Abstract
Background
Gay, bisexual and other men who have sex with men (GBMSM) are at increased risk of mental health disorders and drug use. In GBMSM taking pre-exposure prophylaxis (PrEP) for HIV, the proportion engaging in risk behaviors could increase due to decreased perception in HIV risk. In turn, this could leave them further susceptible to mental health disorders.
Methods
The AMsterdam PrEP study (AMPrEP) is a demonstration project offering a choice of daily PrEP or event-driven PrEP regimen at the STI clinic of the Public Health Service of Amsterdam. Eligible participants were HIV-negative GBMSM and transgender people at risk of HIV, aged ≥18 years. We assessed anxiety and depressive mood disorders (Mental Health Inventory 5), sexual compulsivity (Sexual Compulsivity Scale), alcohol use disorder (Alcohol Use Disorder Identification Test), and drug use disorder (Drug Use Disorder Identification Test) using yearly self-administered assessments (August 2015–September 2018). The proportion of mental health problems were analyzed and changes over time and between regimen were assessed using a logistic regression model. Variables associated with the development or recovery of disorders were assessed using a multistate Markov model.
Outcomes
Of 376 enrolled, we analyzed 341 participants with data at baseline and at least one follow-up visit. During a median follow-up of 2.5 years (IQR=2.3–2.7), the proportion assessed with sexual compulsivity decreased from 23% at baseline to 10% at the last visit (p<0.001) and drug use disorder decreased from 38% at baseline to 31% at the last visit (p = 0.004). No changes occurred in proportion assessed with anxiety/depressive mood disorders (20% at baseline, 18% at last visit, p = 0.358) or alcohol use disorder (28% at baseline, 22% at the last visit, p = 0.106). During follow-up, participants reported significant less use of alcohol (p<0.001), nitrites (p<0.001) and ecstasy (p<0.001). We found no differences between daily and event-driven PrEP users. The development and recovery of disorders during follow-up were highly interrelated.
Interpretation
Mental health disorders are prevalent among those initiating PrEP. We did not find increases in mental health disorders during PrEP use, but rather a decrease in sexual compulsivity and drug use disorders. The initial prevalence of mental health disorders in our study point at the continuous need to address mental health disorders within PrEP programs.
Funding
ZonMw, H-TEAM, Internal GGD research funds, Aidsfonds, Stichting AmsterdamDiner Foundation, Gilead Sciences, Janssen Pharmaceutica, M A C AIDS Fund, and ViiV Healthcare.
1. Introduction
]. Qualitative research has shown that PrEP minimizes HIV-related fear and could trigger problematic increases in preoccupation with sex and recreational drug use, influencing sexual at-risk behavior [i.e. condomless anal sex (CAS), increased number of sexual partners] and sexually transmitted infections (STI) and affecting general health [
]. While the relation between PrEP use, CAS and consequently STI-incidence has been extensively studied in GBMSM [
,
- Hoornenborg E.
- Coyer L.
- Achterbergh R.C.A.
- Matser A.
- Schim van der Loeff M.F.
- Boyd A.
- et al.
], the effect on mental health problems, such as sexual compulsivity, drug use and general well-being are less known.
,
]. This could be explained by the unique stressors experienced by sexual minorities (i.e. prejudice, victimization and discrimination) that lead to harmful effects on mental health, as described in Meyer’s minority model [
]. These mental health problems (such as depression, sexual compulsivity, drug use and intimate partner violence (IPV)) are associated with both increased sexual at-risk behavior, HIV and STI among GBMSM [
,
]. These afflictions can interact with one another to increase and or maintain each other, which is the heart of the syndemic theory. The syndemic theory implies that two or more afflictions – be it social, biological or mental – can reinforce each other synergistically and contribute to an excess burden of disease [
]. Studying these interactions, such as depression, drug use and sexual compulsivity, requires assessment of a broad range of mental health disorders within the same context.
,
,
,
]; none of these studies have assessed these outcomes longitudinally.
