Sexual behaviour and incidence of sexually transmitted infections among men who have sex with men (MSM) using daily and event-driven pre-exposure prophylaxis (PrEP): Four-year follow-up of the Amsterdam PrEP (AMPrEP) demonstration project cohort.

BACKGROUND: An increasing number of countries are currently implementing or scaling-up HIV pre-exposure prophylaxis (PrEP) care. With the introduction of PrEP, there was apprehension that condom use would decline and sexually transmitted infections (STIs) would increase. To inform sexual health counselling and STI screening programmes, we aimed to study sexual behaviour and STI incidence among men who have sex with men (MSM) and transgender women who use long-term daily or event-driven PrEP. METHODS AND FINDINGS: The Amsterdam PrEP demonstration project (AMPrEP) was a prospective, closed cohort study, providing oral daily PrEP and event-driven PrEP to MSM and transgender women from 2015 to 2020. Participants could choose their PrEP regimen and could switch at each three-monthly visit. STI testing occurred at and, upon request, in-between 3-monthly study visits. We assessed changes in numbers of sex partners and condomless anal sex (CAS) acts with casual partners over time using negative binomial regression, adjusted for age. We assessed HIV incidence and changes in incidence rates (IRs) of any STI (i.e., chlamydia, gonorrhoea, or infectious syphilis) and individual STIs over time using Poisson regression, adjusted for age and testing frequency. A total of 367 participants (365 MSM) commenced PrEP and were followed for a median 3.9 years (interquartile range [IQR] = 3.4-4.0). Median age was 40 years (IQR = 32-48), 315 participants (85.8%) self-declared ethnicity as white and 280 (76.3%) had a university or university of applied sciences degree. Overall median number of sex partners (past 3 months) was 13 (IQR = 6-26) and decreased per additional year on PrEP (adjusted rate ratio [aRR] = 0.86/year, 95% confidence interval [CI] = 0.83-0.88). Overall median number of CAS acts with casual partners (past 3 months) was 10 (IQR = 3-20.5) and also decreased (aRR = 0.92/year, 95% CI = 0.88-0.97). We diagnosed any STI in 1,092 consultations during 1,258 person years, resulting in an IR of 87/100 person years (95% CI = 82-92). IRs of any STI did not increase over time for daily PrEP or event-driven PrEP users. Two daily PrEP users, and no event-driven PrEP users, were diagnosed with HIV during their first year on PrEP. Study limitations include censoring follow-up due to COVID-19 measures and an underrepresentation of younger, non-white, practically educated, and transgender individuals. CONCLUSIONS: In this prospective cohort with a comparatively long follow-up period of 4 years, we observed very low HIV incidence and decreases in the numbers of casual sex partners and CAS acts over time. Although the STI incidence was high, it did not increase over time. TRIAL REGISTRATION: The study was registered at the Netherlands Trial Register (NL5413) https://www.onderzoekmetmensen.nl/en/trial/22706.

Concordance between daily diary reported pre-exposure prophylaxis intake and intraerythrocytic tenofovir diphosphate in the Amsterdam Pre-exposure Prophylaxis demonstration project.

OBJECTIVE: We assessed the association and concordance between self-reported oral pre-exposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations. DESIGN: AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020). METHODS: Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48 months and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6 weeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250 fmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa. RESULTS: Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration ( ß â€Š= 0.77, 95% CI = 0.70-0.84, P  < 0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate ( κ  = 0.44, 95% CI = 0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect ( κ  = 0.83, 95% CI 0.76-0.90). CONCLUSION: Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals.

Differences in STI/HIV Burden and Sexual Health Care-Seeking Behavior Among First- and Second-Generation Migrant and Western-Born Male Sex Workers Who Have Sex With Men in the Netherlands: A Retrospective Cohort Study.

