Treating major depressive disorder improves outcomes in HIV patients

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Despite the prevalence of depression in people with HIV (estimates of up to 42%), few data exist on antidepressant efficacy in this population.1 Previous studies of depression in people with HIV have tended to be from US men who have sex with men. As a result, clinicians still are unclear about how antidepressants affect both men and women with HIV, and which agents are effective and work well with antiretroviral therapy (ART).1

Although a recent global meta-analysis of 10 studies and 709 participants found antidepressants to be beneficial to people with HIV and depression, it could not definitively advise which specific antidepressants were most effective.1 Most of the studies were from the US, and 7 of the studies had mostly male participants. Only 3 of the 10 studies compared different classes of antidepressants, so clinicians still do not know whether selective serotonin re-uptake inhibitors are more effective than tricyclic antidepressants. Moreover, the studies did not assess the effect depression therapy had on patients’ virologic suppression.1

“Now that ART is being provided early during HIV infection, it would follow that HIV-positive people suffering from depression are similar to HIV-negative people with depression in the same setting,” noted lead author Dr Ingrid Eshun-Wilson, an epidemiologist from Stellenbosch University in Cape Town, South Africa.

In a 6-year study of 1494 patients with HIV with major depressive disorder (MDD), Dr Arthur Owora, found that the comorbid psychiatric illness could predict patients’ disease progression.2 Characteristics that predicted a low CD4 count included being male (adjusted odds ratio [aOR] 1.25; 95% CI, 1.03-1.52), being a minority race (American Indian [aOR 1.85; 95% CI, 1.38-2.49], African American [aOR 1.58; 95% CI, 1.33-1.87], Latino [aOR 1.52; 95% CI, 1.06-2.18]), and being divorced or separated (aOR 1.62; 95% CI, 1.16-2.28).2

“Our study findings suggest that the pattern of MDD diagnoses, specifically, increasing frequency of illness over time, and not a diagnosis at any single point, predicts HIV disease progression,” explained Owora, assistant professor of public health at Syracuse University in New York. “Clinicians are encouraged to follow existing American Psychiatric Association (2010) guidelines with regular follow-up among depressed patients, instituting individualised therapies as needed and making appropriate referrals for social support. Appropriate treatment and care management can help curtail increasing recurrence of major depression and reduce risk of HIV disease progression.”

Now that ART has been simplified so that most people with HIV take 1 tablet daily, clinicians often forget about other complexities surrounding their care.3 An Australian study of 211 patients with HIV (89.5% men; median age, 47.2 years) found, however, that ostensibly healthy patients can develop serious physical and mental health comorbidities that predict poor outcomes.3 Patients with at least 1 mental illness had a higher odds ratio (OR) of being hospitalized (OR, 1.79; 95% CI, 1.22-2.62; P =.003) and had poor adherence to ART (OR, 2.34; 95% CI, 1.52-3.59; P =.001). More than half the patients in the study had ≥1 psychiatric illness, with one third having anxiety disorder and another third having major depression.3

“Clinicians need to be aware that mental health problems are one of the most important reasons for failing to engage in long-term control of their virus,” said Dr Don E Smith, from the School of Public Health and Community Medicine, University of New South Wales in Sydney, Australia. “Access to mental health services is an important part of HIV management. Simple management algorithms for common comorbidities such as hypertension, diabetes, (and) hypercholesterolemia are needed in all good HIV services.”

Depression can be a warning sign that patients with HIV may be abusing substances and engaging in risky sexual behaviors.4 In a Canadian study of 719 men who have sex with men, high depression scores correlated with substance use, which increased riskier sexual practices among men who have sex with men by 13-fold.4

“Our findings highlight the need for better screening to identify concurrent patterns of substance use and mental health conditions,” explained lead author Dr Kiffer G Card, from the British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia. “This is particularly so, given our observation that individuals who have multiple concurrent health problems are more likely to engage in behaviours which might put themselves or their partners at risk for HIV.”

A small study from the adolescent and young adult medical literature might suggest a way to provide sustainable and durable depression treatment.5 Researchers randomly assigned 44 patients with HIV (69% male; mean age, 21.5 years) and depression to a combination of cognitive behaviour therapy and antidepressants or to treatment as usual, which was medication-only therapy.5 At the end of the 24-week treatment, patients who had combination therapy were more likely to achieve remission compared with their treatment-as-usual peers (65% vs 10%; P <.001), as measured by the Quick Inventory for Depression Symptomatology. At the 48-week follow-up, 71% vs 7% of patients in the combination therapy group and treatment-as-usual group were less likely to report depression, respectively.5

“Often patients with depression are reluctant to try medication, even when it is recommended by their physician,” noted Dr Larry K Brown, director of the division of child and adolescent psychiatry at Bradley and Hasbro Children’s Hospitals and professor and vice chair of the department of psychiatry and human behaviour at the Alpert Medical School of Brown University, Providence, Rhode Island. “This study found that referral to therapists was helpful in motivating patients to use strategies to improve their health, such as trying antidepressant medication and taking medicine to treat HIV. Physicians found that deciding about whether to begin, increase, or change medications was straightforward, using the medication framework and following the patient’s depressive symptom scores.”

