<p> Electronic Supplementary Materials Title: The Impact of DSM-IV Mental Disorders on Adherence to Combination Antiretroviral Therapy among Adult Persons Living with HIV/AIDS: A Systematic Review Authors: Sandra A..Springer, Azem Dushaj, Marwan Azar</p><p>*This material supplements but does not replace the content of the peer-reviewed paper published in AIDS and Behavior.</p><p>Electronic Appendix:</p><p>SEARCH TERMS</p><p>1. To assess studies involving adherence, we used the following search terms: adherence, compliance, persistence</p><p>2. To assess studies involving HIV, we used the following search terms: acquired immunodeficiency syndrome, AIDS, antiretroviral therapy, antiretroviral treatment, ART, HAART, highly active antiretroviral therapy, HIV, HIV treatment, human immunodeficiency virus</p><p>3. To assess studies involving mental illness, we used the following search terms:</p><p> acute anxiety disorder body dysmorphic disorder GAD affective disorder borderline personality generalized anxiety disorder antisocial personality dependent personality histrionic personality anxiety depression hypochondriac avoidant personality depressive disorder hypochondriasis bipolar disorder dysthymia manic disorder mental health mental illness mood disorder mood disorder narcissistic personality panic disorder personality disorder personality disorders post traumatic anxiety disorder posttraumatic anxiety disorder post-traumatic anxiety disorder psychiatric disease psychiatric disorder psychiatric illness psychosis psychotic disorder</p><p>PTSD schizophrenia somatization somatoform disorders Table 2: Impact of Specific Mental Illnesses Other Than Depression on cART Adherence: Study Characteristics</p><p>Author, Study Design PLWHA Adherence: Mental Illness (MI) Impact of Mental Illness on Adherence Publication and Population, Measurement & Scale (S) Used to Year, Location Evaluation Sample Size (M), Definition Measure Mental Anxiety Bipolar Psychotic Personality Period (D) and Time Illness Disorders Disorder Disorders Disorders period (T) Boarts, J. M., E. Prospective 57 M: Self-report MI:PTSD MVA: PTSD X X X M. Sledjeski, et cohort study participants* (AACTG S: Post-traumatic symptoms al. (2006) USA (3-month adapted self- Diagnostic Scale predicted follow-up) report) lower interview adherence at D: Continuous follow-up only variable when baseline T: Previous levels of week adherence were removed from the analyses (p≤ 0.05). Boarts, J. M., B. Prospective 84 M: Self-report MI:PTSD MVA: The non- X X X A. Buckley- cohort study participants (AACTG S: Post-traumatic HIV-related Fischer, et al. (3-4 month divided into adapted self- Diagnostic Scale PTSD group (2009) USA follow-up) 3 groups (59 report) and IES reported completed interview significantly study): D: Continuous lower 1-No PTSD, n variable adherence =38 T: Previous compared to 2-HIV-related week the non-PTSD PTSD, n=13 group (p< 3-Non-HIV- 0.05). In the related PTSD, HIV-related n =23 PTSD group, adherence increased over time; while the in non-HIV- related PTSD group adherence decreased over time. Campos, L. N., Prospective 293 M: Self-report. MI: Anxiety BVA: Severe X X X M. D. cohort study participants D: Non- S: HADS anxiety was Guimaraes, et (May 2001- adherence: independently al. (2010) Brazil May 2002) <95% associated with adherence non-adherence T : Previous 3 (RH= 1.87, 95% days CI= 1.14–3.06; p < 0.05). Carrieri, M. P., Cohort study 96 initially M: Self-report. MI: Anxiety MVA: Anxiety X X X M. A. Chesney, (Oct 1995, adherent D: Adherence S: self-administered was not et al. (2003) followed -up IDUs failure: <80% questionnaire and significantly France for the first participants adherence or the face-to-face related to 18 months did not interview of adherence on cART) “totally” follow somatic symptoms failure. their of anxiety prescribed regimen</p><p>Catz, S. L., T. G. Cross- 84 M: Self-report MI1: Anxiety BVA: X X X Heckman, et al. sectional participants (six-point Likert MI2: Somatization Adherence was (2001) USA study (1997) scale) S: Symptom Check associated with D: List-90-Revised lower levels of Dichotomized somatization “consistent (OR = 0.45, p < adherence”: 0.05), but not No skipped with anxiety. dose; or “inconsistent adherence”: at least 1 skipped dose. T: Previous 7 days Escobar, I., M. Cross- 283 M: Pharmacy MI: Anxiety BVA: Non- X X X Campo, et al. sectional participants refill S: State-Trait adherence risk (2003) Spain study (Nov on cART for D: Non- Anxiety increased 3.49- 2000 - Jan at least 6 adherence: questionnaire fold (95% 2001) months <95% (STAI) CI=2.02-6.02) in adherence those who T: Previous 4–6 scored >75% months. on the anxiety scales. Ingersoll, K. Cross – 120 M1: Electronic MI: Anxiety MVA: In a X X X (2004) USA sectional participants medical record Disorders stepwise study and self-report. S: CIDI-SF logistic D: Four regression dichotomous anxiety non-adherent significantly behaviors: (1) predicted running out of adherence. medications, (2) not always taking medications as directed, (3) ≤ 95% adherence or (4) having notations of non- compliance in the medical record. T: Previous week. Keuroghlian, A. Cross- 38 M: Self-report MI1: PTSD MVA: PTSD was X X MVA: PTSD S., C. S. Kamen, sectional participants (AACTG MI2: Dissociative associated with symptoms were et al. (2011) study questionnaire) experience lower odds of significantly associated with USA D: Adherent: S1: IES-R cART lower odds of no missed S2: DES-II adherence adherence in doses (OR = 0.92, individuals T: Previous 4 p < 0.05). reporting high days levels of dissociation (OR = .86, p < .05) but not in those reporting low levels of dissociation (OR = 1.02, p > . 05).Dissociation moderated the effect of PTSD on adherence, resulting in lower odds of adherence (OR =0 .95, p < 0.05).</p><p>Mellins, C. A., J. Cross- 542 M: Self-report MI1: Bipolar MVA: GAD, MVA: x MVA: Borderline F. Havens, et sectional participants (AACTG Disorder Panic Disorder, Bipolar PD and Antisocial al. (2009) USA study (Data questionnaire) MI2: GAD Agoraphobia, Disorder PD were not from a D: 100% MI3: Panic Disorder PTSD and was not associated with multisite adherence MI4: Agoraphobia Adjustment associated adherence. cohort study T: Previous 3 MI5: PTSD and Disorder were with of 1138 HIV days MI6: Adjustment Ds not associated adherence. infected MI7: Borderline PD with adults) MI8: Antisocial PD. adherence. S: SCID Moore, D. J., C. Cross- 77 M: EDMs MI1: Bipolar X MVA: X X Posada, et al. sectional participants D: Adherent: disorder (type I & II) Bipolar (2011) analysis of a >90% S1: SCID Disorder USA cohort adherence S2: YMRS (manic participants study. T: Previous 30 symptoms) were days S3: BDI (depressive significantly symptoms) less likely to be adherent to cART (P<0.001). fNilsson Cross- 193 M: Self-report MI1: PTSD- MVA: X X X Schönnesson, sectional participants (AACTG- S1: Impact of Event Suboptimal L., M. L. study (Nov modified Scale adherence to Williams, et al. 2000-Apr questionnaire) MI2: Anxiety dose (2007) Sweden 2001) D: Suboptimal S2: BSI instructions Adherence: (1) was associated to dose with anxiety instructions symptoms (OR taking <95% of = 5.507, 95% CI the prescribed = 1.787– pills and (2) 16.968). <100% PTSD was not adherence to significantly scheduled associated with instructions. suboptimal T: Previous 4 adherence to days dose instructions. Palmer, N. B., J. Cross- 107 M: Self-report MI1: Bipolar I and BVA: Panic BVA: Bipolar BVA: BVA: BPD was Salcedo, et al. sectional diagnosed (AACTG II, disorder I and II Nonmood significantly (2003) USA study with questionnaire) MI2: Panic disorder With diagnoses Psychotic associated with HIV/AIDS, D: ≥ 95% +/- Agoraphobia, Agoraphobia, were not disorder and non-adherence to substance adherence PTSD, GAD, and Panic disorder associated mood HIV meds abuse and T: Previous 3 adjustment without with disorder with (p<0.05). But psychiatric days disorders Agoraphobia, adherence. psychotic antisocial PD was diseases (all MI3: Nonmood PTSD, GAD, and features were not. on psychotic disorder, adjustment not associated