BACKGROUND: Globally, migrant sex workers have a higher burden of sexually transmitted infections (STI)/human immunodeficiency virus (HIV). This large study aimed to assess demographics, STI/HIV burden, and sexual health care-seeking behavior of first-generation migrant and second-generation migrant male sex workers who have sex with men (MSW-MSM) versus Western-born MSW-MSM. METHODS: Coded STI clinic consultations (n = 6970) from 3116 individual MSW-MSM attending any Dutch STI clinic between 2016 and 2021 were included. First-generation migrant: born outside of northern/central/southern/western Europe/North America/Oceania. Second-generation migrant: ≥1parent born outside of northern/central/southern/western Europe/North America/Oceania. Multivariable logistic regression analysis assessed associations between MSW-MSM groups and STI in first consultation in the data. A Cox proportional hazard regression compared the incidence of a first repeat consultation between migration groups, stratified by STI in first consultation. All analyses were adjusted for age and urbanity of STI clinic region. RESULTS: First-generation migrant MSW-MSM (n = 1085) were mostly born in Latin America (50%), whereas second-generation migrant MSW-MSM (n = 368) mostly originated from North Africa (30.4%). The proportion of STI diagnoses differed (33.2%, 29.3%, 23.3%; P < 0.001) between the first-generation migrant, second-generation migrant, and Western-born MSW-MSM. First-generation migrant MSW-MSM versus Western-born had an adjusted odds ratio of 1.6 (95% confidence interval, 1.3-1.9) of STI diagnosis in the first consultation. First-generation migrant MSW-MSM versus Western-born had an adjusted hazard ratio of 1.5 (95% confidence interval, 1.3-1.8) of having a first repeat consultation at any time, when stratified for no STI in the first consultation. CONCLUSIONS: The STI/HIV burden is high among all 3 MSW-MSM groups. First-generation migrants have higher odds of STI, but retention in care seems similar. Results highlight the importance of low-threshold STI testing and care for (migrant) MSW-MSM.

Transient Changes in Preexposure Prophylaxis Use and Daily Sexual Behavior After the Implementation of COVID-19 Restrictions Among Men Who Have Sex With Men.

BACKGROUND: We assessed how the Dutch restrictions imposed on March 15, 2020, affected sexual behavior, preexposure prophylaxis (PrEP), and condom use among PrEP users in Amsterdam. METHODS: We used data on (1) PrEP use, (2) anal sex acts, and (3) condom use, per partner type [steady partners (SPs), known casual partners (KCPs), and unknown casual partners (UCPs)], collected daily through a mobile application used between December 1, 2019, and June 30, 2020. We compared the period before versus after March 15, 2020, regarding average proportion of days per week at which each end point was reported and average proportion of anal sex acts covered by PrEP and/or condoms. RESULTS: We included data from 136 men who have sex with men. After March 15, 2020, the proportion of days with anal sex increased with SPs [odds ratio (OR) = 1.26; 95% confidence interval (CI) = 1.10 to 1.44) and decreased with KCPs (OR = 0.73; 95% CI = 0.64 to 0.82) and UCPs (OR = 0.54; 95% CI = 0.48 to 0.61). Shifts in partner types were most profound immediately after March 15, 2020, whereas returning to prerestriction levels mid-May 2020. The proportion of days with PrEP use decreased from 74% before to 58% after March 15, 2020 (P < 0.001). After March 15, 2020, PrEP use during sex decreased with UCPs (ß = -0.36; 95% CI = -0.72 to 0.00) but not with SPs and KCPs. Condom use during sex decreased with KCPs (ß = -0.36; 95% CI = -0.67 to 0.04) and UCPs (ß = -0.24; 95% CI = -0.46 to 0.03) but not with SPs. CONCLUSIONS: MSM decreased sex with casual partners and increased sex with SP, but changes were transient. Decreases in sex acts with casual partners paralleled decreases in PrEP use. However, condom use during sex with casual partners decreased, indicating the importance of continued sexual health services, including sexually transmitted infections screening and PrEP care, during COVID-19 restrictions.

