Antiretroviral therapy adherence in Brazil

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1 Antiretroviral therapy adherence in Brazil Maria I.B. Nemes, Heráclito B. Carvalho and Maria F.M. Souza Objectives: This study evaluated the adherence to antiretroviral therapy (ART) in 322 Brazilian outpatient services located in seven states providing care to patients (72%) under ART. Methods: A previous study classified the 322 health services into four levels of quality of care. Sixty of them were randomly chosen on the basis of these levels. A crosssection of 1972 patients under ART visiting these services was interviewed using a structured questionnaire. Patients who reported taking more than 95% of the prescribed antiretroviral pills in the past 3 days were considered adherent. The chi-square test was first used to compare the prevalence of non-adherence among two or more categories of variables. A chi-square test for linear trend was used for ordinal variables. Three multivariate models were applied using health services predictors, treatment predictors, and personal characteristics predictors. The predictors were fitted into logistic regression models using backward elimination procedures. Results: The adherence prevalence was 75% (95% confidence interval ). The level of quality of care was not associated with non-adherence. The models showed the following predictors of non-adherence: related to health services: services with 100 patients or less and missed appointments; related to treatment: more complex regimens and a high number of pills; related to personal characteristics: under 2 years of formal education. Conclusion: The adherence prevalence was similar to the rates currently obtained in developed countries. However, services with few patients need to be carefully monitored to maintain high rates. Care planning that prioritizes patients at risk also needs to be improved. & 2004 Lippincott Williams & Wilkins AIDS 2004, 18 (suppl 3):S15 S20 Keywords: adherence, AIDS, anti-hiv agents therapeutic use, antiretroviral therapy, compliance Introduction Currently, Brazilians receive antiretroviral therapy (ART) from 540 service sites throughout the country. Since 1998, the Qualiaids group has conducted evaluations of the Sexually Transmitted Disease/AIDS Brazilian Programme focusing on issues of quality of care and adherence [1 4]. The first year Brazilian study examining ART adherence was conducted in 27 health service sites and interviewed 1041 patients. It used 80% of the prescribed pills as the cut-off point for measuring adherence, and found an adherence prevalence rate of 69% among the patients studied [1 3]. This present study evaluated adherence to ART in 322 Brazilian outpatient sites that provided care to patients (72% of all patients enrolled in the programme) in seven Brazilian states (São Paulo; Rio de Janeiro; Rio Grande do Sul; Mato Grosso do Sul; Ceará; Maranhão; Pará) in all five Brazilian regions (southeast, From the Department of Preventive Medicine Medical School, University of São Paulo, Brazil. Qualiaids is a multidisciplinary group formed by professors and AIDS programme professionals that deals with research and training in AIDS programmes evaluation and monitoring. Correspondence to Professor Dr Maria Ines Battistella Nemes, Departamento de Medicina Preventiva da FMUSP Brasil, Avenida Dr Arnaldo, o. andar Cerqueira Cezar, São Paulo, Brasil CEP Tel: ; fax: ; mibnemes@usp.br DOI: /01.aids ISSN & 2004 Lippincott Williams & Wilkins S15

2 S16 AIDS 2004, Vol 18 (suppl 3) south, centre west, northeast and north region, respectively). These health services were government run. A previous study analysed the quality of care of these services. The team of each service answered 112 structured questions describing the characteristics of the service delivery, resource availability and management. Focus groups with patients and doctors and a pilot study in 20 randomly chosen health services helped define the questionnaire. The answers from the services were classified into three scores of quality: 0 (lowest), 1 (medium), 2 (highest). The services were ranked according to the mean of scores of all variables, and were grouped based on K-means cluster analysis. The model of analysis was validated by comparison with a qualitative evaluation previously carried out in 27 services. The services have shown high means in the indicators related to structure (availability of medicines, laboratory tests and human resources). The indicators related to the process of care and management have shown lower means. The total average was (56% of the maximum). The lowest was (28%) and the highest was (84%). The K-means cluster analysis distinguished four groups of quality. The very good group included 76 health services (23.6%), the