Caitlin M. Dugdale, MD; Andrea L. Ciaranello, MD, MPH; Linda-Gail Bekker, MD, PhD; Madeline E. Stern, BA; Landon Myer, MBChB, PhD; Robin Wood, MMed, DSc (Med); Paul E. Sax, MD; Elaine J. Abrams, MD; Kenneth A. Freedberg, MD, MSc; Rochelle P. Walensky, MD, MPH
Note: The corresponding author had access to all data and accepts responsibility for submission of this manuscript for publication.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH), WHO, or Massachusetts General Hospital (MGH).
Acknowledgment: The authors thank Taige Hou, CEPAC software engineer, for his significant contributions to the CEPAC models. They also thank the CEPAC-Pediatric and CEPAC-International research teams for their role in model development and revisions.
Financial Support: By the NIH through the National Institute of Allergy and Infectious Diseases (NIAID) (grants T32 AI007433, R37 AI058736, R01 AI042006, and R37 AI093269) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (grant R01 HD079214), and by the Steve and Deborah Gorlin MGH Research Scholars Award. This research was funded in part by a 2017 developmental grant from the Harvard University Center for AIDS Research (CFAR), an NIH-funded program (grant P30 AI060354) supported by the following NIH cofunding and participating institutes and centers: NIAID; National Cancer Institute; NICHD; National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; National Institute of Mental Health (NIMH); National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute on Minority Health and Health Disparities; Fogarty International Center; and Office of AIDS Research.
Disclosures: Dr. Dugdale reports grants from NIAID and Harvard University CFAR during the conduct of the study and grants from NIMH and NIH/IMPAACT Network outside the submitted work. Dr. Ciaranello reports grants from NIH during the conduct of the study, and from the Elizabeth Glaser Pediatric AIDS Foundation, the Foundation for AIDS Research (amfAR), and WHO outside the submitted work. Dr. Bekker reports personal fees from Merck and free drug from Gilead for demonstration studies outside the submitted work. Dr. Sax reports nonfinancial support from Bristol-Myers Squibb, grants and personal fees from Gilead and ViiV/GlaxoSmithKline, and personal fees from Janssen and Merck, outside the submitted work. Dr. Abrams reports personal fees from ViiV outside the submitted work. Dr. Freedberg reports grants from NIH, the Elizabeth Glaser Pediatric AIDS Foundation, and WHO/Unitaid during the conduct of the study, and grants from NIH outside the submitted work. Dr. Walensky reports grants from NIH and was a Steve and Deborah Gorlin MGH Research Scholar during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-3358.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement:Study protocol: Not applicable. Statistical code: Sample model code is available at www.massgeneral.org/mpec/cepac/. Data set: Comprehensive ART efficacy data derivations and model inputs are available in the Supplement (available at Annals.org).
Corresponding Author: Caitlin M. Dugdale, MD, Medical Practice Evaluation Center, 100 Cambridge Street, Suite 1600, Boston, MA 02114; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Dugdale, Freedberg, and Walensky and Ms. Stern: Medical Practice Evaluation Center, 100 Cambridge Street, Suite 1600, Boston, MA 02114.
Dr. Ciaranello: Medical Practice Evaluation Center, 100 Cambridge Street, Room 1670, Boston, MA 02114.
Dr. Bekker: Health Science Faculty, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
Dr. Myer: Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
Dr. Wood: Desmond Tutu HIV Centre, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
Dr. Sax: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Dr. Abrams: Mailman School of Public Health, 722 West 168th Street, New York, NY 10032.
Author Contributions: Conception and design: C.M. Dugdale, A.L. Ciaranello, M.E. Stern, R. Wood, P.E. Sax, K.A. Freedberg, R.P. Walensky.
Analysis and interpretation of the data: C.M. Dugdale, A.L. Ciaranello, L.G. Bekker, M.E. Stern, L. Myer, R. Wood, P.E. Sax, E.J. Abrams, K.A. Freedberg, R.P. Walensky.
Drafting of the article: C.M. Dugdale, A.L. Ciaranello, L. Myer, P.E. Sax, R.P. Walensky.
Critical revision for important intellectual content: C.M. Dugdale, A.L. Ciaranello, L.G. Bekker, L. Myer, R. Wood, P.E. Sax, E.J. Abrams, K.A. Freedberg, R.P. Walensky.
Final approval of the article: C.M. Dugdale, A.L. Ciaranello, L.G. Bekker, M.E. Stern, L. Myer, R. Wood, P.E. Sax, E.J. Abrams, K.A. Freedberg, R.P. Walensky.
Provision of study materials or patients: L.G. Bekker, L. Myer, R. Wood.
Statistical expertise: A.L. Ciaranello, K.A. Freedberg, R.P. Walensky.
Obtaining of funding: A.L. Ciaranello, K.A. Freedberg, R.P. Walensky.
Administrative, technical, or logistic support: A.L. Ciaranello, M.E. Stern.
Collection and assembly of data: C.M. Dugdale, A.L. Ciaranello, M.E. Stern, L. Myer, R. Wood, P.E. Sax.
Dolutegravir is superior to efavirenz for HIV antiretroviral therapy (ART) but may be associated with an increased risk for neural tube defects (NTDs) in newborns if used by women at conception.
To project clinical outcomes of ART policies for women of child-bearing potential in South Africa.
Model of 3 strategies: efavirenz for all women of child-bearing potential (EFV), dolutegravir for all women of child-bearing potential (DTG), or World Health Organization (WHO)-recommended efavirenz without contraception or dolutegravir with contraception (WHO approach).
Published data on NTD risks (efavirenz, 0.05%; dolutegravir, 0.67% [Tsepamo study]), 48-week ART efficacy with initiation (efavirenz, 60% to 91%; dolutegravir, 96%), and age-stratified fertility rates (2 to 139 per 1000 women).
3.1 million South African women with HIV (aged 15 to 49 years) starting or continuing first-line ART, and their children.
EFV, DTG, and WHO approach.
Deaths among women and children, sexual and pediatric HIV transmissions, and NTDs.
Compared with EFV, DTG averted 13 700 women's deaths (0.44% decrease) and 57 700 sexual HIV transmissions, but increased total pediatric deaths by 4400 because of more NTDs. The WHO approach offered some benefits compared with EFV, averting 4900 women's deaths and 20 500 sexual transmissions while adding 300 pediatric deaths. Overall, combined deaths among women and children were lowest with DTG (358 000 deaths) compared with the WHO approach (362 800 deaths) or EFV (367 300 deaths).
Women's deaths averted with DTG exceeded pediatric deaths added with EFV unless dolutegravir-associated NTD risk was 1.5% or greater.
Uncertainty in NTD risks and dolutegravir efficacy in resource-limited settings, each examined in sensitivity analyses.
Although NTD risks may be higher with dolutegravir than efavirenz, dolutegravir will lead to many fewer deaths among women, as well as fewer overall HIV transmissions. These results argue against a uniform policy of avoiding dolutegravir in women of child-bearing potential.
National Institutes of Health, National Institute of Allergy and Infectious Diseases and Eunice Kennedy Shriver National Institute of Child Health and Human Development; Massachusetts General Hospital; and Harvard University Center for AIDS Research.
Dugdale CM, Ciaranello AL, Bekker L, Stern ME, Myer L, Wood R, et al. Risks and Benefits of Dolutegravir- and Efavirenz-Based Strategies for South African Women With HIV of Child-Bearing Potential: A Modeling Study. Ann Intern Med. [Epub ahead of print 2 April 2019]:. doi: 10.7326/M18-3358
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Published: Ann Intern Med. 2019.
HIV, Infectious Disease.
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