Correlation of pre-exposure prophylaxis adherence to a mental health diagnosis or experience of childhood trauma in high-risk youth

Abstract

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine is 99% effective in preventing HIV when taken daily. Young men/transgender women of color who have sex with men are the most at risk to become infected with HIV, with the lowest PrEP adherence. We investigated the association of depression, anxiety, and history of childhood trauma with PrEP adherence. PrEP adherence was measured by urine TDF testing. Patients were evaluated for depression (Patient Health Questionnaire-9 [PHQ-9]), anxiety (Generalized Anxiety Disorder-7 [GAD-7]), and history of childhood trauma (Adverse Childhood Experiences [ACEs]). Urine TDF levels were compared across scores on each screening tool using a Student’s t-test. A p-value of ≤ 0.05 was considered significant. Thirty-one subjects (mean age: 21.7 years, SD: 2.8) were enrolled between 3/2015 and 7/2016. Lower PrEP adherence was associated with a GAD-7 score diagnostic for generalized anxiety (80.7% versus 92.7%, p = 0.04) and a high ACE score (4+) (84.5% versus 95.7%, p = 0.05). A PHQ-9 score diagnostic for major depression was not associated with PrEP adherence. The presence of generalized anxiety and a history of childhood trauma, but not major depression, were associated with decreased PrEP adherence. The benefits of mental health interventions and trauma-informed care in PrEP programs should be considered in larger studies to potentially increase adherence.

Keywords

North America antiretroviral therapy men prevention HIV

Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), when taken daily as pre-exposure prophylaxis (PrEP), has been shown to greatly reduce HIV transmission with high tolerability and minimal side effects.¹ With daily consistent use, PrEP has been shown to be up to 99% effective in reducing sexual transmission of HIV.¹ It has also been well established that the level of adherence to PrEP correlates closely with its efficacy. Young men of color who have sex with men (yMSMc) have the lowest rate of adherence to PrEP when compared to other racial and ethnic groups.^2–7 In the Adolescent Trials Network 110 study looking at PrEP adherence among 200 high-risk MSM aged 15–22, Black participants, on average, were the only racial group who did not achieve adequate drug concentrations at any point in the study.² Furthermore, by week 48, drug levels indicated almost none of the Black participants were still taking PrEP,² which is particularly troubling because there are more new HIV infections among yMSMc aged 13–30 years than in any other age or racial group.^8,9 Data from Atlanta reveal that nearly one in ten Black MSM under age 25 is infected with HIV annually¹⁰ and, if current infection rates persist, one in two young Black MSM will be infected with HIV by age 30.¹¹

Little is known about the relationship between PrEP adherence and depression and anxiety. The antiretroviral therapy (ART) literature suggests that mental health disorders may lead to ART non-adherence and results in poorer health.¹² Additionally, it is projected that over half of persons living with HIV in the United States that suffer from depression may have not received an official diagnosis of their depression.¹³ As a causal link between mental health and ART adherence is still unclear, two studies with moderately sized HIV-infected populations self-reporting adherence to ART reported somewhat contradictory findings. Campos et al.¹⁴ showed in Brazil that a diagnosis of severe anxiety but not severe depression correlated with non-adherence, though the number of individuals exhibiting symptoms of severe depression was low. Nel and Kagee¹⁵ showed in South Africa that depression correlated with non-adherence to ART while there was no association with anxiety.

Strong correlations exist between mental health, as well as many other medical comorbidities, in adults and the experience of adverse childhood experiences (ACEs).^16–20 ACEs are a survey of an individual’s experience of abuse, violence, mental illness, and incarceration within one’s childhood household. It has been shown to correlate with many types of physical and mental health problems, such as heart disease, stroke, and cancer, in a dose–response fashion.¹⁶ ACEs have also been shown to correlate with decreased adherence to ART and increased risk behaviors in a dose–response fashion in people living with HIV (PLWH).^16,17 Individuals reporting one ACE were nearly twice as likely as individuals with a score of zero to report injection drug use, be treated within the past year for a sexually transmitted infection (STI), report condomless anal intercourse within the previous year, and report having exchanged sex for money or drugs.¹¹