Improving adherence to daily preexposure prophylaxis among MSM in Amsterdam by providing feedback via a mobile application.

OBJECTIVE: Improving adherence to preexposure prophylaxis (PrEP) by providing automated feedback on self-reported PrEP use via a mobile application (app). DESIGN: Randomized clinical trial among MSM participating in the Amsterdam PrEP demonstration project (AMPrEP). METHODS: Eligible participants were randomized 1 : 1 to the control or intervention app. Both allowed daily reporting of sexual behaviour and medication intake; the intervention app also provided visual feedback. Dried blood spots collected at 12 and 24 months yielded intracellular tenofovir diphosphate concentrations (TFV-DP). We assessed proportions of participants with poor (TFV-DP <700 fmol/punch; primary outcome), good (TFV-DP ≥700 fmol/punch) and excellent (TFV-DP ≥1250 fmol/punch; secondary outcome) adherence at both time-points, and the association with the control or intervention app. RESULTS: We randomized 229 participants, 118 to the intervention and 111 to the control arm. The primary, per-protocol, analysis included 83 participants per arm. In total, 22/166 (13%) of participants adhered poorly, 144/166 (87%) good and 66/166 (40%) excellently. App feedback did not result in a lower proportion of participants with poor adherence [control: 9 of 83 (11%); intervention: 13 of 83 (16%); P = 0.36]. App feedback did result in a larger proportion of participants with excellent adherence [control: 26/83 (31%); intervention: 40/83 (48%); P = 0.026]. CONCLUSION: In this highly adherent population, app feedback did not improve the proportion of participants with poor adherence to PrEP.Clinical Trial Number Netherlands Trial Register: NL5413.

Understanding pre-exposure prophylaxis (PrEP) regimen use: Switching and discontinuing daily and event-driven PrEP among men who have sex with men.

BACKGROUND: Optimising HIV pre-exposure prophylaxis (PrEP) provision requires insight into preferences of PrEP regimens and PrEP discontinuation. We assessed regimen switching and discontinuation and their determinants among men who have sex with men (MSM) participating in the Amsterdam PrEP demonstration project. METHODS: Between 3-August-2015 and 31-May-2016, we enrolled MSM (n = 374) and TGP (n = 2) in a prospective, longitudinal study. Participants could choose between daily or event-driven PrEP regimens at enrolment and every 3 months. We assessed transition intensities (TI) and determinants of switching (i) between regimens, and (ii) from either regimen to discontinuing PrEP using a multi-state Markov model. PrEP discontinuation was defined as formally stopping study participation or having no study visit for ≥6 months. FINDINGS: Of 367 analysed participants, 73·3% chose daily and 26·7% event-driven PrEP at enrolment. Median follow-up was 3·1 years (IQR 2·9-3·2). 121 participants switched their PrEP regimen at least once (cumulative probability 34·2%, 95% CI 29·4-39·6), with 90 switches from event-driven to daily PrEP (TI 0·35/PY, 95% CI 0·29-0·44) and 113 switches from daily to event-driven PrEP (TI 0·16/PY, 95% CI 0·13-0·20). Switching from event-driven to daily PrEP was associated with younger age, not reporting sex with HIV-positive partners, chemsex, and sexual compulsivity. Switching from daily to event-driven PrEP were associated with younger age and lower sexual satisfaction. 67 participants discontinued PrEP (cumulative probability 17·7%, 95% CI 14·1-22·2), with no difference between regimens: event-driven (n = 23, TI 0·08/PY, 95% CI 0·05-0·13) and daily PrEP (n = 44, TI 0·06/PY, 95% CI 0·04-0·08). Discontinuing daily PrEP was associated with younger age, fewer casual partners, and higher number of condomless anal sex acts with casual partners. INTERPRETATION: Switching between PrEP regimens was common, while going from event-driven to daily PrEP use was associated with certain sexual-related determinants (i.e. chemsex, sexual compulsivity, no known HIV-positive partners). PrEP discontinuation rates were low and independent of regimens. PrEP care should consider the reasons for choice and switch of regimen and involve education on safely switching or discontinuing PrEP, especially among younger MSM. FUNDING: ZonMw, H-TEAM, RIVM, GGD research funds, Aidsfonds, Amsterdam Diner Foundation, Gilead Sciences, Gilead Sciences Europe Ltd, Janssen Pharmaceuticals, MAC AIDS Fund, ViiV Healthcare.

