Using observational data to emulate a randomized trial of dynamic treatmentswitching strategies: An application to antiretroviral therapy

Lauren E. Cain, Michael S. Saag, Maya Petersen, Margaret T. May, Suzanne M. Ingle, Roger Logan, James M. Robins, Sophie Abgrall, Bryan E. Shepherd, Steven G. Deeks, M. John Gill, Giota Touloumi, Georgia Vourli, François Dabis, Marie Anne Vandenhende, Peter Reiss, Ard van Sighem, Hasina Samji, Robert S. Hogg, Jan RybnikerCaroline A. Sabin, Sophie Jose, Julia del Amo, Santiago Moreno, Benigno Rodríguez, Alessandro Cozzi-Lepri, Stephen L. Boswell, Christoph Stephan, Santiago Pérez-Hoyos, Inma Jarrin, Jodie L. Guest, Antonella D'ArminioMonforte, Andrea Antinori, Richard D Moore, Colin N.J. Campbell, Jordi Casabona, Laurence Meyer, Rémonie Seng, Andrew N. Phillips, Heiner C. Bucher, Matthias Egger, Michael J. Mugavero, Richard Haubrich, Elvin H. Geng, Ashley Olson, Joseph J. Eron, Sonia Napravnik, Mari M. Kitahata, Stephen E. Van Rompaey, Ramó n. Teira, Amy C. Justice, Janet P. Tate, Dominique Costagliola, Jonathan A.C. Sterne, Miguel A. Hernán

Research output: Contribution to journalArticle

Abstract

Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

Original languageEnglish (US)
Article numberdyv295
Pages (from-to)2038-2049
Number of pages12
JournalInternational Journal of Epidemiology
Volume45
Issue number6
DOIs
StatePublished - Dec 1 2016

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Acquired Immunodeficiency Syndrome
Therapeutics
HIV
Safety Management
Control Groups
Sample Size
HIV-1
RNA
Confidence Intervals
Mortality
Research

Keywords

  • Antiretroviral therapy
  • Dynamic strategies
  • HIV
  • Inverse-probability weighting
  • Mortality
  • Observational studies

ASJC Scopus subject areas

  • Epidemiology
  • Medicine(all)

Cite this

Using observational data to emulate a randomized trial of dynamic treatmentswitching strategies : An application to antiretroviral therapy. / Cain, Lauren E.; Saag, Michael S.; Petersen, Maya; May, Margaret T.; Ingle, Suzanne M.; Logan, Roger; Robins, James M.; Abgrall, Sophie; Shepherd, Bryan E.; Deeks, Steven G.; Gill, M. John; Touloumi, Giota; Vourli, Georgia; Dabis, François; Vandenhende, Marie Anne; Reiss, Peter; van Sighem, Ard; Samji, Hasina; Hogg, Robert S.; Rybniker, Jan; Sabin, Caroline A.; Jose, Sophie; del Amo, Julia; Moreno, Santiago; Rodríguez, Benigno; Cozzi-Lepri, Alessandro; Boswell, Stephen L.; Stephan, Christoph; Pérez-Hoyos, Santiago; Jarrin, Inma; Guest, Jodie L.; D'ArminioMonforte, Antonella; Antinori, Andrea; Moore, Richard D; Campbell, Colin N.J.; Casabona, Jordi; Meyer, Laurence; Seng, Rémonie; Phillips, Andrew N.; Bucher, Heiner C.; Egger, Matthias; Mugavero, Michael J.; Haubrich, Richard; Geng, Elvin H.; Olson, Ashley; Eron, Joseph J.; Napravnik, Sonia; Kitahata, Mari M.; Van Rompaey, Stephen E.; Teira, Ramó n.; Justice, Amy C.; Tate, Janet P.; Costagliola, Dominique; Sterne, Jonathan A.C.; Hernán, Miguel A.

In: International Journal of Epidemiology, Vol. 45, No. 6, dyv295, 01.12.2016, p. 2038-2049.

