||The association between the use of efavirenz and the occurrence of depressive disorders among HIV-treated patients
||Graduate Institute of Public Health
Human immunodeficiency virus
Active antiretroviral therapy
Cox proportional hazard model
高效能抗反轉錄病毒療法(highly active antiretroviral therapy)問世後大幅改善人類免疫人類免疫不全病毒感染者（以下簡稱愛滋感染者）之存活。抗反轉錄病毒藥物efavirenz可能產生短期的中樞神經副作用，然而，長期使用是否會增加感染者憂鬱甚至是自殺的風險還尚未有定論。本研究目的旨在研究愛滋病感染者發生憂鬱和使用efavirenz的關聯性。本研究利用2000年至2010年台灣健保資料庫，研究分析了7286位追蹤時間大於6個月且服用藥物大於6個月的愛滋感染者，將其分為efavirenz暴露組和efavirenz非暴露組，暴露組服藥後新發生憂鬱的發生率是每千人年12.2，非暴露組為每千人年12.5，兩組之發生率並無顯著差異（p=0.822）。Cox比例風險模型分析發現：愛滋感染者服藥後發生憂鬱的獨立危險因子包括：投保金額低於新台幣17820元(調整後風險比值為2.59，95% 信賴區間1.79-3.76, p<0.001)、以及介於新台幣17821至26400元之間(調整後風險比值為1.55，95% 信賴區間 1.04-2.31 p=0.030)、住在南台灣(調整後風險比值為1.49，95%信賴區間 1.21-1.84 p=0.002)、以及過去有除了憂鬱以外的精神病史(調整後風險比值為4.59，95% 信賴區間 3.51-6.01 p<0.001)。本研究長期觀察資料顯示愛滋感染者使用efavirenz並不會增加憂鬱症發生的風險，反之，過去有精神病史的愛滋感染者有顯著較高的風險在治療過程中發生憂鬱症之診斷。
The use of highly active antiretroviral therapy (HAART) could improve the survival among people living with human immunodeficiency virus (HIV). One of the antiretroviral drugs – efavirenz could cause short-term side effects of central nervous system. However, it remained controversial as to whether efavirenz would cause depression or even suicidal attempt when applied for a longer period of time. The study purpose was to determine the association between the use of efavirenz and depressive disorders. This study analyzed HIV-infected patients who stayed in the registry for more than 6 months after HIV diagnosis and took HAART for more than 6 months. Data were retrieved from the National Health Insurance Research Database from 2000 to 2010. The HIV-infected patients were categorized into efavirenz-treated group and non-efavirenz-treated group. After up to 11 years of follow-up, the incidence rate of depressive disorders for the efavirenz-treated group was estimated at 12.2/1,000 person-year (PY) while that for the control group was 12.5/1,000 PY (p=0.822). The Cox proportional hazard model suggested that the independent risk factors for the onset of depressive disorders among people living with HIV after HAART included a insurance premium of less than 17820 New Taiwan Dollars (NTD) (adjusted hazard ratio [aHR] 2.59 95% confidence interval [CI] 1.79-3.76, p<0.001), and between 17821 and 26400 NTD (aHR 1.55 95% CI 1.04-2.31, p=0.030), living in Southern Taiwan (aHR 1.49 95% CI 1.21-1.84, p=0.002), and with a past history of psychiatric disorders (excluding depressive disorders) (aHR 4.59 95% CI 3.51-6.01, p=0.030). We concluded the use of efavirenz did not increase the risk of depressive disorders among HIV-treated patients. Instead, patients with a past history of psychiatric disorders were at increased risk of developing depressive disorders.
Chapter 1 Preface 1
1.1 Background and significance 1
1.2 Research Aim 3
Chapter 2 Literature Review 4
2.1 The risk factors influencing the prognosis of people living with HIV 4
2.2 HIV infection and depressive disorders 5
2.3 The associations between efavirenz and depressive disorders 6
Chapter 3 Methodology 9
3.1 Data source 9
3.2 Study population 9
3.3 Research variables 10
3.4 Statistical analysis 11
3.5 Sensitivity analysis 11
Chapter 4 Results 13
4.1 Study population 13
4.2 Incidence and risk factors for developing depressive disorders 14
4.3 Sensitivity analysis 16
4.3.1 The first scenario for sensitivity analysis 16
4.3.2 The second scenario for sensitivity analysis 17
4.3.3 The third scenario for sensitivity analysis 17
Chapter 5 Discussion 19
Ammassari A, Murri R, Pezzotti P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Defic Syndr 2001; 28: 445-9.
Arendt G, Nocker D, Von Giesen HJ, et al. Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf 2007; 6: 147-54.
Beyer JL, Taylor L, Gersing KR, et al. Prevalence of HIV infection in a general psychiatric outpatient population. Psychosomatics 2007; 48: 31-7.
Chen MH, Su TP, Chen TJ, et al. Identification of psychiatric disorders among human immunodeficiency virus-infected individuals in Taiwan, a nine-year nationwide population-based study. AIDS care 2012; 24: 1543-9.
