Pharmacy refill adherence outperforms self-reported methods in predicting HIV therapy outcome in resource-limited settings

Raphael Z Sangeda, Fausta Mosha, Mattia Prosperi, Said Aboud, Jurgen Vercauteren, Ricardo J Camacho, Eligius F Lyamuya, Eric Van Wijngaerden, Anne-Mieke Vandamme, Raphael Z Sangeda, Fausta Mosha, Mattia Prosperi, Said Aboud, Jurgen Vercauteren, Ricardo J Camacho, Eligius F Lyamuya, Eric Van Wijngaerden, Anne-Mieke Vandamme

Abstract

Background: Optimal adherence to antiretroviral therapy is critical to prevent HIV drug resistance (HIVDR) epidemic. The objective of the study was to investigate the best performing adherence assessment method for predicting virological failure in resource-limited settings (RLS).

Method: This study was a single-centre prospective cohort, enrolling 220 HIV-infected adult patients attending an HIV/AIDS Care and Treatment Centre in Dar es Salaam, Tanzania, in 2010. Pharmacy refill, self-report (via visual analog scale [VAS] and the Swiss HIV Cohort study-adherence questionnaire), pill count, and appointment keeping adherence measurements were taken. Univariate logistic regression (LR) was done to explore a cut-off that gives a better trade-off between sensitivity and specificity, and a higher area under the curve (AUC) based on receiver operating characteristic curve in predicting virological failure. Additionally, the adherence models were evaluated by fitting multivariate LR with stepwise functions, decision trees, and random forests models, assessing 10-fold multiple cross validation (MCV). Patient factors associated with virological failure were determined using LR.

Results: Viral load measurements at baseline and one year after recruitment were available for 162 patients, of whom 55 (34%) had detectable viral load and 17 (10.5%) had immunological failure at one year after recruitment. The optimal cut-off points significantly predictive of virological failure were 95%, 80%, 95% and 90% for VAS, appointment keeping, pharmacy refill, and pill count adherence respectively. The AUC for these methods ranged from 0.52 to 0.61, with pharmacy refill giving the best performance at AUC 0.61. Multivariate logistic regression with boost stepwise MCV had higher AUC (0.64) compared to all univariate adherence models, except pharmacy refill adherence univariate model, which was comparable to the multivariate model (AUC = 0.64). Decision trees and random forests models were inferior to boost stepwise model. Pharmacy refill adherence (<95%) emerged as the best method for predicting virological failure. Other significant predictors in multivariate LR were having a baseline CD4 T lymphocytes count < 200 cells/μl, being unable to recall the diagnosis date, and a higher weight.

Conclusion: Pharmacy refill has the potential to predict virological failure and to identify patients to be considered for viral load monitoring and HIVDR testing in RLS.

Figures

Figure 1
Figure 1
Patients sampling flowchart.
Figure 2
Figure 2
Virological outcome in association with different pharmacy refill adherence rates. Lowest viral load detection limit was 400 copies/ml.
Figure 3
Figure 3
Kaplan Meier survival curves showing the time to recover immunologically by 50 or 100 cells/μL at pharmacy refill at adherence cut-off of 95%.