Although depression is common in people living with HIV, few studies have been performed to determine the efficacy of antidepressants in this population. The few studies that have been conducted in patients with HIV tended to come from men who have sex with men in the US. More studies of antidepressants need to be conducted in other parts of the world and in both men and women with HIV.

Abstract 1
Background: Rates of major depression among people living with HIV (PLWH) are substantially higher than those seen in the general population and this may adversely affect antiretroviral treatment outcomes. Several unique clinical and psychosocial factors may contribute to the development and persistence of depression in PLWH. Given these influences, it is unclear if antidepressant therapy is as effective for PLWH as the general population.
Objectives: To assess the efficacy of antidepressant therapy for treatment of depression in PLWH.
Search methods: We searched The Cochrane Common Mental Disorders Group’s specialised register (CCMD-CTR), the Cochrane Library, PubMed, Embase and ran a cited reference search on the Web of Science for reports of all included studies. We conducted additional searches of the international trial registers including;, World Health Organization Trials Portal (ICTRP), and the HIV and AIDS – Clinical trials register. We searched grey literature and reference lists to identify additional studies and contacted authors to obtain missing data. We applied no restrictions on date, language or publication status to the searches, which included studies conducted between 1 January 1980 and 18 April 2017.
Selection criteria: We included randomized controlled trials of antidepressant drug therapy compared to placebo or another antidepressant drug class. Participants eligible for inclusion had to be aged 18 years and older, from any setting, and have both HIV and depression. Depression was defined according to Diagnostic and Statistical Manual of Mental Disorders or International Statistical Classification of Diseases criteria.
Data collection and analysis: Two review authors independently applied the inclusion criteria and extracted data. We presented categorical outcomes as risk ratios (RR) with 95% confidence intervals (CIs). Continuous outcomes were presented mean (MD) or standardized mean differences (SMD) with standard deviations (SD). We assessed quality of evidence using the GRADE approach.
Main results: We included 10 studies with 709 participants in this review. Of the 10 studies, eight were conducted in high income countries (USA and Italy), seven were conducted prior to 2000 and seven had predominantly men. Seven studies assessed antidepressants versus placebo, two compared different antidepressant classes and one had three arms comparing two antidepressant classes with placebo.
Antidepressant therapy may result in a greater improvement in depression compared to placebo. There was a moderate improvement in depression when assessed with the Hamilton Depression Rating Scale (HAM-D) score as a continuous outcome (SMD 0.59, 95% CI 0.21 to 0.96; participants = 357; studies = 6; I2 = 62%, low quality evidence). However, there was no evidence of improvement when this was assessed with HAM-D score as a dichotomized outcome (RR 1.10, 95% CI 0.89 to 1.35; participants = 434; studies = 5; I2 = 0%, low quality evidence) or Clinical Global Impression of Improvement (CGI-I) score (RR 1.28, 95% CI 0.93 to 1.77; participants = 346; studies = 4; I2 = 29%, low quality evidence). There was little to no difference in the proportion of study dropouts between study arms (RR 1.28, 95% CI 0.91 to 1.80; participants = 306; studies = 4; I2 = 0%, moderate quality evidence).
The methods of reporting adverse events varied substantially between studies, this resulted in very low quality evidence contributing to a pooled estimate (RR 0.88, 95% CI 0.64 to 1.21; participants = 167; studies = 2; I2 = 34%; very low quality evidence). Based on this, we were unable to determine if there was a difference in the proportion of participants experiencing adverse events in the antidepressant versus placebo arms. However, sexual dysfunction was reported commonly in people receiving selective serotonin reuptake inhibitors (SSRIs). People receiving tricyclic antidepressants (TCAs) frequently reported anticholinergic adverse effects such as dry mouth and constipation. There were no reported grade 3 or 4 adverse events in any study group.
There was no evidence of a difference in follow-up CD4 count at study termination (MD -6.31 cells/mm3, 95% CI -72.76 to 60.14; participants = 176; studies = 3; I2 = 0%; low quality evidence). Only one study evaluated quality of life score (MD 3.60, 95% CI -0.38 to 7.58; participants = 87; studies = 1; very low quality evidence), due to the poor quality evidence we could not draw conclusions for this outcome.
There were few studies comparing different antidepressant classes. We are uncertain if SSRIs differ from TCAs with regard to improvement in depression as evaluated by HAM-D score (MD -3.20, 95% CI -10.87 to 4.47; participants = 14; studies = 1; very low quality evidence). There was some evidence that mirtazapine resulted in a greater improvement in depression compared to an SSRI (MD 9.00, 95% CI 3.61 to 14.39; participants = 70; studies = 1; low quality evidence); however, this finding was not consistent for all measures of improvement in depression for this comparison.
No studies reported on virological suppression or any other HIV specific outcomes.
The studies included in this review had an overall unclear or high risk of bias due to under-reporting of study methods, high risk of attrition bias and inadequate sequence generation methods. Heterogeneity between studies and the limited number of participants, and events lead to downgrading of the quality of the evidence for several outcomes.
Authors’ conclusions: This review demonstrates that antidepressant therapy may be more beneficial than placebo for the treatment of depression in PLWH. The low quality of the evidence contributing to this assessment and the lack of studies representing PLWH from generalized epidemics in low- to middle-income countries make the relevance of these finding in today’s context limited. Future studies that evaluate the effectiveness of antidepressant therapy should be designed and conducted rigorously. Such studies should incorporate evaluation of stepped care models and health system strengthening interventions in the study design. In addition, outcomes related to HIV care and antiretroviral therapy should be reported.

