Secondary Logo

Relationship between ever reporting depressive symptoms and all-cause mortality in a cohort of HIV-infected adults in routine care

Bengtson, Angela M.; Pence, Brian W.; Moore, Richard; Mimiaga, Matthew J.; Mathews, William Christopher; Heine, Amy; Gaynes, Bradley N.; Napravnik, Sonia; Christopoulos, Katerina; Crane, Heidi M.; Mugavero, Michael J.

doi: 10.1097/QAD.0000000000001431
EPIDEMIOLOGY AND SOCIAL
Free
SDC

Objective: The aim of this study was to assess whether ever reporting depressive symptoms affects mortality in the modern HIV treatment era.

Design: A cohort study of HIV-infected adults in routine clinical care at seven sites in the USA.

Methods: We examined the effect of ever reporting depressive symptoms on all-cause mortality using data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. We included individuals with at least one depression measure between 2005 and 2014. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ)-9. We used weighted Kaplan–Meier curves and marginal structural Cox models with inverse probability weights to estimate the effect of ever reporting depressive symptoms (PHQ-9 ≥10) on all-cause mortality.

Results: A total of 10 895 individuals were included. Participants were followed for a median of 3.1 years (35 621 total person-years). There were 491 (4.5%) deaths during the follow-up period (crude incidence rate 13.8/1000 person-years). At baseline, 28% of the population reported depressive symptoms. In the weighted analysis, there was no evidence that ever reporting depressive symptoms increased the hazard of all-cause mortality (hazard ratio 0.82, 95% confidence interval 0.55–1.24).

Conclusion: In a large cohort of HIV-infected adults in care in the modern treatment era, we observed no evidence that ever reporting depressive symptoms increased the likelihood of all-cause mortality, controlling for a range of time-varying factors. Antiretroviral therapy that is increasingly robust to moderate adherence and improved access to depression treatment may help to explain changes in the relationship between depressive symptoms and mortality in the modern treatment era.

aDepartment of Epidemiology, University of North Carolina, Chapel Hill, North Carolina

bDepartment of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland

cDepartments of Behavioral & Social Sciences and Epidemiology School of Public Health

dDepartment of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Providence, Rhode Island

eThe Fenway Institute, Fenway Health, Boston, Massachusetts

fDepartment of Medicine, School of Medicine, University of California, San Diego, San Diego, California

gDivision of Infectious Diseases

hDepartment of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

iHIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, San Francisco, California

jDepartment of Medicine, School of Medicine, University of Washington, Seattle, Washington

kDepartment of Medicine and UAB Center for AIDS Research, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Correspondence to Angela M. Bengtson, Department of Epidemiology, Gillings School of Global Public Health, 2101 McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA. Tel: +1 612 751 9873; fax: +1 919 966 6714; e-mail: abengtso@live.unc.edu

Received 7 October, 2016

Revised 23 January, 2017

Accepted 30 January, 2017

Back to Top | Article Outline

Introduction

Depression affects 20–30% of people living with HIV (PLWH) and is the most commonly reported mental health condition among HIV-infected adults in care in the United States [1,2]. For PLWH, depression is a debilitating condition that adversely affects quality of life [3,4], antiretroviral therapy (ART) adherence [5,6] and viral suppression [7–9]. Depression has also been associated with higher mortality in the precombination ART (cART) and early cART eras [7,10–13].

Depression may affect mortality through two primary pathways, both of which may be altered in the modern HIV treatment era. First, depression is associated with suboptimal engagement in HIV care and ART adherence, which influences long-term survival [14–16]. However, as HIV treatment has become simpler, more tolerable and more potent, the negative consequences of missing ART doses have diminished [17,18]. Second, depression has been hypothesized to adversely affect innate immunity among HIV-infected adults, which may translate into faster HIV progression and an increased risk of mortality [19,20]. It is possible that the increasing recognition of the high prevalence of mental health conditions among PLWH [21] has led to improved access to mental health treatment over time [22–25].

Given these changes in both HIV and mental health treatment, there is a need to understand the relationship between depression and mortality in the modern HIV treatment era. The goal of this analysis was to estimate the effect of ever reporting depressive symptoms on all-cause mortality among HIV-infected adults in routine care in the United States in the cART-era.

