Adherence to Antiretroviral Medications for HIV Pre-Exposure Prophylaxis
2012; Elsevier BV; Volume: 44; Issue: 1 Linguagem: Inglês
10.1016/j.amepre.2012.09.047
ISSN1873-2607
AutoresLinda J. Koenig, Cynthia M. Lyles, Dawn K. Smith,
Tópico(s)HIV Research and Treatment
ResumoBackgroundSeveral recent clinical trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF–FTC) can reduce the risk for sexually acquired HIV infection in men and women. However, the efficacy of PrEP has varied widely across trials,1Campbell J.D. Herbst J.H. Koppenhaver R.T. Smith D.K. Antiretroviral prophylaxis for sexual and injection drug use acquisition of HIV.Am J Prev Med. 2013; 44: S63-S69Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar and it is affected heavily by adherence to daily doses of TDF–FTC. To better understand the importance of medication adherence to achieving the PrEP efficacy required for public health impact, and to provide the best guidance for supporting optimal adherence in real-world contexts when PrEP is implemented more broadly, the current paper reviews and summarizes findings from (1) adherence analyses from PrEP clinical trials and (2) the antiretroviral treatment adherence literature.Pre-Exposure Prophylaxis TrialsAdherence and HIV Prevention EfficacyPublished data from four completed trials of daily antiretroviral PrEP with TDF–FTC2Van Damme L. Corneli A. Ahmed K. et al.Preexposure prophylaxis for HIV infection among African women.N Engl J Med. 2012; 367: 411-422Crossref PubMed Scopus (1172) Google Scholar, 3Grant R.M. Lama J.R. Anderson P.L. et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.N Engl J Med. 2010; 363: 2587-2599Crossref PubMed Scopus (3593) Google Scholar, 4Baeten J. Donnell D. Ndase P. et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.N Engl J Med. 2012; 367: 399-410Crossref PubMed Scopus (2217) Google Scholar, 5Thigpen M.C. Kebaabetswe P.M. Paxton L.A. et al.Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.N Engl J Med. 2012; 367: 423-434Crossref PubMed Scopus (1455) Google Scholar reported overall efficacy (regardless of reported adherence). Three of the four trials reported presence or absence of efficacy conditioned on a specific level of adherence as measured by a variety of methods. All trials measured self-reported medication adherence; some also used counts of pills dispensed and/or returned at monthly visits.In addition, some trials conducted substudies to determine the level of tenofovir detectable in blood specimens at selected visits,6Food and Drug AdministrationBackground package for NDA 21-752/Supplement 30.2011Google Scholar an objective adherence measure that is not influenced highly by motivational (e.g., social desirability) or cognitive (e.g., memory) biases. (Tenofovir is the moiety detectable in blood after ingestion of TDF [the orally bioavailable prodrug].) The proportion of samples tested from trial participants randomized to receive TDF–FTC that were found to have detectable levels of tenofovir varied widely across the trials, from 26% to 81%, and corresponded generally with overall efficacy in that trial.1Campbell J.D. Herbst J.H. Koppenhaver R.T. Smith D.K. Antiretroviral prophylaxis for sexual and injection drug use acquisition of HIV.Am J Prev Med. 2013; 44: S63-S69Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Further, in three of the trials where drug levels were assessed in case–control substudies, the relative risk reduction in HIV acquisition for treatment-group participants with detectable drug levels compared to those who received placebo was high (84%–92%) and higher than the corresponding overall protective efficacy shown in the trials (Figure 1).In the Partners PrEP study, where detectable drug was assessed at multiple visits for selected participants in the case–control study, there was a clear pattern of higher efficacy with higher consistency of adherence6Food and Drug AdministrationBackground package for NDA 21-752/Supplement 30.2011Google Scholar (Figure 2). In addition, across trials, tenofovir was detectable in a smaller proportion of intervention-group participants who became infected with HIV than in matched comparison subsamples