good group 53 (16.5%), the poor group 113 (35.1%) and the very poor group 80 (24.8%) [4 6]. Methods A cross-sectional study was carried out involving 1972 outpatients on ART sampled from 60 health services sites, randomly chosen according to the four levels of quality of care [4 6]. A structured questionnaire was administered to the patients who had been visiting these services. Inclusion criteria Patients were eligible to participate in the study if they were older than 18 years, were not pregnant and had been on ART for at least 2 months. They were approached during either a pre-booked medical appointment or an emergency appointment in the clinic. The study objectives were explained and those patients interested in participating signed a voluntary informed consent form. Instruments A structured questionnaire consisting of 68 questions and five different sections was developed. Patients were asked to report the number and type of antiretroviral pills taken in the past 3 days. In order to facilitate the identification of the drugs, an antiretroviral drug folder with pictures and pill samples was used. To avoid information bias, Qualiaids interviewers who had been trained in previous studies performed the interviews. Adherence measure Patients who reported taking more than 95% of their prescribed pills in the past 3 days were considered to be adherent. Predictor variables The potential non-adherence predictors chosen were: (i) patient personal characteristics: age, sex, risk of transmission and literacy; (ii) health service characteristics and patient relationship with care received: level of quality of care (four categories according to previous study [5,6]), number of patients, previous non-adherence in the past 6 months and missed appointments in the past 6 months; (iii) treatment characteristics: time on ART, number of pills prescribed, probable lipodystrophy and regimen. The probable lipodystrophy variable was obtained as a dichotomous variable (yes/ no) assessed by self-report of morphological abnormality in the face after ART. The other treatment-related variable was the ART regimen composed of five categories according to the combination of nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). The fifth category others contained many different drug combinations, most of them being rescue regimens, with each having a low frequency of prescription. Data analysis The crude prevalence of non-adherence was estimated and its 95% confidence interval (CI) calculated. The associations between non-adherence and variables relating to health services, treatment and patient personal characteristics were examined. The chi-square test was first applied to compare the prevalence of non-adherence among two or more categories of variables. The chi-square test for linear trend was used for ordinal variables. Three multivariate models were applied (health services predictors, treatment predictors, personal characteristics predictors). The predictors were fitted into three different logistic regression models using a backwards elimination procedure. The analysis used Stata 8.0 software (StataCorp LP, College Station, Texas, USA). Stratified analysis examined the relationship between non-adherence, the level of quality of care and the number of patients using the Mantel Haenzel odds ratio. Results A total of 1972 patients under ART from 60 health services sites were interviewed. Three per cent of the patients refused to participate. This was fewer than expected from the sample estimate of 13%. The adherence prevalence estimate was 75.05% (95% CI

3 Antiretroviral therapy adherence in Brazil Nemes et al. S ). The results below took into account the three different groups of variables. Patient characteristics The mean age of the sample was 39.3 years (95% CI ) and the mean years of education was 5.8 (95% CI ). The sample included more men (62% or 1221 men) than women (38% or 751 women). The participants reported their risk of transmission as follows: 53.7% heterosexual, 25% men who have sex with men, and 10.8% injection drug users. The variables associated with non-adherence were the educational level (P, 0.01), and the age quartile (P ¼ 0.044, without linear trend). The patients with fewer years of education were more likely to be nonadherent than those with more years of formal education. Being years old showed a slight chance of protection against non-adherence compared with those in the youngest quartile. In relation to the reported risk of transmission, injecting drug use showed a slightly higher chance of non-adherence than reported heterosexual transmission (Table 1). Logistic regression analysis In the logistic regression model, the category with less than 2 years of education (defined as functionally illiterate), and age quartile years were retained in the model. Less than 2 years of formal education was a non-adherence predictor, and the age quartile years was a protective non-adherence predictor (Table 2). Health services and the patient s relationship with care received The level of quality of care did not reveal differences in the prevalence of non-adherence. The health services with 100 patients or less, previous non-adherence, and missed appointments were associated with non-adherence (Table 1). A linear trend was observed for the association with previous non-adherence. The higher the previous nonadherence, the higher the current non-adherence (P, 0.001). The variable missed appointments also showed a linear trend; however, the ability to predict the current non-adherence was weaker than the previous non-adherence (Table 1). Logistic regression analysis The variable previous non-adherence was the only variable retained in the final model for the health services. Table 2 shows a model in which two other variables emerged after removing the previous nonadherence. The variables missed appointments and services with 100 patients or less were significantly associated with current non-adherence when previous non-adherence was withdrawn. Stratified analysis Compared with health services with 500 patients or more, health services with 100 patients or less were more likely to have non-adherent patients, independently of the level of quality of care. (Table 3). Treatment The regimen two NTRI and one NNTRI was chosen as the baseline category because the Brazilian consensus on ART recommends this as the starting regimen. As shown in Table 1, the prevalence of non-adherence with this regimen was 22%. The regimens two NTRI and one NNTRI and two NTRI and one PI represented 80% of all prescribed regimens. The antiretroviral drug category others was associated with non-adherence. Also patients taking two NTRI and one PI were more likely to be nonadherent (Table 1). The number of pills and the time on treatment showed a linear trend for non-adherence (P, 0.001). The higher the number of pills, the higher is the nonadherence. In relation to time, only patients who had been more than 6.5 years on treatment were more likely to be non-adherent. Probable lipodystrophy was not associated with non-adherence (Table 1). Logistic regression analysis The logistic regression model observed a higher chance for non-adherence associated with the number of pills. The antiretroviral regimen was not found to be a nonadherence predictor, except for the category others (Table 2). Discussion The adherence rate obtained in this study was similar to rates currently obtained in recent studies from developed countries that used similar methodology, i.e. self-report, and that were conducted in several sites [7 13]. In addition, these results suggest an increase in the Brazilian prevalence of adherence when compared with the previous study conducted in São Paulo, Brazil, in 1999 [1,3], despite different comparison parameters. With regard to the quality of care, there was no statistical significant difference among the rates observed in the health services grouping. The appropriate availability of all the antiretroviral medicines throughout the country, as noted in the previous study on quality of care [4,5], is probably the main reason for this homogeneous rate. On the other hand, a classification of 322 services into only four levels of care could not take into account

4 S18 AIDS 2004, Vol 18 (suppl 3) Table 1. Non-adherence prevalence and odds ratio according to health services, treatment and personal characteristics predictor variables in Brazil, Variable Total Prevalence n (%) Odds ratio 95% CI Health services predictors Quality of care a A (26.82) 1.00 B (22.80) C (26.57) D (24.23) Number of patients (23.78) (22.34) (26.24) < (32.35) Previous non-adherence No (13.14) day (24.28) days (28.33) days (56.75) Missed appointments No (21.84) 1.00 Once (29.71) More than once (36.43)) Treatment predictors Regimen 2 NRTI 1 NNRTI (22.07) NRTI 1 IP (28.05) NRTI (18.98) NRTI 1 NNRTI 1 IP (25.81) Others (41.38) Number of pills (16.06) (24.62) (28.48) (31.17) Time on treatment (years) < (22.57) (22.43) (24.60) (28.77) (30.08) Probable lipodystrophy No (24.89) 1.00 Yes (24.89) Personal characteristics predictors Age (quartiles) (24.75) (26.95) (27.60) (20.49) Sex Male (23.83) 1.00 Female (26.67) Education (years) (22.15) (23.48) (25.52) (23.29) (30.02) Risk of transmission Heterosexual (24.57) 1.00 MSM (22.97) Transfusion (24.88) IDU (31.13) a A, Best +; B, best; C, worst; D, worst. CI, Confidence interval; IDU, injection drug users; MSM, men who have sex with men; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; Others, contains many different drug combinations; PI, protease inhibitors.

