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b Usefulness of pharmacy dispensing records in the evaluation of adherence to antiretroviral therapy in Brazilian children and adolescents
  braz j infect dis.  2012; 16(4) :315–320 The Brazilian Journal of  INFECTIOUS DISEASES www.elsevier.com/locate/bjid Original article Usefulness of pharmacy dispensing records in theevaluation of adherence to antiretroviral therapyin Brazilian children and adolescents  Aline Santarem Ernesto a , Renata Muller Banzato Pinto de Lemos b ,Maria Ivone Huehara c , André Moreno Morcillo a , Maria Marluce dos Santos Vilela a ,Marcos Tadeu Nolasco da Silva a , ∗ a Center for Investigation in Pediatrics, Graduate Program in Child and Adolescent Health, Medical School, Universidade Estadual deCampinas (UNICAMP), São Paulo, Brazil b Municipal Secretary of Health, Campinas, São Paulo, Brazil c Pharmacy, University Hospital, UNICAMP, São Paulo, Brazil a r t i c l e i n f o  Article history: Received 23 March 2012Accepted 14 April 2012 Keywords: Acquired immunodeficiencysyndromeChildAdolescentHighly active antiretroviral therapyMedication adherence a b s t r a c t Introduction:  Adherence, which is crucial to the success of antiretroviral therapy (HAART), iscurrently a major challenge in the care of children and adolescents living with HIV/AIDS. Objective:  To evaluate the prevalence of nonadherence to HAART using complementaryinstruments in a cohort of children and adolescents with HIV/AIDS followed in a referenceservice in Campinas, Brazil. Methods:  The level of adherence of 108 patients and caregivers was evaluated by an adaptedstandardized questionnaire and pharmacy dispensing records (PDR). Non-adherence wasdefined as a drug intake lower than 95% (on 24-hour or seven-day questionnaires), or asan interval of 38 days or more for pharmacy refills. The association between adherenceand clinical, immunological, virological, and psychosocial characteristics was assessed bymultivariate analysis. Results:  Non-adherence prevalence varied from 11.1% (non-adherent in three instruments),15.8% (24-hour self-report), 27.8% (seven-day self-report), 45.4% (PDR), and 56.3% (at leastone of the outcomes). 24-hour and seven-day self-reports, when compared to PDR, showedlow sensitivity (29% and 43%, respectively) but high specificity (95% and 85%, respectively).In multivariate analysis, medication intolerance, difficulty of administration by caregiver,HAARTintakebythepatient,lowersocioeconomicalclass,lackofvirologicalcontrol,missedappointments in the past six months, and lack of religious practice by caregiver were sig-nificantly associated with non-adherence. Conclusion:  A high prevalence of HAART non-adherence was observed in the study popula-tion, and PDR was the most sensitive of the tested instruments. The instruments employedwere complementary in the identification of non-adherence.© 2012 Elsevier Editora Ltda. All rights reserved. ∗ Corresponding author at:  Centro de Investigac¸ão em Pediatria (CIPED), Rua Tessalia Vieira de Camargo, 126, Campinas,SP, 13083-887, Brazil.E-mail address: nolasco@fcm.unicamp.br (M.T. Nolasco da Silva).1413-8670/$ – see front matter © 2012 Elsevier Editora Ltda. All rights reserved.http://dx.doi.org/10.1016/j.bjid.2012.06.006  316  braz j infect dis.  2012; 16(4) :315–320 Introduction Upon the beginning of the fourth decade of the acquiredimmunodeficiency syndrome (AIDS) pandemic, the propor-tion of children and families affected by human immunodefi-ciencyvirus(HIV)infectionremainsanincreasinglyimportantglobal public health problem. It is estimated that there aremore than 33 million people living with the disease acrossthe world. 1 In Brazil every year, around 35,000 new cases arereported,withanestimateof635,000people(0.33%ofthegen-eral population) living with HIV. 2 Since the beginning of theepidemic, around 18,000 AIDS cases were reported in Brazil-ian children younger than 13 years old, approximately 95% of which were vertically acquired. Around 16,600 children bornto HIV-infected mothers were yearly reported, and 815 newpediatriccaseswerereportedin2010alone,foraverticaltrans-mission rate of 4.9%. Such a rate is higher than the targetedgoal, since a national protocol for prevention of vertical trans-mission began to be implemented in 1999. 3,4 The introduction of highly active antiretroviral therapy(HAART) led to a significant reduction in mortality andincrease in the quality of life of people affected by thedisease. 4,5 According to data from the World Health Orga-nization, more than five million people are now receiving treatment, but this is estimated to be only 35% of people whoneedtherapy. 6 InBrazil,asapartofapublichealthpolicycoor-dinated by the Department of Sexually Transmitted Diseases,AIDS, and Viral Hepatitis of the Ministry of Health, access toantiretroviraltherapyisuniversalandfreeofcharge,currentlybenefiting around 200,000 patients. 7 In the current scenario, a major challenge faced by healthservices is to ensure proper adherence to therapy, indispens-able for adequate control of the disease. Studies show thatchildren and adolescents comprise a group with increasedvulnerability in adherence to treatment, who require effec-tive monitoring to maintain the sustainability of a lifelong therapy. 8,9 Inappropriate adherence to antiretroviral therapycauses serious consequences to people living with HIV/AIDS,with increased risk of viral resistance, immune deterioration,opportunisticinfectionsanddeath,sincetheaimsofthetreat-ment are the control of virus replication, and preservation orrecovery of immunocompetence. 10,11 Several studies analyzing the factors associated with non-adherence, using different assessment methods, individuallyor in association, are found in the literature. In most of thereportsadherenceofpatientsorcaregiverswasascertainedbymeans of response to questionnaires, either by self-report orbyinterviewsledbyhealthprofessionals. 12–16 Otherresourcesinclude data from pharmacy dispensing records (PDR); 17,18 electronic drug monitoring (EDM); 19–21 subjective assess-ment by health professionals; 22 counting of pills returnedby patients, in the patient’s home or by telephone; 23,24 andserum drug level determination. 25 Overall, the results fromthe above studies demonstrate a high degree of heterogeneityin adherence outcomes, suggesting the potential usefulnessof complementary approaches.The objective of this study was to assess adherence toHAART and the factors associated with non-adherence, using complementary methods, in a population of HIV-infectedBrazilian children and adolescents attending a reference cen-ter. Materials and methods An observational, cross-sectional study was performed at thePediatricImmunodeficiencyClinicattheHospitaldaUniversi-dade Estadual de Campinas, which is responsible for the careof HIV-infected children and adolescents from the metropoli-tan area of the city of Campinas, state of São Paulo, Brazil. All129childrenandadolescentsfollowedatthisreferencecenter,aged 7 to 19 years-old, were initially selected to participate inthestudy.Patientswithmentalretardation,implyingcognitiveimpairment and neurological diseases, which hindered theunderstanding of the issues proposed, were excluded. A totalof 108 patients (60 males) were evaluated during the periodfrom November, 2008, to December, 2009.Adherence was assessed using an adapted standardizedquestionnaire, 26 and by PDR for antiretrovirals, using datafrom the Logistic Antiretroviral Medicines Control System(Sistema de Controle Logístico de Medicamentos–SICLOM),a centralized pharmacy dispensing system with nationwidecoverage. Interviewed patients and/or their caregivers wereasked about the administration of prescribed medication inthe last 24hours and also in the last seven days. The ques-tionnaire format provided a result in terms of percent of adherence, from 0% to 100%. Patients were considered non-adherent if, in response to the questionnaire, they reportedreceiving less than 95% of prescribed doses in the previous24hours or seven days. The cutoff value of 95% was chosendue to its association with the effective control of viral repli-cationandpreventionofresistancetoHAART. 27 Intheanalysisof SICLOM records, patients were considered non-adherentif an interval of 38 days or more had elapsed from the lastrefill of antiretrovirals, according to recommendations issuedby the Brazilian Ministry of Health. 28 Due to the characteris-tic of the SICLOM records, which are independent both fromthepatient’sreportandtheexaminer’srecords,PDRdatawereusedasstandardsfortheevaluationoftheaccuracyof24-hourand seven-day questionnaire data. Sensitivity, specificity, andpositive and negative predictive values were thus calculatedfor 24-hour and seven-day questionnaire outcomes.Data were also collected on the following independentvariables, related to demographical, social, clinical, immuno-logical and virological conditions: gender, age, socioeconomicstatus, 29 patient and caregiver schooling, caregiver employ-ment status, family income, knowledge of the diagnosis bythe patient, HIV caregiver status, HAART use by caregiver,illicit drug use by caregiver, quality of life scores (using the PedsQL 4.0 TM inventory), 30 orphaned state of patient,adoptive caregivers, missed clinic appointments, religiouspractice by patient or caregiver, difficulties in the admin-istration of medicines, person in charge for administering medicines, medication intolerance, clinical and immunolog-ical classification, 31 HAART complexity, number of previousantiretroviral regimens, protease inhibitor usage, recent HIVviral load and lymphocyte subpopulation counts, and HIVresistance.All interviews were conducted by the first author of thestudy, in a designated room, for approximately 30minutes.  braz j infect dis.  2012; 16(4) :315–320  317 All patients and/or caregivers were informed of the detailsof the study, and those, or their legal representatives, whoagreed to participate were asked to sign an informed consent.The study was approved by the local Committee of Ethics inResearch (statement 711/2008).Study data were stored and analyzed with the StatisticalPackage for the Social Sciences (SPSS) for Windows, version16.0(SPSSInc.,Chicago–IL,USA).Riskwasassessedbycalcula-tion of odds ratios (OR) and 95% confidence intervals. Raw ORvalues were determined by univariate logistic regression, bythe“Enter”method.AdjustedORand95%confidenceintervalswere obtained by multivariate logistic regression, “forwardWald” method, with inclusion p-values of 0.05 and exclusionp-values of 0.10. Results A total of 108 patient-caregiver dyads were interviewed. Themain clinical and demographic characteristics of the studypopulation are shown in Table 1.The prevalence of non-adherence varied from 15.8% (24-hour questionnaire), and 27.8% (seven-day questionnaire)to 45.4%, according to PDR. A total of 11.1% of patientswere considered non-adherent in all three instruments, and54.6% were considered non-adherent in at least one of them.Statistically significant non-adherence risk factors for com-plementary instruments after multivariate analysis were:difficulty of medicine administration by the caregiver, del-egation of responsibility of medicine administration to thechild or adolescent patient, lower socioeconomic class, lackof virological control, lack of religious practice by the care-giver,missedclinicappointments,andmedicationintolerance(Table 2).In relation to PDR, data from 24-hour and seven-day ques-tionnaires showed low sensitivity, but good specificity andpositive predictive values (Table 3). Discussion In the population studied, the evaluation of PDR proved to beaninstrumentcapableofdetectingahigherprevalenceoffail-ure to adhere to ART (45.4%), when compared to standardizedquestionnaires (15.8% for 24-hour recall and 27.8% for seven-day recall). The lowest prevalence of non-adherence wasobserved when considering the three simultaneous instru-ments (11.1%), and the highest prevalence (56.3%) whenindividuals were considered non-adherent by at least one of the instruments. To the authors’ knowledge, this is the firststudy to make such comparison in Latin America. Severalpediatric studies have shown, similarly, the usefulness of PDRanalysis as an indicator of adherence with ART, highlighting its direct association with control of viral replication, in bothdeveloped and developing countries. 15,20,32–34 The usefulness of PDR analysis was also emphasized byGrossberg et al. 17 in a study with adults in the U.S., whichobserved a higher sensitivity and better association with thevirologic response of PDR, when compared to self-report.Bisson et al., 35 and Rougemont et al., 36 also with adults,observed PDR to be more sensitive than the CD4 + Table 1 – Clinical and demographic characteristics of 108study subjects. Variable Values Male gender * 60(55.5%)  Age in years † 13.22 (7.9–19.6) Socioeconomic level *A+B 25(23.1%)C+D 83(76.9%) Caregiver education level *High School or higher 30(27.8%)Elementary School or lower 78(72.2%) Patient education level *High School or higher 24(22.2%)Elementary School or lower 84(77.8%) Monthly per capita income  (US dollars) † 185.18 (11.1–1.296.27) Knowledge of diagnosis by patient * 65(60.2%) HIV-infected primary caregiver * 57(52.8%) Use of HAART by caregiver * 52(48.1%) Employed caregiver * 52(48.1%) Illicit drug use by the caregiver * 1(0.9%) PedsQL 4.0 score - caregiver † 85.8 (9.78–98.9) PedsQL 4.0 score - patient † 84.7 (34.7–100) Orphanhood in relation to at least onebiological parent *61(56.5%) Foster or institutional caregiver * 44(40.7%) One or more missed appointments in the last6 months *32(29.6%) Practice of religion by the caregiver  60(55.6%) Practice of religion by the patient * 59(54.6%) Difficulty in drug administration by caregiver * 19(17.6%) HAART administered by caregiver * 76(70.4%) CDC clinical classification *N, A or B 77(71.3%)C 31(28.7%) Therapeutic regimen *Low complexity (less than 4 ARVs) 72(66.7%)High complexity (4 or more ARVs) 36(33.3%) Number of prior ART regimens *Four or more 59(54.6%)Less than 4 49(45.4%) Use of a protease inhibitor * 66(61.1%) Intolerance to medication * 19(17.6%) CD4 + lymphocyte count <500/mm 3 * 24(22.2%) CD4/CD8 ratio ≥ 1* 22(20.4%) Controlled viral replication  (<50copies/mL)* 54(50%) Resistance to ARVs  (34 subjects) † Classes 3(0–4)NRTI 5(0–6)NNRTI 2(0–2)PI 3(0–8)Total ARV 10(0–16)*proportions;  † median and extreme; CDC, Centers for DiseaseControl and Prevention/Ministry of Health; HAART, highly activeantiretroviral therapy; NRTI, reverse transcriptase inhibitors,nucleoside analog; NNRTI, reverse transcriptase inhibitors, non-nucleoside; IP, protease inhibitor. T-lymphocyte count as a predictor of virologic failure. Incontrast, Acri et al., 21 reported low correlation between EDMandPDRinastudyinadults.However,theauthorspointedoutthat the PDR data in that report were obtained retrospectively  318  braz j infect dis.  2012; 16(4) :315–320 Table 2 – Comparison of complementary adherence outcomes after multivariate analysis. Independent variable 24-hour questionnaire 7-day questionnaire Pharmacy dispensing recordsOdds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CIIntolerance to medication 9.11 2.87–28.98Difficulty in administering medication 2.91 1.05–8.12Medicine administration by patient 3.59 1.47–8.78Lower socioeconomic class 3.54 0.97–2.85Lack of virological control ( ≥ 50 copies/mL) 3.73 1.68–8.31Caregiver without religious practice 3.19 1.36–7.50One or more missed appointments in thelast 6 months3.27 1.38–7.78 Table 3 – Parameters of comparison between 24-hourand seven-day questionnaires, using pharmacydispensing records as standards. 24-hourquestionnaire7-dayquestionnairePositive predictive value 82% 70%Negative predictive value 38% 64%Sensitivity 29% 43%Specificity 95% 85% from commercial pharmacies, rather than from a centralizedPDR, which was the case in the present study.In a recent review, Bangsberg  37 highlighted the practi-cality of using PDR, with the advantage of not relying onexpensive devices, and also, in relation to self-report, of itsindependence from patient cooperation. The characteristicsof such pharmacy registry in the health services of hospitalsof the present study, with universal distribution of antiretro-virals and centralized dispensation with physical proximityto the outpatient service, plus the 30-day provision limitsand computerized control, make this quite simple procedurea practical and feasible instrument for adherence control.Due to these characteristics, PDR monitoring has been rec-ommended by the Ministry of Health. 31 The 45.4% non-adherence rate detected in the presentstudy by PDR appears to be higher than usually reported.Systematic reviews of international pediatric studies relatedvariability in the prevalence of adherence between 49%and 100%, with 76% of studies reporting adherence above75%, with a trend towards greater adherence in developing countries. 32,34 These contrasting results are probably mainlyduetotheusuallyhighersensitivityofPDR,whencomparedtothe most commonly used self-report or interview methods. 37 In order to identify not only the prevalence of adherencefailure, but also the associated risk factors, providing a foun-dation for successful interventions, there is a tendency in theliteraturetorecommendthecombinationofmethods,asusedin this study. The results of several studies with different sce-narios reinforce these recommendations. 23,38 Noteworthy arethedataobtainedbyLlabreetal. 