of those who remained uninfected (Figure 3). According to these analyses of adherence, PrEP was nonefficacious when adherence was low (FEM-PrEP); had modest efficacy when adherence was moderate (iPrEx); and was most efficacious when adherence was high (TDF2); and Partners PrEP study.Figure 2Relative risk reduction in acquiring HIV infection (compared with placebo) based on plasma tenofovir concentrations, from the Partners PrEP studyShow full captionTFV, tenofovirView Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Percentage of blood specimens with plasma tenofovir detected, by HIV status, in PrEP trial case–control sub-analysesShow full captionTFV, tenofovirView Large Image Figure ViewerDownload Hi-res image Download (PPT)Adherence Levels and PatternsSelf-reported adherence was high in all of the PrEP trials,2Van Damme L. Corneli A. Ahmed K. et al.Preexposure prophylaxis for HIV infection among African women.N Engl J Med. 2012; 367: 411-422Crossref PubMed Scopus (1172) Google Scholar, 3Grant R.M. Lama J.R. Anderson P.L. et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.N Engl J Med. 2010; 363: 2587-2599Crossref PubMed Scopus (3593) Google Scholar, 4Baeten J. Donnell D. Ndase P. et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.N Engl J Med. 2012; 367: 399-410Crossref PubMed Scopus (2217) Google Scholar, 5Thigpen M.C. Kebaabetswe P.M. Paxton L.A. et al.Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.N Engl J Med. 2012; 367: 423-434Crossref PubMed Scopus (1455) Google Scholar but it was not a valid measure as it did not correspond with more-objective measures of medication adherence such as pill counts or measurable drug levels. There was, however, variability across study subpopulations, and in the iPrEx study, adherence was higher among U.S. participants (94%) than those from other geographic regions, whether measured by self-report or drug detection.7Gilead Sciences. Gilead presentations. Proceedings of the Meeting of the Antiviral Drugs Advisory Committee; 2012 May 10.Google Scholar Adherence was also very high in the Partners PrEP study in which 98% of dispensed study bottles were returned, of which 97% of dispensed study tablets were calculated to have been taken and medication was estimated to have been in use during 92.1% of the follow-up period.4Baeten J. Donnell D. Ndase P. et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.N Engl J Med. 2012; 367: 399-410Crossref PubMed Scopus (2217) Google Scholar Data from a three-site Partners PrEP adherence substudy (Ancilliary Adherence Study) that measured medication adherence with home-based unannounced pill counts and electronic monitoring of pill bottle openings using Medication Event Monitoring System caps, reported that only about 10.2% of the ancillary study participants had adherence <80% by unannounced pill count.8Bangsberg D, Haberer JE, Psaros C, et al. High adherence and high effectiveness observed in HIV disordant couples: Partners PrEP study, adherence monitoring and counseling substudy. Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; 2012; Seattle WA.Google ScholarFurther longitudinal analyses in Partners PrEP identified three adherence patterns.9Donnell D, Baeten J, Hendrix C, et al. Session 30 Webcast: Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; 2012; Seattle WA.Google Scholar By Month 1, 70% of treatment-group participants had high levels of detectable drug, and most continued to have high levels throughout the study. Only 20% had no detectable drug at Month 1; these participants continued to have no evidence of drug use over time. Continuing PrEP prescription would not be recommended for individuals with consistent non-use in clinical care settings. The very smallest group, about 10%, was characterized by low drug levels at Month 1 and a pattern of inconsistent drug use at subsequent study visits. Individuals with this last adherence pattern will require more-intensive adherence counseling if they are to use this prevention strategy successfully.Factors Associated with Adherence Differences in Pre-Exposure Prophylaxis TrialsPopulation characteristics also may have played a role in influencing adherence across trials. One