Changes in mental health and drug use among men who have sex with men using daily and event-driven pre-exposure prophylaxis: Results from a prospective demonstration project in Amsterdam, the Netherlands.

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.

Sex, drugs, and sexually transmitted infections: A latent class analysis among men who have sex with men in Amsterdam and surrounding urban regions, the Netherlands.

BACKGROUND: Men who have sex with men (MSM) are at high risk for sexually transmitted infections (STI) and often have sex while under the influence of drugs (sexualized drug use). We aimed to identify classes of MSM in Amsterdam and in surrounding urban regions with distinctive patterns of sexualized drug use and their association with STI. METHODS: In this cross-sectional study, data on MSM were collected at STI clinics in the Netherlands between September-December 2017. Information on drug use, sociodemographics and sexual risk behavior, including lab-confirmed STI (chlamydia, gonorrhea, syphilis and HIV) was collected and compared between Amsterdam and surrounding urban regions. Latent class analysis was used to identify classes with similar drug use patterns, which were then linked to sexual behavior and STI. RESULTS: We included 4461 MSM who were a median 35 years old (IQR = 27-47) and mostly Dutch (56.9 %). Use of all drugs was more often reported in Amsterdam compared to surrounding regions (p<0.001). We identified four different classes based on sexualized drug use among Amsterdam participants and three classes in surrounding regions. In both regions, polydrug use classes (compared to classes of no drug use; alcohol use; or few, various drugs) were defined by higher numbers of sexual partners (median range 8-15 vs 4-6, respectively) and higher STI prevalence (range 30.5%-31.8% vs 18.6%-22.8%, respectively). CONCLUSION: Given the high prevalence of risk behavior and STIs, MSM in urban settings partaking in sexualized polydrug use might benefit from tailored outreach, screening, and safe sex and drug use interventions.

Effects of nutritional status on acetaminophen measurement and exposure.

INTRODUCTION: Fasting, as well as a high-fat diet, might increase the risk on acetaminophen-induced toxicity after an acute overdose. Therefore, it has been suggested to lower the threshold for acetylcysteine treatment to prevent liver injury in case of fasting. This study aims to investigate the effects of 36 hours of fasting and three days of a hypercaloric high-fat diet on acetaminophen measurement and exposure. METHODS: Nine healthy male subjects were enrolled in a randomized crossover intervention study. Subjects received 1000mg oral acetaminophen after an overnight fast following: (1) regular diet,(2) 36h of fasting and (3) three days of a hypercaloric high-fat diet consisting of 500ml of cream (1715 kcal) supplemented to their regular diet. Pharmacokinetic parameters were determined by non-compartmental analysis. Samples were analyzed by an enzymatic colorimetric method used in routine practice and by LC-MS/MS being the gold standard. Agreement between these methods was assessed by the Bland-Altman method. RESULTS: Short-term fasting increased acetaminophen exposure by 20% (ΔAUC0-8 hours, p = .04) in comparison with the control diet. Three days of hypercaloric high-fat diet did not affect acetaminophen exposure (ΔAUC0-8 hours= 9%, p = .67). The intraclass correlation coefficient between the enzymatic assay and LC-MS/MS methods of the fasting samples was 0.46 (0.28-0.61), compared to 0.87 (0.81-0.92) and 0.87 (0.79-0.91) in the control and high-fat samples respectively. CONCLUSIONS: Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect is observed after a high-fat diet. Furthermore, short-term fasting decreases the accuracy of the enzymatic colorimetric method when measuring relatively low acetaminophen concentrations. This suggests considering nutritional status when assessing the risk of acetaminophen-induced toxicity, although further research at toxic doses is needed.

Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR.

INTRODUCTION: Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. METHODS: To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65). RESULTS: Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR-/- mice. The decrease in Cyp1a2 was diminished in CAR-/- in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR-/- compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR-/- mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR-/-. The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole. CONCLUSION: We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR.