Ingrid Eshun-Wilson, Nandi Siegfried, Dickens H Akena, Dan J Stein, Ekwaro A Obuku, John A Joska

Abstract 2
Contradictory evidence exists on the role of Major depression disorder (MDD) as a predictor of human immunodeficiency virus (HIV) disease progression, particularly regarding the effect of MDD presence versus pattern of illness. The objective of this study was to examine whether MDD status and pattern of illness differentially predict HIV disease progression. Retrospective cohort data from a six-year follow-up of HIV patients at an outpatient clinic were analyzed. MDD trajectories were identified by latent class growth analysis and generalized linear mixed models were used to examine their relation to low CD4+ T-lymphocyte counts (<200 cells/μL) during follow-up. Among 1,494 HIV patients, four MDD trajectory groups were identified: Low-Chronic, Moderate-Ascending, High-Episodic, and High-Chronic. Trajectory group membership was predicted by male sex (P = .04), minority race (P < .01), older age (P < .01) and low baseline CD4 count (P = .04). The High-Chronic group had lower odds of having a low CD4 count than the Low-Chronic group (adjusted Odds Ratio [aOR]: 0.63; 95%CI: 0.49-0.81) while the Moderate-Ascending group had higher odds (aOR: 1.53; 95%CI: 1.08-2.19). The odds of having a low CD4 count were higher among male (aOR: 1.25; 95%CI: 1.03-1.52), minority races (American Indian [aOR: 1.85; 95%CI: 1.38-2.49] and African Americans [aOR: 1.58; 95%CI: 1.33-1.87]), Hispanic (aOR: 1.52; 95%CI: 1.06-2.18), and divorced/separated patients (aOR: 1.62; 95%CI: 1.16-2.28) but decreased over time (P < .01) across trajectory groups. In this study, because MDD trajectories and CD4 counts were determined based on secondary data abstracted from electronic medical records, the results should be interpreted cautiously due to the potential for selection and misclassification bias. Overall, study findings suggest the pattern of MDD illness among HIV patients can be classified into clinically meaningful trajectory groups that appear to be programmed by known risk factors, and are useful for predicting HIV disease progression. Targeted interventions among at-risk patients may be critical to altering MDD illness patterns and curtailing HIV disease progression.

Owora AH

Abstract 3
Objective: To assess the prevalence of non-AIDS co-morbidities (NACs) and predictors of adverse health outcomes amongst people living with HIV in order to identify health needs and potential gaps in patient management.
Design: Retrospective, non-consecutive medical record audit of patients attending a publicly funded HIV clinic in metropolitan Sydney analysed for predictors of adverse health outcomes. We developed a scoring system based on the validated Charlson score method for NACs, mental health and social issues and confounders were selected using directed acyclic graph theory under the principles of causal inference.
Results: 211 patient files were audited non-consecutively over 6 weeks. 89.5% were male; 41.8% culturally and linguistically diverse and 4.1% were of Aboriginal/Torres Strait Islander origin. Half of patients had no general practitioner and 25% were ineligible for Medicare subsidised care. The most common NACs were: cardiovascular disease (25%), hepatic disease (21%), and endocrinopathies (20%). One-third of patients had clinical anxiety, one-third major depression and almost half of patients had a lifetime history of tobacco smoking. Five predictors of poor health outcomes were identified: (1) co-morbidity score was associated with hospitalisation (odds ratio, OR 1.58; 95% CI 1.01–2.46; p = 0.044); (2) mental health score was associated with hospitalisation (OR 1.79; 95% CI 1.22–2.62; p = 0.003) and poor adherence to ART (OR 2.34; 95% CI 1.52–3.59; p = 0.001); (3) social issues score was associated with genotypic resistance (OR 2.61; 95% CI 1.48–4.59; p = 0.001), co-morbidity score (OR 1.69; 95% CI 1.24–2.3; p = 0.001) and hospitalisation (OR 1.72; 95% CI 1.1–2.7; p = 0.018); (4) body mass index < 20 was associated with genotypic resistance (OR 6.25; 95% CI 1.49–26.24; p = 0.012); and (5) Medicare eligibility was associated with co-morbidity score (OR 2.21; 95% CI 1.24–3.95; p = 0.007).
Conclusion: Most HIV patients are healthy due to effective antiretroviral therapy; however, NACs and social/mental health issues are adding to patient complexity. The current findings underpin the need for multidisciplinary management beyond routine viral load and CD4 count monitoring.

