Introduction
Depression is a highly prevalent condition that presents with psychological, behavioral, and physical symptoms that can be debilitating, interfere with self-care, influence social interactions, and lead to suicide [
1]. Depression is the second leading cause of disability worldwide [
2].
Studies conducted in the United States suggest that the prevalence of depression is substantially higher among men and transgender women who have sex with men (MSM/TGW) compared to men in the general population [
3‐
5]. Population-based mental health surveys have found higher rates of major depression; anxiety; substance use; childhood emotional, sexual and physical mistreatment; and suicidal behaviors in individuals disclosing same-sex sexual behaviors or identifying as gay [
3,
6‐
9]. In addition, MSM/TGW carry a disproportionate burden of the HIV epidemic, and contend with victimization, harassment, rejection and fear of rejection, and discrimination [
10,
11]. Psychosocial health problems, including depression, increase risk for HIV acquisition via sexual practices [
8,
12,
13], however the effects of depression on HIV acquisition may differ depending on depression severity. The EXPLORE study found a curvilinear relationship between the severity of depression and sexual risk taking in African–American MSM in the US, whereby moderately depressed individuals reported the most risky sexual behaviors compared to non-depressed or severely depressed individuals [
14]. Childhood sexual abuse (CSA) in MSM/TGW has also been identified as a factor strongly associated with increased risk for HIV acquisition [
15,
16]. History of CSA in MSM/TGW is associated with an increased likelihood of engaging in sexual behaviors that put them at risk for HIV infection [
15].
Daily, oral Truvada
® (a coformulation of emtricitabine and tenofovir disoproxil fumarate, or FTC/TDF) is safe and effective for HIV pre-exposure prophylaxis (PrEP) [
17‐
20]. The iPrEx study was a multinational, randomized, placebo-controlled trial that investigated the safety and efficacy of FTC/TDF PrEP in a cohort of MSM/TGW. Depression was one of the most frequently reported adverse events (AEs) in the study [
18]. Previous studies of antiretroviral therapies (ARTs), including FTC and TDF in HIV-infected participants have reported high rates of depression-related AEs and raised concerns regarding the possible influence of these antiretroviral regimens on depression [
21‐
23]. While subsequent studies have reported that efavirenz shows the strongest association with mental health diagnoses [
24], the prescribing information and medication guide for FTC/TDF includes depression as a potential AE in HIV-infected individuals. Previous studies have not examined the effect of FTC/TDF on depression in absence of other ARTs or outside of the context of HIV infection. The iPrEx study presented a unique opportunity to look at the impact of FTC/TDF specifically on depression in a randomized manner in HIV-uninfected individuals.
As FTC/TDF for PrEP becomes increasingly popular, it is important to understand the role of depression in HIV acquisition risk and if PrEP affects depression. This analysis addresses these questions with three primary aims in the iPrEx cohort: (1) determine if FTC/TDF is associated with depression (compared to placebo), (2) describe the prevalence of and the risk factors for depression, and (3) examine how depression may be associated with sexual practices. These findings will be important in establishing the safety profile of FTC/TDF PrEP in HIV-uninfected MSM/TGW at risk for depression, and in understanding how depression may impact the risk of acquiring HIV in these populations.
Discussion
During the iPrEx trial, daily oral FTC/TDF PrEP was not associated with depression; there were no significant differences in total number of depression-related AEs, CES-D scores, or suicidal ideation scores between study arms. As-treated analyses confirmed these findings, ruling out that similarity between groups could be attributable to lack of detectable drug exposure. Depression had been previously observed in trials of HIV-infected MSM receiving FTC/TDF in combination with other drugs for HIV treatment [
21‐
23]. Antiretroviral medications used with FTC/TDF in these studies included efavirenz, which could have been responsible for these observations [
38,
39]. In fact, recent evidence has linked efavirenz to neuropsychiatric effects and mental health diagnoses, including suicidal ideation, attempts or completion [
24].