Postoperative arrhythmias in adults with congenital heart disease: incidence and risk factors.

BACKGROUND: Little is known about the clinical impact of arrhythmias after surgery for congenital heart disease (CHD) in adults. Therefore, we investigated the prevalence of in-hospital arrhythmias after CHD surgery and their impact on clinical outcome. METHODS: This was a multicenter retrospective study and included adults who underwent congenital cardiac surgery between January 2009 and December 2011. Clinical events were defined as all cause mortality, heart failure (HF) requiring medical treatment, thrombo-embolic event, major infections and permanent pacemaker (PM) implantation. RESULTS: Overall, 419 patients were included (mean age 38 ± 14 years, 55% male). Arrhythmias occurred in 134 patients (32%) and included supraventricular tachycardia (SVT, n = 100), bradycardias (n = 47) and ventricular tachycardia (VT, n = 19). In multivariate analysis age ≥40 years at surgery (OR 2.48, 95% Cl 1.40-4.60, P = 0.003), NYHA class ≥ II (OR 2.42, 95% Cl 1.18-4.67, P = 0.009), significant subpulmonary AV-valve regurgitation (OR 2.84, 95% Cl 1.19-6.72, P = 0.018), coronary bypass time (OR 1.35/60 minute increase, 95% Cl 1.06-1.82, P = 0.019) and CK-MB (OR 1.05 per 10 U/L increase, 95% Cl 1.01-1.09, P = 0.021) were associated with in-hospital arrhythmias. Overall, 58 clinical events occurred in 55 patients (13%) and included in the majority of the cases permanent PM implantation (5%), HF (4%) and death (2%). In-hospital arrhythmias were independently associated with clinical events (OR 7.80, 95% CI 2.41-25.54, P = 0.001). CONCLUSION: Arrhythmias are highly prevalent after congenital heart surgery in adults and are associated with worse clinical outcome. Older and symptomatic patients with significant valvular heart disease at baseline are at risk of in-hospital arrhythmias.

Clustering of additional autoimmunity behaves differently in Hashimoto's patients compared with Graves' patients.

OBJECTIVE: It is unclear whether Hashimoto's thyroiditis and Graves' disease (often referred to as autoimmune thyroid disease, AITD) cluster to the same extent with other autoimmune disorders. METHODS: We assessed adrenal, ß-cell, celiac and gastric antibodies in a cohort of 523 adult patients with Graves' disease and 359 patients with Hashimoto's disease and compared their clustering. RESULTS: Adrenal autoimmunity associated more often with Hashimoto's disease (9.0%) than with Graves' disease (3.3%, P=0.001). ß-cell autoimmunity was seen more frequently in Hashimoto's disease (25.4%) than in Graves' disease (15.6%, P=0.001) patients. We found low prevalences of celiac autoimmunity (1.2% for Graves' and 1.2% for Hashimoto's disease). Celiac and gastric autoimmunity were not statistically different in Hashimoto's and Graves' disease patients. Although gastric autoimmunity itself was equally prevalent (around 20%), Hashimoto's disease often showed significantly more clustering of adrenal autoimmunity with gastric autoimmunity (5.3%) than Graves' disease (1.2%, P=0.001). Similarly, clustering of adrenal autoimmunity was seen with ß-cell autoimmunity in Hashimoto's patients (3.2%), while such clustering was much less encountered in 359 Graves' patients (0.9%, P=0.029). CONCLUSION: In conclusion, Hashimoto's disease shows a markedly higher clustering of additional autoimmunity, especially with adrenal and ß-cell autoimmunity. Combined clustering of gastric and adrenal autoimmunity and combined clustering of adrenal and ß-cell autoimmunity were both seen more often in Hashimoto's patients. Clustering with celiac disease appears to be low. These findings indicate that Hashimoto's and Graves' disease differ in their clinical expression regarding additional autoimmunity, which argues against the indiscriminate use of AITD as an entity.