Individuals reporting an ACE score of four or more were 4.34 times more likely to engage in high-risk HIV behavior, 5.12 times more likely to carry a diagnosis of depression, 7.4 times more likely to consider themselves an alcoholic, and 12.2 times more likely to have ever attempted suicide.^16,17 Rates of ACEs in MSM are estimated to be higher than in the general population, with estimates of up to 46% of MSM having experienced childhood sexual abuse, and with a higher incidence of psychological and physical abuse from caretakers than same-sex heterosexual siblings.¹⁸ MSM of color, specifically, are more likely to experience psychosocial stressors such as lack of emotional support, limited positive encouragement from friends and family, and fewer meaningful personal relationships.^19,20 However, there are no data on the effect of ACEs on PrEP adherence, particularly among yMSMc, a vulnerable population at high risk of acquiring HIV.

It is critical to engage and support this population in HIV prevention efforts through a better understanding of reasons for non-adherence to PrEP, including the extent to which mental health and ACEs affect adherence, given a greater number of new HIV infections occurring among yMSMc than in any other age and risk group.²¹ To our knowledge, this is the first study to look at the relationship between mental health disorders, ACEs, and adherence to PrEP in this population.

Methods

This is a cross-sectional analysis assessing prevalence of mental health disorders and ACEs among YMSM, predominantly of color, receiving PrEP. Additionally, this study sought to explore the relationships between mental health symptoms, ACEs, and adherence as measured by urine tenofovir (TFV) testing. Written informed consent was obtained from all participants. This study was approved by the Philadelphia FIGHT Institutional Review Board.

Participant selection and mental health evaluation

Recruitment, enrollment, and study visits were conducted at an urban, community-based, federally qualified health center that provides comprehensive care to patients living with and at risk for HIV infection (http://fight.org/). Thirty-one HIV-negative participants assigned male at birth between the ages of 18 and 30 who were concurrently enrolled in an observational study monitoring longitudinal PrEP program retention and medication adherence were recruited (citation for trial: 10.1097/QAI.0000000000001772). Participants met at least one of the following risk criteria for participation in the longitudinal study: a sexual partner known to be living with HIV, inconsistent condom use with partners of unknown HIV sero-status, diagnosis of an STI in the six months preceding enrollment, or the exchange of sex for goods/housing/etc. Participants utilized private (obtained through school or employment), state, or family (policy held by a parent or guardian) insurance to secure TDF/FTC for PrEP, and patients without insurance obtained PrEP through the manufacturer’s patient assistance program.

At a single time point during the aforementioned study, patients were approached in person or by phone to assess their interest in participating in the present study. If they agreed, informed consent was obtained from each participant in person. During a 1 h extension of that same or a subsequent PrEP study visit, a licensed clinical social worker or Doctor of clinical psychology assessed for mental health diagnoses and experience of ACEs in each participant by assisting participants with completing the standardized survey tools described below, and offering support for participants experiencing distress at the time of completion. Retention and adherence data preceding and following the mental health assessment were collected as part of the concurrent study in which these study. No additional laboratory testing was done specific to this study.

Mental health analysis

The three standard screening tools and cutoffs utilized in this study include:

Patient Health Questionnaire-9 (PHQ-9): The PHQ-9 is a well-studied nine-question screening tool and has been validated in the diagnosis of major depressive disorder (MDD) based on DSM-IV-TR diagnostic criteria in both the self- and interviewer-administered settings.^22,23 The PHQ-9 scores each questions such as ‘Over the last 2 weeks, how often have you been bothered by any of the following problems: little interest or pleasure in doing things; feeling down, depressed, or hopeless’ from 0 to 3 (0 indicating ‘not at all,’ and 3 indicating ‘nearly every day’), based upon reported frequency of symptoms; therefore, the total score on the PHQ-9 ranges from 0 to 27.²³ A score of 10 or higher on the PHQ-9 is sensitive and specific for MDD, and the most common cutoff utilized for diagnostic purposes.^23–25 Participants having a score greater than or equal to 10 met criteria for a depressive disorder.²⁴