Back to Top | Article Outline

Materials and methods

Data for the present analysis come from the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) cohort. The CNICS cohort includes over 31 000 HIV-infected adults in routine HIV clinical care at eight sites in the United States [26]. CNICS collects detailed information on demographic characteristics, ART, antidepressant medications, HIV/AIDS clinical events, comorbid conditions, HIV-related laboratory values and vital status on patients who consent to participate (approximately 95% across sites, M. Saag, personal communication). Patients in CNICS also complete a battery of self-administered socio-behavioural questionnaires, called patient-reported outcomes (PROs). HIV-infected patients complete PROs on touch-screen tablets during routine care visits approximately every 4–6 months, although frequency varies based on clinical follow-up. Participants provide written informed consent to participate in CNICS. Ethical approval for the use of routinely collected clinical data was provided by the institutional review board at each CNICS site.

Back to Top | Article Outline

Study population and design

The present analysis includes all HIV-infected individuals in CNICS with at least one PRO measure. PRO collection began between 2005 and 2011 at seven of eight CNICS sites; one site did not collect depression measures during their PRO assessment and was excluded. PRO assessments provided clinicians with routine assessments of patients’ depressive symptoms. A patient's first PRO may capture either incident or prevalent depressive symptoms. Our study design is therefore analogous to a treatment decision design [27], where a participant's depressive symptom severity at their first PRO represents a point where informed decisions about depression treatment may have been made, rather than onset of depressive symptoms exclusively. Participants were followed from the date of their first PRO until administrative censoring between June and November, 2014 (depending on site) or death, whichever date came first. Vital status is regularly ascertained for all CNICS participants, regardless of whether they are currently in care or not. Therefore, we did not censor individuals at loss to follow-up (LTFU) from CNICS (≥12 months with no HIV appointment) [15]. Person-time after a participant was LTFU was considered a period with missing exposure and covariate information and accounted for in the analysis.

Back to Top | Article Outline

Measures

The outcome of interest was all-cause mortality. Deaths were ascertained from the United States Social Security Death Index or National Death Index for all CNICS participants. The exposure of interest was first report of moderate to severe depressive symptoms (hereafter ‘depressive symptoms’) within the study period, measured using the Patient Health Questionnaire-9 (PHQ-9) during the PRO assessment [28]. A PHQ-9 score of at least 10 has 88% sensitivity and specificity to detect a major depressive episode and was used to define depressive symptoms [28].

As a part of the PRO assessment, CNICS also collects validated measures of panic disorder (Patient Health Questionnaire-5) [29], high-risk alcohol use (Alcohol Use Disorders Identification Test (AUDIT) and defined as an AUDIT score ≥4 for males and ≥3 for females) [30] and current, past or no illicit drug use, including cocaine/crack, heroin/opiates, crystal/amphetamine use, but excluding marijuana (The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)) [31,32]. For this analysis, we defined undetectable viral load as less than 50 copies/ml and ART adherence as no missed doses in the past week. Information on antidepressant prescription is available in CNICS. However, antidepressant use was not considered as a confounder in our analysis because it is unlikely to independently predict mortality and therefore does not represent a confounding pathway.

Back to Top | Article Outline

Statistical analysis

The goal of our analysis was to estimate the effect of ever reporting depressive symptoms on mortality. We used weighted Kaplan–Meier curves and marginal structural Cox models with inverse probability weights [33] to approximate a randomized controlled trial, intent-to-treat analysis in which individuals are considered to be randomized at baseline to ever report depressive symptoms over the study period or not. Inverse probability of treatment weights were estimated as the inverse probability of first reporting depressive symptoms at a given visit, conditional on time-fixed (site, sex, race/ethnicity, HIV acquisition risk group and age at baseline) and time-varying variables (high alcohol use, drug use, panic disorder, ART use and adherence, CD4+ cell count and viral load suppression, and depressive symptoms score at the previous visit), as well as calendar year and length of time in CNICS care [34]. Depressive symptom scores were modelled using a linear term and age and CD4+ cell count were modelled using restricted cubic splines. IPTWs were stabilized by baseline covariates and multiplied across visits to account for a participant's exposure history.

