Cumulative Depression Increases Mortality in Women With HIV

depression, depressed woman
depression, depressed woman
Findings highlight the clinical importance of enhanced treatment protocols designed to reduce the duration and frequency of depressive episodes in women living with HIV.

Quantifying depression as a cumulative rather than binary exposure may provide a better indication of the clinical benefit of enhanced depression treatment protocols delivered in routine HIV care settings, according to a study recently published in Clinical Infectious Diseases.1

Affecting more women (30% to 60%) than men, depression is the most common psychiatric comorbidity in people living with HIV.2 In addition, a strong association between depression and mortality is seen, particularly in women living with HIV (WLWH). Studies have shown that depression more than tripled the rate of all-cause mortality in WLWH.3 Furthermore, women with chronic depressive symptoms have shown a 70% greater risk for AIDS-related mortality over 7.5 years compared with women with no depressive symptoms.4

Prior studies examining the depression and mortality relationship used a binary (yes/no) or categorical (chronic, intermittent, etc.) measure to characterize depression. However, since depression is a chronic and cyclical condition, its effect on mortality is unlikely to be captured realistically by a dichotomous representation. Therefore, this study explored the dose-response relationship between the cumulative burden of depression and all-cause mortality in WLWH.

Data from the Women’s Interagency HIV Study (WIHS), a cohort of WLWH recruited from 6 US cities, was used. This analysis was limited to the first 3 enrollment phases (1994-1995, 2001-2011, and 2011-2012). WIHS participants completed interviews at semi-annual visits to assess a range of sociodemographic and clinical characteristics, medication utilization history, and self-reported disease symptom severity. Analysis began with the participants’ first visit and continued for a maximum of 10 visits (approximately 5 years) or until death or failure to follow-up (2 consecutive missed visits). Women who were prevalent users of antiretroviral therapy at their first visit were excluded in order to mitigate survivor bias.

The study’s interest was cumulative days with depression (CDWD), which is the running sum of accumulated days with depression experienced either consecutively or over intermittent episodes. CDWD was calculated using participants’ semi-annual Center of Epidemiologic Studies Depression (CES-D) scores (range: 0-60), a validated instrument for assessing depressive symptoms. An area under this curve approach was used to translate CES-D scores into a time-updated measure of CDWD. The effect of CDWD on all-cause mortality was estimated using marginal structural Cox proportional hazard models.

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The median age, CD4 count, and HIV RNA load of the 818 participants was 38, 438 cells/µL3, and 3.5 log10 copies/mL, respectively. Median length of follow-up was 4.8 years.

More time spent depressed, either consecutively or intermittently, was found to increase the hazard of mortality in a dose-response fashion. There were 94 deaths equating to an all-cause mortality rate of 2.9 deaths/100 women-years. At the last observed visit, median CDWD was 435. The probability of survival began to decrease at a faster rate in the highest CDWD category (>365 CDWD) compared with the lower categories at 1 year follow-up (P <.001). Each additional 365 CDWD led to a 72% increase in the hazard of all-cause mortality (hazard ratio 1.72; 95% CI 1.34-2.20).

The study investigators concluded that “more frequent monitoring and enhanced depression treatment protocols designed to reduce CDWD may interrupt the accumulation mortality risk among WLWH.”


  1. Mills JC, Pence BW, Todd JV, et al. Cumulative burden of depression and all-cause mortality in women living with HIV [published online March 30, 2018]. Clin Infect Dis. doi:10.1093/cid/ciy264
  2. Ickovics JR, Hamburger ME, Vlahov D, et al; HIV Epidemiology Research Study Group. Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA. 2001;285(11):1466-1474.
  3. Todd JV, Cole SR, Pence BW, et al. Effects of antiretroviral therapy and depressive symptoms on all-cause mortality among HIV-infected women. Am J Epidemiol. 2017;185(10):869-878.
  4. 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(7):1133-1140.