharmacy Supplies. Andalusian Health System.

Correspondence

 

 

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ABSTRACT

Objectives: To analyze the relationship between pharmacotherapeutical complexity and compliance of therapeutic objectives in HIV+ patients on antiretroviral treatment and concomitant dyslipidemia therapy.
Materials and methods: A retrospective observational study including HIV patients on stable antiretroviral treatment during the past 6 months, and dyslipidemia treatment between January and December, 2013. The complexity index was calculated with the tool developed by McDonald et al. Other variables analyzed were: age, gender, risk factor of HIV, smoking, alcoholism and drugs, psychiatric disorders, adherence to antiretroviral treatment and lipid lowering drugs, and clinical parameters (HIV viral load, CD4 count, plasma levels of total cholesterol, LDL, HDL, and triglycerides). In order to determine the predictive factors associated with the compliance of therapeutic objectives, univariate analysis was conducted through logistical regression, followed by a multivariate analysis.
Results: The study included 89 patients; 56.8% of them met the therapeutic objectives for dyslipidemia. The complexity index was significantly higher (p = 0.02) in those patients who did not reach the objective values (median 51.8 vs. 38.9). Adherence to lipid lowering treatment was significantly associated with compliance of the therapeutic objectives established for dyslipidemia treatment. A 67.0% of patients met the objectives for their antiretroviral treatment; however, the complexity index was not significantly higher (p = 0.06) in those patients who did not meet said objectives.
Conclusions: Pharmacotherapeutical complexity represents a key factor in terms of achieving health objectives in HIV+ patients on treatment for dyslipidemia.

Key words: HIV; Dyslipidemia; Pharmacotherapeutical complexity; Adherence.

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RESUMEN

Objetivos: Analizar la relación entre complejidad farmacoterapéutica y cumplimiento de los objetivos terapéuticos en pacientes VIH+ con tratamiento antirretroviral activo y concomitante para la dislipemia.
Material y métodos: Estudio observacional retrospectivo. Se seleccionaron pacientes con VIH en tratamiento antirretroviral estable durante los últimos 6 meses y tratamiento para la dislipemia entre enero-diciembre de 2013. Se calculó el índice de complejidad a través de la herramienta desarrollada por Mc Donald et al. Otras variables analizadas fueron: edad; sexo; factor de riesgo de adquisición del VIH; consumo de tabaco, alcohol y drogas; alteraciones psiquiátricas; adherencia al TAR y a fármacos hipolipemiantes y parámetros clínicos (carga viral VIH, recuento de CD4, niveles plasmáticos de colesterol total, LDL, HDL, y triglicéridos). Para determinar factores predictivos asociados con el cumplimiento de los objetivos terapéuticos se realizó un análisis univariante mediante regresión logística y, posteriormente, un análisis multivariante.
Resultados: Se incluyeron 89 pacientes. El 56,8% cumplieron los objetivos terapéuticos para la dislipemia. El índice de complejidad fue significativamente mayor (p = 0,02) en pacientes que no alcanzaron los valores objetivo (mediana de 51,8 vs 38,9). La adherencia al tratamiento hipolipemiante fue relacionada de forma significativa con el cumplimiento de los objetivos terapéuticos establecidos para el tratamiento de la dislipemia. El 67,0% cumplieron los objetivos para el TAR, sin embargo el índice de complejidad no fue significativamente mayor (p = 0,06) en los pacientes que no cumplían objetivos.
Conclusiones: La complejidad farmacoterapéutica constituye un factor clave en la consecución de los objetivos de salud en pacientes VIH+ que reciben tratamiento para la dislipemia.

Palabras clave: VIH; Dislipemia; Complejidad farmacoterapéutica; Adherencia.

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Contribution to scientific literature

Comorbidities associated with HIV are currently requiring a global pharmacotherapeutical follow-up of these patients, not only focused on their antiretroviral medication, due to the chronification of this disease and the population aging, among other factors. One of the most prevalent comorbidities in this group of patients is dyslipidemia. On 2011, the last American Consensus was published, recommending that pharmacotherapeutical follow-up for patients should be prioritized according to the complexity indexes of treatment. There is one tool already available for this, developed by McDonald et al, which allows to calculate the complexity index for any type of treatment regimen. However, no study has used said approach in order to demonstrate the relationship between pharmacotherapeutical complexity and compliance of pharmacotherapeutical objectives in the HIV setting.

This study demonstrates the utility and relationship between the pharmacotherapeutical complexity of treatments prescribed and the compliance of therapeutic objectives established for HIV+ patients on dyslipidemia treatment. Our outcomes indicate that the majority of patients present an adequate control of their HIV; however, practically half of them are not meeting the therapeutic objectives for dyslipidemia; the probability for this is higher in those with a higher pharmacotherapeutical complexity index.