Participants in CNICS present for care with varying frequency. Therefore, a report of depressive symptoms may be more common among individuals with more regular visits due to more frequent assessment. To account for the varying frequency of visits within CNICS, we used inverse probability of observation weights (IPOW), under the assumption that participants should complete a PRO at least once every 6 months [35]. We allowed all time-varying covariates to be valid (i.e. carried forward) for up to 6 months (182 days). After 182 days with no depressive symptoms, alcohol, drug, panic disorder or ART use and adherence measures participants were considered to have a missing PRO assessment. Multiple imputation (n = 20 imputations) was used to fill in missing values for individual variables for all observed PRO assessments [36]. IPOW were estimated as the inverse probability of having an observed PRO within 6 months, conditional on time-fixed site, gender, race, HIV acquisition risk group, age at baseline, mental health diagnoses prior to baseline and time-varying history of having a previous PRO measurement, exposure status (binary), depressive symptoms score (continuous), alcohol use, drug use, panic disorder, being on an antidepressant, ART use and adherence, CD4+ cell count and viral load suppression at the previous visit. Depressive symptoms scores and CD4+ cell count were modelled using restricted cubic splines and age was modelled using a quadratic term. IPTW and IPOW were multiplied together to create a single combined set of weights. All weights were progressively truncated until the mean was 1.00 and the range was reasonable [34].

We conducted two secondary analyses. First, we examined whether the effect of ever reporting depressive symptoms on mortality differed by sex or baseline psychiatric comorbidities (defined as a history of a mental health diagnosis, panic symptoms or disorder). Second, to better understand which factors most strongly confounded the depressive symptoms and mortality relationship, we excluded time-varying measures of alcohol use, drug use and panic disorder from the estimation of the IPTW. For both the primary and secondary analyses, we compared unadjusted estimates, unweighted multivariable estimates adjusted for baseline covariates only and weighted estimates adjusted for baseline and time-varying covariates. Analyses were conducted using Stata version 13 (StataCorp, College Station, Texas, USA) and SAS version 9.4 (SAS Institute, Cary, North Carolina, USA).

Back to Top | Article Outline

Results

A total of 10 895 individuals in CNICS had at least one PRO assessment between 2005 and 2014 and were included. Participants were followed for a median of 3.1 years (interquartile range 1.5–4.9) and contributed a total of 35 621 person-years. There were 491 (4.5%) deaths during the follow-up period (crude incidence rate 13.8 per 1000 person-years). Depressive symptoms were reported by 28% of the population at baseline and at 39% of visits over the follow-up period (Table 1). Over 8 years, 59% of person-time was spent having ‘ever reported depressive symptoms’ (Fig. 1). Among those who ever developed depressive symptoms, participants reported current depressive symptoms at 61% of subsequent PRO assessments.

Table 1

Table 1

Fig. 1

Fig. 1

The cohort was predominately male (85%), white non-Hispanic (51%) and self-reported contracting HIV through male-to-male sexual contact (63%) (Table 1). Mental health and substance abuse issues were common. Over a quarter (28%) of participants were high-risk alcohol users, 56% were current or past drug users and 30% had some panic symptoms or panic disorder. At baseline, 24% of participants were on antidepressants, of whom 43% had depressive symptoms. Mental health diagnoses recorded in CNICS prior to baseline were rare (6%). The majority of participants at baseline were on ART and adherent (64%). The median CD4+ cell count at baseline was 479 (IQR 303–684) and overall 55% of participants had an undetectable viral load.

Of the 491 deaths that occurred, 232 occurred after reporting depressive symptoms over 13 071 person-years (crude incidence rate 17.75 per 1000 person-years) and 259 occurred among individuals who never reported depressive symptoms prior to death over 22 549.32 person-years (crude incidence rate 11.49 per 1000 person-years). Cause of death information was available for only 28% of participants.

In the unadjusted (crude) analysis, ever reporting depressive symptoms was associated with an increase in mortality [hazard ratio 1.33, 95% confidence interval (95% CI) 1.11–1.59; Table 2]. When baseline factors only were accounted for, ever reporting depressive symptoms increased the hazard of mortality by 22% (hazard ratio 1.22, 95% CI 0.99–1.49). After adjustment with a combined weight to account for both time-varying confounding and unobserved PRO assessments, there was no evidence that ever reporting depressive symptoms increased the hazard of all-cause mortality (hazard ratio 0.82, 95% CI 0.55–1.24; Table 2, Fig. 2). There was also no evidence that the effect of ever reporting depressive symptoms on all-cause mortality differed by sex (interaction P = 0.35) or baseline psychiatric comorbidities (interaction P = 0.21). In a secondary analysis when alcohol use, drug use and panic disorder were removed from the weights, effect estimates were also similar (hazard ratio 0.96, 95% CI 0.75–1.25).

