Depression increases mortality risk in non-adherent individuals on first-line ART

Symptoms of depression are associated with an increased risk of death among non-adherent antiretroviral-naive individuals initiating potent antiretroviral therapy (ART), according to a prospective cohort study published in the May 31^st edition of the journal AIDS. The study, from British Columbia, Canada, found that although non-adherent individuals without depression were 4.5 times more likely to die than adherent individuals without symptoms of depression, those with both depressive symptoms and poor adherence were almost six times more likely to die than those who were adherent and not depressed.

Depression is up to three times more common in HIV-positive individuals than in the general population. Several studies have found that depressive symptoms in HIV-positive individuals are associated with disease progression and death. This is thought to be because untreated depression is associated with reduced adherence to ART.

However, until now no study had specifically evaluated the extent to which the association between depressive symptoms and survival in HIV-positive individuals is modified by adherence to therapy, or whether depressive symptoms have an impact upon survival exclusively among antiretroviral-naive individuals.

A total of 1,011 antiretroviral-naive adults initiated triple-combination therapy consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) between August 1996 and June 2002.

At baseline, individuals were asked to fill out a questionnaire measuring current levels of depressive symptoms (the Center for Epidemiologic Studies Depression Scale). A cut-off of 16 points (out of possible total of 60) was used to indicate the presence of depressive symptoms. However, 448 (44%) individuals were excluded from the study because they did not complete all 20 questions.

The remaining 563 individuals (91% of whom were male) were followed for a median of four years [interquartile range (IQR), 3-6 years]. At baseline, median age was 38 years; CD4 cell count was 230 cells/mm³; HIV RNA plasma viral load was 120,000 copies/ml; and physician experience was 77 patients per physician.

Just over one third (35%) had an average annual income below the Canadian poverty line (less than C$10,000); 29% did not complete high school; 28% had a history of injection drug use; 13.7% reported being aboriginal; 20% had an AIDS diagnosis; and 23% of participants were considered non-adherent. Participants were defined as non-adherent if ART pharmacy refills were less than 95% during their first year of therapy.

When participants who did not complete the depression survey were compared with those who completed it, they tended to be female; have no high school completion; lower income; higher baseline CD4 cell count; lower baseline HIV RNA plasma viral load; less experienced physicians, lower adherence and longer survival (all p

The primary endpoint of the study was time to all-cause mortality, and the overall all-cause mortality rate was 10% during follow-up. The investigators note, “it was not possible to run the analysis in this study for only HIV-related deaths due to the lack of power in this latter analysis.”

At baseline, 289 individuals (51%) reported depressive symptoms. These were associated with not having completed high school (p

In univariate analysis, older age (Hazard Ratio [HR] 1.04; 95% CI, 1.01-1.07); CD4 cell count (HR 1.16; 95% CI, 1.00-1.16, per 100 cell decrease); high school completion (HR 0.49; 95% CI, 0.29-0.84); income above poverty line (HR 0.44; 95% CI, 0.26-0.75); a history of injection drug use (HR 2.06; 95% CI, 1.20-3.51); aboriginal status (HR 2.16; (95% CI, 1.15-4.03); non-adherence and depressive symptoms were associated with mortality.

In multivariate analysis, after controlling for age, gender, aboriginal status and history of injection drug use, the association between depressive symptoms and adherence with mortality remained very strong. Non-adherent individuals with depressive symptoms had the highest risk of mortality (HR 5.92; 95% CI, 2.52-13.94), followed by non-adherent individuals without depressive symptoms (HR 4.47; 95% CI, 1.76-11.39).

However, there was no association between depression and adherence and mortality in individuals who were depressed and adherent (HR 1.41; 95% 0.62-3.17).

The investigators point out several limitations to their study. The depression survey used in the study is not considered to be a diagnostic tool and has been found to overestimate the number of individuals who actually have clinical depression. “However,” they write, “the majority of our sample did not score in the severe range of depressive symptoms, and our analysis suggests that the observed relationship was not driven by the more severe group.”

They also note that their study “might be limited by a certain degree of response bias” because it only included participants who answered all 20 questions in the depression survey. “It is possible,” they write, “that people with severe depressive symptoms were not motivated enough to complete the baseline survey. If this is true, our results would have been biased toward a less depressed sample. However, based on the results shown in this study we believe that this bias, if present, did not play a significant role in biasing our results downward, since we were able to prove a strong association between depressive symptoms with mortality.”

A 2005 study from the United States published in the Journal of Acquired Immune Deficiency Syndromes found that adherence to antiretroviral therapy was significantly improved by antidepressant treatment in HIV-positive individuals diagnosed with depression.

Consequently, the investigators conclude that, “efforts to diagnose and treat depression, especially in individuals with sub-optimal adherence may be an important strategy for reducing psychiatric morbidity, as well as improving adherence and, potentially, disease outcomes.”