Abstract
Background:
Evidence regarding potential adverse neuropsychiatric effects of efavirenz is conflicting, and data from sub-Saharan Africa, where 70% of persons living with HIV (PLHIV) reside and efavirenz is used as first-line therapy, are limited.
Objective:
To estimate associations between efavirenz use and depression and suicidal ideation among PLHIV in Uganda.
Design:
Prospective observational cohort study. (ClinicalTrials.gov: NCT01596322)
Setting:
Mbarara, Uganda.
Participants:
Adult PLHIV enrolled at the start of antiretroviral therapy (ART) and observed every 3 to 4 months from 2005 to 2015.
Measurements:
The exposure of interest was time-varying efavirenz use, defined as use during the 7 days and in 60 or more of the 90 days before a study visit, compared with nevirapine use. Self-reported outcomes were depression, defined as a mean score greater than 1.75 on the Hopkins Symptom Checklist depression subscale, and suicidal ideation. Multivariable-adjusted generalized estimating equations (GEE) logistic regression, Cox proportional hazards regression, and marginal structural models were fit to estimate the association between efavirenz use and the risk for depression and suicidal ideation.
Results:
694 participants (median age, 33 years; median pretreatment CD4+ count, 1.8 × 109 cells/L) contributed 1200 person-years of observation (460 person-years receiving efavirenz). No baseline differences in depression or suicidal ideation were found between patients ever exposed to efavirenz and those never exposed to efavirenz and receiving nevirapine (P > 0.80 for both). Of 305 participants ever-exposed to efavirenz, 61 (20.0%) and 19 (6.2%) had depression and suicidal ideation, respectively, on at least 1 follow-up visit, compared with 125 (32.1%) and 47 (12.1%) of the 389 who received nevirapine. In adjusted GEE models, efavirenz use was associated with decreased odds of depression compared with nevirapine use (adjusted odds ratio, 0.62 [95% CI, 0.40 to 0.96]) and was not significantly associated with suicidal ideation (adjusted odds ratio, 0.61 [CI, 0.30 to 1.25]). Time-to-event and marginal structural models yielded similar estimates.
Limitation:
Nonrandom assignment to treatment and substantial differences between the efavirenz and nevirapine groups.
Conclusion:
No evidence was found that use of efavirenz in first-line ART increased the risk for depression or suicidal ideation compared with nevirapine use among PLHIV in Uganda.
Primary Funding Source:
National Institutes of Health.
References
- 1.
Nelson LJ ,Beusenberg M ,Habiyambere V ,Shaffer N ,Vitoria MA ,Montero RG ,et al . Adoption of national recommendations related to use of antiretroviral therapy before and shortly following the launch of the 2013 WHO consolidated guidelines. AIDS. 2014;28 Suppl 2:S217-24. [PMID: 24849481] doi:10.1097/QAD.0000000000000239 CrossrefMedlineGoogle Scholar - 2.
Mollan KR ,Smurzynski M ,Eron JJ ,Daar ES ,Campbell TB ,Sax PE ,et al . 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. 2014;161:1-10. [PMID: 24979445]. doi:10.7326/M14-0293 LinkGoogle Scholar - 3.
Kenedi CA ,Goforth HW . A systematic review of the psychiatric side-effects of efavirenz. AIDS Behav. 2011;15:1803-18. [PMID: 21484283] doi:10.1007/s10461-011-9939-5 CrossrefMedlineGoogle Scholar - 4.
Nkhoma ET ,Coumbis J ,Farr AM ,Johnston SS ,Chu BC ,Rosenblatt LC ,et al . No evidence of an association between efavirenz exposure and suicidality among HIV patients initiating antiretroviral therapy in a retrospective cohort study of real world data. Medicine (Baltimore). 2016;95:e2480. [PMID: 26817882] doi:10.1097/MD.0000000000002480 CrossrefMedlineGoogle Scholar - 5.
Napoli AA ,Wood JJ ,Coumbis JJ ,Soitkar AM ,Seekins DW ,Tilson HH . No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214. [PMID: 25192857] doi:10.7448/IAS.17.1.19214 CrossrefMedlineGoogle Scholar - 6.
Smith C ,Ryom L ,Monforte Ad ,Reiss P ,Mocroft A ,El-Sadr W ,et al . Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study. J Int AIDS Soc. 2014;17:19512. [PMID: 25394021] doi:10.7448/IAS.17.4.19512 CrossrefMedlineGoogle Scholar - 7.