Table 2

Table 2

Fig. 2

Fig. 2

Not having a PRO measure at least once in a 6-month period was common over the follow-up period. Out of a possible 214 233 PRO measures (assuming a measurement at least once every 6 months) 115 193 (54%) were ‘missed’ (i.e. not observed) and 99 040 (46%) visits were observed. Of the 99 040 observed PRO measures, 73 209 (74%) had complete data and 25 831 (26%) had at least one missing covariate value. The proportion of observed PRO measures among persons who ever reported depressive symptoms (48%) was similar to the proportion among those who never reported depressive symptoms (45%). Effect estimates were similar when only observed PRO measures were considered (e.g. complete case) and IPOW were not used (hazard ratio 0.98, 95% CI 0.65–1.47).

Back to Top | Article Outline

Discussion

In our cohort of HIV-infected adults in routine care in the United States, depressive symptoms were experienced at 39% of visits over a 9-year period. Over the follow-up period, the crude mortality rate was 13.8 deaths per 1000 person years. In unadjusted analyses, ever reporting depressive symptoms increased the hazard of all-cause mortality by 33%. After accounting for time-varying confounding and unobserved PRO assessments, there was no evidence that ever reporting depressive symptoms increased the hazard of all-cause mortality. These results did not differ by sex or baseline psychiatric comorbidities and remained consistent when alcohol use, drug use and panic disorder were excluded as potential confounders.

Depression has been associated with an increased risk of mortality in a number of previous analyses [7,10–14,37]. There are several possible reasons why our results did not confirm previous findings. Depression status is affected by multiple factors, including comorbid mental and physical health conditions, social support, demographic factors and HIV status [38], many of which may change over time. Time-varying factors, such as ART adherence, may influence the relationship between depression and mortality, and were not fully accounted for in several earlier analyses [7,11,13,14] that did not use IPTWs to address time-varying confounding.

More efficacious ART and improved engagement in HIV care in the modern HIV treatment era may also help to explain a changing relationship between depression and mortality. ART's efficacy has improved in recent years, making it more robust to moderate adherence. With ART more forgiving of adherence lapses, it is possible that the adverse effects of depression on adherence have become less clinically significant for survival [17,18]. Depression has also been associated with increased LTFU from HIV care, which could affect access to treatment [39–42]. In our analysis, participants were not censored at LTFU, regardless of depressive symptoms, because mortality status was ascertained irrespective of in-care status. Further, missing PRO assessments were not more common among those who reported depressive symptoms, compared with those with no depressive symptoms.

Depression is also thought to affect mortality by harming elements of innate immunity [19,20]. However, these negative effects are reversed once the depressive episode subsides [43]. Although difficult to confirm, it is possible that access to depression treatment for PLWH has improved over time. Improved access to treatment may result in shorter depressive episodes, which in turn may minimize depression's deleterious effect on innate immunity. A recent analysis of HIV-infected women, which began follow-up in 1998 (possibly when depression treatment was less common) and measured the effect of always being depressed (e.g. a persistent depression), found a strong effect on mortality (hazard ratio increased hazard ratio 3.23, 95% CI 1.61–6.47) and lends support to this hypothesis [44].

Depression may also affect mortality through its relationships with substance abuse and comorbid psychiatric conditions. Psychiatric illness and substance abuse have been linked to higher mortality among PLWH [45,46], possibly due to their deleterious effect on ART adherence [12,14]. In a secondary analysis that did not account for substance abuse (drug and alcohol use) and panic disorder, but did account for ART use and adherence, we observed no evidence of an effect of ever reporting depressive symptoms on all-cause mortality. However, measurement error of mental health comorbidities in our cohort is possible. Chart-documented mental health issues prior to baseline were rare (6% of the population) and PRO assessment of additional mental health issues in CNICS is limited to depression and panic disorder. Further, information on depressive symptoms prior to entering CNICS or counselling-based therapy while in CNICS is not available in our data.

