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  Conference on Retroviruses
and Opportunistic Infections (CROI)
February 22-25, 2016, Boston MA
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Impact of Depression on Mortality, Viral Load,
and Adherence: Three CROI Studies
  Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston
Mark Mascolini
Three large US cohort studies detailed at CROI 2016 advanced the understanding of how depression affects people with HIV. For the first time, a study of a big contemporary cohort linked depression to mortality independently of other death risk factors [1]. Other studies of well-established US HIV cohorts determined that people with depression run a higher risk of suboptimal antiretroviral adherence [2,3] and poor virologic response [2]. A Women's Interagency HIV Study (WIHS) tied internalized stigma to depression, which predicted shaky adherence--but only in black and Hispanic women, not in non-Hispanic whites [3].
Depression boosts death risk by two thirds
A 4001-person analysis of the CFAR Network of Integrated Clinical Systems (CNICS) cohort found that test-determined depression raised the risk of all-cause mortality independently of antiretroviral adherence, CD4 count, viral load, and several other death risk factors [1]. Three studies from the early combination antiretroviral era tied depression to HIV-related mortality [4-6]. And a 2010-2013 Swiss HIV Cohort Study of 4422 people calculated a one third higher all-cause death rate with versus without depression (1.17 versus 0.86 per 100 person-years, P = 0.033) [7]. But the Swiss team did not perform an adjusted analysis to see if depression independently predicts death.
The CNICS study involved 4001 adults who began HIV care between October 2004 and November 2014. Follow-up continued until death or May to November 2014, depending on study site. CNICS cohort members completed the Patient Health Questionnaire-9 (PHQ-9), and researchers defined depression as a score of 10 or higher. The investigators used Cox proportional hazards models to determine the association between depression and all-cause mortality within 1 year of starting HIV care.
Median age of the study group stood around 40 years, about 15% were women, almost half white, about one third black, and about 17% Hispanic. Two thirds of cohort members picked up HIV infection during sex between men. Among the 4001 study participants, 1240 (31%) had depression during their first year in CNICS, a prevalence similar to rates found in other HIV cohorts. A Cox model to explore the association between depression and mortality adjusted for study site, gender, race/ethnicity, HIV acquisition risk, alcohol dependence, panic disorder, antiretroviral treatment status and adherence, viral load, and CD4 count at enrollment. This analysis independently linked depression to a two thirds higher risk of all-cause mortality (adjusted hazard ratio 1.64, 95% confidence interval [CI] 1.06 to 2.53).
The CNICS researchers proposed that "interventions to improve depression treatment and reduce depression are urgently needed to reduce the risk of mortality among HIV-infected persons" [1].
Depression predicts poor viral suppression
Analysis of 18,095 HIV-positive adults in the US Medical Monitoring Project found that those diagnosed with depression were more likely to be prescribed antiretroviral therapy but less likely to achieve sustained viral suppression than people without depression [2]. Before this Centers for Disease Control and Prevention (CDC) study, the largest analysis of how depression affects viral control involved 3359 HIV patients in the Kaiser Permanente healthcare system who started their first antiretrovirals between January 2000 and December 2003 [8]. A model adjusted for age, gender, antiretroviral regimen, CD4 count, and temporal trend determined that people with depression and not taking an SSRI antidepressant had 23% lower odds of reaching a viral load below 500 copies 12 months after starting ART than HIV-positive people without depression (adjusted odds ratio [aOR] 0.77, 95% CI 0.62 to 0.95, P = 0.02).
The Medical Monitoring Project provides a nationally representative sample of people with HIV in the United States. The depression analysis involved 18,095 people seen between June 2009 and May 2013 [2]. The CDC determined how many had been prescribed ART within the past 12 months, how many took all their antiretroviral doses in the 3 days before the study interview, and how many had a viral load below 200 copies on every measure in the past 12 months.
One quarter of cohort members had a depression diagnosis, and 91%, had been prescribed ART in the past year. Among those prescribed ART, 69% had durable viral suppression. ART prescription proved significantly more likely to people with than without depression (93% versus 90%, P < 0.0001). But among antiretroviral-treated people, a significantly lower proportion with depression had 100% adherence in the past 3 days (84% versus 88%, P < 0.0001) and a significantly lower proportion had sustained viral suppression (66% versus 70%, P = 0.0001).
An analysis adjusted for health insurance status determined that people with depression had a 3% higher chance of having an antiretroviral prescription (adjusted prevalence ratio 1.03, 95% CI 1.01 to 1.04). And an analysis adjusted for adherence and race determined that depression cut chances of sustained viral suppression 7% (adjusted prevalence ratio 0.93, 95% CI 0.91 to 0.96). This analysis indicated that adherence alone did not account for the lower likelihood of sustained viral suppression in people with depression.