Generalized Anxiety Disorder-7 (GAD-7): The GAD-7 is a seven-question survey designed and validated to diagnose GAD in the primary care setting based upon the DSM IV-TR diagnostic criteria.²¹ Similar to the PHQ-9, the GAD-7 scores each question from 0 to 3 (0 indicating ‘not at all,’ and 3 indicating ‘nearly every day’) based upon the reported frequency of symptoms such as ‘feeling nervous, anxious, or on edge; not being able to stop or control worrying,’ with the total score on the GAD-7 ranging from 0 to 21.²⁶ While the operating characteristics for the GAD-7 have been studied at multiple cut-off points, a score of 10 or greater has been shown to have good combined sensitivity and specificity for the diagnosis of GAD, as well as good performance in the diagnosis of three other anxiety disorders including panic disorder, social anxiety disorder, and posttraumatic stress disorder, with sensitivities and specificities for all diagnoses exceeding 0.75.^26,27 Participants having a score greater than or equal to 10 met criteria for an anxiety disorder.²⁶

Adverse Childhood Experiences (ACEs) Survey: The ACEs survey comprises ten ‘yes’ or ‘no’ questions distributed throughout different categories of childhood exposures including psychological abuse, sexual abuse, physical abuse, substance abuse, mental illness in a household member, mother having been treated violently, and criminal behavior in the household. Scores range on the survey from 0 to 10. Based on Felitti et al.¹⁷ a cutoff of 4 or greater ‘yes’ answers on the ACEs tool was considered a ‘high’ score as it is correlated with poor medical and psychological long-term outcomes.

Objective adherence measurement

A high-performance liquid chromatography–tandem mass spectrometry plasma and urine TFV assay has been previously validated²⁸ and was used as an objective marker of TDF/FTC PrEP adherence in this study. The assay reports urine TFV levels at >1000 ng/ml (indicating recent adherence within 48 h), >10 to >100 ng/ml (last medication use 2–7 days prior to testing), and <10 ng/ml (no adherence in preceding 7–10 days).²⁸

Medical visit attendance

All participants received TDF/FTC as PrEP as part of the parent study; TDF/FTC was collected from local commercial pharmacies on behalf of participants and dispensed at the clinic in 7-, 14-, or 30-tablet supplies. Study participants were considered to have attended their medical visit if they presented at any time during the week designated as a medication pick-up week. Additional services provided through the parent longitudinal study included, but were not limited to: HIV testing, kidney function testing per the prescribing guidelines for TDF/FTC as PrEP, targeted physical examinations as needed, STI testing and treatment, and linkage to social services. Medical visit attendance was assessed by the percentage of medication pick-up visits attended on time and adjusted for out-of-window medication pick-ups.

Statistical analyses

Urine TFV levels were compared across scores on each screening tool using a two-tailed Student’s t-test. Continuous variables were described with mean ± standard deviation. A p-value of ≤0.05 was considered significant for all tests. All analyses were performed using Stata version 14.1 (Statacorp; College Station, TX).

Results

Thirty-one participants were enrolled in this cross-sectional study between 30 March 2015 and 14 July 2016 (Table 1). The majority identified as male (n = 27, 87.5%) with the remainder identifying as male-to-female transgender (n = 4, 12.5%). The study group was predominantly African-American (n = 23, 74%) with an age distribution of 21.7 ± 2.8 years. Overall, 74% of the study group demonstrated protective levels of urine TFV at their cross-sectional visit, 14% demonstrated some but not recent adherence in the previous 7–10 days, and 11% demonstrated non-adherence to PrEP in the previous 7–10 days. On average, participants attended 91% of their scheduled medical visits during the 48 weeks.

Table 1.

Participant characteristics (N = 31).