Deaths in our cohort were rare compared with earlier reported estimates. The unadjusted mortality rate was 13.8 deaths per 1000 person years over 9 years of follow-up. By contrast, the unadjusted mortality rate in a recent analysis of HIV-infected women was 28.9 per 1000 person-years over 13 years of follow-up, with follow-up starting in 1998 [44]. Although death rates are declining for HIV-infected adults [11], the lower death rate observed in our cohort may also reflect some under-counting of deaths. Vital status in CNICS is queried for all participants regardless of their LTFU status, but delays in reporting of vital status to national registries may result in an artificially low number of deaths among participants who are LTFU [15]. In our cohort, 72 deaths (15%) occurred among participants without a clinic visit for at least 12 months. Compared with those in care in CNICS, there was no evidence of a lower death rate among participants out of care, suggesting that patients may have been engaged in care elsewhere [15].

Depression is more common among HIV-infected women than men [47] and among persons with comorbid mental health conditions [45,46]. In our analysis, there was no evidence that sex or psychiatric comorbidities at baseline modified the effect of ever reporting depressive symptoms on mortality. However, CNICS contains only 15% women, and although baseline psychiatric comorbidities were common (20%), deaths were rare (4.5%). Consequently, our analysis may have been underpowered to detect modification by sex or psychiatric comorbidities.

As with all observational studies, our findings rest on several assumptions. These assumptions are no unmeasured confounding (exchangeability), that depression could be eliminated from the population by a well defined intervention (here conceptualized as antidepressant treatment) and any variation in how antidepressant treatment reduced depression would not change its effect on mortality (consistency and treatment-variation irrelevance) and that conditional on all measured covariates, all participants have a nonzero probability of being exposed (positivity) [48,49]. The assumptions of exchangeability and consistency are inherently unverifiable. In addition, while an intervention that completely eliminates depression in a population is not realistic, antidepressant treatment could be expected to reduce depression through various means (e.g. different drugs or doses), all with the same probable effect on mortality. We note that there is likely some unmeasured confounding by comorbid mental health issues in our analysis; in the absence of observing an effect of ever reporting depressive symptoms on mortality, unmeasured confounding is unlikely to have induced appreciable bias.

Back to Top | Article Outline

Conclusion

In a large cohort of HIV-infected adults in care in the modern treatment era, we observed no evidence that ever reporting depressive symptoms increased the likelihood of all-cause mortality, controlling for a range of time-varying factors. As HIV treatment has become more effective and forgiving to moderate ART adherence, it is possible that depression's effect on mortality through its role in adherence has diminished. It is also possible that increased clinical awareness about treating depression among PLWH and improved prognosis for survival has led to shorter depressive episodes, mitigating depression's cumulative effect on innate immunity. Future analyses should consider examining the cumulative burden of depression's effect on mortality. Finally, given the high burden of depression among HIV-infected adults, effectively treating depression among PLWH continues to be a public health priority.

Back to Top | Article Outline

Acknowledgements

BWP, HMC, MJM contributed to the acquisition of the data; AMB, BWP designed the analysis; AMB drafted the manuscript; BWP RM, MMM, WCM, AH, BNG, SN, KC, HMC, MJM assisted with the interpretation of the data and critically revised the manuscript for important intellectual content. All authors take responsibility for and approve the final version of the manuscript. We thank the National Institutes of Mental Health [grant number R01MH100970] and the National Institute of Allergy and Infectious Diseases [grant number R24AI067039] for their support of this work.

Back to Top | Article Outline

Conflicts of interest

The authors report no conflicts of interest.

A version of this work was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, February, 2016.