39 that,inalongitudinalstudy,used different methods for measuring adherence (self-report,interviews and EDM), on multiple occasions. Consistently, theuse of at least two methods was significantly associated withcontrol of viral replication.Among the independent variables analyzed in the presentstudy, multivariate analysis found seven risk factors fornon-adherence: difficulty of medicine administration by thecaregiver, delegation of responsibility of medicine adminis-trationtothechildoradolescentpatient,lowersocioeconomicclass,lackofvirologicalcontrol,lackofreligiouspracticebythecaregiver, missed clinic appointments, and medication intol-erance.Thedifficultyofadministrationofmedicationwasreportedas a non-adherence risk factor, associated with higher viralloads, by Allison et al., 40 in a study with caregiver interviews.In contrast with the present study, Biadgilign et al. 41 reportedthat 97.4% of participants had positive attitudes regarding theadministrationofantiretroviraldrugs,despite22.3%reporting particular difficulties, such as children spitting the medica-tion, resistance and refusal, and the need for simultaneousadministration of several drugs.Although this analysis reveals the delegation of responsi-bility of administration of ART to pediatric patients as a riskfactor for adherence failure, no other reports in the litera-ture that have directly addressed this important associationwere found. An analogous situation, however, is reported byWilliams et al., 42 who identified improved adherence in situ-ations of care provided by caregivers without a biological con-nection,orincasesofsocialsupportsystemsaimedathelping adolescents to remember the timing of medication doses. Inthe authors’ interpretation, delegating to adolescents theirowncareinsituationsofchronicdisease,withoutclosesuper-vision, may constitute an excessive responsibility burden.Anassociationbetweenlowersocioeconomicclassandriskof non-adherence was observed. Similar findings were alsoreported by Cupsa et al., 43 in a pediatric adherence study inRomania.Intheauthors’view,lowerfamilyincomemayactasa social stress feature, with potential harmful consequencesto a succesful therapy.The group of patients whose caregivers reported regu-lar religious practice showed a significantly lower prevalenceof non-adherence. These results are consistent with thoseobserved by Park and Nachman, 44 who analyzed the pat-terns of adherence to ART in relation to religious beliefs inanadolescentHIV-infectedpopulation.Individualswithexcel-lent adherence had significantly higher scores of religiousbeliefs than those who had low adherence. No specific dataabout caregivers was found in the literature, but it is possiblethat religious practice provides stronger community support,which may be helpful in the setting of a chronic disease.  braz j infect dis.  2012; 16(4) :315–320  319 The association of missed appointments with adherencefailure is straightforward. Absentees are at greater risk of fail-ingtofollowthetreatmentproperly.Vreemanetal. 32 reportedthatmorethanhalfofthechildrenhavelostatleastamonthlyconsultation, but these authors did not approach the associa-tion with treatment adherence.Intolerance to antiretrovirals was significantly associatedwith lower adherence, according to the evaluation measuresin the 24hours preceding the interview. A qualitative analy-sis in order to obtain a deeper understanding of the factorsthat influence adherence to antiretroviral therapy in a pedi-atric population in Southern India described factors relatedto the drugs that influence adherence, showing comparableresults. The difficulty of adherence was associated with sideeffects, size and arrangements of the tablets, and flavor andtaste of pediatric formulations. 45 Viral load, as a frequent clinical analysis procedure, of utmost importance in its relationship to a successful treat-ment, appears as an important adherence factor in moststudiesrelatedtoART.Thepresentstudyrevealedasignificantdirect association between virological control and adherenceto treatment, as measured by pharmacy data. Similar resultswere presented by several other reports. 15,17,20,24,25,33,40,42 The main limitation of this study is its cross-sectionaldesign, causing susceptibility to confounding factors. Also,noneoftheadherenceinstrumentsusedisflawless.Theuseof questionnaires in interviews involves subjective factors suchas memory difficulties and embarrassment of the patient orcaregiver,whomayfearthejudgmentonthepartofthehealthprofessional. 