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Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIV



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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  • Abers MS, Shandera WX, Kass JS (2014) Neurological and psychiatric adverse effects of antiretroviral drugs. CNS Drugs 28:131–145

    Article  CAS  PubMed  Google Scholar 

  • Adimora AA, Ramirez C, Benning L, Greenblatt RM, Kempf MC, Tien PC, Kassaye SG, Anastos K, Cohen M, Minkoff H, Wingood G, Ofotokun I, Fischl MA, Gange S (2018) Cohort Profile: The Women’s Interagency HIV Study (WIHS). Int J Epidemiol 47:393–394i

    Article  PubMed  PubMed Central  Google Scholar 

  • Amusan P, Power C, Gill JM, Gomez D, Johnson E, Rubin LH, Fujiwara E (2020) Lifetime antiretroviral exposure and neurocognitive impairment in HIV. Journal of Neurovirology ahead of print

  • Arenas-Pinto A, Grund B, Sharma S, Martinez E, Cummins N, Fox J, Klingman KL, Sedlacek D, Collins S, Flynn PM, Chasanov WM, Kedem E, Katlama C, Sierra-Madero J, Afonso C, Brouwers P, Cooper DA, group ISs, (2018) Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial. Clin Infect Dis 67:420–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bacon MC, von Wyl V, Alden C, Sharp G, Robison E, Hessol N, Gange S, Barranday Y, Holman S, Weber K, Young MA (2005) The Women’s Interagency HIV Study: an observational cohort brings clinical sciences to the bench. Clin Diagn Lab Immunol 12:1013–1019

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barkan SE, Melnick SL, Preston-Martin S, Weber K, Kalish LA, Miotti P, Young M, Greenblatt R, Sacks H, Feldman J (1998) The Women’s Interagency HIV Study. WIHS Collaborative Study Group Epidemiology 9:117–125

    CAS  Google Scholar 

  • Bengtson AM, Pence BW, Mollan KR, Edwards JK, Moore RD, O’Cleirigh C, Eaton EF, Eron JJ, Kitahata MM, Mathews WC, Crane H, Mugavero MJ (2017) The Relationship Between Efavirenz as Initial Antiretroviral Therapy and Suicidal Thoughts Among HIV-Infected Adults in Routine Care. J Acquir Immune Defic Syndr 76:402–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B 57:125–133

    Google Scholar 

  • Borghetti A, Baldin G, Lombardi F, Ciccullo A, Capetti A, Rusconi S, Sterrantino G, Latini A, Cossu MV, Gagliardini R, De Luca A, Di Giambenedetto S (2018) Efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multicentre cohort of patients with suppressed HIV-1 replication. HIV Med

  • Borghetti A, Baldin G, Capetti A, Sterrantino G, Rusconi S, Latini A, Giacometti A, Madeddu G, Picarelli C, De Marco R, Cossu MV, Lagi F, Cauda R, De Luca A, Di Giambenedetto S, Odoacre Study G (2017) Efficacy and tolerability of dolutegravir and two nucleos(t)ide reverse transcriptase inhibitors in HIV-1-positive, virologically suppressed patients. AIDS 31:457–459

    Article  Google Scholar 

  • Cohen C, Elion R, Ruane P, Shamblaw D, DeJesus E, Rashbaum B, Chuck SL, Yale K, Liu HC, Warren DR, Ramanathan S, Kearney BP (2011) Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 25:F7-12

    Article  CAS  PubMed  Google Scholar 

  • Cohen S, Williamson G (1988) Perceived stress in a probability sample of the United States. In: The social psychology of health: Claremont Symposium on applied social psychology (Spacapan S, Oskamp S, eds). Newbury Park, CA: Sage

  • Cohen S, Kamarck T, Mermelstein R (1983) A global measure of perceived stress. J Health Soc Behav 24:385–396

    Article  CAS  PubMed  Google Scholar 

  • de Boer MG, van den Berk GE, van Holten N, Oryszcyn JE, Dorama W, Moha DA, Brinkman K (2016) Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice. AIDS 30:2831–2834

