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Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIV

Journal of Neuroimmune Pharmacology volume 18, pages 1–8 (2023)Cite this article

Abstract

Objective

Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women’s Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects(CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35–55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms(P’s < 0.01); dolutegravir was also associated with greater re-experiencing symptoms(P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities(P’s < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years(P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk–benefit ratio of dolutegravir and elvitegravir in WWH. 

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Acknowledgements

This work was supported by the Johns Hopkins University NIMH Center for novel therapeutics for HIV-associated cognitive disorders (P30MH075773) 2018 pilot award to Dr. Rubin, a 2019 NSF grant (DMS1918854) to Drs. Xu and Rubin, and the Johns Hopkins University Center for AIDS Research NIH/NIAID fund (P30AI094189) 2019 faculty development award to Dr. Xu. Dr. Williams effort was supported by R00DA044838. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). MWCCS (Principal Investigators): Atlanta CRS (Ighovwerha Ofotokun, Anandi Sheth, and Gina Wingood), U01-HL146241; Baltimore CRS (Todd Brown and Joseph Margolick), U01-HL146201; Bronx CRS (Kathryn Anastos and Anjali Sharma), U01-HL146204; Brooklyn CRS (Deborah Gustafson and Tracey Wilson), U01-HL146202; Data Analysis and Coordination Center (Gypsyamber D’Souza, Stephen Gange and Elizabeth Golub), U01-HL146193; Chicago-Cook County CRS (Mardge Cohen and Audrey French), U01-HL146245; Chicago-Northwestern CRS (Steven Wolinsky), U01-HL146240; Northern California CRS (Bradley Aouizerat, Jennifer Price, and Phyllis Tien), U01-HL146242; Los Angeles CRS (Roger Detels and Matthew Mimiaga), U01-HL146333; Metropolitan Washington CRS (Seble Kassaye and Daniel Merenstein), U01-HL146205; Miami CRS (Maria Alcaide, Margaret Fischl, and Deborah Jones), U01-HL146203; Pittsburgh CRS (Jeremy Martinson and Charles Rinaldo), U01-HL146208; UAB-MS CRS (Mirjam-Colette Kempf, Jodie Dionne-Odom, and Deborah Konkle-Parker), U01-HL146192; UNC CRS (Adaora Adimora), U01-HL146194. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Institute On Aging (NIA), National Institute Of Dental & Craniofacial Research (NIDCR), National Institute Of Allergy And Infectious Diseases (NIAID), National Institute Of Neurological Disorders And Stroke (NINDS), National Institute Of Mental Health (NIMH), National Institute On Drug Abuse (NIDA), National Institute Of Nursing Research (NINR), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Minority Health and Health Disparities (NIMHD), and in coordination and alignment with the research priorities of the National Institutes of Health, Office of AIDS Research (OAR). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR003098 (JHU ICTR), UL1-TR001881 (UCLA CTSI), P30-AI-050409 (Atlanta CFAR), P30-AI-073961 (Miami CFAR), P30-AI-050410 (UNC CFAR), P30-AI-027767 (UAB CFAR), and P30-MH-116867 (Miami CHARM).

Funding

AS has received funding from Gilead Sciences, Inc for unrelated work. The remaining authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Leah H. Rubin, Kathryn C. Fitzgerald, Raha Dastgheyb & Alexandra L. Damron

  2. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MDD, USA

    Leah H. Rubin

  3. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MDD, USA

    Leah H. Rubin

  4. Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Jane A. O’Halloran

  5. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MDD, USA

    Dionna W. Williams

  6. Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MDD, USA

    Dionna W. Williams

  7. Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MDD, USA

    Yuliang Li & Yanxun Xu

  8. Departments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, ILD, USA

    Pauline M. Maki

  9. Department of Medicine, Division of Infectious Disease and Travel Medicine, Georgetown University, Washington, DCD, USA

    Amanda B. Spence

  10. Albert Einstein College of Medicine, Bronx, NY, USA

    Anjali Sharma

  11. Department of Neurology, State University of New York Downstate Health Sciences University, New York City, , USA

    Deborah R. Gustafson

  12. Institute for Health Promotion & Disease Prevention Research, University of Southern California, Los Angeles, CA, USA

    Joel Milam

  13. CORE Center, Cook County Health and Hektoen Institute of Medicine, Chicago, IL, USA

    Kathleen M. Weber

  14. Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Adaora A. Adimora

  15. Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA, USA

    Igho Ofotokun

  16. University of Miami Miller School of Medicine, Miami, FLD, USA

    Margaret A. Fischl

  17. Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, MS, USA

    Deborah Konkle-Parker

  18. Division of Biostatistics and Bioinformatics at The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MDD, USA

    Yanxun Xu

Authors
  1. Leah H. Rubin
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  2. Jane A. O’Halloran
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  3. Dionna W. Williams
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  4. Yuliang Li
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  8. Pauline M. Maki
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  9. Amanda B. Spence
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  10. Anjali Sharma
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  11. Deborah R. Gustafson
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  12. Joel Milam
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  13. Kathleen M. Weber
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  14. Adaora A. Adimora
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  15. Igho Ofotokun
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  16. Margaret A. Fischl
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  17. Deborah Konkle-Parker
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  18. Yanxun Xu
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Contributions

Dr. Rubin conceived the study idea and wrote the first draft of the manuscript with Drs. Xu, O’Halloran, and Williams and Mr. Li. Dr. Xu and Mr. Li take responsibility for the integrity of the statistical analyses. All authors contributed to the writing of the manuscript and approved the final version of the article.

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Correspondence to Leah H. Rubin.

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Rubin, L.H., O’Halloran, J.A., Williams, D.W. et al. Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIV. J Neuroimmune Pharmacol 18, 1–8 (2023). https://doi.org/10.1007/s11481-021-10042-3

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