We conducted a large, prospective cohort study of GBMSM using PrEP who were administered four standardized questionnaires on (1) anxiety and depressive mood disorder, (2) sexual compulsivity, (3) alcohol use and (4) drug use disorders at yearly intervals. We aimed to describe changes in these mental health disorders and drug use during the first years of PrEP use. We also aimed to identify factors associated with the development of, and recovery from these four mental health disorders, and to assess which participants are vulnerable to any of these mental health disorders, and might therefor benefit from extra guidance during follow-up of PrEP.
2. Methods
2.1 Study design and population
]. Eligible individuals were HIV-negative GBMSM and transgender persons who had sex with men, were ≥18 years old and met one or more of the following criteria in the six months preceding inclusion: condomless anal sex (CAS) with casual partners, at least one bacterial STI, use of post-exposure prophylaxis after a sexual incident, or an HIV-positive sexual partner with a detectable viral load. Inclusion took place from August 2015 through June 2016. After written informed consent was obtained, participants had a follow-up visit every three months. The study was originally planned until June 2018 (phase-1), but was later extended for two years (phase-2). For this analysis, we used data from phase-1, including the end of phase-1 visit. Data collection occurred between August 2015 through September 2018.
2.2 Procedures
We offered participants a choice of daily (one tablet per day) or event-driven PrEP (two tablets taken between 24 and two hours before sexual intercourse, followed by one tablet every 24 h up to 48 h after the last sexual intercourse). Participants were allowed to switch PrEP regimens at each trimonthly study visit.
At each trimonthly study visit, participants received sexual health counseling based on motivational interviewing, were tested for STI according to routine procedures, and completed computer-assisted self-administered questionnaires on sexual behavior in the preceding 3 months.
2.3 Primary outcome measurements
], sexual compulsivity using the sexual compulsivity scale (SCS) [
], alcohol use disorder using the Alcohol Use Disorder Identification Test (AUDIT) [
], and drug use disorder using the Drug Use Disorder Identification Test (DUDIT) [
]. Presence of anxiety or depressive mood disorder was defined as an MHI-5
2.4 Secondary outcome measurements
We measured concern about acquiring HIV using a 7-point Likert scale (1=“very concerned” to 7=“not concerned at all”). Substance use in the previous 3 months was recorded, including type of substance [alcohol, cannabis, cocaine, erectile dysfunction drugs (EDD), gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL), methamphetamine, mephedrone, nitrites and 3,4-methylenedioxy-N-methylamphetamine (XTC/MDMA), or other], the frequency of use (once per month or less, 2–4 times a month, 2–3 times a week, 4 times a week or more) and injecting drug use.
At the end of phase-1, participants were asked additional questions on whether they experienced sexual abuse, intimate partner violence, or a drug-induced blackout (i.e. unconsciousness) and whether they sought help for mental health problems during the past year.
2.5 Statistical analysis
Baseline characteristics of participants with follow-up data on MHI5, SCS, AUDIT or DUDIT questionnaires were compared to participants without follow-up data.
We considered PrEP regimens as time-updated for all longitudinal analysis (i.e. PrEP regimen at the according time point). To describe trends in proportion of mental health problems over time, we used a logistic regression model including study visit (baseline, month-12, month-24, and end phase-1), PrEP regimen and the interaction between the two with a random-intercept for each participant accounting for baseline differences in MHI5, SCS, AUDIT and DUDIT. We modeled changes in concern about HIV as a continuous variable, to ensure no loss of information, using a linear regression model including study visit, PrEP regimen and the interaction between the two with a random-intercept for each participant. To describe changes in frequency of drug use, we used an interval regression model estimating the frequency of use within intervals of lower and upper bounds of all possible responses. We kept the time-frame consistent (per month), which required transforming responses as follows: 0, >0–1; ≥2-<6; ≥6-<14 and ≥14–30 times per month. This model included study visit, PrEP regimen and the interaction between the two with a random-intercept. For all models, we tested for changes over study visits with a Wald test on marginal linear predictions, first simultaneously as single tests within PrEP regimens and as a joint test across PrEP regimens, and second as an interaction between PrEP regimens, using the ‘contrast’ command in STATA. Missing data were not imputed. No further adjustments were made on these models.