Bengtson AM ,Pence BW ,Mollan KR ,Edwards JK ,Moore RD ,O'Cleirigh C ,et al . The relationship between efavirenz as initial antiretroviral therapy and suicidal thoughts among HIV-infected adults in routine care. J Acquir Immune Defic Syndr. 2017;76:402-8. [PMID: 28749824] doi:10.1097/QAI.0000000000001510 CrossrefMedlineGoogle Scholar - 8. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Accessed at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf on 19 May 2018. Google Scholar
- 9.
World Health Organization . Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Geneva: World Health Organization; 2016. Google Scholar - 10. UNAIDS. Global AIDS Update 2016. Geneva: World Health Organization; 2016. Accessed at www.unaids.org/sites/default/files/media_asset/UNAIDS_Gap_report_en.pdf on 19 May 2018. Google Scholar
- 11.
Tsai AC . Reliability and validity of depression assessment among persons with HIV in sub-Saharan Africa: systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2014;66:503-11. [PMID: 24853307] doi:10.1097/QAI.0000000000000210 CrossrefMedlineGoogle Scholar - 12.
Tsai AC ,Weiser SD ,Petersen ML ,Ragland K ,Kushel MB ,Bangsberg DR . A marginal structural model to estimate the causal effect of antidepressant medication treatment on viral suppression among homeless and marginally housed persons with HIV. Arch Gen Psychiatry. 2010;67:1282-90. [PMID: 21135328] doi:10.1001/archgenpsychiatry.2010.160 CrossrefMedlineGoogle Scholar - 13.
Todd JV ,Cole SR ,Pence BW ,Lesko CR ,Bacchetti P ,Cohen MH ,et al . Effects of antiretroviral therapy and depressive symptoms on all-cause mortality among HIV-infected women. Am J Epidemiol. 2017;185:869-78. [PMID: 28430844] doi:10.1093/aje/kww192 CrossrefMedlineGoogle Scholar - 14.
Tsai AC ,Weiser SD ,Steward WT ,Mukiibi NF ,Kawuma A ,Kembabazi A ,et al . Evidence for the reliability and validity of the internalized AIDS-related stigma scale in rural Uganda. AIDS Behav. 2013;17:427-33. [PMID: 22869104] doi:10.1007/s10461-012-0281-3 CrossrefMedlineGoogle Scholar - 15.
Kaida A ,Matthews LT ,Ashaba S ,Tsai AC ,Kanters S ,Robak M ,et al . Depression during pregnancy and the postpartum among HIV-infected women on antiretroviral therapy in Uganda. J Acquir Immune Defic Syndr. 2014;67 Suppl 4:S179-87. [PMID: 25436816] doi:10.1097/QAI.0000000000000370 CrossrefMedlineGoogle Scholar - 16.
Martinez P ,Andia I ,Emenyonu N ,Hahn JA ,Hauff E ,Pepper L ,et al . Alcohol use, depressive symptoms and the receipt of anti-retroviral therapy in southwest Uganda. AIDS Behav. 2008;12:605-12. [PMID: 17968651] CrossrefMedlineGoogle Scholar - 17.
Tsai AC ,Bangsberg DR ,Frongillo EA ,Hunt PW ,Muzoora C ,Martin JN ,et al . Food insecurity, depression and the modifying role of social support among people living with HIV/AIDS in rural Uganda. Soc Sci Med. 2012;74:2012-9. [PMID: 22513248] doi:10.1016/j.socscimed.2012.02.033 CrossrefMedlineGoogle Scholar - 18.
Ashaba S ,Kakuhikire B ,Vorechovská D ,Perkins JM ,Cooper-Vince CE ,Maling S ,et al . Reliability, validity, and factor structure of the Hopkins symptom checklist-25: population-based study of persons living with HIV in rural uganda. AIDS Behav. 2018;22:1467-74. [PMID: 28667469] doi:10.1007/s10461-017-1843-1 CrossrefMedlineGoogle Scholar - 19.
Bolton P ,Ndogoni L . Cross-Cultural Assessment of Trauma-Related Mental Illness. Baltimore: Johns Hopkins Univ Pr; 2000. Google Scholar - 20.
Derogatis LR ,Lipman RS ,Rickels K ,Uhlenhuth EH ,Covi L . The Hopkins symptom checklist (HSCL): a self-report symptom inventory. Behav Sci. 1974;19:1-15. [PMID: 4808738] CrossrefMedlineGoogle Scholar - 21.
Filmer D ,Pritchett LH . Estimating wealth effects without expenditure data—or tears: an application to educational enrollments in states of India. Demography. 2001;38:115-32. [PMID: 11227840] MedlineGoogle Scholar - 22.
