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      Lower Pill Burden and Once-Daily Antiretroviral Treatment Regimens for HIV Infection: A Meta-Analysis of Randomized Controlled Trials

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          Once-daily compared with twice-daily antiretroviral therapy regimens increased adherence; however, the difference was modest and not associated with a difference in virological suppression. In addition, higher pill burden was associated with lower rates of virological suppression, whether once- or twice-daily regimens.


          Background.  Contemporary antiretroviral treatment regimens are simpler than in the past, with lower pill burden and once-daily dosing frequency common. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of pill burden and once-daily vs twice-daily dosing on ART adherence and virological outcomes.

          Methods.  A literature search of 4 electronic databases through 31 March 2013 was used. RCTs comparing once-daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study design, study population characteristics, intervention, outcome measures, and study quality were extracted. Study quality was rated using the Cochrane risk-of-bias tool.

          Results.  Nineteen studies met our inclusion criteria (N = 6312 adult patients). Higher pill burden was associated with both lower adherence rates ( P = .004) and worse virological suppression ( P < .0001) in both once-daily and twice-daily subgroups, although the association with adherence in the once-daily subgroup was not statistically significant. The average adherence was modestly higher in once-daily regimens than twice-daily regimens (weighted mean difference = 2.55%; 95% confidence interval [CI], 1.23 to 3.87; P = .0002). Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens (relative risk [RR] = 1.01; 95% CI, 0.99 to 1.03; P = .50). Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing.

          Conclusions.  Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens.

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              This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.

                Author and article information

                Clin Infect Dis
                Clin. Infect. Dis
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press
                1 May 2014
                22 January 2014
                22 January 2014
                : 58
                : 9
                : 1297-1307
                [1 ]Department of Epidemiology, Pittsburgh University Graduate School of Public Health , Pennsylvania
                [2 ]Departments of Epidemiology and International Health, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland
                [3 ]Department of Medicine,
                [4 ]Centre for Infectious Diseases, Faculty of Medicine & Health Sciences, Stellenbosch University , Cape Town, South Africa
                [5 ]Department of Biostatistics and Clinical Research, Côte de Nacre University, Côte de Nacre Teaching Hospital
                [6 ]Faculté de Médecine, Université de Caen Basse-Normandie, EA 4655 Risque Microbien , Caen, France
                [7 ]Division of Health Sciences, Warwick-Centre for Applied Health Research and Delivery (WCARHD), Warwick Medical School, The University of Warwick , Coventry
                [8 ]Liverpool School of Tropical Medicine, International Health Group , United Kingdom
                [9 ]Centre for Evidence-based Health Care, Faculty of Health Sciences, Stellenbosch University , Cape Town, South Africa
                [10 ]Perelman School of Medicine, and Philadelphia Veterans Affairs Medical Center, University of Pennsylvania
                [11 ]Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts
                [12 ]Southwest CARE Center , Santa Fe, New Mexico
                [13 ]University of Alabama at Birmingham
                [14 ]Faculty of Health Sciences, University of Ottawa , Ontario, Canada
                [15 ]Department of Medicine, Baylor College of Medicine, and The Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center , Houston, Texas
                Author notes

                J. B. N. and J.-J. P. contributed equally to this work.

                Preliminary results of this work were accepted for presentation at the XIX International AIDS Conference (AIDS 2012), held in Washington, DC, 22–27 July 2012. Abstract#18392 ( as well as at the 14th European AIDS Clinical Society Conference held in Brussels, Belgium, 16–19 October 2013. Abstract# PS 4/5 (

                Correspondence: Jean B. Nachega, MD, PhD, MPH, Associate Professor of Medicine, Infectious Diseases, Microbiology and Epidemiology, Pittsburgh University Graduate School of Public Health, Department of Epidemiology, Infectious Diseases Epidemiology Program, 130 DeSoto Street, 503 Parran Hall, Pittsburgh, PA 15261 ( jbn16@ ).
                © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.



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