Understanding this aspect will allow specialists to select those patients who require a closer and more intensive pharmaceutical care.

 

Introduction

High-activity antiretroviral treatment (ART) has reduced to a high extent the morbimortality caused by HIV infection, and turned it into a chronic disease^1,2,3,4,5. This fact has changed significantly the current view of HIV as a disease, and the development of other comorbidities common to the rest of the overall population has acquired an increasingly higher importance.

In this sense, HIV+ patients present an increased cardiovascular risk compared to the overall population⁶. Some of the reasons leading to this increase are the metabolic alterations caused by the virus, as well as the dyslipidemia caused by some antiretroviral drugs^7,8. The presence of these concomitant diseases varies according to the different populations analyzed. In the D:A:D cohort⁹ there was a 33% prevalence of patients with hypertriglyceridemia and 22% with hypercholesterolemia. Similar outcomes were found in another recently published study, where there was a 35% prevalence of dyslipidemia¹⁰. However, in a study conducted in 2009 with HIV patients >70-year-old, there was a 54% prevalence of dyslipidemia¹¹, a value significantly above those obtained in other studies.

Currently, ART simplification is already a reality for certain patient types. However, due to the individualized nature of the prescription of this type of drugs, there are many treatment regimens that continue being complex. And we must add to this fact the difficulty represented by the treatment of concomitant conditions, such as hypercholesterolemia and/or hypertriglyceridemia, in terms of patients understanding their therapeutic regimens.

An optimal adherence to antiretroviral treatment, allowing to maintain its strict compliance, is essential in order to achieve the therapeutical objectives intended with this type of therapies: virological suppression and immunological recovery¹². However, even though hospital pharmacists have focused a major part of their activity in HIV patient follow-up, the outcomes of the Andhalusida study¹³ have demonstrated that lack of training and time are impairing the development of support measures for antiretroviral adherence.

According to the latest American Consensus on pharmaceutical practice¹⁴, pharmacotherapeutical follow-up of patients must be conducted based on therapy complexity criteria, as well as the severity of the disease and other comorbidities. On 2007, Martin et al published¹⁵ an approximation to an Antiretroviral Complexity Index, which was the first step to determine the relationship between the complexity of antiretroviral treatments, adherence, and the clinical outcomes obtained. Among others, the following data were taken into account when preparing this index: dosing regimen, pharmaceutical formulation, storage conditions, or instructions on how to take the medication adequately. As stated in the publication by Martin el al.¹⁵, this index presents a series of limitations. Firstly, only retroviral medication is taken into account, it has not been developed or validated for the rest of the concomitant medication (moreover, the antiretroviral armamentarium currently available is much more varied than the one existing back in 2007). Secondly, it must be explained how treatment complexity affects adherence, and to determine a cut-off point in the index to indicate which patients are at higher risk of lack of compliance due to their treatment complexity. Subsequently, Mc Donald et al.¹⁶ developed a tool which allowed to calculate the complexity index for any type of regimen. However, there is still no knowledge about the impact of complexity on adherence and therapeutic success.

The objective of this study is to analyze the relationship between the pharmacotherapeutical complexity of the treatments prescribed and the compliance of therapeutic objectives established for HIV+ patients on dyslipidemia treatment (hypercholesterolemia and/or hypertriglyceridemia).

 

Materials and methods

An observational, single-centre, retrospective study, which included all patients who met the previously defined inclusion criteria between January and December, 2013. The study also included those >18-year-old patients on active antiretroviral treatment seen as outpatients in Pharmacy Care Units who had undergone a stable antiretroviral treatment without any modifications during the past 6 months. Additionally, patients should have a prescription by their HIV specialist or Primary Care physician for dyslipidemia treatment (hypercholesterolemia and/or hypertriglyceridemia): statins, fibrates, ezetimibe and/or resins.

All patients should have records for antiretroviral drug dispensed during the period studied (prepared by the Hospital Pharmacy Unit), and a record of prescribed drugs, through electronic prescription, targeted to the concomitant conditions studied (dyslipidemias), dispensed at retail pharmacies.

All those patients included in clinical trials during the period of this study were excluded.