    Article  PubMed  Google Scholar 

  • Elzi L, Erb S, Furrer H, Cavassini M, Calmy A, Vernazza P, Gunthard H, Bernasconi E, Battegay M, Swiss HIVCSG (2017) Adverse events of raltegravir and dolutegravir. AIDS 31:1853–1858

    Article  CAS  PubMed  Google Scholar 

  • Fettiplace A, Stainsby C, Winston A, Givens N, Puccini S, Vannappagari V, Hsu R, Fusco J, Quercia R, Aboud M, Curtis L (2017) Psychiatric Symptoms in Patients Receiving Dolutegravir. J Acquir Immune Defic Syndr 74:423–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gounden V, van Niekerk C, Snyman T, George JA (2010) Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther 7:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Heim C, Shugart M, Craighead WE, Nemeroff CB (2010) Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol 52:671–690

    Article  PubMed  Google Scholar 

  • Hoffmann C, Llibre JM (2019) Neuropsychiatric Adverse Events with Dolutegravir and Other Integrase Strand Transfer Inhibitors. AIDS Rev 21:4–10

    Article  PubMed  Google Scholar 

  • Hoffmann C, Welz T, Sabranski M, Kolb M, Wolf E, Stellbrink HJ, Wyen C (2017) Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med 18:56–63

    Article  CAS  PubMed  Google Scholar 

  • Klein K, Lang T, Saussele T, Barbosa-Sicard E, Schunck WH, Eichelbaum M, Schwab M, Zanger UM (2005) Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics 15:861–873

    Article  CAS  PubMed  Google Scholar 

  • Li J, Menard V, Benish RL, Jurevic RJ, Guillemette C, Stoneking M, Zimmerman PA, Mehlotra RK (2012) Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: implications for HIV/AIDS treatment. Pharmacogenomics 13:555–570

    Article  CAS  PubMed  Google Scholar 

  • Madeddu G, Menzaghi B, Ricci E, Carenzi L, Martinelli C, di Biagio A, Parruti G, Orofino G, Mura MS, Bonfanti P, Group CISAI (2012) Raltegravir central nervous system tolerability in clinical practice: results from a multicenter observational study. AIDS 26:2412–2415

    Article  Google Scholar 

  • Menard A, Montagnac C, Solas C, Meddeb L, Dhiver C, Tomei C, Ravaux I, Tissot-Dupont H, Mokhtari S, Colson P, Stein A (2017) Neuropsychiatric adverse effects on dolutegravir: an emerging concern in Europe. AIDS 31:1201–1203

    Article  PubMed  Google Scholar 

  • Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, Gulick RM, Na L, O’Keefe L, Robertson KR, Tierney C (2014) Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med 161:1–10

    Article  PubMed  PubMed Central  Google Scholar 

  • Muche EA, Kiflu M, Ayalew MB (2020) Patient Reported Central Nervous System Adverse Events of Efavirenz-Based Antiretroviral Therapy in People Living with HIV in Northwest Ethiopia. HIV AIDS (auckl) 12:601–609

    CAS  PubMed  Google Scholar 

  • Neigh GN, Gillespie CF, Nemeroff CB (2009) The neurobiological toll of child abuse and neglect. Trauma Violence Abuse 10:389–410

    Article  PubMed  PubMed Central  Google Scholar 

  • O’Halloran JA, Wang K, Spence AB, Williams DW, Dastgheyb R, Fitzgerald KC, Kamkwalala AR, Maki PM, Sharma A, Gustafson DR, Milam J, Weber KM, Adimora AA, Ofotokun I, Fischl MA, Konkle-Parker D, Lahiri CD, Sheth AN, Xu Y, Rubin LH (2021) Integrase Strand Transfer Inhibitor Start or Switch Impacts Learning in Women With HIV. J Acquir Immune Defic Syndr 86:593–599

    Article  PubMed  PubMed Central  Google Scholar 

  • Penafiel J, de Lazzari E, Padilla M, Rojas J, Gonzalez-Cordon A, Blanco JL, Blanch J, Marcos MA, Lonca M, Martinez-Rebollar M, Laguno M, Tricas A, Rodriguez A, Mallolas J, Gatell JM, Martinez E (2017) Tolerability of integrase inhibitors in a real-life setting. J Antimicrob Chemother 72:1752–1759