unique feature of the HIV-discordant couples in the Partners PrEP trial is that the HIV-positive partner was available to provide adherence support to their uninfected partner taking PrEP. As part of a qualitative substudy of 60 Partners PrEP participants, respondents reported that HIV-positive partners often reminded, supported, and reinforced their HIV-uninfected partners' medication adherence. Further, the motivation to stay together was strong for many of these couples, as they had been involved in long-term relationships (average duration close to 10 years) and 80% had children. Thus, both partners of an HIV-discordant couple may perceive benefit in that prophylaxis can be a way to both preserve the relationship and protect the seronegative partner.10Ware N.C. Wyatt M.A. Haberer J.E. et al.What's love got to do with it? Explaining adherence to oral antiretroviral pre-exposure prophylaxis for HIV-serodiscordant couples.J Acquir Immune Defic Syndr. 2012; 59: 463-468Crossref PubMed Scopus (197) Google ScholarPerception of risk may be a particularly important facilitator of adherence, which may explain adherence differences among trials. In Partners PrEP, risk was likely to be highly salient given the known HIV infection of their partner and the ongoing potential for HIV exposure in the relationship. In addition, data from the Partners PrEP ancillary study indicated that not having sex (and thus presumably not perceiving oneself to be at risk) was an independent predictor of poor adherence.11Haberer J, Baeten J, Celum C, et al. High adherence among HIV-1 serodiscordant couples in the partners PrEP Ancillary Adherence Study. Proceedings of the 7th International Conference on HIV Treatment and Prevention Adherence; 2012; Miami FL.Google ScholarIn FEM-PrEP, on the other hand, 70% of women thought they had little risk for acquiring HIV, even though about 12% engaged in transactional sex and only half reported condom use.2Van Damme L. Corneli A. Ahmed K. et al.Preexposure prophylaxis for HIV infection among African women.N Engl J Med. 2012; 367: 411-422Crossref PubMed Scopus (1172) Google Scholar Further, the proportion of men in iPrEx with detectable drug levels significantly increased as risk behavior increased (38% for those who had not engaged in sex, 42% for those who had sex but no unprotected receptive anal intercourse, and 54% for those who had engaged in this type of intercourse, p=0.0037). Factors associated with either poor adherence or lower efficacy in more than one PrEP trial2Van Damme L. Corneli A. Ahmed K. et al.Preexposure prophylaxis for HIV infection among African women.N Engl J Med. 2012; 367: 411-422Crossref PubMed Scopus (1172) Google Scholar, 3Grant R.M. Lama J.R. Anderson P.L. et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.N Engl J Med. 2010; 363: 2587-2599Crossref PubMed Scopus (3593) Google Scholar, 4Baeten J. Donnell D. Ndase P. et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.N Engl J Med. 2012; 367: 399-410Crossref PubMed Scopus (2217) Google Scholar, 5Thigpen M.C. Kebaabetswe P.M. Paxton L.A. et al.Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.N Engl J Med. 2012; 367: 423-434Crossref PubMed Scopus (1455) Google Scholar included younger age and heavy alcohol use.7Gilead Sciences. Gilead presentations. Proceedings of the Meeting of the Antiviral Drugs Advisory Committee; 2012 May 10.Google Scholar, 11Haberer J, Baeten J, Celum C, et al. High adherence among HIV-1 serodiscordant couples in the partners PrEP Ancillary Adherence Study. Proceedings of the 7th International Conference on HIV Treatment and Prevention Adherence; 2012; Miami FL.Google Scholar For couples in Partners PrEP, sex outside the partnership and an age difference of <10 years were associated with poorer adherence,11Haberer J, Baeten J, Celum C, et al. High adherence among HIV-1 serodiscordant couples in the partners PrEP Ancillary Adherence Study. Proceedings of the 7th International Conference on HIV Treatment and Prevention Adherence; 2012; Miami FL.Google Scholar as was being a non-U.S. participant in iPrEx.3Grant R.M. Lama J.R. Anderson P.L. et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.N Engl