Research output: Contribution to journalArticle

Cain, LE, Saag, MS, Petersen, M, May, MT, Ingle, SM, Logan, R, Robins, JM, Abgrall, S, Shepherd, BE, Deeks, SG, Gill, MJ, Touloumi, G, Vourli, G, Dabis, F, Vandenhende, MA, Reiss, P, van Sighem, A, Samji, H, Hogg, RS, Rybniker, J, Sabin, CA, Jose, S, del Amo, J, Moreno, S, Rodríguez, B, Cozzi-Lepri, A, Boswell, SL, Stephan, C, Pérez-Hoyos, S, Jarrin, I, Guest, JL, D'ArminioMonforte, A, Antinori, A, Moore, RD, Campbell, CNJ, Casabona, J, Meyer, L, Seng, R, Phillips, AN, Bucher, HC, Egger, M, Mugavero, MJ, Haubrich, R, Geng, EH, Olson, A, Eron, JJ, Napravnik, S, Kitahata, MM, Van Rompaey, SE, Teira, RN, Justice, AC, Tate, JP, Costagliola, D, Sterne, JAC & Hernán, MA 2016, 'Using observational data to emulate a randomized trial of dynamic treatmentswitching strategies: An application to antiretroviral therapy', International Journal of Epidemiology, vol. 45, no. 6, dyv295, pp. 2038-2049. https://doi.org/10.1093/ije/dyv295
Cain, Lauren E. ; Saag, Michael S. ; Petersen, Maya ; May, Margaret T. ; Ingle, Suzanne M. ; Logan, Roger ; Robins, James M. ; Abgrall, Sophie ; Shepherd, Bryan E. ; Deeks, Steven G. ; Gill, M. John ; Touloumi, Giota ; Vourli, Georgia ; Dabis, François ; Vandenhende, Marie Anne ; Reiss, Peter ; van Sighem, Ard ; Samji, Hasina ; Hogg, Robert S. ; Rybniker, Jan ; Sabin, Caroline A. ; Jose, Sophie ; del Amo, Julia ; Moreno, Santiago ; Rodríguez, Benigno ; Cozzi-Lepri, Alessandro ; Boswell, Stephen L. ; Stephan, Christoph ; Pérez-Hoyos, Santiago ; Jarrin, Inma ; Guest, Jodie L. ; D'ArminioMonforte, Antonella ; Antinori, Andrea ; Moore, Richard D ; Campbell, Colin N.J. ; Casabona, Jordi ; Meyer, Laurence ; Seng, Rémonie ; Phillips, Andrew N. ; Bucher, Heiner C. ; Egger, Matthias ; Mugavero, Michael J. ; Haubrich, Richard ; Geng, Elvin H. ; Olson, Ashley ; Eron, Joseph J. ; Napravnik, Sonia ; Kitahata, Mari M. ; Van Rompaey, Stephen E. ; Teira, Ramó n. ; Justice, Amy C. ; Tate, Janet P. ; Costagliola, Dominique ; Sterne, Jonathan A.C. ; Hernán, Miguel A. / Using observational data to emulate a randomized trial of dynamic treatmentswitching strategies : An application to antiretroviral therapy. In: International Journal of Epidemiology. 2016 ; Vol. 45, No. 6. pp. 2038-2049.
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abstract = "Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95{\%} confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.",
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TY - JOUR

T1 - Using observational data to emulate a randomized trial of dynamic treatmentswitching strategies

T2 - An application to antiretroviral therapy

AU - Cain, Lauren E.

AU - Saag, Michael S.

AU - Petersen, Maya

AU - May, Margaret T.

AU - Ingle, Suzanne M.

AU - Logan, Roger

AU - Robins, James M.

AU - Abgrall, Sophie

AU - Shepherd, Bryan E.

AU - Deeks, Steven G.

AU - Gill, M. John

AU - Touloumi, Giota

AU - Vourli, Georgia

AU - Dabis, François

AU - Vandenhende, Marie Anne

AU - Reiss, Peter

AU - van Sighem, Ard

AU - Samji, Hasina

AU - Hogg, Robert S.

AU - Rybniker, Jan

AU - Sabin, Caroline A.

AU - Jose, Sophie

AU - del Amo, Julia

AU - Moreno, Santiago

AU - Rodríguez, Benigno

AU - Cozzi-Lepri, Alessandro

AU - Boswell, Stephen L.

AU - Stephan, Christoph

AU - Pérez-Hoyos, Santiago

AU - Jarrin, Inma

AU - Guest, Jodie L.

AU - D'ArminioMonforte, Antonella

AU - Antinori, Andrea

AU - Moore, Richard D

AU - Campbell, Colin N.J.

AU - Casabona, Jordi

AU - Meyer, Laurence

AU - Seng, Rémonie

AU - Phillips, Andrew N.

AU - Bucher, Heiner C.

AU - Egger, Matthias

AU - Mugavero, Michael J.

AU - Haubrich, Richard

AU - Geng, Elvin H.

AU - Olson, Ashley

AU - Eron, Joseph J.

AU - Napravnik, Sonia

AU - Kitahata, Mari M.

AU - Van Rompaey, Stephen E.

AU - Teira, Ramó n.

AU - Justice, Amy C.

AU - Tate, Janet P.

AU - Costagliola, Dominique

AU - Sterne, Jonathan A.C.

AU - Hernán, Miguel A.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

AB - Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

KW - Antiretroviral therapy

KW - Dynamic strategies

KW - HIV

KW - Inverse-probability weighting

KW - Mortality

KW - Observational studies

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