methadone) mood disorder with disorders were adherence. psychotic features. not associated MI4: Borderline PD with MI5: Antisocial PD adherence. S: SCID Sledjeski, E. M., Cross- 69 M: Self-report MI: PTSD MVA: PTSD X X X D. L. Delahanty, sectional participants (AACTG- S: IES group was et al. (2005) comparative divided into adapted significantly USA study 4 groups: questionnaire) more likely to 1-Control D: be adherent (low Dichotomized: during the past PTSD/low 100% week (OR=23.9, depression); adherence or 95% CI= 1.607– n =22 less than 100% 356.075) and 2-PTSD (high adherence during the past PTSD/low T: Previous 2 2 weeks depression), days, 1 week (OR=27.55; n=11 and 2 weeks 95% CI=1.99– 3-Depressed 381.82) (low compared to PTSD/high the depressed depression), (reference) n =12), group. 4-Mixed (high PTSD/high depression), n=24 Tucker, J. S., M. Cohort study 1910 M: Self-report MI1:GAD, MVA: Patients X X X A. Burnam, et (Jan 1996- participants to 3 adherence MI2: Panic disorder with GAD al. (2003) USA Jan 1998) questions S:Short-Form (OR=2.4; 95% D: 100% (Followed by full C= 1.2-5.0), or adherence version) of the panic disorder T: Previous WHO CIDI-SF. (OR=2.0; 95% week CI= 1.4 -3.0) were more likely to be non-adherent than those without a MI. Van Servellen, Cross- 182 M: Self-report MI: Anxiety MVA: Anxiety X X X G., B. Chang, et sectional participants and medical S: HADS was not al. (2002) USA study records. associated with D: Non- adherence. adherence: presence of non-adherence behavior in the medical records or self- report T: Previous 3 months Vranceanu, A. Randomized 156 M: EDMs MI: PTSD: MVA: X X X M., S. A. cohort participants adherence S: SPAN, a brief Continuous Safren, et al. crossover Group 1: D: Continuous self-report PTSD score was (2008) trial (Nov Two variable screening measure not associated 2002-Jan physician (percent (a short form of the with percent 2005) visits with adherence) widely used adherence PTSD T: Previous 30 Davidson Trauma either alone or screening days Scale) in a model that then included crossover to depression. Group 2 Group 2: Two physician visits without PTSD screening then crossover to Group 1 Wagner, G. J., Cross- 47 mentally M: Self-report MI1:Bipolar X BVA: Mean BVA: Mean X D. E. Kanouse, sectional 2- ill and EDMs depression, rates of rates of et al. (2003) week study participants D: Continuous MI2:Schizophrenia, adherence adherence USA variable MI3:Schizoaffective varied varied widely (expressed as a disorder widely by by psychiatric percentage and MI4: Major psychiatric diagnosis but mean rates of depression with diagnosis were not % adherence) psychotic features. but were statistically T: Previous 3 S: Confirmed by the not significant. days and 2 referring mental statistically weeks health professional significant. Wagner, G. J., Cohort study 214 African M: EDMs MI1: PTSD BVA: X X X L. M. Bogart, et American D: Continuous S: PDS Combination al. (2011) USA males variable ART adherence T: Previous 6 did not differ months. between those who met criteria for a PTSD diagnosis (M = 58%, SD = 31%) and those who did not (M = 61%, SD =28%)</p><p>Waldrop- Cross- 58 IDUs M: Self-report. MI: Anxiety MVA: Anxiety X X X Valverde, D. sectional D: 100 % S:State-Trait was not and E. Valverde study adherence Anxiety Inventory significantly (2005) USA T: Previous related to day. adherence. Walkup, J. T., Cohort study 2459 M: Self-report MI1: Schizophrenia X MVA: MVA: X U. (Jan 1996- Medicaid D: cART MI2: Severe Patients Schizophrenia Sambamoorthi, Dec 1998) beneficiaries persistence: affective disorder with severe was not et al. (2004) binary variable (Bipolar affective affective associated USA indicating use disorder and major disorder with of PIs/NNRTIs depressive were persistence of for each disorder, recurrent significantly PI/NNRTI quarter after episode) less therapy. initiating S: ICD-9-CM persistent in therapy. their use of T: 6-36 PI/NNRTI months. therapy than those without serious mental illness (OR = 0.73, 95% CI = 0.57- 0.94, p<0.01). *Participants: People Living with HIV/AIDS (PLWHA) >18 years old AACTG: Adult AIDS Clinical Trials Group (A)OR: (Adjusted) Odds Ratio ART: Antiretroviral Therapy BSI: Brief Symptom Inventory BVA: Bivariate analysis CIDI-SF: Composite International Diagnostic Interview DES-II: The Dissociative Experiences Scale-II EDMs: Electronic Drug Monitors GAD: Generalized Anxiety Disorder cART: combination Antiretroviral Therapy HADS: Hospital Anxiety and Depression Scale ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification IDUs: Injection drug users IES: Impact of Event Scale MVA: Multivariate analysis NNRTIs: Non–Nucleoside Reverse Transcriptase Inhibitors NRTIs: Nucleoside Reverse Transcriptase Inhibitors PD: Personality Disorder PDS/PTDS: Post-traumatic Stress Diagnostic Scale PI: Protease Inhibitor PLWHA: People Living with HIV/AIDS PTSD: Post-Traumatic Stress Disorder SCID-IV: Structured Clinical Interview for DSM-IV YMRS: Young Mania Rating Scale Table 3: Impact of Unspecified Mental Illness on cART Adherence/Persistence: Study Characteristics Author, Study Design PLWHA Adherence: Mental illness (MI) Impact of MI on Adherence Publication and Population, measurement (M), Studied and Scale (S) year, Evaluation Sample Size definition (D) and Location Period time period (T)</p><p>I. Impact of Unspecified Mental Illness on cART Adherence Adewuya, A. Cross- 182 M: Self-report (Morisky MI: Psychopathology BVA: Presence of psychopathology O., M. O. sectional participants* Medication Adherence S: General Health was significantly associated with low Afolabi, et al. study Questionnaire) Questionnaire (GHQ– adherence (OR = 4.36, 95% CI = (2010) D: Ordinal variable as 12) 1.83–10.43, B = 3.33 p<0.001) Nigeria “low” “medium” and “high” adherence T: Previous week Grierson, J., R. Cross- 867 M: Self-report MI: Lifetime diagnosis MVA: Lifetime diagnosis of a mental L. Koelmeyer, sectional participants D: Non-adherence: of a mental disorder disorder was significantly associated et al. (2011) study (Oct difficulty taking cART with difficulty taking cART (p<0.05). Australia 2008 - Apr T: Previous 2 days 2009) Kumar, V. and Cross- 1,192 M: Self-report to 4 MI: Depressive and/or MVA: Patients with high W. Encinosa sectional participants questions anxiety symptoms depressive/anxiety symptoms had (2010) USA study, (Aug D: Ordinal variable: 1 = S: Two “Mental health lower odds of adherence than those 1997-Jan did not miss any, 2 = problems scales” were with low symptoms at mean 1998) missed dose/s for only constructed based on medication complexity (OR= 0.78; p≤ 1 day, 3 = missed dose/s symptom frequency 0.05). This association, however, for two or 3 days, and 4 varied by cART medication = missed dose/s for four complexity. or more days T: Previous week Soto Blanco, J. Cross- 281 inmates M: Self-report (SMAQ MI: Anxiety and MVA: Non-adherence was M., I. Ruiz sectional questionnaire) Depression significantly associated with Pérez, et al. study (2002) D: Non-adherence: >2 S: Structured suffering anxiety or depression in the (2005) Spain doses missed in the past questionnaire with previous week (OR= 2.07, 95% CI= week, or > 2 days of interviewer 1.18–3.66, p= 0.01). total non-medication in (unspecified) the last 3 months T: Previous 1 week, 3 months Mellins, C. A., Cohort Study 97 mothers M: Self-report (AACTG MI: Depression; BVA: Presence of psychiatric E. Kang, et al. (1998-1999) questionnaire) Anxiety disorders diagnosis at baseline was (2003) USA D: Continuous variable (panic, PTSD etc); and significantly associated to the _ENREF_41 (percentage adherence) psychosis percentage of missed pills (in past 2 T: Previous 2 days S: Clinical Diagnostic days) at Follow-up 2. (OR=14.30, Questionnaire- 95% CI= 2.88–71.00, p< 0.01). *Participants: People Living with HIV/AIDS (PLWHA) >18 years old</p><p>AACTG: Adult AIDS Clinical Trials Group (A)OR: (Adjusted) Odds Ratio BDI: Beck Depression Index BVA: Bivariate analysis cART: combination Antiretroviral Therapy ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification EDMs: Electronic