    Article  CAS  PubMed  Google Scholar 

  • Penza KM, Heim C, Nemeroff CB (2003) Neurobiological effects of childhood abuse: implications for the pathophysiology of depression and anxiety. Arch Womens Ment Health 6:15–22

    Article  CAS  PubMed  Google Scholar 

  • Revuelta-Herrero JL, Chamorro-de-Vega E, Rodriguez-Gonzalez CG, Alonso R, Herranz-Alonso A, Sanjurjo-Saez M (2018) Effectiveness, Safety, and Costs of a Treatment Switch to Dolutegravir Plus Rilpivirine Dual Therapy in Treatment-Experienced HIV Patients. Ann Pharmacother 52:11–18

    Article  CAS  PubMed  Google Scholar 

  • Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA, Ritchie MD, Zanger UM, Acosta EP, Morse GD, Gulick RM, Robbins GK, Clifford D, Haas DW (2010) Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis 202:717–722

    Article  CAS  PubMed  Google Scholar 

  • Rubin LH, Cook JA, Weber KM, Cohen MH, Martin E, Valcour V, Milam J, Anastos K, Young MA, Alden C, Gustafson DR, Maki PM (2015) The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women. J Neurovirol 21:422–432

    Article  PubMed  PubMed Central  Google Scholar 

  • Rubin LH, Pyra M, Cook JA, Weber KM, Cohen MH, Martin E, Valcour V, Milam J, Anastos K, Young MA, Alden C, Gustafson DR, Maki PM (2016) Post-traumatic stress is associated with verbal learning, memory, and psychomotor speed in HIV-infected and HIV-uninfected women. J Neurovirol 22:159–169

    Article  PubMed  Google Scholar 

  • Rubin LH, Cook JA, Springer G, Weber KM, Cohen MH, Martin EM, Valcour VG, Benning L, Alden C, Milam J, Anastos K, Young MA, Gustafson DR, Sundermann EE, Maki PM (2017) Perceived and post-traumatic stress are associated with decreased learning, memory, and fluency in HIV-infected women. AIDS 31:2393–1401

    Article  PubMed  Google Scholar 

  • Rubin LH, Li Y, Fitzgerald KC, Dastgheyb R, Spence AB, Maki PM, Sharma A, Gustafson DR, Milam J, Weber KM, Adimora AA, Haughey NJ, Ofotokun I, Fischl MA, Konkle-Parker D, Xu Y, Williams DW (2020) Associations between Antiretrovirals and Cognitive Function in Women with HIV. J Neuroimmune Pharmacol

  • Ruggiero KJ, Del Ben K, Scotti JR, Rabalais AE (2003) Psychometric properties of the PTSD Checklist-Civilian Version. J Trauma Stress 16:495–502

    Article  PubMed  Google Scholar 

  • Senneker T, Tseng A (2021) An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors. Curr Opin HIV AIDS 16:309–320

    Article  CAS  PubMed  Google Scholar 

  • Teppler H, Brown DD, Leavitt RY, Sklar P, Wan H, Xu X, Lievano F, Lehman HP, Mast TC, Nguyen BY (2011) Long-term safety from the raltegravir clinical development program. Curr HIV Res 9:40–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vujkovic M, Bellamy SL, Zuppa AF, Gastonguay MR, Moorthy GS, Ratshaa B, Han X, Steenhoff AP, Mosepele M, Strom BL, Bisson GP, Aplenc R, Gross R (2018) Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana. Pharmacogenomics J 18:678–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z (2003) The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287–300

    Article  CAS  PubMed  Google Scholar 

  • Weathers FW, Huska JA, Keane TM (1991) PCL-C for DSM-IV. In: (Division NCfPBS, ed). Boston

  • Williams DW, Li Y, Dastgheyb R, Fitzgerald KC, Maki PM, Spence AB, Gustafson DR, Milam J, Sharma A, Adimora AA, Ofotokun I, Fischl MA, Konkle-Parker D, Weber KM, Xu Y, Rubin LH (2020) Associations between Antiretroviral Drugs on Depressive Symptomatology in Homogenous Subgroups of Women with HIV. J Neuroimmune Pharmacol

  • Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M (2007) Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 8:743–759

    Article  CAS  PubMed  Google Scholar 

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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).


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

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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).

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