5 Antiretroviral therapy adherence in Brazil Nemes et al. S19 Table 2. Logistic models for non-adherence according to health services, treatment and patient predictors in Brazil, Predictors OR crude OR adjusted* 95% CI adjusted* Health services predictors a Number of patients < Missed appointments Once More than once Treatment predictors b Regimen Others Number of pills Patient predictors c Age Education level 0 2 years *Adjusted by logistic regression models for related variables. a Quality of care, number of patients, previous non-adherence, missed appointments. b Regimen, number of pills, time on treatment, probable lipodystrophy. c Age, sex, education, transmission risk. Table 3. Odds ratio for non-adherence according to number of patients of health services in Brazil, Number of patients OR crude OR adjusted a 95% CI adjusted a < * CI, Confidence interval; OR, odds ratio. a Adjusted for the level of quality of care; *P ¼ many relevant dimensions of care. In order to examine the relationship between adherence and quality of care more thoroughly, it would be necessary to conduct a more complete evaluation that would imply having more than four levels to classify the quality of care. In the previously mentioned earlier Brazilian study, the 27 participating health services grouped the services into nine levels of quality of care. This much more detailed assessment of quality of care enabled the study to show the association between quality and adherence. The health services rated the worst in terms of quality of care showed a chance of non-adherence 20 times more than the health services classified in the level of best quality of care [1,2]. The observed association of non-adherence and health services with 100 patients or less and missed appointments when previous non-adherence was removed indicated that previous non-adherence is not a predictor, but rather a global indicator of problems that might P be associated with current non-adherence. In addition, the results showed that missed appointments could be a simple and reliable indicator that could be controlled by the health service. This result agreed with those of the previous Brazilian study [1,2]. In relation to treatment predictors, the number of pills is probably a global indicator because it involves the regimen itself, i.e. the number of pills and the frequency and time that they must be taken. An association was observed between the antiretroviral regimen and the number of pills (P, 0.001). The combinations with PI contained more pills than the regimens without PI. On the other hand, the regimen others, which was the only regimen retained in the logistic model, grouped most of the rescue regimens that were more likely to have been taken by patients with a longer time on treatment. Probable lipodystrophy was not associated with nonadherence, a finding that was the opposite of several previous studies [14]. This result could have been caused by the definition used (self-reported abnormality in the face). However, this difference may also reflect a local side-effect characteristic. A very low education level was a predictor of nonadherence. In Brazil, education level has been considered in several studies as the best indicator of social status. In addition, the spread of epidemics has shown an increasing incidence in groups with low education [15]. Although several studies from developed countries have not observed an association between social status and adherence [16 20], results from poorer countries seem to be different. This is supported by earlier Brazilian studies [1,2,21]. Despite free access to antiretroviral drugs, other economic barriers can be a threat to adherence [16]. This issue should be considered now when access in the public sector is expanding in developing countries. As in several previous studies, the risk of transmission was not associated with non-adherence [1,2,22 25]. The results also support other studies [17,26] that showed the protective effect of age. This study is a work in progress. The researchers are now analysing the results as a whole, as well as examining their relationship with the results of their qualitative studies. So far, the results have provided guidance to the Brazilian ART programme in order to improve adherence. In relation to programme policy, it is recommended to keep on providing universal access to all antiretroviral drug regimens, and to monitor indicators of quality of care and adherence carefully, especially when health service settings with few patients are used. In relation to health services management, it is recommended to have care planning that prioritizes

6 S20 AIDS 2004, Vol 18 (suppl 3) patients at risk, especially those who have missed appointments or who have been taking more complex antiretroviral regimens. In relation to the health team, it is recommended that they communicate well in order to be understood by all patients, especially those who are functionally illiterate. Sponsorship: This study was funded by the Brazilian Ministry of Health and FAPESP (São Paulo State Research Foundation) no. 99/ References 1. Nemes MIB. Aderência ao tratamento por anti-retrovirais em serviços públicos no estado de ARVT [Adherence in public health services of Sao Paulo State]. Health Report Série Avaliação 1. Ministry of São Paulo. Available at: Nemes MIB, Marinho MFS, Kalichman A, Granjeiro R, Alencar S, Castanheira L, et al. Antiretroviral (ARV) adherence prevalence in Sao Paulo, Brazil. In: 13th International AIDS Conference. Durban, South Africa, 2000 [Abstract ThPeB4976]. 3. 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