References

    1. Chaiwarith R, Wachirakaphan C, Kotarathititum W, Praparatanaphan J, Sirisanthana T, Supparatpinyo K. Sensitivity and specificity of using CD4+ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. Int J Infect Dis. 2007;11:413–416. doi: 10.1016/j.ijid.2006.11.003.
    1. Rawizza HE, Chaplin B, Meloni ST, Eisen G, Rao T, Sankalé J-L, Dieng-Sarr A, Agbaji O, Onwujekwe DI, Gashau W, Nkado R, Ekong E, Okonkwo P, Murphy RL, Kanki PJ. Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings. Clin Infect Dis. 2011;53:1283–1290. doi: 10.1093/cid/cir729.
    1. De Luca A, Marazzi MC, Mancinelli S, Ceffa S, Altan AMD, Buonomo E, Prosperi MCF, Pedruzzi B, Noorjehan AM, Scarcella P, Liotta G, Palombi L. Prognostic value of virological and immunological responses after 6 months of antiretroviral treatment in adults with HIV-1 infection in sub-Saharan Africa. J Acquir Immune Defic Syndr. 2012;59:236–244. doi: 10.1097/QAI.0b013e31824276e9.
    1. Nachega JB, Hislop M, Dowdy DW, Chaisson RE, Regensberg L, Maartens G. Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med. 2007;146:564–573. doi: 10.7326/0003-4819-146-8-200704170-00007.
    1. Chi BH, Cantrell RA, Zulu I, Mulenga LB, Levy JW, Tambatamba BC, Reid S, Mwango A, Mwinga A, Bulterys M, Saag MS, Stringer JSA. Adherence to first-line antiretroviral therapy affects non-virologic outcomes among patients on treatment for more than 12 months in Lusaka, Zambia. Int J Epidemiol. 2009;38:746–756. doi: 10.1093/ije/dyp004.
    1. Oyugi JH, Byakika-Tusiime J, Ragland K, Laeyendecker O, Mugerwa R, Kityo C, Mugyenyi P, Quinn TC, Bangsberg DR. Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda. AIDS. 2007;21:965–971. doi: 10.1097/QAD.0b013e32802e6bfa.
    1. Bangsberg DR. Preventing HIV antiretroviral resistance through better monitoring of treatment adherence. J Infect Dis. 2008;197(Suppl 3):S272–S278. doi: 10.1086/533415.
    1. Kiwuwa-Muyingo S, Walker AS, Oja H, Levin J, Miiro G, Katabira E, Kityo C, Hakim J, Todd J. The impact of first year adherence to antiretroviral therapy on long-term clinical and immunological outcomes in the DART trial in Uganda and Zimbabwe. Trop Med Int Health. 2012;17:584–594. doi: 10.1111/j.1365-3156.2012.02974.x.
    1. Nachega JB, Hislop M, Dowdy DW, Lo M, Omer SB, Regensberg L, Chaisson RE, Maartens G. Adherence to highly active antiretroviral therapy assessed by pharmacy claims predicts survival in HIV-infected South African adults. J Acquir Immune Defic Syndr. 2006;43:78–84. doi: 10.1097/01.qai.0000225015.43266.46.
    1. Grossberg R, Zhang Y, Gross R. A time-to-prescription-refill measure of antiretroviral adherence predicted changes in viral load in HIV. J Clin Epidemiol. 2004;57:1107–1110. doi: 10.1016/j.jclinepi.2004.04.002.
    1. Nachega JB, Mills EJ, Schechter M. Antiretroviral therapy adherence and retention in care in middle-income and low-income countries: current status of knowledge and research priorities. Curr Opin HIV AIDS. 2010;5:70–77. doi: 10.1097/COH.0b013e328333ad61.
    1. Bärnighausen T, Chaiyachati K, Chimbindi N, Peoples A, Haberer J, Newell M-L. Interventions to increase antiretroviral adherence in sub-Saharan Africa: a systematic review of evaluation studies. Lancet Infect Dis. 2011;11:942–951. doi: 10.1016/S1473-3099(11)70181-5.
    1. Grossberg R, Gross R. Use of pharmacy refill data as a measure of antiretroviral adherence. Curr HIV/AIDS Rep. 2007;4:187–191. doi: 10.1007/s11904-007-0027-4.
    1. Chesney MA, Ickovics JR, Chambers DB. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: The AACTG Adherence Instruments. Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG) AIDS Care. 2000;12:255–266. doi: 10.1080/09540120050042891.