Though not related to oral FTC/TDF PrEP use, depression was one of the major AEs reported in iPrEx. Half of iPrEx participants who completed at least one CES-D had scores greater than or equal to 16 at some point over the course of the study, which is the cut-off considered to reflect clinically significant depressive symptoms in some settings [
12,
26,
33]. In the iPrEx cohort, having been forced to have sex at anal sexual debut and ncRAI was associated with higher CES-D scores and there were trends toward higher scores among younger people and TGW. Our observations are consistent with previous findings that depressive symptoms are common in MSM/TGW, especially young people and those who identify as transgender women [
10,
40]. MSM/TGW are at increased risk for social isolation, history of childhood abuse (including sexual abuse), and ongoing discrimination, which increase vulnerability to depression and suicide [
6,
7,
9]. On the other hand, in this analysis, we did not see an association between alcohol use and CES-D scores. In-depth analyses of substance and alcohol use in iPrEx, and the subsequent iPrEx open label extension (OLE), as well as analyses of depression, other co-morbidities, and adherence are currently underway.
CSA is a traumatic early life event that adversely influences psychological and physical health in addition to socioeconomic well-being [
41,
42]. CSA has been shown to be an important correlate of sexual risk-taking behaviors and HIV infection [
15,
16]. CASI questions related to sexual debut may be relevant to assessing CSA; underage and forced sexual experience with an adult has been defined as CSA [
15]. There is an association between having reported being “manipulated” or “forced” at anal sex debut and higher CES-D scores and increased likelihood of reporting suicidal ideation in the iPrEx cohort. The clinical significance of the observed 3-point average difference on CES-D scores is unclear. This relatively small difference seen on the CES-D may suggest that the influence of CSA on sexual behavior is mediated by other social and psychological variables, and not necessarily by depression [
16,
43]. We did not see any association with any other questions pertaining to possible traumatic experiences; however these questions were not instruments specifically designed to screen for such events.
There were more frequent reports of ncRAI among those in the highest quartile of CES-D scores. This finding is consistent with previous studies showing depression to be associated with sexual practices that can increase acquisition of HIV infection [
14,
33,
44]. Having more depressive symptoms may put the person at higher risk for acquiring HIV during sex, possibly because depression may undermine self-care, communication with partners, or perception of risk. Depression may interfere with discussions about condom use, and asserting a desire for protective use of condoms. In addition, depression may trigger use of substances, which could impair perceptions of risk or impulse control.
During iPrEx, three participants on the FTC/TDF arm seroconverted while on a protocol-required study drug interruption triggered by depression-related AEs. Several findings support a recommendation to continue PrEP during periods of depression. We saw no evidence that PrEP was less efficacious among participants having a CES-D score above 16 during the iPrEx trial (Mantel–Haenszel test for heterogeneity p = 0.92). There was no link between oral FTC/TDF PrEP and depression or depressive symptoms. Behavior linked to HIV risk was more commonly reported among people with depressive symptoms. Indeed, 3 HIV infections occurred during protocol mandated interruptions in study medication due to depression. The protocol requirement to stop PrEP during periods of depression was amended as the iPrEx trial transitioned from the randomized phase to OLE, based on the findings reported here. In the iPrEx OLE study, drug was only interrupted if participants reported suicidal ideation with a concrete plan.
Adherence to HIV treatment can be affected by depression [
5,
45,
46]. Given the blinded placebo-controlled design of the iPrEx trial and the protocol requirement that study medication be stopped in participants with grade 4 depression AEs, the analysis of adherence to PrEP amongst depressed people during the randomized phase of iPrEx is difficult and subject to bias. However, analyses from iPrEx OLE examining the role of depression on adherence to open-label PrEP are currently underway.
Because iPrEx was conducted at 11 study sites across the globe, our analyses are somewhat limited by a wide variation in the cultural context, access to mental health services, and access to anti-depressant medications. Studies of depression in the Hispanic Health and Nutrition Examination Survey (HHANES) using CES-D scales suggest that results may need to be interpreted differently in Hispanic populations [
47‐
49]. Though validated in Spanish, Thai, and Portuguese, CES-D scores and their clinical significance should be interpreted carefully cross-culturally. This limitation was partially addressed by analyzing the CES-D scores as continuous variables or divided into quartiles, and controlling analyses for random effects by study site.