Mean age (years)
	21.7 ± 2.8
Gender, % (n)
Male	87% (27)
Transgender (MtF)	13% (4)
Race, % (n)
African-American	74% (23)
White	13% (4)
Multiracial	6.5% (2)
Other	6.5% (2)
Ethnicity, % (n)
Hispanic	16% (5)

MtF: male-to-female transgender.

The presence of anxiety (GAD-7 score ≥ 10) was associated with lower levels of adherence to PrEP, with 61.5% of participants with anxiety demonstrating protective TFV levels compared to 81.8% of participants with lower GAD-7 scores (p = 0.05). Likewise, participants with a history of childhood trauma (ACEs score ≥ 4) were less likely to demonstrate protective levels of PrEP, with 65.5% of those participants demonstrating protective levels of urine TFV compared to 90.8% of participants with a lower ACEs score (p = 0.01). The same trends persisted when the analysis was expanded to include participants with any level of urine detection (consistent with any adherence in the previous 7–10 days, not necessarily protective). Depression questionnaire (PHQ-9) scores did not predict adherence at any urine TFV concentration. Medical visit attendance was not statistically associated with any measure of patient mental health (Table 2).

Table 2.

Percentage participants with various levels of tenofovir detection in urine versus mental health scores.

	Patient Health Questionnaire-9 (PHQ-9)			Generalized Anxiety Disorder-7 (GAD-7)			Adverse Childhood Experiences (ACEs)
	No depression <9 (n = 24)	Depression 10+ (n = 7)	p	No anxiety <9 (n = 21)	Anxiety 10+ (n = 10)	p	Low trauma 0–3 (n = 12)	Trauma 4+ (n = 19)	p
PrEP adherence
Protective against HIV (PrEP taken in last 48 h)% with Urine protective TFV	78.1 ± 23.9%	65.4 ± 36.8%	0.28	81.8 ± 22.5%	61.5 ± 32.1%	0.05	90.8 ± 7.8%	65.5 ± 30.6%	0.01
Potential protection against HIV (any PrEP taken within last 7–10 days) % Urine with any detectable TFV	90.1 ± 13.8%	84.3 ± 20.4%	0.38	92.7 ± 12.8%	80.7 ± 17.8%	0.04	95.7 ± 7.9%	84.5 ± 17.5%	0.05
Suboptimal HIV protection (any PrEP taken in last 7–10 days, but not in last 48 h)% with Urine with low-level of TFV detection	12.0 ± 13.2%	18.9 ± 22.0%	0.31	10.9 ± 12.4%	19.2 ± 20.1%	0.17	4.9 ± 6.7%	19.1 ± 17.0%	0.01
No HIV protection (no PrEP taken in last 7–10 days)% with urine with undetectable TFV level	9.8 ± 13.8%	14.7 ± 16.9%	0.43	7.2 ± 12.7%	18.6 ± 15.3%	0.04	4.4 ± 8.0%	15.0 ± 16.1%	0.04
Visit retention
% Visits attended	93.0 ± 15.1%	83.9 ± 24.6%	0.19	94.7 ± 14.3%	82.2 ± 21.7%	0.06	95.1 ± 11.4%	87.8 ± 20.5%	0.27
% Visits on time	85.7 ± 14.0%	81.3 ± 8.8%	0.44	86.8 ± 12.9%	80.3 ± 12.7%	0.2	87.4 ± 15.3%	83.0 ± 11.5%	0.37

HIV: human immunodeficiency virus; PHQ-9: Patient Health Questionnaire-9; PrEP: pre-exposure prophylaxis; TFV: tenofovir.

Values in bold-face are statistically significant using p ≤ 0.05.

