A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of human immunodeficiency virus-infected mothers

Paige L Williams, George R Seage 3rd, Russell B Van Dyke, George K Siberry, Raymond Griner, Katherine Tassiopoulos, Cenk Yildirim, Jennifer S Read, Yanling Huo, Rohan Hazra, Denise L Jacobson, Lynne M Mofenson, Kenneth Rich, Pediatric HIV/AIDS Cohort Study, William Shearer, Norma Cooper, Lynette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Doyle Patton, Richard Rutstein, Carol Vincent, Nancy Silverman, Ram Yogev, Kathleen Malee, Scott Hunter, Eric Cagwin, Andrew Wiznia, Marlene Burey, Molly Nozyce, William Borkowsky, Sandra Deygoo, Helen Rozelman, Katherine Knapp, Kim Allison, Patricia Garvie, Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Sharon Nachman, Margaret Oliver, Helen Rozelman, Russell Van Dyke, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Emily Barr, Robin McEvoy, Mobeen Rathore, Kathleen Thoma, Ann Usitalo, Kenneth Rich, Delmyra Turpin, Renee Smith, Douglas Watson, LaToya Stubbs, Rose Belanger, Arry Dieudonne, Linda Bettica, Susan Adubato, Gwendolyn Scott, Erika Lopez, Elizabeth Willen, Toinette Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio, Paige L Williams, George R Seage 3rd, Russell B Van Dyke, George K Siberry, Raymond Griner, Katherine Tassiopoulos, Cenk Yildirim, Jennifer S Read, Yanling Huo, Rohan Hazra, Denise L Jacobson, Lynne M Mofenson, Kenneth Rich, Pediatric HIV/AIDS Cohort Study, William Shearer, Norma Cooper, Lynette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Doyle Patton, Richard Rutstein, Carol Vincent, Nancy Silverman, Ram Yogev, Kathleen Malee, Scott Hunter, Eric Cagwin, Andrew Wiznia, Marlene Burey, Molly Nozyce, William Borkowsky, Sandra Deygoo, Helen Rozelman, Katherine Knapp, Kim Allison, Patricia Garvie, Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Sharon Nachman, Margaret Oliver, Helen Rozelman, Russell Van Dyke, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Emily Barr, Robin McEvoy, Mobeen Rathore, Kathleen Thoma, Ann Usitalo, Kenneth Rich, Delmyra Turpin, Renee Smith, Douglas Watson, LaToya Stubbs, Rose Belanger, Arry Dieudonne, Linda Bettica, Susan Adubato, Gwendolyn Scott, Erika Lopez, Elizabeth Willen, Toinette Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio

Abstract

The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites between 2007 and 2011 that was designed to evaluate the safety of in utero antiretroviral drug exposure in children not infected with human immunodeficiency virus who were born to mothers who were infected. This ongoing study uses a "trigger-based" design; that is, initial assessments are conducted on all children, and only those meeting certain thresholds or "triggers" undergo more intensive evaluations to determine whether they have had an adverse event (AE). The authors present the estimated rates of AEs for each domain of interest in the Surveillance Monitoring of ART Toxicities Study. They also evaluated the efficiency of this trigger-based design for estimating AE rates and for testing associations between in utero exposures to antiretroviral drugs and AEs. The authors demonstrate that estimated AE rates from the trigger-based design are unbiased after correction for the sensitivity of the trigger for identifying AEs. Even without correcting for bias based on trigger sensitivity, the trigger approach is generally more efficient for estimating AE rates than is evaluating a random sample of the same size. Minor losses in efficiency when comparing AE rates between persons exposed and unexposed in utero to particular antiretroviral drugs or drug classes were observed under most scenarios.

Figures

Figure 1.
Figure 1.
Hypothetical example of a study with 1,000 subjects and a trigger rate of 10% for a particular adverse event (AE). Shaded boxes show unobserved outcomes.
Figure 2.
Figure 2.
Efficiency of a trigger-based study design versus random subset design for estimating the rate of adverse events (AEs) (A) and for estimating log odds ratio (OR) (B), based on sample sizes of 1,000 and a true adverse event rate of 0.04. Shown is the ratio of the mean squared error (MSE) of the random subset design to the trigger-based design, with values above 1indicating greater efficiency of the trigger-based design.
Figure 3.
Figure 3.
Power for detecting an exposure effect based on a trigger-based design versus a full cohort design and random subset design as a function of sensitivity of the trigger assuming a background adverse event (AE) rate in the unexposed of 4%, n = 1,500, and relative risk = 2.

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Source: PubMed

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