    1. Berg KM, Arnsten JH. Practical and conceptual challenges in measuring antiretroviral adherence. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S79–S87. doi: 10.1097/01.qai.0000248337.97814.66.
    1. Simoni JM, Kurth AE, Pearson CR, Pantalone DW, Merrill JO, Frick PA. Self-report measures of antiretroviral therapy adherence: A review with recommendations for HIV research and clinical management. AIDS Behav. 2006;10:227–245. doi: 10.1007/s10461-006-9078-6.
    1. Wagner GJ. Utility of self-reported antiretroviral adherence: Comment on Simoni et al. (2006) AIDS Behav. 2006;10:247–248. doi: 10.1007/s10461-006-9122-6.
    1. Santa Helena ET, Nemes MI, Eluf-Neto J. Development and validation of a multidimensional questionnaire assessing non-adherence to medicines. Rev Saude Publica. 2008;42:764–767. doi: 10.1590/S0034-89102008000400025.
    1. Mills EJ, Nachega JB, Buchan I, Orbinski J, Attaran A, Singh S, Rachlis B, Wu P, Cooper C, Thabane L, Wilson K, Guyatt GH, Bangsberg DR. Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a meta-analysis. JAMA. 2006;296:679–690. doi: 10.1001/jama.296.6.679.
    1. Watt MH, Maman S, Golin CE, Earp JA, Eng E, Bangdiwala SI, Jacobson M. Factors associated with self-reported adherence to antiretroviral therapy in a Tanzanian setting. AIDS Care. 2010;22:381–389. doi: 10.1080/09540120903193708.
    1. Bisson GP, Rowh A, Weinstein R, Gaolathe T, Frank I, Gross R. Antiretroviral failure despite high levels of adherence: discordant adherence-response relationship in Botswana. J Acquir Immune Defic Syndr. 2008;49:107–110. doi: 10.1097/QAI.0b013e3181820141.
    1. WHO HIV Drug resistance report 2012 []
    1. Goldman JD, Cantrell RA, Mulenga LB, Tambatamba BC, Reid SE, Levy JW, Limbada M, Taylor A, Saag MS, Vermund SH, Stringer JSA, Chi BH. Simple adherence assessments to predict virologic failure among HIV-infected adults with discordant immunologic and clinical responses to antiretroviral therapy. AIDS Res Hum Retroviruses. 2008;24:1031–1035. doi: 10.1089/aid.2008.0035.
    1. McMahon JH, Jordan MR, Kelley K, Bertagnolio S, Hong SY, Wanke CA, Lewin SR, Elliott JH. Pharmacy adherence measures to assess adherence to antiretroviral therapy: review of the literature and implications for treatment monitoring. Clin Infect Dis. 2011;52:493–506. doi: 10.1093/cid/ciq167.
    1. Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherence in pharmacy administrative databases: a proposal for standard definitions and preferred measures. Ann Pharmacother. 2006;40:1280–1288. doi: 10.1345/aph.1H018.
    1. Deschamps AE, De Geest S, Vandamme A-M, Bobbaers H, Peetermans WE, Van Wijngaerden E. Diagnostic value of different adherence measures using electronic monitoring and virologic failure as reference standards. AIDS Patient Care STDS. 2008;22:735–743. doi: 10.1089/apc.2007.0229.
    1. Acri TL, TenHave TR, Chapman JC, Bogner HR, Gross R. Lack of association between retrospectively collected pharmacy refill data and electronic drug monitoring of antiretroviral adherence. AIDS Behav. 2010;14:748–754. doi: 10.1007/s10461-008-9502-1.
    1. El-Khatib Z, Ekstrom AM, Ledwaba J, Mohapi L, Laher F, Karstaedt A, Charalambous S, Petzold M, Katzenstein D, Morris L, Ekström AM. Viremia and drug resistance among HIV-1 patients on antiretroviral treatment: a cross-sectional study in Soweto, South Africa. AIDS. 2010;24:1679–1687. doi: 10.1097/QAD.0b013e32833a097b.
    1. Mee P, Fielding KL, Charalambous S, Churchyard GJ, Grant AD. Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS. 2008;22:1971–1977. doi: 10.1097/QAD.0b013e32830e4cd8.
    1. Glass TR, De Geest S, Weber R, Vernazza PL, Rickenbach M, Furrer H, Bernasconi E, Cavassini M, Hirschel B, Battegay M, Bucher HC. Correlates of self-reported nonadherence to antiretroviral therapy in HIV-infected patients: the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2006;41:385–392. doi: 10.1097/01.qai.0000186371.95301.52.