46 PDR, which is considered to be a preferredinstrument, is also susceptible to errors. It is not possible toprove whether the dispensed drug was effectively ingested,at the right schedule, and that it reached therapeutic levels.There is a risk of overestimating adherence failures, espe-cially in short-term approaches in the case of patients whohave small stocks of medicines at home. The authors believe,however, that most of these deficiencies are overcome in thiscountry, by the centralization of dispensing and the comput-erized control of refills. Conclusions In the population studied there was a high prevalence of fail-ure of adherence to ART, with higher detection sensitivitywhen using pharmacy dispensation records. The instrumentsused were complementary in identifying risk factors for non-adherence.Adherence failure can result in catastrophic consequencesfor the patient and the community, potentially resulting inhigher morbidity and even death. In a scenario of universalaccess to treatment, as in Brazil, a public health initiativewhose merit is internationally recognized, such an outcomeshould not be accepted. These facts highlight the importanceof encouraging health services to adopt a proactive stance topreventuncontrolledviralreplication,assuringbettersurvivaland quality of life for patients who need a lifelong courseof therapy. To achieve this goal, the risk factors associatedwith non-adherence, as identified in this study, should beroutinely considered during the follow-up of patients andtheir caregivers in order to plan specific interventions. Dueto its sensitivity and feasibility, adherence assessment by PDRshouldbeincludedintheroutinepreparationofpatientvisits. Conflict of interest  All authors declare to have no conflict of interest. Acknowledgements This study was supported by the Fundac¸ão de Amparo àPesquisa do Estado de São Paulo (FAPESP), scholarship No.2009/06948-0, and by the Fundo de Apoio ao Ensino, Pesquisae Extensão (FAEPEX) UNICAMP, grant No. 0449/08. references 1. The Joint United Nations Programme on HIV/Aids. UNAIDS.AIDS epidemic update [Internet]. [cited 27 June 2011]Available at: www.unAids.org/globalreport/documents/20101123 globalreport full en.pdf 2. Brazil, Brazilian Ministry of Health, Division of HealthSurveillance, National Program on STD/AIDS. EpidemiologicBulletin AIDS. Year VI No 01. July to December 2008/January to June 2009. Brasília; 2009.3. Brazil, Brazilian Ministry of Health, Division of HealthSurveillance, National Program on STD/AIDS. EpidemiologicBulletin AIDS. Year VII No 01. July to December 2009/Januaryto June 2010. Brasília; 2010.4. Ramos AN, Matida LH, Hearst N, Heukelbach J. AIDS inBrazilian children: history, surveillance, antiretroviral therapyand epidemiologic transition, 1984-2008. AIDS Patient CareSTDS. 2011;25:245–55.5. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV:children, adolescents, and young adults with perinatallyacquired HIV infection. Annu Rev Med. 2010;61:169–85.6. The Joint United Nations Programme on HIV/Aids. UNAIDS.AIDS epidemic update. December 2007.7. Greco DB, Simão M. Brazilian policy of universal access toAIDS treatment: sustainability challenges and perspectives.AIDS. 2007;21 Suppl 4:S37–45.8. Reference and Training Center STD/AIDS. Adherence–fromtheory to practice. Successful experiences in the State of SãoPaulo/organization Joselita Maria Magalhães CaracioloShimma and Emi. São Paulo, 2007. [cited 17 July 2011]Available from: http://www.crt.saude.sp.gov.br/resources/crt Aids/pdfs/adesao.pdf 9. Reisner SL, Mimiaga MJ, Skeer M, Perkovich B, Johnson CV,Safren SA. A review of HIV antiretroviral adherence andintervention studies among HIV-infected youth. Top HIV Med.2009;17:14–25.10. Esteban Gómez MJ, Escobar Rodríguez I, Vicario ZubizarretaMJ, Climente Pollán J, Herreros de Tejada A. Influence of antiretroviral therapy characteristics on pediatric patientadherence. Farm Hosp. 2004;28 6 Suppl 1:34–9.11. Malee K, Williams P, Montepiedra G, McCabe M, Nichols S,Sirois PA, et al. Medication adherence in children andadolescents with HIV infection: associations with behavioralimpairment. AIDS Patient Care STDs. 2011;25:191–200.12. Brigido LF, Rodrigues R, Casseb J, Oliveira D, Rossetti M,Menezes P, et al. Impact of adherence to antiretroviraltherapy in HIV-1–infected patients at a university publicservice in Brazil. AIDS Patient Care STDS. 2001;15, 597–593.
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