Back to Top | Article Outline

References

1. Bing EG, Burnam MA, Longshore D, D, Fleishman JA, Sherbourne CD, London AS, et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry 2001; 58:721–728.
2. Ciesla JA, Roberts JE. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry 2001; 158:725–730.
3. Bengtson AM, Pence BW, O’Donnell J, Thielman N, Heine A, Zinski A, et al. Improvements in depression and changes in quality of life among HIV-infected adults. AIDS Care 2015; 27:47–53.
4. Zimpel RR, Fleck MP. Depression as a major impact on the quality of life of HIV-positive Brazilians. Psychol Health Med 2014; 19:47–58.
5. Gonzalez F S, Batchelder A W, Psaros C, Safren S A. Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquir Immune Defic Syndr 2011; 58:181–187.
6. Horberg MA, Silverberg MJ, Hurley LB, Towner WJ, Klein DB, Bersoff-Matcha S, et al. Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients. J Acquir Immune Defic Syndr 2008; 47:384–390.
7. Ickovics JR, Hamburger ME, Vlahov D, Schoenbaum EE, Schuman P, Boland RJ, et al. Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA 2001; 285:1466–1474.
8. Ironson G, O’Cleirigh C, Fletcher MA, Laurenceau JP, Balbin E, Klimas N, et al. Psychosocial factors predict CD4 and viral load change in men and women with human immunodeficiency virus in the era of highly active antiretroviral treatment. Psychosom Med 2005; 67:1013–1021.
9. Leserman J, Jackson ED, Petitto JM, Golden RN, Silva SG, Perkins DO, et al. Progression to AIDS: the effects of stress, depressive symptoms, and social support. Psychosom Med 1999; 61:397–406.
10. Murphy K, Hoover DR, Shi Q, Cohen M, Gandhi M, Golub ET, et al. Association of self-reported race with AIDS death in continuous HAART users in a cohort of HIV-infected women in the United States. AIDS 2013; 27:2413–2423.
11. French AL, Gawel SH, Hershow R, Benning L, Hessol NA, Levine AM, et al. Trends in mortality and causes of death among women with HIV in the United States: a 10-year study. J Acquir Immune Defic Syndr 2009; 51:399–406.
12. Villes V, Spire B, Lewden C, Perronne C, Besnier JM, Garre M, et al. The effect of depressive symptoms at ART initiation on HIV clinical progression and mortality: implications in clinical practice. Antivir Ther 2007; 12:1067–1074.
13. Antelman G, Kaaya S, Wei R, Mbwambo J, Msamanga GI, Fawzi WW, et al. Depressive symptoms increase risk of HIV disease progression and mortality among women in Tanzania. J Acquir Immune Defic Syndr 2007; 44:470–477.
14. Lima VD, Geller J, Bangsberg DR, Patterson TL, Daniel M, Kerr T, et al. The effect of adherence on the association between depressive symptoms and mortality among HIV-infected individuals first initiating HAART. AIDS 2007; 21:1175–1183.
15. Edwards JK, Cole SR, Westreich D, Moore R, Mathews C, Geng E, et al. Loss to clinic and five-year mortality among HIV-infected antiretroviral therapy initiators. PLoS One 2014; 9:e102305.
16. Ojikutu B, Higgins-Biddle M, Greeson D, Phelps BR, Amzel A, Okechukwu E, et al. The association between quality of HIV care, loss to follow-up and mortality in pediatric and adolescent patients receiving antiretroviral therapy in Nigeria. PLoS One 2014; 9:e100039.
17. Nelson M, Girard PM, Demasi R, Chen L, Smets E, Sekar V, et al. Suboptimal adherence to darunavir/ritonavir has minimal effect on efficacy compared with lopinavir/ritonavir in treatment-naive, HIV-infected patients: 96 week ARTEMIS data. The Journal of antimicrobial chemotherapy 2010; 65:1505–1509.
18. Parienti JJ, Ragland K, Lucht F, de la Blanchardiere A, Dargere S, Yazdanpanah Y, et al. Average adherence to boosted protease inhibitor therapy, rather than the pattern of missed doses, as a predictor of HIV RNA replication. Clin Infect Dis 2010; 50:1192–1197.
19. Cruess DG, Douglas SD, Petitto JM, Leserman J, Ten Have T, Gettes D, et al. Association of depression, CD8+ T lymphocytes, and natural killer cell activity: implications for morbidity and mortality in human immunodeficiency virus disease. Curr Psychiatry Rep 2003; 5:445–450.
20. Evans DL, Ten Have TR, Douglas SD, Gettes DR, Morrison M, Chiappini MS, et al. Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Am J Psychiatry 2002; 159:1752–1759.
21. Pence BW, O’Donnell JK, Gaynes BN. The depression treatment cascade in primary care: a public health perspective. Current psychiatry reports 2012; 14:328–335.
22. Burnam MA, Bing EG, Morton SC, Sherbourne C, Fleishman JA, London AS, et al. Use of mental health and substance abuse treatment services among adults with HIV in the United States. Arch Gen Psychiatry 2001; 58:729–736.