In order to determine the relationship existing between pharmacotherapeutical complexity and the compliance of therapeutic objectives, for HIV infection we have defined it as: undetectable viral load, defined as a value <50 copies/ml, and a normalized level of CD4 lymphocytes (defined as CD4 > 200 cells/μL). For dyslipidemia treatment, it was defined as follows: in the case of hypercholesterolemia, the target LDL level was defined individually for each patient, based on their cardiovascular risk estimated through the SCORE (Systemic Coronary Risk Estimation) System. The following values were determined, based on cardiovascular risk^17,18: very high risk: LDL< 70 mg/dL, high risk: LDL < 100 mg/dL, moderate risk: LDL < 130 mg/dl. For hypertriglyceridemia treatment, the target value of triglycerides was <150 mg/dl.

The following were collected as independent variables: age, gender, complexity index, risk factors of HIV, use of drugs or alcohol, smoking, psychiatric condition, treatment compliance to ART (defined as an adherence rate superior or equal to 90%, according to dispensing records), adherence to lipid lowering treatment (defined as an adherence rate superior or equal to 80%¹⁹), and co-infection by HCV.

Complexity index determination was established by assigning a score to each patient, based on the complexity of their drug therapy. This was conducted through the web tool developed by the University of Colorado¹⁶ available at: http://www.ucdenver.edu/academics/colleges/pharmacy/Research/researchareas/Pages/researchareas.aspx

Patient selection and the assessment of therapeutic adherence regarding antiretroviral treatment were conducted through the Program for Outpatient Dispensing of the Hospital Pharmacy Unit. The identification of patients on treatment with any lipid lowering drug during this specific period, as well as the quantification of adherence to said treatments, was conducted using the Electronic Prescription Program of the Andalusian Health System (Diraya^®).

Clinical and lab test data were collected from the electronic clinical records and lab test reviews.

For statistical analysis, quantitative variables were initially summed up with mean values and typical deviations, or, in case of asymmetrical distributions, with median values and percentiles (P25 and P75); and qualitative variables, with percentages.

In order to compare mean values of quantitative variables among sub-groups, the Student's t test was used for independent samples, or the Mann-Whitney non-parametric U Test in case of non-normal distributions. If any significant differences were observed, 95% Confidence Intervals were found for differences in mean (or median, if relevant) values. On the other hand, contingency tables were prepared and the Chi-Square Test was used in order to analyze the relationship between qualitative variables: or otherwise, the Monte Carlo Asymptotic Method and Exact Test. Table interpretation was conducted through corrected typified residues. Finally, and with the aim to find factors predicting poor compliance, a model of binary logistical regression was conducted after a previous univariate analysis, which identified those independent variables associated with not achieving pharmacotherapeutical objectives, which were then entered into the multivariate model for final selection (the criterion for inclusion of variables in the multivariate model was: those which presented a p<0.25 value in the univariate model).

Given that the objective of the study was to prepare a multivariate logistical regression model in order to identify independent variables to predict compliance with the specified pharmacotherapeutical objectives (yes/no), sample size was determined through Freeman's Rule 10*(k+1), where k is the number of potential predictor variables. As there were 9 predictor variables, the size of the sample should be 100 patients, and accepting 20% losses, it should be 120 patients.

This study was approved by the Andalusian Ethics Committee of Biomedical Research.

 

Results

Eighty-nine (89) patients were included in the study. The majority of patients were male (76.4%). Basal characteristics of patients are shown in Table 1. Regarding type of lipid lowering treatment prescribed, 86.5% of patients received treatment with a statin, 10.1% with fibrates, and 3.4% with combinations of statins and fibrates.

 

 

Out of these patients, 56.2% met the objectives established for dyslipidemia treatment. Table 2 shows a summary of the baseline characteristics of patients based on compliance or lack of compliance with therapeutic objectives. Demographic characteristics of patients, way of infection, use of drugs or alcohol, presence of psychiatric condition, or HCV co-infection, were similar in both groups; no statistically significant differences were found. On the other hand, the median complexity index was significantly higher in those patients who did not meet therapeutic objectives (10.0 vs. 14.7 p=0.027). Likewise, the proportion of patients with adherence to lipid lowering treatment was significantly higher among patients who met the therapeutic objectives (40 vs. 19; p=0.020).

 

 

On the other hand, the outcomes obtained from the multivariate analysis (Table 3) showed that both the complexity index and the adherence to lipid lowering treatment perform as independent predictive factors of compliance with those therapeutic objectives established for dyslipidemia treatment.

 

 

A 67.0% of patients met the objectives established for their antiretroviral treatment. The baseline characteristics of patients, based on compliance or lack of compliance with the objectives, were similar for the majority (Table 4). The mean complexity index was higher in those patients who did not meet the objectives; however, this difference did not reach statistical significance. Regarding adherence, 82% of patients had good adherence to treatment, and no statistically significant differences were found in the proportion of adherent patients who met the objectives and those who did not.