J Med. 2010; 363: 2587-2599Crossref PubMed Scopus (3593) Google Scholar, 7Gilead Sciences. Gilead presentations. Proceedings of the Meeting of the Antiviral Drugs Advisory Committee; 2012 May 10.Google ScholarTrial Interventions to Improve Pre-Exposure Prophylaxis Medication AdherenceThe Partners PrEP Ancillary Adherence Study employed additional objective measures of adherence (home-based unannounced pill counts and electronic monitoring of pill bottle openings using Medication Event Monitoring System pill bottle caps) and provided additional counseling for 81% of the 10.8% who had <80% adherence by unannounced pill counts.8Bangsberg D, Haberer JE, Psaros C, et al. High adherence and high effectiveness observed in HIV disordant couples: Partners PrEP study, adherence monitoring and counseling substudy. Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; 2012; Seattle WA.Google Scholar, 11Haberer J, Baeten J, Celum C, et al. High adherence among HIV-1 serodiscordant couples in the partners PrEP Ancillary Adherence Study. Proceedings of the 7th International Conference on HIV Treatment and Prevention Adherence; 2012; Miami FL.Google Scholar Adherence improved to ≥80% in 92% of individuals who received additional counseling and remained at ≥80% for 82% of substudy participants. PrEP efficacy was 100% for those in the ancillary study (with and without additional counseling).Antiretroviral Treatment Adherence LiteratureApproximately 15 years ago, highly effective antiretroviral therapy (ART) became widely available for the treatment of people living with HIV in developed countries. Since that time, there have been a multitude of studies and multiple reviews of the literature identifying facilitators and barriers to adherence and the effects of interventions for improving adherence. Adherence is critical for success for both HIV treatment and prevention, and studies of ART adherence indicate that as in some of the PrEP trials, it is not as high as it should be. A recent meta-analysis indicated that in North America, the mean proportion of people living with HIV reporting ≥90% adherence to ART is only 59%.12Ortego C. Huedo-Medina T.B. Llorca J. et al.Adherence to highly active antiretroviral therapy (HAART): a meta-analysis.AIDS Behav. 2011; 15: 1381-1396Crossref PubMed Scopus (226) Google ScholarFor this reason, the ART adherence literature was reviewed for the current paper in order to (1) identify the most-consistent predictors of ART adherence and (2) integrate the findings with the limited PrEP adherence literature to derive potential "lessons learned" that may be applicable for enhancing adherence to PrEP. To meet the first objective, the current literature searches were limited to reviews that identified (1) correlates of ART adherence and (2) characteristics of effective ART adherence interventions. The process included a query of CDC's HIV/AIDS Prevention Research Synthesis (PRS) project database (www.cdc.gov/hiv/topics/research/prs/index.htm); a search on PubMed; and a review of the references of all identified review articles (qualitative or quantitative) for correlates of ART adherence behaviors and studies evaluating ART adherence interventions.Correlates of Antiretroviral Therapy Non-AdherenceMany studies have examined people's reasons for non-adherence. "Forgetting" is the most common reason given by patients for missing medications.13Reisner S.L. Mimiaga M.J. Skeer M. Perkovich B. Johnson C.V. Safren S.A. A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth.Top HIV Med. 2009; 17: 14-25PubMed Google Scholar, 14Chesney M.A. Factors affecting adherence to antiretroviral therapy.Clin Infect Dis. 2000; 30: S171-S176Crossref PubMed Scopus (502) Google Scholar, 15Kyser M. Buchacz K. 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Zuniga J.M. et al.HIV treatment adherence, patient health literacy, and health care provider-patient communication: results from the 2010 AIDS Treatment for Life International Survey.J Int Assoc Physicians AIDS Care. 2012; 11: 128-133Crossref Scopus (35) Google Scholar, 20Weiss L. French T. Waters M. Netherland J. Agins B. Finkelstein R. Adherence to HAART: perspectives from clients in treatment support programs.Psychol Health Med. 2006; 11: 155-170Crossref PubMed Scopus (10) Google Scholar Sixteen reviews were identified in the published literature that focused on identifying factors associated with ART non-adherence.12Ortego C. Huedo-Medina T.B. Llorca J. et al.Adherence to highly active antiretroviral therapy (HAART): a meta-analysis.AIDS Behav. 