Derek J Chan, Virginia Furner, Don E Smith, Mithilesh Dronavalli, Rohan I Bopage, Jeffrey J Post, Anjali K Bhardwaj

Abstract 4
Introduction: Among gay, bisexual, and other men who have sex with men (GBM), collinearity between polysubstance use and mental health concerns has obscured their combined effects on HIV risk with multivariable results often highlighting only one or the other.
Methods: We used mediation and moderation analyses to examine the effects of polysubstance use and depressive symptoms on high-risk sex (i.e., condomless anal sex with serodiscordant/unknown status partner) in a sample of sexually-active GBM, aged ≥16 years, recruited in Metro Vancouver using respondent driven sampling. Hospital Anxiety and Depression Scale scores assessed mental health. Alcohol Use Disorder Identification Test scores assessed alcohol disorders. Poly-use of multiple drug types (e.g., stimulants, sedatives, opiates, hallucinogens) was assessed over the previous six months.
Results: Among 719 predominantly white (68.0%), gay-identified (80.7%) GBM, alcohol use was not associated with increased prevalence of high-risk sex. Controlling for demographic factors and partner number, an interaction between polysubstance use and depressive symptoms revealed that the combined effects were additively associated with increased odds for high-risk sex. Mediation models showed that polysubstance use partially mediated the relationship between depressive symptoms and high-risk sex.
Conclusion: An interaction effect between polysubstance use (defined by using 3 or more substances in the past six months) and depressive symptoms (defined by HADS scores) revealed that the combination of these factors was associated with increased risk for high-risk sex – supporting a syndemic understanding of the production of HIV risk.

Kiffer G Card, Nathan J Lachowsky, Heather L Armstrong, Zishan Cuj, Lu Wang, Paul Sereda, Jody Jollimore, Thomas L Patterson, Trevor Corneil, Robert S Hogg, Eric A Roth, David M Moore

Abstract 5
Objective: Preliminary test of a manualized, measurement-guided treatment for depression for adolescents and young adults in care at 4 sites of the Adolescent Trials Network for HIV/AIDS Interventions.
Design: The US sites were randomly assigned to either a 24-week, combination cognitive behavioral therapy and medication management algorithm (COMB) tailored for youth living with HIV (YLWH) or to treatment as usual (TAU).
Methods: Youth at TAU sites had access to therapists and medication management as needed. COMB-site clinicians were trained in the manualized intervention and participated in supervision calls to monitor intervention fidelity.
Results: Over the course of the study with 44 participants, those in COMB, compared with those in TAU, reported fewer depressive symptoms, P < 0.01 (as measured by the Quick Inventory for Depression symptoms) and were more likely to be in remission, P < 0.001 (65% vs. 10% at week 24, end of treatment, and 71% vs. 7% at week 48, final follow-up). A greater proportion of COMB participants received psychotherapy (95% vs. 45%, P < 0.001) and attended more sessions (12.6 vs. 5, P < 0.001) than those in TAU. Viral load decreased in both groups and was associated (P < 0.05) with reduction in depressive symptoms.
Conclusions: A 24-week manualized, measurement-guided psychotherapy and medication management algorithm tailored for YLWH was more effective in achieving and sustaining remission from depression than TAU at HIV care clinic sites. Given observed treatment efficacy, this structured combination treatment could be disseminated to medical clinics to successfully treat YLWH, who are at particular risk for depression.

Brown, Larry K; Kennard, Betsy D; Emslie, Graham J; Mayes, Taryn L; Whiteley, Laura B; Bethel, James; Xu, Jiahong; Thornton, Sarah; Tanney, Mary R; Hawkins, Linda A; Garvie, Patricia A; Subramaniam, Geetha A; Worrell, Carol J; Stoff, Laura W

Infectious Disease Advisor material
Cochrane abstract
Europe PMC abstract
AIDS Research and Therapy abstract
Addictive Behaviours abstract
Journal of Acquired Immune Deficiency Syndrome abstract

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