 

 

Discussion

In this study, drug therapy complexity and adherence to lipid lowering treatment have been identified as factors predicting compliance with the therapeutic objectives established for dyslipidemia treatment in HIV+ patients on active ART. So far, the majority of studies conducted on HIV patients have focused exclusively on assessing adherence to ART, as well as on determining the factors associated with ART success. However, the disease chronification, and the gradual increase in the number of patients who present other chronic comorbidities, leads to the need to acquire a more general view, and to conduct pharmacotherapeutical follow-up for each one of the chronic conditions presented by patients, rather than to focus exclusively on antiretroviral medication.

On one hand, polypharmacy, typically defined as the use of 5 or more medications²⁰ , has been associated with a higher risk of lack of adherence in the overall population^21,22,23, and is currently considered one of the greatest challenges in pharmacotherapeutical follow-up for HIV+ patients, at the same level as population aging^24,25. Though this has been less studied in HIV+ patients, polypharmacy has been recently associated with a lower adherence to ARTs²⁶. However, the term polypharmacy refers exclusively to the number of different medications taken by the patient. On the contrary, the concept of therapeutic complexity is more accurate, and currently we already have tools which allow us to determine objectively a numeric value^27,28. Although it has been identified²⁶ that therapeutic regimen complexity has a significant impact on adherence to ART, we continued further in our study, and determined the influence of complexity upon HIV control, and did not find any statistically significant differences; however, we must point out that therapeutic complexity tends to be higher in those patients with no HIV control. At the same time, adherence was not associated with adequate HIV control either. Maybe the reason for these outcomes could be that the majority of patients presented an adequate HIV control.

On the contrary, almost half of patients did not present an adequate control of their dyslipidemia. These outcomes differ from the ones found in other study conducted also with HIV patients¹⁰, where 75% of patients treated with lipid lowering drugs met their therapeutic objectives. However, we must state that these objectives were not as strict as the ones used in our study, and this could justify the difference found. Regarding its influence on dyslipidemia control, we found that the complexity index was significantly higher in those who did not meet the objectives for the treatment of this condition. No studies have determined so far the influence of therapy complexity upon the therapeutic success of the lipid lowering therapy, either in HIV patients or in the overall population.

Adherence to lipid lowering treatment was also another factor predicting therapeutic success²⁹. The adherence rate for lipid lowering treatment is similar to the outcomes of a meta-analysis conducted in non-HIV population, where the mean adherence was 46%. On the other hand, even though in our study we have not determined if there is any relationship between complexity and adherence to lipid lowering treatment, there are published articles where complexity was associated with a lower adherence to this type of drugs^30,31. However, one of the main aspects determining the potential comparison of the outcomes found in different studies is the heterogeneity in the manner of evaluating therapeutic complexity.

All these outcomes and their analysis suggest the need to conduct a closer pharmacotherapeutical follow-up of all the concomitant medication used by the patient, and not only of the ART. Moreover, the complexity index is identified in our study as a key factor in the success of the lipid lowering therapy; therefore, its calculation can represent an essential tool in the pharmacotherapeutical follow-up of patients, in order to stratify them and thus offer the level of pharmaceutical care adequate to their individual needs.

One of the main limitations of this study is its retrospective and single-centre design. Lack of data for some patients led to their exclusion from the study, and to not completing the sample size defined according to Freeman's Rule. However, despite this, the statistical tests applied in multivariate analysis allowed to determine the validity of statistical analysis with the population included in the study (the Hosmer-Lemeshow Test (p=0.435) indicates that the outcomes are valid and reliable). On the other hand, some factors which might have an influence in achieving the therapeutic objectives for dyslipidemia were not taken into account, such as diet or the specific effect of some antiretrovirals on this comorbidity; moreover, there was no analysis of the rest of the medication, other than that targeted at the treatment of dyslipidemia or HIV, which also have an impact on pharmacotherapeutical complexity. Finally, adherence could only be determined through dispensing records, given the study design.

Our results suggest the need to develop future lines of research, with the aim to further understand the cutoff points, within the pharmacotherapeutical complexity index, which delimit therapeutic success and failure. It is also important to determine which factor or factors could be useful at the time of selecting those patients who will require a more complex and intensive pharmaceutical care.

Summing up, while the majority of patients present an adequate HIV control, practically half of HIV+ patients are not meeting the therapeutic objectives for dyslipidemia, particularly those with a higher pharmacotherapeutical complexity index.

 

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Correspondence:
Correo electrónico: ralejandro.morillo.sspa@juntadeandalucia.es
(Ramón Morillo Verdugo).

Recibido el 21 de septiembre de 2015;
aceptado el 4 de noviembre de 2015.