2011; 15: 1381-1396Crossref PubMed Scopus (226) Google Scholar, 14Chesney M.A. Factors affecting adherence to antiretroviral therapy.Clin Infect Dis. 2000; 30: S171-S176Crossref PubMed Scopus (502) Google Scholar, 21Ammassari A. Trotta M.P. 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Adherence to antiretroviral therapy for pediatric HIV infection: a qualitative systematic review with recommendations for research and clinical management.Pediatrics. 2007; 119: e1371-e1383Crossref PubMed Scopus (169) Google Scholar, 33Steele R.G. Grauer D. Adherence to antiretroviral therapy for pediatric HIV infection: review of the literature and recommendations for research.Clin Child Fam Psychol Rev. 2003; 6: 17-30Crossref PubMed Scopus (67) Google Scholar, 34Wutoh A.K. Elekwachi O. Clarke-Tasker V. Daftary M. Powell N.J. Campusano G. Assessment and predictors of antiretroviral adherence in older HIV-infected patients.J Acquir Immune Defic Syndr. 2003; 33: S106-S114Crossref PubMed Scopus (38) Google Scholar The non-adherence factors most often reported were having psychological symptoms such as depression or anxiety,13Reisner S.L. Mimiaga M.J. Skeer M. Perkovich B. Johnson C.V. Safren S.A. A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth.Top HIV Med. 2009; 17: 14-25PubMed Google Scholar, 21Ammassari A. Trotta M.P. Murri R. et al.Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature.J Acquir Immune Defic Syndr. 2002; 31: S123-S127Crossref PubMed Scopus (397) Google Scholar, 22Atkinson M.J. Petrozzino J.J. An evidence-based review of treatment-related determinants of patients' nonadherence to HIV medications.AIDS Patient Care STDS. 2009; 23: 903-914Crossref PubMed Scopus (74) Google Scholar, 25Fogarty L. Roter D. Larson S. Burke J. Gillespie J. Levy R. Patient adherence to HIV medication regimens: a review of published and abstract reports.Patient Educ Couns. 2002; 46: 93-108Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 26Gruber V.A. Sorensen J.L. Haug N.A. Psychosocial predictors of adherence to highly active antiretroviral therapy.J HIV AIDS Soc Serv. 2007; 6: 23-37Crossref Scopus (1) Google Scholar, 27Malta M. Strathdee S.A. Magnanini M.M. Bastos F.I. Adherence to antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome among drug users: a systematic review.Addiction. 2008; 103: 1242-1257Crossref PubMed Scopus (196) Google Scholar, 28Malta M. Magnanini M.M. Strathdee S.A. Bastos F.I. Adherence to antiretroviral therapy among HIV-infected drug users: a meta-analysis.AIDS Behav. 2010; 14: 731-747Crossref PubMed Scopus (164) Google Scholar, 32Simoni J.M. Montgomery A. Martin E. New M. Demas P.A. Rana S. Adherence to antiretroviral therapy for pediatric HIV infection: a qualitative systematic review with recommendations for research and clinical management.Pediatrics. 2007; 119: e1371-e1383Crossref PubMed Scopus (169) Google Scholar an active alcohol or substance abuse problem,13Reisner S.L. Mimiaga M.J. Skeer M. Perkovich B. Johnson C.V. Safren S.A. A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth.Top HIV Med. 2009; 17: 14-25PubMed Google Scholar, 22Atkinson M.J. Petrozzino J.J. An evidence-based review of treatment-related determinants of patients' nonadherence to HIV medications.AIDS Patient Care STDS. 2009; 23: 903-914Crossref PubMed Scopus (74) Google Scholar, 23Azar M.M. Springer S.A. Meyer J.P. Altice F.L. A systematic review of the impact of alcohol use disorders on HIV treatment outcomes, adherence to antiretroviral therapy and health care utilization.Drug Alcohol Depend. 2010; 112: 178-193Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 25Fogarty L. Roter D. Larson S. Burke J. Gillespie J. Levy R. Patient adherence to HIV medication regimens: a review of published and abstract reports.Patient Educ Couns. 2002; 46: 93-108Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 26Gruber V.A. Sorensen J.L. Haug N.A. Psychosocial predictors of adherence to highly active antiretroviral therapy.J HIV AIDS Soc Serv. 2007; 6: 23-37Crossref Scopus (1) Google Scholar, 27Malta M. Strathdee S.A. Magnanini M.M. Bastos F.I. Adherence to antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome among drug users: a systematic review.Addiction. 2008; 103: 1242-1257Crossref PubMed Scopus (196) Google Scholar, 28Malta M. Magnanini M.M. Strathdee S.A. Bastos F.I. Adherence to antiretroviral therapy among HIV-infected drug users: a meta-analysis.AIDS Behav. 2010; 14: 731-747Crossref PubMed Scopus (164) Google Scholar, 29Mills E.J. Nachega J.B. Bangsberg D.R. et al.Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators.PLoS Med. 2006; 3: e438Crossref PubMed Scopus (576) Google Scholar, 31Sandelowski M. Voils C.I. Chang Y. Lee E.J. A systematic review comparing antiretroviral adherence descriptive and intervention studies conducted in the U.S..AIDS Care. 2009; 21: 953-966Crossref PubMed Scopus (37) Google Scholar, 32Simoni J.M. Montgomery A. Martin E. New M. Demas P.A. Rana S. Adherence to antiretroviral therapy for pediatric HIV infection: a qualitative systematic review with recommendations for research and clinical management.Pediatrics. 2007; 119: e1371-e1383Crossref PubMed Scopus (169) Google Scholar frequent or severe side effects,13Reisner S.L. Mimiaga M.J. Skeer M. Perkovich B. Johnson C.V. Safren S.A. A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth.Top HIV Med. 2009; 17: 14-25PubMed Google Scholar, 21Ammassari A. Trotta M.P. Murri R. et al.Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature.J Acquir Immune Defic Syndr. 2002; 31: S123-S127Crossref PubMed Scopus (397) Google Scholar, 22Atkinson M.J. Petrozzino J.J. An evidence-based review of treatment-related determinants of patients' nonadherence to HIV medications.AIDS Patient Care STDS. 2009; 23: 903-914Crossref PubMed Scopus (74) Google Scholar, 25Fogarty L. Roter D. Larson S. Burke J. Gillespie J. Levy R. Patient adherence to HIV medication regimens: a review of published and abstract reports.Patient Educ Couns. 2002; 46: 93-108Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 29Mills E.J. Nachega J.B. Bangsberg D.R. et al.Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators.PLoS Med. 2006; 3: e438Crossref PubMed Scopus (576) Google Scholar, 31Sandelowski M. Voils C.I. Chang Y. Lee E.J. A systematic review comparing antiretroviral adherence descriptive and intervention studies conducted in the U.S..AIDS Care. 2009; 21: 953-966Crossref PubMed Scopus (37) Google Scholar, 34Wutoh A.K. Elekwachi O. Clarke-Tasker V. Daftary M. Powell N.J. Campusano G. Assessment and predictors of antiretroviral adherence in older HIV-infected patients.J Acquir Immune Defic Syndr. 2003; 33: S106-S114Crossref PubMed Scopus (38) Google Scholar and a more complex medication regimen.13Reisner S.L. Mimiaga M.J. Skeer M. Perkovich B. Johnson C.V. Safren S.A. A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth.Top HIV Med. 2009; 17: 14-25PubMed Google Scholar, 14Chesney M.A. Factors affecting adherence to antiretroviral therapy.Clin Infect Dis. 2000; 30: S171-S176Crossref PubMed Scopus (502) Google Scholar, 21Ammassari A. Trotta M.P. Murri R. et al.Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature.J Acquir Immune Defic Syndr. 2002; 31: S123-S127Crossref PubMed Scopus (397) Google Scholar, 22Atkinson M.J. Petrozzino J.J. An evidence-based review of treatment-related determinants of patients' nonadherence to HIV medications.AIDS Patient Care STDS. 2009; 23: 903-914Crossref PubMed Scopus (74) Google Scholar, 25Fogarty L. Roter D. Larson S. Burke J. Gillespie J. Levy R. Patient adherence to HIV medication regimens: a review of published and abstract reports.Patient Educ Couns. 2002; 46: 93-108Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 29Mills E.J. Nachega J.B. Bangsberg D.R. et al.Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators.PLoS Med. 2006; 3: e438Crossref PubMed Scopus (576) Google Scholar, 30Parienti J.J. Bangsberg
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