Use of anti-depressants was low overall (8 % of entire cohort), being reported in only one half of people with depression-related AEs grade 2 or higher. Anti-depressant medication use varied dramatically by site (but not by study arm), with study sites in the USA reporting the highest proportions of psychotropic medication use. Anti-depressant medication use had no effect on our study findings. No drug interactions are expected between FTC/TDF and commonly used anti-depressant medications [
50]. Individuals who are under care for depression should be evaluated for PrEP indications. In settings having a substantial prevalence of HIV infection, PrEP indications include inconsistent condom use outside of mutually monogamous relationship with a recently tested HIV-negative partner, any sexual partner who is HIV-positive or whose HIV status is unknown, any sexually transmitted infection by self-report or laboratory testing, use of post-exposure prophylaxis, or any sharing of needles for injection drug use [
51]. Antidepressant therapy may improve PrEP adherence and uptake, as it has for antiretroviral therapy for HIV infection (reviewed in [
52]).
A limitation of the current analysis is that plans to examine depression symptoms systematically using CES-D and the suicidal ideation screener were made after the trial was already underway, and were triggered in part by the high rates of depression-related AEs (depression AEs were evaluated throughout the entire study follow-up and therefore do not suffer from this same limitation). Although 15 % of participants never completed a CES-D, the available information this was evenly distributed across the FTC/TDF and placebo arms. Furthermore, CES-D scores, when available, did not predict earlier study drop out after controlling for age and study site. Additionally, when examining pre-existing conditions of depression that were recorded for all study participants, we see no difference in frequency of pre-existing conditions in participants who never received a CES-D versus those who did. These findings suggest that our finding that depressive symptoms were not associated with oral FTC/TDF PrEP is not likely to be substantially biased by missing CES-D scores.
Oral FTC/TDF PrEP does not affect depression incidence or severity and depressive symptoms are associated with sexual practices that increase risk for HIV acquisition. The additional protection conferred by PrEP could avert infections during these especially vulnerable times, while fostering engagement in health services. Adherence to PrEP and other safer sex recommendations may be especially challenging during periods of depression, so specific attention to promoting adherence during these periods is important. Given the high prevalence of depression and HIV incidence among MSM/TGW, especially young people, PrEP services should include screening and management of trauma, including CSA. PrEP programs may provide infrastructure for increasing access to mental health services, enabling synergistic diagnoses, and management of co-morbidities.
Acknowledgments
This paper is dedicated to the memory of James Jeff McConnell. The authors thank the iPrEx participants without whom none of these studies would have been possible. This work was supported by the Division of Acquired Immunodeficiency Syndrome (DAIDS), National Institute of Allergy and Infectious Diseases, National Institutes of Health, as a cooperative agreement (UO1 AI64002) and by the Bill and Melinda Gates Foundation. Study drugs were donated by Gilead Sciences. These agencies were not involved in the analysis of data or the preparation of this manuscript. Some of the data was presented as a poster, at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, 2011, Rome. The authors also thank all study sites teams for their outstanding work in conducting the iPrEx trial. RG, DG, and VMM designed and coordinated the iPrEx and iPrEx OLE trials. AYL, PD and RG conceived the present depression study. RA provided consultancy. DB was the study sponsor Medical Officer and provided study oversight. AYL, LV, KM, PC, TF, VAS contributed to site leadership, procedural implementation and data collection. MM and DG performed the statistical analysis. PD and MM wrote the manuscript. All authors critically reviewed, revised, and approved the final manuscript. This work was supported by NIH U01 AI64002 and the Bill and Melinda Gates Foundation. Study drug was donated by Gilead Sciences. These agencies were not involved in the analysis of data or the preparation of this manuscript.