Chiang T. Taiwan's 1995 healthcare reform. Health Policy 1997; 39: 225-239.
Clifford DB, Evans S, Yang Y, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 2005; 143: 714-21.
Clifford DB, Evans S, Yang Y, et al. Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials 2009; 10: 343-55.
Collaboration ATC. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis 2010; 50: 1387-96.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. . Accessed 31 August 2014.
Guidelines Version 7.02. Available at: http://www.eacsociety.org/Portals/0/140601_EACS EN7.02.pdf 31 August 2014.
Fu JJ, Bazazi AR, Altice FL, et al. Absence of antiretroviral therapy and other risk factors for morbidity and mortality in malaysian compulsory drug detention and rehabilitation centers. PLoS One 2012; 7: e44249.
Funes HA, Apostolova N, Alegre F, et al. Neuronal bioenergetics and acute mitochondrial dysfunction: A clue to understanding the central nervous system side effects of efavirenz. J Infect Dis 2014; 210: 1385-95.
Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: 251-60.
Gibbie T, Mijch A, Ellen S, et al. Depression and neurocognitive performance in individuals with HIV/AIDS: 2-year follow-up. HIV Med 2006; 7: 112-21.
Gunthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA 2014; 312: 410-25.
Gutierrez F, Garcia L, Padilla S, et.al. Risk of clinically significant depression in HIV-infected patients: effect of antiretroviral drugs. HIV Med 2014; 15: 213-23.
Helleberg M, Kronborg G, Larsen CS, et al. Causes of death among Danish HIV patients compared with population controls in the period 1995-2008. Infection 2012; 40: 627-34.
Journot V, Chene G, De Castro N, et al. 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.
Kacanek D, Jacobson D, Spiegelman D, et al. Incident depression symptoms are associated with poorer HAART adherence: a longitudinal analysis form the Nutrition for Healthy Living study. J Acquir Immune Defic Syndr 2010; 53: 266-72.
Ko NY, Lai YY, Liu HY, et al. Impact of the nurse-led case management program with retention in care on mortality among people with HIV-1 infection: a prospective cohort study. Int J Nurs Stud 2012; 49: 656-63.
Liu CY, Hung YT, Chuang YL, et al. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag 2006; 4: e22.
Lopes M, Olfson M, Tabkin J, et al. Gender, HIV status, and psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related conditions. J Clin Psychiatry 2012; 73: 384-91.
Martinez E, Milinkovic A, Buira E, et al. Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area. HIV Med 2007; 8: 251-8.
Melekhin VV, Stepherd BE, Stinnette SE, et al. Hemoglobin may contribute to sex differences in mortality among HIV-infected persons in care. PLoS One 2012; 7 e44999.
Mollan KR, Smurzynski M, Eron JJ, 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.
Nomoto SH1, Longhi RM, de Barros BP, et al. Socioeconomic disadvantage increasing risk for depression among recently diagnosed HIV patients in an urban area in Brazil: cross-sectional study. AIDS care 2015; 27: 979-85.
Ogoina D, Obiako RO, Muktar HM, et al. Morbidity and mortality patterns of hospitalised adult HIV/AIDS patients in the era of highly active antiretroviral therapy: a 4-year retrospective review from Zaria, northern Nigeria. AIDS Res Treat 2012; 2012: 940580.
O'Mahony SM, Myint A, Steinbusch H, et al. Efavirenz induces depressive like behaviour, increased stress response and changes in the immune response in rats. Neuroimmunomodulation 2005; 12: 293-8.
Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60.
Petoumenos K, Law MG. Risk factors and causes of death in the Australian HIV observational database. Sex Health 2006; 3: 103-12.
Purnell PR, Fox HS. Efavirenz induces neuronal autophagy and mitochondrial alterations. J Pharmocol Exp Ther 2014; 351: 250-8.
Rasmussen D, Kronborg G, Larsen C, et al. Utilization of psychotropic drugs prescribed to persons with and without HIV infection: a Danish nationwide population-based cohort study. HIV Med 2014; 15: 458-69.
Reekie J, Kowalska JD, Karpov I, et al. Regional differences in AIDS and non-AIDS related mortality in HIV-positive individuals across Europe and Argentina: The EuroSIDA Study. PLoS One 2012; 7: e41673.
Sabin CA, Smith CJ, Youle M, et al. Deaths in the era of HAART: contribution of late presentation, treatment exposure, resistance and abnormal laboratory markers. AIDS 2006; 20: 67-71.
Weber R, Ruppik M, Rickenbach M, et al. Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Med 2013; 14: 195-207.
Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Available at: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf. Accessed 31 August 2014.
World Health Organiation. Global summary of the AIDS epidemic. Available at http://www.who.int/hiv/data/epi_core_dec2014.png?ua=1. Accessed 28 May 2015.
Wright E, Brew B Arayawichanont A, et al. Neurologic disorders are prevalent in HIV-positive outpatients in the Asia-Pacific region. Neurology 2008; 71: 50-6.