Wu AW ,Rubin HR ,Mathews WC ,Ware JE ,Brysk LT ,Hardy WD ,et al . A health status questionnaire using 30 items from the Medical Outcomes Study. Preliminary validation in persons with early HIV infection. Med Care. 1991;29:786-98. [PMID: 1875745] CrossrefMedlineGoogle Scholar - 23.
Bush K ,Kivlahan DR ,McDonell MB ,Fihn SD ,Bradley KA . The AUDIT alcohol consumption questions (AUDIT-c): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med. 1998;158:1789-95. [PMID: 9738608] CrossrefMedlineGoogle Scholar - 24.
Fumaz CR ,Muñoz-Moreno JA ,Moltó J ,Negredo E ,Ferrer MJ ,Sirera G ,et al . Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr. 2005;38:560-5. [PMID: 15793366] CrossrefMedlineGoogle Scholar - 25.
VanderWeele TJ ,Ding P . Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167:268-74. [PMID: 28693043]. doi:10.7326/M16-2607 LinkGoogle Scholar - 26.
Gross R ,Bellamy SL ,Ratshaa B ,Han X ,Vujkovic M ,Aplenc R ,et al . CYP2B6 genotypes and early efavirenz-based HIV treatment outcomes in Botswana. AIDS. 2017;31:2107-13. [PMID: 28692529] doi:10.1097/QAD.0000000000001593 CrossrefMedlineGoogle Scholar - 27.
Rotger M ,Colombo S ,Furrer H ,Bleiber G ,Buclin T ,Lee BL ,et al ;Swiss HIV Cohort Study . Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics. 2005;15:1-5. [PMID: 15864119] CrossrefMedlineGoogle Scholar - 28.
Haas DW ,Ribaudo HJ ,Kim RB ,Tierney C ,Wilkinson GR ,Gulick RM ,et al . Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18:2391-400. [PMID: 15622315] MedlineGoogle Scholar - 29.
Mukonzo JK ,Okwera A ,Nakasujja N ,Luzze H ,Sebuwufu D ,Ogwal-Okeng J ,et al . Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study. BMC Infect Dis. 2013;13:261. [PMID: 23734829] doi:10.1186/1471-2334-13-261 CrossrefMedlineGoogle Scholar - 30.
Sarfo FS ,Zhang Y ,Egan D ,Tetteh LA ,Phillips R ,Bedu-Addo G ,et al . Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients. J Antimicrob Chemother. 2014;69:491-9. [PMID: 24080498] doi:10.1093/jac/dkt372 CrossrefMedlineGoogle Scholar - 31.
Ribaudo HJ ,Liu H ,Schwab M ,Schaeffeler E ,Eichelbaum M ,Motsinger-Reif AA ,et al . Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis. 2010;202:717-22. [PMID: 20662624] doi:10.1086/655470 CrossrefMedlineGoogle Scholar - 32.
Gatch MB ,Kozlenkov A ,Huang RQ ,Yang W ,Nguyen JD ,González-Maeso J ,et al . The HIV antiretroviral drug efavirenz has LSD-like properties. Neuropsychopharmacology. 2013;38:2373-84. [PMID: 23702798] doi:10.1038/npp.2013.135 CrossrefMedlineGoogle Scholar - 33.
Huang R ,Chen Z ,Dolan S ,Schetz JA ,Dillon GH . The dual modulatory effects of efavirenz on GABAA receptors are mediated via two distinct sites. Neuropharmacology. 2017;121:167-78. [PMID: 28456686] doi:10.1016/j.neuropharm.2017.04.038 CrossrefMedlineGoogle Scholar - 34.
Ford N ,Shubber Z ,Pozniak A ,Vitoria M ,Doherty M ,Kirby C ,et al . Comparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line antiretroviral therapy: a systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2015;69:422-9. [PMID: 25850607] doi:10.1097/QAI.0000000000000606 CrossrefMedlineGoogle Scholar - 35.
Journot V ,Chene G ,DeCastro N ,Rancinan C ,Cassuto JP ,Allard C ,et al ;ALIZE Study Group . Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099. Clin Infect Dis. 2006;42:1790-9. [PMID: 16705588] CrossrefMedlineGoogle Scholar - 36.
Poupard M ,NgomGueye NF ,Thiam D ,Ndiaye B ,Girard PM ,Delaporte E ,et al . Quality of life and depression among HIV-infected patients receiving efavirenz- or protease inhibitor-based therapy in Senegal. HIV Med. 2007;8:92-5. [PMID: 17352765] CrossrefMedlineGoogle Scholar - 37.