23. Himelhoch S, Josephs JS, Chander G, Korthuis PT, Gebo KA. Use of outpatient mental health services and psychotropic medications among HIV-infected patients in a multisite, multistate study. Gen Hosp Psychiatry 2009; 31:538–545.
24. Taylor SL, Burnam MA, Sherbourne C, Andersen R, Cunningham WE. The relationship between type of mental health provider and met and unmet mental health needs in a nationally representative sample of HIV-positive patients. J Behav Health Serv Res 2004; 31:149–163.
25. Weaver MR, Conover CJ, Proescholdbell RJ, Arno PS, Ang A, Ettner SL. Utilization of mental health and substance abuse care for people living with HIV/AIDS, chronic mental illness, and substance abuse disorders. J Acquir Immune Defic Syndr 2008; 47:449–458.
26. Kitahata MM, Rodriguez B, Haubrich R, Boswell S, Mathews WC, Lederman MM, et al. Cohort profile: the Centers for AIDS Research Network of Integrated Clinical Systems. Int J Epidemiol 2008; 37:948–955.
27. Brookhart MA. Counterpoint: the treatment decision design. Am J Epidemiol 2015; 182:840–845.
28. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613.
29. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 1999; 282:1737–1744.
30. Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro MG. AUDIT, The Alcohol Use Disorders Identification Test. Guidelines for use in primary care. Geneva, Switzerland: World Health Organization; 2001.
31. WHO Assist Working Group. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): development, reliability and feasibility. Addiction 2002; 97:1183–1194.
32. Humeniuk R, Ali R, Babor TF, Farrell M, Formigoni ML, Jittiwutikarn J, et al. Validation of the Alcohol, Smoking And Substance Involvement Screening Test (ASSIST). Addiction 2008; 103:1039–1047.
33. Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology (Cambridge, Mass) 2000; 11:561–570.
34. Cole SR, Hernan MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol 2008; 168:656–664.
35. Hernan MA, McAdams M, McGrath N, Lanoy E, Costagliola D. Observation plans in longitudinal studies with time-varying treatments. Stat Methods Med Res 2009; 18:27–52.
36. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995; 142:1255–1264.
37. Bouhnik AD, Preau M, Vincent E, Carrieri MP, Gallais H, Lepeu G, et al. Depression and clinical progression in HIV-infected drug users treated with highly active antiretroviral therapy. Antivir Ther 2005; 10:53–61.
38. Hartzell JD, Janke IE, Weintrob AC. Impact of depression on HIV outcomes in the HAART era. J Antimicrob Chemother 2008; 62:246–255.
39. Traeger L, O’Cleirigh C, Skeer MR, Mayer KH, Safren SA. Risk factors for missed HIV primary care visits among men who have sex with men. J Behav Med 2012; 35:548–556.
40. Zuniga JA, Yoo-Jeong M, Dai T, Guo Y, Waldrop-Valverde D. The role of depression in retention in care for persons living with HIV. AIDS Patient Care STDS 2016; 30:34–38.
41. Dombrowski JC, Simoni JM, Katz DA, Golden MR. Barriers to HIV care and treatment among participants in a public health HIV care relinkage program. AIDS Patient Care STDS 2015; 29:279–287.
42. Yehia BR, Stewart L, Momplaisir F, Mody A, Holtzman CW, Jacobs LM, et al. Barriers and facilitators to patient retention in HIV care. BMC Infect Dis 2015; 15:246.
43. Cruess DG, Douglas SD, Petitto JM, Have TT, Gettes D, Dube B, et al. Association of resolution of major depression with increased natural killer cell activity among HIV-seropositive women. Am J Psychiatry 2005; 162:2125–2130.
44. 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 2016; (in press).
45. DeLorenze GN, Satre DD, Quesenberry CP, Tsai AL, Weisner CM. Mortality after diagnosis of psychiatric disorders and co-occurring substance use disorders among HIV-infected patients. AIDS Patient Care STDS 2010; 24:705–712.
46. Nurutdinova D, Chrusciel T, Zeringue A, Scherrer JF, Al-Aly Z, McDonald JR, et al. Mental health disorders and the risk of AIDS-defining illness and death in HIV-infected veterans. AIDS 2012; 26:229–234.
47. Bengtson AM, Pence PW, Crane HM, Christopoulos K, Fredericksen R, Gaynes BN, et al. Disparities in depression diagnosis and treatment by gender and race/ethnicity among HIV-infected adults in the United States. PLoS One 2016; 11:e0160738.
48. Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000; 11:550–560.
49. VanderWeele TJ. Concerning the consistency assumption in causal inference. Epidemiology 2009; 20:880–883.
Keywords:

depression; depressive symptoms; HIV; mental health; mortality

Copyright © 2017 Wolters Kluwer Health, Inc.