Since mental health problems may fluctuate over time, we modeled outcomes each mental health problem separately as a Markov process between states of problems going from absent to present (defined as “developing” a problem) and going from present to absent (defined as “recovering” from a problem). These transitions were modeled using a two-state, time-homogenous Markov model during continuous time, allowing instantaneous rates of transitioning, or transition intensities (TI), to and from states to be estimated. To identify determinants for transitions between states, the TI over time between levels of factors can be modeled as a proportional hazards using maximum likelihood methods. From this model, we calculated hazard ratios (HR) and their 95% confidence intervals (CI) comparing average TIs over time between levels of factors. Univariable and multivariable HRs were calculated for time-fixed variables [age at inclusion, self-declared ethnicity, education level, being in a steady relationship at inclusion, employment at inclusion and residence (Amsterdam vs not Amsterdam)] and time-varying co-variables (natural logarithm of number of anal sex partners and CAS acts and PrEP regimen). Covariates whose 95%CI did not cross 1 were selected in a forward stepwise fashion to create a multivariable model.
Statistical analyses were performed with STATA (v13.1, STATA Corporation, College Station, TX, USA) and R (v3.5.2, Vienna, Austria). Significance was defined as a p-value <0.05.
2.6 Role of the funding source
The study funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors had full access to all data and were responsible for the decision to submit for publication.
4. Discussion
In this prospective demonstration project, we described that more than half of GBMSM initiating PrEP were assessed with a mental health problem. At the end of follow-up, we observed a 13% reduction in the proportion with sexual compulsivity and 7% reduction with drug use disorder, but no significant difference in the proportion with anxiety or depressive mood disorders or alcohol use disorder. These findings provide important clinical insight on the extent of mental health problems and their changes among both daily and event-driven PrEP users.
]. PrEP use, through the diminished fear of acquiring HIV, could buoy loss of sexual inhibition and confidence and replace the perceived need for drug use. The diminishing preoccupation in failure to use condoms and concern around HIV might give way to a decrease in sexual compulsivity [
,
. An additional explanation could be tri-monthly counseling and motivational interviewing by medical staff. However, given the decreasing trend in sexual compulsivity amid stable number of anal sex acts previously observed in this cohort [
- Hoornenborg E.
- Coyer L.
- Achterbergh R.C.A.
- Matser A.
- Schim van der Loeff M.F.
- Boyd A.
- et al.
], more studies would be needed to disentangle the relationship between sexual behavior and compulsivity within the context of PrEP.
]. We also observed no decrease in the proportion with anxiety and depressive disorders. Previous studies have shown associations between internalizing disorders, such as depression, and drug use in GBMSM [
]. Nevertheless, it is unclear why the proportion of those with drug-use disorder was declining while that of anxiety or depression did not change during PrEP use. These diverging trends need to be confirmed in other studies.
,
,
]. The development and inability to recover from certain mental health disorders could be linked to the presence of others. Indeed, being assessed with anxiety or depressive mood disorder made it less likely to recover from sexual compulsivity and vice versa. This finding illustrates that the syndemic nature and complexity of individual mental health problems cannot be fully captured in population estimates.
]. While on PrEP, daily users have a higher incidence in STIs and higher numbers of total sexual partners and condomless anal sex acts compared to event-driven users [
- Hoornenborg E.
- Coyer L.
- Achterbergh R.C.A.
- Matser A.
- Schim van der Loeff M.F.
- Boyd A.
- et al.
,
]. On the contrary, we demonstrate that there is no difference between daily and event-driven PrEP in the proportion with mental health disorders across visits and thus mental health problems appear to affect all PrEP users irrespective of PrEP regimen.
]. From our study and others, the prevalence of depression among PrEP using GBMSM could be considered comparable to the general U.S. GBMSM population (11–40%), while prevalence of sexual compulsivity (31%), alcohol use disorder (28–40%), and drug use disorder (36–37%) were all higher [
,
,
]. Notwithstanding the differences in mental health assessments and demographic composition between studies, the relatively higher prevalence of these disorders emphasizes the importance of addressing mental health in GBMSM who initiate PrEP.
,
,
]. In our study, participants reported using most of their drugs 2–4 times a month or less. This could indicate that some individuals can effectively manage drug use in a positive, recreational manner [
]. However, with 28/290 (10%) experiencing a blackout due to drug use in the past year, problems like hospitalization, and neurological damage should not be underestimated [
].
]. Barriers to help seeking behavior need to be addressed in future studies [
]. Currently, standard screening or referral for mental health problems is not recommended in PrEP guidelines. Given their overall prevalence, and the entanglement of disorders, PrEP services offer a unique opportunity to integrate mental health care using a syndemic-based approach.
]. The questionnaires on sexual health and drug use could have influenced respondents, leading them to rethink behavioral choices [
]. As motivational interviewing might not be standard of care and assessments on sexual health and drug use are not likely to be implemented in real-life settings, we urge caution in the generalizability of our findings to clinical settings.
]. In that study, we aimed to increase help-seeking behaviour by screening for psychosocial problems in addition to personalized feedback. Similarly in AMPrEP, we also offered trimonthly motivational-based counseling regarding sexual health with comprehensive assessments of mental health, substance use and sexual behaviour. The impact of supportive assessments, motivational interviewing and the role of a long-term patient – healthcare provider relationship within a sexual health context warrants further research.
Although mental health problems were prevalent, with decreases over time in sexual compulsivity and drug use disorder, we observed no evidence to suggest that risk compensation involving drug use or the development or worsening of mental health problems occurred with time on PrEP. Based on our findings, PrEP guidelines should address mental health and drug use problems in GBMSM both at PrEP initiation and during PrEP follow-up. Given the interrelatedness of disorders, PrEP services should consider integrating mental health and addiction services.
Declaration of Competing Interest
Dr. Achterbergh and Dr. Hoornenborg reports grants and non-financial support (study medication) from Gilead Sciences all provided to their institution. Dr. Boyd, L. Coyer, Dr. van Rooijen and Dr. de Vries report grants from ZonMW, grants from National Institute for Public Health and the Environment and GGD research funds, non-financial support and grants from Gilead Sciences, grants from Aidsfonds Netherlands, grants from Stichting Amsterdam Dinner Foundation, grants from Gilead Sciences Europe Ltd, grants from Janssen Pharmaceuticals, grants from M.A.C. AIDS Fund and grants from ViiV Healthcare provided to their institution during the conduct of the study. Dr. Davidovich reports non-financial support and unconditioned grants for conduction of AMPrEP study and speaker fees, all provided/paid to his institution. Dr. Prins reports unrestricted research grants and speaker fees from Gilead Sciences, Roche, Abbvie and MSD, all of which were paid to her institute, during the conduct of the study. The other authors reported no conflicts of interests.
Acknowledgements
The authors thank the following persons for their invaluable support to this study: Kees de Jong, Ilya Peters, Princella Felipa, Paul Oostvogel, Sylvia Bruisten, Wendy van der Veldt, Homeyra Amir, Marjo Broeren, Michelle Kroone, Myra van Leeuwen, Adriaan Tempert, Dominique Loomans, Ertan Ersan and Gerben Rienk Visser as well as the teams of the STI outpatient clinic and research department of the department of infectious diseases of Public Health Service of Amsterdam.
We thank all AMPrEP participants.
Funding
The AMPrEP study received funding as part of the H-team initiative from ZonMw (grant number: 522002003 ), the National Institute for Public Health and the Environment and GGD research funds. The study drug was provided by Gilead Sciences. The H-TEAM initiative is supported by the Aidsfonds Netherlands (grant number: 2013169 ), Stichting Amsterdam Dinner Foundation , Gilead Sciences Europe Ltd (grant number: PA-HIV-PREP-16–0024), Gilead Sciences (protocol numbers: CO-NL-276-4222 , CO-US-276-1712 ), Janssen Pharmaceuticals (reference number: PHNL/JAN/0714/0005b/1912fde ), M.A.C. AIDS Fund , and ViiV Healthcare (PO numbers: 3000268822 , 3000747780 ).