Discussion

Mental health disorders are a potentially significant contributor to non-adherence in yMSMc which, if proactively addressed through PrEP program evaluation and treatment as well as trauma-informed care models, may help to prevent incident HIV infections. Overall, decreased medication adherence as measured by urine TFV testing was statistically associated with the presence of anxiety (GAD-7 ≥ 10) and a history of childhood trauma (ACEs ≥ 4), but not associated with the presence of depression (PHQ-9 ≥ 10). Of note, due to an overall small sample size, only seven individuals exhibited PHQ-9 scores diagnostic for depression. It is possible our study was underpowered to show decreased adherence with higher PHQ-9 scores (i.e. more severe depression). Our results are partially consistent with a study analyzing the association between adherence in the iPrEx cohort using the Center for Epidemiologic Studies Depression Scale (CES-D).²⁹ This study found that CES-D scores consistent with moderate depression in MSM correlated with increased adherence to PrEP, while CES-D scores consistent with severe depression correlated with decreased adherence to PrEP. Unfortunately, while the CES-D scale is sensitive for both depression and anxiety symptoms, it cannot distinguish between the two, and the authors suggest that concomitant depression and anxiety may have mixed effects on adherence that were difficult to parse out.

In the iPrEx study group, a pre-existing diagnosis of anxiety was a strong predictor of increased adherence.³⁰ This is inconsistent with our finding that anxiety is associated with lower adherence to PrEP. It is possible that for patients with anxiety, taking PrEP could either exacerbate symptoms due to the daily reminder of being at risk of HIV, or conversely could ameliorate anxiety symptoms.^31,32 It is also possible that anxiety affects adherence differently in this population due to differences between demographic makeup in the two studies, most notably a younger average age and higher proportion of patients of color in the current study. Facilitators of and barriers to adherence to PrEP have been shown to differ by race.³³ Additionally, younger age is associated with decreased willingness to take PrEP regardless of cost or side effects, and the presence of anxiety, depression, or a history of childhood trauma may affect adherence differently in adolescents/young adults compared to older adults.³⁴ To our knowledge, our study represents the only other formal analysis of adherence to PrEP based on mental health diagnoses, and more work needs to be devoted to better understanding this relationship.

We did not find an association between mental health status and decreased visit attendance. Most participants who had a mental health diagnosis and poor adherence demonstrated average or greater than average visit attendance. We know in PLWH that adherence and retention in care do not consistently track together,³⁵ and these data suggest this may also be true in HIV-negative individuals on PrEP. Our data also suggest there may be untapped opportunity to modify adherence given that individuals exhibiting poorer adherence are still present and attending their visits.

The current study has several limitations. As previously mentioned, the small sample size may have led our analyses to not be powered to show certain differences, for example between adherence in patients with and without depression. Furthermore, our study did not explore the reasons for non-adherence to PrEP and it is possible that participants made informed decisions to stop PrEP based on their self-assessment of HIV risk, i.e. decreased sexual activity among depressed patients leading to lower perceived HIV risk and subsequent lower adherence to PrEP. Finally, because our sample was derived from an existing clinical trial, it is possible our sample was biased due to increased contact with health care and research professionals and may not be a true representation of the population under study. Additionally, our study did not include those under 18 years of age, a group also experiencing disproportionate HIV infections who may have unique developmental and structural issues affecting adherence.

Development of health care delivery systems that can support increased adherence to PrEP among those most at risk must be informed by the intersections of race, sexuality, age, mental health, and lived experiences. Recent work is studying a possible association between PrEP adherence in yMSMc and social supports in a person’s life such as family and friends.³⁶ The presence of anxiety, depression, and experiences of childhood trauma may affect, and be affected by, social stigma stemming from racism or discrimination regarding gender identity and sexuality.³⁷ Understanding the factors that lie at the heart of reduced adherence to PrEP in yMSMc will allow for structural changes that can continue to overcome these barriers. In addition, if further research supports a relationship between childhood trauma/adverse experiences and adherence to PrEP for prevention of HIV among adolescents and adults, there are opportunities for cross-specialty collaboration between adult and adolescent/pediatric providers, and between the HIV community and the public health professionals addressing causes and prevention of trauma among our nation’s youth and young adults.

Implications and contribution

These data suggest benefits to assessing the presence of mental health diagnoses at PrEP initiation and ensuring adequate longitudinal mental health services for people taking PrEP. Further research may explore these relationships on a larger scale, and to examine the benefit of routine mental health screening following PrEP initiation.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Linden Lalley-Chareczko

Gregory S Troutman

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