    1. R Development Core Team . R: A Language and Environment for Statistical Computing. 2012.
    1. Hall M, Frank E, Holmes G, Pfahringer B, Reutemann P, Witten IH. The WEKA data mining software. ACM SIGKDD Explor Newsl. 2009;11:10. doi: 10.1145/1656274.1656278.
    1. Fairley CK, Permana A, Read TRH. Long-term utility of measuring adherence by self-report compared with pharmacy record in a routine clinic setting. HIV Med. 2005;6:366–369. doi: 10.1111/j.1468-1293.2005.00322.x.
    1. Kerr SJ, Avihingsanon A, Putcharoen O, Chetchotisakd P, Layton M, Ubolyam S, Ruxrungtham K, Cooper DA, Phanuphak P, Duncombe C. Assessing adherence in Thai patients taking combination antiretroviral therapy. Int J STD AIDS. 2012;23:160–165. doi: 10.1258/ijsa.2009.009152.
    1. Gross R, Yip B, Lo Re V, Wood E, Alexander CS, Harrigan PR, Bangsberg DR, Montaner JSG, Hogg RS. A simple, dynamic measure of antiretroviral therapy adherence predicts failure to maintain HIV-1 suppression. J Infect Dis. 2006;194:1108–1114. doi: 10.1086/507680.
    1. Gutierrez EB, Sartori AMC, Schmidt AL, Piloto BM, França BB, de Oliveira AS, Pouza AR, Moreno RV, de Melo PC, de Almeida Ribeiro MCS. Measuring adherence to antiretroviral treatment: the role of pharmacy records of drug withdrawals. AIDS Behav. 2012;16:1482–1490. doi: 10.1007/s10461-012-0168-3.
    1. Rougemont M, Stoll BE, Elia N, Ngang P. Antiretroviral treatment adherence and its determinants in Sub-Saharan Africa: a prospective study at Yaounde Central Hospital Cameroon. AIDS Res Ther. 2009;6:21. doi: 10.1186/1742-6405-6-21.
    1. Bangsberg DR. Less than 95% adherence to nonnucleoside reverse-transcriptase inhibitor therapy can lead to viral suppression. Clin Infect Dis. 2006;43:939–941. doi: 10.1086/507526.
    1. Chalker J, Wagner A, Tomson G, Laing R, Johnson K, Wahlström R, Ross-Degnan D. Urgent need for coordination in adopting standardized antiretroviral adherence performance indicators. J Acquir Immune Defic Syndr. 2010;53:159–161. doi: 10.1097/QAI.0b013e3181befa12.
    1. Luebbert J, Tweya H, Phiri S, Chaweza T, Mwafilaso J, Hosseinipour MC, Ramroth H, Schnitzler P, Neuhann F. Virological failure and drug resistance in patients on antiretroviral therapy after treatment interruption in Lilongwe, Malawi. Clin Infect Dis. 2012;55:441–448. doi: 10.1093/cid/cis438.
    1. Balikuddembe R, Kayiwa J, Musoke D, Ntale M, Baveewo S, Waako P, Obua C. Plasma drug level validates self-reported adherence but predicts limited specificity for nonadherence to antiretroviral therapy. ISRN Pharmacol. 2012;2012:274978. doi: 10.5402/2012/274978.
    1. Minzi OMS, Naazneen AS. Validation of self-report and hospital pill count using unannounced home pill count as methods for determination of adherence to antiretroviral therapy. Tanzan J Health Res. 2008;10:84–88. doi: 10.4314/thrb.v10i2.14350.
    1. Kalichman SC, Amaral CM, Stearns H, White D, Flanagan J, Pope H, Cherry C, Cain D, Eaton L, Kalichman MO. Adherence to antiretroviral therapy assessed by unannounced pill counts conducted by telephone. J Gen Intern Med. 2007;22:1003–1006. doi: 10.1007/s11606-007-0171-y.
    1. Bangsberg DR, Perry S, Charlebois ED, Clark RA, Roberston M, Zolopa AR, Moss A. Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS. 2001;15:1181–1183. doi: 10.1097/00002030-200106150-00015.
    1. Kunutsor S, Walley J, Katabira E, Muchuro S, Balidawa H, Namagala E, Ikoona E. Clinic Attendance for Medication Refills and Medication Adherence amongst an Antiretroviral Treatment Cohort in Uganda: A Prospective Study. AIDS Res Treat. 2010;2010:872396.
Pre-publication history
    1. The pre-publication history for this paper can be accessed here:

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera