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Lifetime HIV Antiretroviral Therapy Adherence Intervention: Timing Is Everything: Comment on “Managed Problem Solving for Antiretroviral Therapy Adherence”

Lifetime HIV Antiretroviral Therapy Adherence Intervention: Timing Is Everything: Comment on... Modern, potent antiretroviral therapy regimens can suppress human immunodeficiency virus (HIV) replication indefinitely. For those who have access to these drugs and who are able to adhere on a daily basis to these drugs, life expectancy now approaches that of individuals without HIV infection, particularly if they start therapy early.1,2 Full lifetime viral suppression offers the potentially transformative public health benefit of reducing transmission leading to a decline in number of new HIV infections.3 For many patients, however, adequate adherence to sustain viral suppression over a lifetime remains a major challenge. Antiretroviral adherence declines over time.4-6 Even people with typically excellent adherence will experience treatment interruptions owing to inevitable disruptions in daily routine, relapse of substance use or mental illness, or simple pill fatigue. Interruptions of several days or more put patients at risk for virologic failure.7,8 As such, adherence support may be necessary for many, if not most, people at some time in the course of life-long treatment in order to achieve the full individual and public health impact of antiretroviral therapy. Providing adherence support over a lifetime of antiretroviral therapy creates 2 major conundrums. First, most adherence interventions are time limited, and benefits do not typically last much beyond the cessation of the intervention.9 Second, we don't know when individuals most need adherence support during a lifetime of treatment. Continuous, lifelong adherence support is neither necessary nor possible. In this issue of the journal, Gross et al10 make significant progress toward a model of effective long-term adherence support. In a US population, they randomized subjects with plasma HIV-1 RNA levels higher than 1000 copies/mL who were initiating or changing therapy to an intervention of Managed Problem Solving (MAPS) vs usual care. Managed Problem Solving consisted of 4 in-person and 12 telephone-based meetings with a trained interventionist, followed by monthly follow-up calls for a year. In the primary intention-to-treat analyses, the odds ratio of being in a higher adherence category was 1.78 (95% CI, 1.07-2.96) times greater for MAPS than usual care, and the odds of having an undetectable HIV RNA level were 1.48 (95% CI, 0.94-2.31) times greater for MAPS than usual care. The effect was sustained for 12 months, involved minimal interaction with the study participants, and did not deteriorate over time. While this intervention achieved a durable behavioral and biologic effect, calling every HIV-infected person on treatment every month of their life may not be feasible or necessary. We believe that to maximize the benefit of the findings reported herein, individuals who might benefit from MAPS need to be offered this intervention in connection with adherence lapses. One such approach is to use life-long, real-time adherence monitoring. Real-time adherence monitoring involves electronic pill containers that transmit a time and date stamp with an anonymous patient identifier to a central server through mobile networks every time the pill container is opened. Monitoring detects missed doses in real time and thus provides a means to link MAPS (or other interventions) to an individual before treatment failure occurs. Support can be provided not on a fixed monthly interval, as in the study by Gross et al,10 but rather only when needed in the midst of an adherence lapse. “Just-in-time” adherence support can be delivered by text message, live counseling over the telephone, or in person, depending on the duration and cause of the adherence lapse. While the cost of electronic monitors is not insignificant, on a large scale, real-time monitoring and adherence-driven support could be provided at costs comparable with those of current laboratory monitoring for HIV. This approach transforms HIV care from largely responding, to proactively preventing virologic failure in real time. It is potentially cost-effective when considering the savings achieved through long-term virologic suppression, which prevents need for resistance testing, avoids the use of more expensive second-line regimens, and avoids devoting substantial resources to managing the complications of disease progression. Initial studies have shown real-time adherence monitoring to be feasible even in areas with limited infrastructure.11 Moving forward, research is needed to establish effectiveness and ultimately scalability outside the research context. The introduction of combination antiretroviral therapy transformed HIV from a terminal to a chronic disease in the late 1990s. Advances in simpler, more potent therapy transformed treatment from success in some to success in most in the 2000s. Advances in just-in-time adherence monitoring and support delivered when and where it is needed may transform treatment from success measured over years to success measured over a lifetime. Back to top Article Information Correspondence: Dr Bangsberg, MGH Center for Global Health, 100 Cambridge St, 15th Floor, Boston, MA 02114 (dbangsberg@partners.org). Published Online: January 28, 2013. doi:10.1001/jamainternmed.2013.2858 Conflict of Interest Disclosures: None reported. Funding/Support: Dr Bangsberg is supported by grant No. K-24 MH 087227, and Dr Haberer is supported by grant No. K-23 MH 087228. The real-time adherence monitoring work is supported by grant No. MH 54807. Additional Contributions: Steven G. Deeks, MD, provided critical input on the manuscript. References 1. Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS. 2012;26(3):335-34322089374PubMedGoogle ScholarCrossref 2. Mills EJ, Bakanda C, Birungi J, et al. Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med. 2011;155(4):209-21621768555PubMedGoogle Scholar 3. Cohen MS, Chen YQ, McCauley M, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-50521767103PubMedGoogle ScholarCrossref 4. Byakika-Tusiime J, Crane J, Oyugi JH, et al. Longitudinal antiretroviral adherence in HIV+ Ugandan parents and their children initiating HAART in the MTCT-Plus family treatment model: role of depression in declining adherence over time. AIDS Behav. 2009;13:(suppl 1) 82-9119301113PubMedGoogle ScholarCrossref 5. Mannheimer S, Friedland G, Matts J, Child C, Chesney M. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clin Infect Dis. 2002;34(8):1115-112111915001PubMedGoogle ScholarCrossref 6. Liu H, Miller LG, Hays RD, et al. Repeated measures longitudinal analyses of HIV virologic response as a function of percent adherence, dose timing, genotypic sensitivity, and other factors. J Acquir Immune Defic Syndr. 2006;41(3):315-32216540932PubMedGoogle ScholarCrossref 7. Dargere S, Parienti JJ, Verdon R. Treatment resistance after sequential interruption of a non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS. 2007;21(7):879-88017415047PubMedGoogle ScholarCrossref 8. Oyugi JH, Byakika-Tusiime J, Ragland K, et al. Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda. AIDS. 2007;21(8):965-97117457090PubMedGoogle ScholarCrossref 9. Simoni JM, Pearson CR, Pantalone DW, Marks G, Crepaz N. Efficacy of interventions in improving highly active antiretroviral therapy adherence and HIV-1 RNA viral load: a meta-analytic review of randomized controlled trials. J Acquir Immune Defic Syndr. 2006;43:(suppl 1) S23-S3517133201PubMedGoogle ScholarCrossref 10. Gross R, Bellamy SL, Chapman J, et al. Managed problem solving for antiretroviral therapy adherence: a randomized trial [published online January 28, 2013]. JAMA Intern Med. 2013;173(4):300-306Google Scholar 11. Haberer JE, Kahane J, Kigozi I, et al. Real-time adherence monitoring for HIV antiretroviral therapy. AIDS Behav. 2010;14(6):1340-134620809380PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

Lifetime HIV Antiretroviral Therapy Adherence Intervention: Timing Is Everything: Comment on “Managed Problem Solving for Antiretroviral Therapy Adherence”

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Publisher
American Medical Association
Copyright
Copyright © 2013 American Medical Association. All Rights Reserved.
ISSN
2168-6106
eISSN
2168-6114
DOI
10.1001/jamainternmed.2013.2858
Publisher site
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Abstract

Modern, potent antiretroviral therapy regimens can suppress human immunodeficiency virus (HIV) replication indefinitely. For those who have access to these drugs and who are able to adhere on a daily basis to these drugs, life expectancy now approaches that of individuals without HIV infection, particularly if they start therapy early.1,2 Full lifetime viral suppression offers the potentially transformative public health benefit of reducing transmission leading to a decline in number of new HIV infections.3 For many patients, however, adequate adherence to sustain viral suppression over a lifetime remains a major challenge. Antiretroviral adherence declines over time.4-6 Even people with typically excellent adherence will experience treatment interruptions owing to inevitable disruptions in daily routine, relapse of substance use or mental illness, or simple pill fatigue. Interruptions of several days or more put patients at risk for virologic failure.7,8 As such, adherence support may be necessary for many, if not most, people at some time in the course of life-long treatment in order to achieve the full individual and public health impact of antiretroviral therapy. Providing adherence support over a lifetime of antiretroviral therapy creates 2 major conundrums. First, most adherence interventions are time limited, and benefits do not typically last much beyond the cessation of the intervention.9 Second, we don't know when individuals most need adherence support during a lifetime of treatment. Continuous, lifelong adherence support is neither necessary nor possible. In this issue of the journal, Gross et al10 make significant progress toward a model of effective long-term adherence support. In a US population, they randomized subjects with plasma HIV-1 RNA levels higher than 1000 copies/mL who were initiating or changing therapy to an intervention of Managed Problem Solving (MAPS) vs usual care. Managed Problem Solving consisted of 4 in-person and 12 telephone-based meetings with a trained interventionist, followed by monthly follow-up calls for a year. In the primary intention-to-treat analyses, the odds ratio of being in a higher adherence category was 1.78 (95% CI, 1.07-2.96) times greater for MAPS than usual care, and the odds of having an undetectable HIV RNA level were 1.48 (95% CI, 0.94-2.31) times greater for MAPS than usual care. The effect was sustained for 12 months, involved minimal interaction with the study participants, and did not deteriorate over time. While this intervention achieved a durable behavioral and biologic effect, calling every HIV-infected person on treatment every month of their life may not be feasible or necessary. We believe that to maximize the benefit of the findings reported herein, individuals who might benefit from MAPS need to be offered this intervention in connection with adherence lapses. One such approach is to use life-long, real-time adherence monitoring. Real-time adherence monitoring involves electronic pill containers that transmit a time and date stamp with an anonymous patient identifier to a central server through mobile networks every time the pill container is opened. Monitoring detects missed doses in real time and thus provides a means to link MAPS (or other interventions) to an individual before treatment failure occurs. Support can be provided not on a fixed monthly interval, as in the study by Gross et al,10 but rather only when needed in the midst of an adherence lapse. “Just-in-time” adherence support can be delivered by text message, live counseling over the telephone, or in person, depending on the duration and cause of the adherence lapse. While the cost of electronic monitors is not insignificant, on a large scale, real-time monitoring and adherence-driven support could be provided at costs comparable with those of current laboratory monitoring for HIV. This approach transforms HIV care from largely responding, to proactively preventing virologic failure in real time. It is potentially cost-effective when considering the savings achieved through long-term virologic suppression, which prevents need for resistance testing, avoids the use of more expensive second-line regimens, and avoids devoting substantial resources to managing the complications of disease progression. Initial studies have shown real-time adherence monitoring to be feasible even in areas with limited infrastructure.11 Moving forward, research is needed to establish effectiveness and ultimately scalability outside the research context. The introduction of combination antiretroviral therapy transformed HIV from a terminal to a chronic disease in the late 1990s. Advances in simpler, more potent therapy transformed treatment from success in some to success in most in the 2000s. Advances in just-in-time adherence monitoring and support delivered when and where it is needed may transform treatment from success measured over years to success measured over a lifetime. Back to top Article Information Correspondence: Dr Bangsberg, MGH Center for Global Health, 100 Cambridge St, 15th Floor, Boston, MA 02114 (dbangsberg@partners.org). Published Online: January 28, 2013. doi:10.1001/jamainternmed.2013.2858 Conflict of Interest Disclosures: None reported. Funding/Support: Dr Bangsberg is supported by grant No. K-24 MH 087227, and Dr Haberer is supported by grant No. K-23 MH 087228. The real-time adherence monitoring work is supported by grant No. MH 54807. Additional Contributions: Steven G. Deeks, MD, provided critical input on the manuscript. References 1. Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS. 2012;26(3):335-34322089374PubMedGoogle ScholarCrossref 2. Mills EJ, Bakanda C, Birungi J, et al. Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med. 2011;155(4):209-21621768555PubMedGoogle Scholar 3. Cohen MS, Chen YQ, McCauley M, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-50521767103PubMedGoogle ScholarCrossref 4. Byakika-Tusiime J, Crane J, Oyugi JH, et al. Longitudinal antiretroviral adherence in HIV+ Ugandan parents and their children initiating HAART in the MTCT-Plus family treatment model: role of depression in declining adherence over time. AIDS Behav. 2009;13:(suppl 1) 82-9119301113PubMedGoogle ScholarCrossref 5. Mannheimer S, Friedland G, Matts J, Child C, Chesney M. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clin Infect Dis. 2002;34(8):1115-112111915001PubMedGoogle ScholarCrossref 6. Liu H, Miller LG, Hays RD, et al. Repeated measures longitudinal analyses of HIV virologic response as a function of percent adherence, dose timing, genotypic sensitivity, and other factors. J Acquir Immune Defic Syndr. 2006;41(3):315-32216540932PubMedGoogle ScholarCrossref 7. Dargere S, Parienti JJ, Verdon R. Treatment resistance after sequential interruption of a non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS. 2007;21(7):879-88017415047PubMedGoogle ScholarCrossref 8. Oyugi JH, Byakika-Tusiime J, Ragland K, et al. Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda. AIDS. 2007;21(8):965-97117457090PubMedGoogle ScholarCrossref 9. Simoni JM, Pearson CR, Pantalone DW, Marks G, Crepaz N. Efficacy of interventions in improving highly active antiretroviral therapy adherence and HIV-1 RNA viral load: a meta-analytic review of randomized controlled trials. J Acquir Immune Defic Syndr. 2006;43:(suppl 1) S23-S3517133201PubMedGoogle ScholarCrossref 10. Gross R, Bellamy SL, Chapman J, et al. Managed problem solving for antiretroviral therapy adherence: a randomized trial [published online January 28, 2013]. JAMA Intern Med. 2013;173(4):300-306Google Scholar 11. Haberer JE, Kahane J, Kigozi I, et al. Real-time adherence monitoring for HIV antiretroviral therapy. AIDS Behav. 2010;14(6):1340-134620809380PubMedGoogle ScholarCrossref

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Feb 25, 2013

Keywords: hiv,problem solving,anti-retroviral agents

References