Human Immunodeficiency Virus-Negative Men Who Have Sex With Men Have an Altered T-Cell Phenotype and Bioenergy Metabolism.

BACKGROUND: We recently reported that the levels of activation, exhaustion, and terminal differentiation within the peripheral T-cell compartment were increased in men who have sex with men (MSM) compared with blood bank donors. During activation and differentiation, T cells undergo metabolic changes to maintain their energy demand. METHODS: The effect of cytomeglovirus (CMV) infection and risk behavior on the immune phenotype of peripheral T cells and the immune bioenergy metabolism profile in human immunodeficiency virus-negative MSM (with high or low sexual risk behavior) and blood bank donors was evaluated. RESULTS: Men who have sex with men exhibited increased levels of T-cell activation and terminal differentiation and an impairment of the bioenergy metabolism (mitochondrial respiration and glycolysis) compared with blood bank donors. Cytomeglovirus infection was associated with increased terminal differentiation of CD4+ (B = 3.41; 95% confidence interval [CI], 1.98-4.85; P < .0001) and CD8+ T cells (CD57+: B = 1.21, 95% CI = 0.41-2.02, P = .004; CD27-CD28-: B = 2.20, 95% CI = 1.21-3.18, P < .0001; and CD57+ of CD28-: B = 1.02, 95% CI = 0.38-1.66, P = .002) and increased glycolysis (B = 0.97; 95% CI, 0.27-1.67; P = .007). Risk behavior was associated with increase activation of CD4+ T cells (B = 0.22; 95% CI, 0.07-0.37; P = .005), increased terminal differentiation of CD4+ (B = 0.82; 95% CI, 0.44-1.20; P < .0001) and CD8+ T cells (B = 1.55; 95% CI, 0.58-2.51; P = .002), and decreased glycolysis (glycolysis: B = -0.40, 95% CI = -0.68 to 0.12, P = .006; and glycolytic capacity: B = -0.54, 95% CI = -0.91 to 0.16, P = .005). CONCLUSIONS: Men who have sex with men show an increased prevalence of bloodborne and sexually transmitted infection, indicating that immunological changes in the T-cell population and the bioenergy metabolism observed in MSM can most likely be attributed to chronic antigen exposure.

Cyclophilin D ablation is associated with increased end-ischemic mitochondrial hexokinase activity.

Both the absence of cyclophilin D (CypD) and the presence of mitochondrial bound hexokinase II (mtHKII) protect the heart against ischemia/reperfusion (I/R) injury. It is unknown whether CypD determines the amount of mtHKII in the heart. We examined whether CypD affects mtHK in normoxic, ischemic and preconditioned isolated mouse hearts. Wild type (WT) and CypD-/- mouse hearts were perfused with glucose only and subjected to 25 min ischemia and reperfusion. At baseline, cytosolic and mtHK was similar between hearts. CypD ablation protected against I/R injury and increased ischemic preconditioning (IPC) effects, without affecting end-ischemic mtHK. When hearts were perfused with glucose, glutamine, pyruvate and lactate, the preparation was more stable and CypD ablation-resulted in more protection that was associated with increased mtHK activity, leaving little room for additional protection by IPC. In conclusion, in glucose only-perfused hearts, deletion of CypD is not associated with end-ischemic mitochondrial-HK binding. In contrast, in the physiologically more relevant multiple-substrate perfusion model, deletion of CypD is associated with an increased mtHK activity, possibly explaining the increased protection against I/R injury.