Venter WDF ,Clayden P ,Serenata C ;OPTIMIZE Consortium . The ADVANCE study: a groundbreaking trial to evaluate a candidate universal antiretroviral regimen. Curr Opin HIV AIDS. 2017;12:351-4. [PMID: 28538284] doi:10.1097/COH.0000000000000389 CrossrefMedlineGoogle Scholar - 38.
Kalichman SC ,Simbayi LC ,Cloete A ,Mthembu PP ,Mkhonta RN ,Ginindza T . Measuring AIDS stigmas in people living with HIV/AIDS: the internalized AIDS-related stigma scale. AIDS Care. 2009;21:87-93. [PMID: 19085224] doi:10.1080/09540120802032627 CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
Jonathan L. Chang,
Duke University School of Medicine, Durham, North Carolina, and Massachusetts General Hospital, Boston, Massachusetts (J.L.C.)
Mbarara University of Science and Technology, Mbarara, Uganda (A.C.T., N.M., C.M., M.B.)
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (J.E.H.)
Mbarara University of Science and Technology, Mbarara, Uganda; Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Epicentre Mbarara, Mbarara, Uganda (Y.B.)
University of California, San Francisco, San Francisco, California (J.N.M., P.W.H.)
Mbarara University of Science and Technology, Mbarara, Uganda, and Oregon Health & Science University, Portland, Oregon (D.R.B.)
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, and Mbarara University of Science and Technology, Mbarara, Uganda (M.J.S.)
Grant Support: By the NIH (grants R01 MH054907, U01 CA066529, and K23 MH099916), University of California, San Francisco, Gladstone Center for AIDS Research (grant P30AI027763), Harvard Center for AIDS Research (grant P30AI060354), and Doris Duke Charitable Foundation.
Disclosures: Dr. Haberer reports grants from NIH during the conduct of the study and personal fees from Merck outside the submitted work. Dr. Martin reports grants from NIH during the conduct of the study. Dr. Hunt reports grants from NIH during the conduct of the study and personal fees from Merck, Gilead, and ViiV outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2252.
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. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available from Dr. Haberer (e-mail, jhaberer@partners.
Corresponding Author: Jonathan L. Chang, MPH, 16 St Elias Drive, Durham, NC 27705; e-mail, jonathan.
Current Author Addresses: Mr. Chang: 16 St Elias Drive, Durham, NC 27705.
Dr. Tsai: 9 Bow Street, Cambridge, MA 02138.
Mr. Musinguzi and Drs. Muzoora and Bwana: Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda.
Dr. Haberer: Massachusetts General Hospital Global Health, 100 Cambridge Street, 15th Floor, Boston, MA 02114.
Dr. Boum: Epicentre Mbarara Research Center, P.O. Box 1856, Mbarara, Uganda.
Dr. Martin: 550 16th Street, San Francisco, CA 94158.
Dr. Hunt: 1001 Potrero Avenue, San Francisco, CA 94110.
Dr. Bangsberg: Office of the Dean, MC: GH230, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.
Dr. Siedner: 55 Fruit Street, Boston, MA 02114.
Author Contributions: Conception and design: J.L. Chang, A.C. Tsai, M.J. Siedner.
Analysis and interpretation of the data: J.L. Chang, A.C. Tsai, J.E. Haberer, C. Muzoora, J.N. Martin, P.W. Hunt, M.J. Siedner.
Drafting of the article: J.L. Chang, J.E. Haberer, Y. Boum, C. Muzoora, J.N. Martin, P.W. Hunt.
Critical revision for important intellectual content: J.L. Chang, A.C. Tsai, Y. Boum, C. Muzoora, J.N. Martin, P.W. Hunt, D.R. Bangsberg, M.J. Siedner.
Final approval of the article: J.L. Chang, A.C. Tsai, N. Musinguzi, J.E. Haberer, Y. Boum, C. Muzoora, M. Bwana, J.N. Martin, P.W. Hunt, D.R. Bangsberg, M.J. Siedner.
Provision of study materials or patients: C. Muzoora, M. Bwana, J.N. Martin.
Statistical expertise: A.C. Tsai, M.J. Siedner.
Obtaining of funding: J.N. Martin, P.W. Hunt, D.R. Bangsberg.
Administrative, technical, or logistic support: C. Muzoora, J.N. Martin.
Collection and assembly of data: N. Musinguzi, J. Haberer, Y. Boum, C. Muzoora, M. Bwana, J.N. Martin, P.W. Hunt, D.R. Bangsberg.
This article was published at Annals.org on 26 June 2018.
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