Drug Monitors MVA: Multivariate analysis PLWHA: People Living with HIV/AIDS PTSD: Post-Traumatic Stress Disorder Table 4: Impact of Treatment of Depression on Adherence to cART Among Depressed HIV+ Persons: Study characteristics Author, Study Design and HIV(+) Population, Adherence: Depressive disorder Impact of Antidepressant Treatment Publication Evaluation Period Sample Size Measurement (M), (MI) Scale (S) and ADT (ADT) on Adherence year, Location Definition (D) and Time treatment (Tx) period (T) Akincigil, A., I. Retrospective, 1150 participants* M: Pharmacy record MI: MDD and MDD MVA: Depression treatment B. Wilson, et al. observational study enrolled in a plan review recurrent disorder (antidepressants and/or (2011) USA (secondary data with prescription D: Adherence: MPR S: ICD-9 codes: 296.2- psychotherapy use) significantly analysis, Jan 2003 - drug and mental >90% MDD single episode, increased the likelihood to be Mar 2007) health benefits for T: For the period 296.3-MDD recurrent adherent to cART (AOR = 2.52, 95% at least 12 months. between cART initiation episode, 311, 300.4, CI 1.40, 4.53). Antidepressant MPR and 293.83, 296.90, 309.1, of >80% were significantly more discontinuation (cART 296.99. likely to be adherent to cART than episode) Tx: Antidepressants those with poor antidepressant and/or psychotherapy adherence (AOR = 2.68, 95% CI 1.82, use 3.94). Psychotherapy was not significantly associated with better cART adherence. Cruess, D. G., S. Prospective cohort 324 participants M: Unannounced pill MI: Depression MVA: Greater adherence to C. Kalichman, study (Mar 2005 - count S: CES-D psychotropic medications regardless et al. (2011) Oct 2008) D: Continuous variable Tx: psychotropic of medication class was positively USA (percentage adherence) medications related to higher T: Previous 3 months cART adherence (β (1, 101)=0.26, p=0.009). Dalessandro, Prospective cohort 17 depressed M: Self-report. MI: Depression BVA: The comparison of the pre- and M., C. M. Conti, study participants (9 D: Non-adherence: S: MADRS post- ADT questionnaires showed a et al. (2007) patients on ADT <100% adherence Tx: Fluvoxamine, significant improvement in the level Italy treatment) T: Previous 2 days Sertraline or of adherence (p< 0.0001). Paroxetine. Glass, T. R., M. Prospective Cohort 6709 participants M: Self-report MI: Psychiatric illness MVA: Starting psychiatric treatment Battegay, et al. study (Jan 2003-Jan (Simplified SHCS S: Having a psychiatric was significantly associated with (2010) 2009, 4.5 year- adherence illness as defined by worsening adherence (OR= 1.26, Switzerland follow-up) questionnaire) medical records? 95% CI= 1.04 -1.52). D: Ordinal variable: Tx: Psychiatric Number of missed treatment was defined doses (daily, more than as seeing a once a week, once a psychiatrist, diagnosis week, once every of depression, or second week, once a taking ADT. month, never) T: Previous 4 weeks Horberg, M. A., Retrospective cohort 3359 participants M: Pharmacy database MI: Depression MVA: Depression without SSRI use M. J. study (Jan 2000 - Dec records S: Coded outpatient or was associated with significantly Silverberg, et 2003) D: >90% adherence inpatient depression decreased odds of achieving >90% al. (2008) USA T: Previous 12 months diagnosis based on adherence to cART (OR= 0.81, 95% clinical evaluation of CI= 0.70 - 0.98, p= 0.03). Depressed the patient. patients compliant with SSRIs had Tx: SSRIs cART adherence statistically similar *Participants: People Living with HIV/AIDS (PLWHA) >18 years old **The article is in press not published yet. ADT: Anti-Depressant Treatment (A)OR: (Adjusted) Odds Ratio BDI (-II): Beck Depression Inventory (2nd Edition) BVA: Bivariate analysis DOT: Directly Observed Treatment cART: combination Antiretroviral Therapy Ham-D: Hamilton Depression Rating Scale ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification MPR: Medication Possession Ratio MVA: Multivariate analysis PLWHA: People Living with HIV/AIDS SSRIs: Selective Serotonin Reuptake Inhibitors</p>