Stigma drives poor adherence, but only in minorities
Internalized HIV stigma trimmed chances of good antiretroviral adherence 30% among black and Hispanic women in the US Women’s Interagency HIV Study (WIHS) but not among white WIHS members [3]. Abundant research links depression to poor antiretroviral adherence, and studies mostly in white men suggest that internalized HIV stigma contributes to this association. To explore the same link in HIV-positive US women, WIHS researchers conducted this 1168-woman study.
The study involved women who made their most recent WIHS visit between April 2013 and March 2014, when researchers began to measure internalized stigma with the negative self-image subscale of the revised HIV Stigma Scale. They rated self-reported adherence in the past 6 months as 95% or higher versus lower, and they used the 20-item Center for Epidemiological Studies (CES-D-20) scale to assess depression. The investigators used the MOS Social Support Survey to assess social support and the R-UCLA Loneliness Scale to assess loneliness.
The 1168 women averaged 49 years in age, 68% were black, 17% Hispanic, and 12% white. The group had taken antiretrovirals for an average 11 years, and 17% reported less than 95% adherence. Initial logistic regression analysis adjusted for race, age, time on ART, drug use, income, and education determined that internalized stigma independently predicted less than 95% adherence (aOR 0.757, 95% CI 0.579 to 0.990, P = 0.042). This association held true in minority women (aOR 0.689, 95% CI 0.521 to 0.911, P = 0.009) but not in non-Hispanic whites (aOR 2.150, 95% CI 0.687 to 6.725, P = 0.188).
Variables that mediated the association between internalized stigma and less than 95% adherence were depressive symptoms, loneliness, and low perceived social support. Serial mediation models using the Process tool determined that internalized stigma predicted less perceived social support, which predicted more depressive symptoms, which predicted suboptimal adherence.
The WIHS researchers believe their findings "suggest that potential predictors of adherence may operate differently by race." They proposed that improving adherence, especially in minority women, may require "multifaceted interventions" targeting steps along the stigma-adherence pathway.
Screening for and diagnosing depression with HIV
Depression rates run 2 to 3 times higher in people with HIV infection than in the general population [9,10]. Because of this high risk, US [11] and European [12] guidelines recommend screening all HIV-positive people for depression. The European AIDS Clinical Society (EACS) offers straightforward advice on screening for, diagnosing, and treating depression in people with HIV, starting on page 62 of the 2015 guidelines [12].
1. Bengtson A, Pence BW, Crane HM, et al. Depression increases the risk of mortality in a large cohort of HIV-infected adults. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 920. Link to e-poster: http://www.croiconference.org/sites/default/files/posters-2016/920.pdf
2. Gokhale R, Bradley H, Garg S, Shouse RL. HIV viral suppression among adults diagnosed with depression in the United States. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 1037. Link to e-poster: http://www.croiconference.org/sites/default/files/posters-2016/1037.pdf
3. Turan JM, Turan B, Smith W, et al. Depression and social isolation mediate effect of HIV stigma on women's ART adherence. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 919. Link to e-poster: http://www.croiconference.org/sites/default/files/posters-2016/919.pdf
4. Ickovics JR, Hamburger ME, Vlahov D, 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.
5. Cook JA, Grey D, Burke J, et al. Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am J Public Health. 2004;94:1133-1140. 6. Leserman J, Pence BW, Whetten K, et al. Relation of lifetime trauma and depressive symptoms to mortality in HIV. Am J Psychiatry. 2007;164:1707-1713.
7. Anagnostopoulos A, Ledergerber B, Jaccard R,. Frequency of and risk factors for depression among participants in the Swiss HIV Cohort Study (SHCS). PLoS One. 2015;10:e0140943.
8. Horberg MA, Silverberg MJ, Hurley LB, 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.
9. Do AN, Rosenberg ES, Sullivan PS, et al. Excess burden of depression among HIV-infected persons receiving medical care in the United States: data from the Medical Monitoring Project and the Behavioral Risk Factor Surveillance System. PLoS One. 2014;9:e92842. 10. Ciesla JA, Roberts JE. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry. 2001;158:725-730.
11. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horben MA. Primary care guidelines for the management of persons infected with HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:1-10. http://www.natap.org/2013/HIV/ClinDis2013Abergcid_cit665.pdf
12. EACS European AIDS Clinical Society. Guidelines. Version 8.0. October 2015. http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html