Low Hepatitis C Virus Prevalence among Men Who Have Sex with Men Attending Public Health Services in The Netherlands

The hepatitis C virus (HCV) prevalence is high among men who have sex with men (MSM) with HIV in the Netherlands. Large reductions in HCV incidence among MSM with HIV, however, have occurred since treatment with direct-acting antivirals. Over the years, a broader understanding of the HCV epidemic has shown that HCV infections are not solely restricted to MSM with HIV, but they also occur among HIV-negative MSM. Currently, HCV testing among HIV-negative MSM is only provided for PrEP users and is not part of routine sexually transmitted infection (STI) screening among HIV-negative MSM who are not using PrEP. In this study, we screened 1885 HIV-negative MSM who did not participate in a PrEP program, with over 1966 STI screening visits at four different public health clinic sites. Among the 1885 MSM, only one person had a new HCV infection, resulting in a 0.05% (95% confidence interval 0.0–0.3) incidence. Based on our findings, we can conclude that systematic HCV testing at STI clinics may not yield significant benefits for this particular population.</p

Determinants of adherence to daily PrEP measured as intracellular tenofovir diphosphate concentrations over 24 months of follow-up among men who have sex with men

Objectives: Adherence is key to the effectiveness of oral pre-exposure prophylaxis (PrEP) to prevent HIV. Therefore, we aimed to explore factors associated with adherence to daily PrEP (dPrEP). Methods: Men who have sex with men (MSM) using dPrEP (emtricitabine/tenofovir disoproxil) within the Amsterdam PrEP demonstration project at the Public Health Service of Amsterdam, provided dried blood spots (DBS) 12 and 24 months after PrEP initiation. From DBS, we determined intracellular tenofovir diphosphate (TFV-DP) concentrations to assess adherence; TFV-DP ≥700 fmol/punch was considered adequate. We assessed associations of sociodemographic, clinical and behavioural characteristics with TFV-DP concentrations using multivariable linear regression. Results: Of 263 participants who attended 12-month or 24-month study visits while on dPrEP, 257 (97.7%) provided DBS at one or both visits (492 DBS in total). Median TFV-DP concentration was 1299 (IQR 1021-1627) fmol/punch (12 months: 1332 (1087-1687); 24 months: 1248 (929-1590]). Higher TFV-DP concentrations were associated with: older age (p=0.0008), condomless anal sex with a casual partner in 6 months preceding PrEP initiation (+166 fmol/punch; 95% CI 36.5 to 296) and using a mobile application providing visualised feedback on PrEP use and sexual behaviour (+146 fmol/punch; 95% CI 28.1 to 263). Lower TFV-DP concentrations were associated with longer duration of PrEP use (24 vs 12 months; -91.5 fmol/punch; 95% CI -155 to -28.1). Time-updated number of sex partners, diagnosed STIs and chemsex were not associated with TFV-DP concentrations. Conclusions: Overall, TFV-DP concentrations were high among MSM using dPrEP, indicating excellent adherence. Especially older participants, those who reported condomless anal sex with a casual partner prior to PrEP initiation and those who used an app with visualised feedback showed higher levels of adherence. As TFV-DP concentrations had decreased slightly at 2 years of PrEP use when compared with 1 year, we emphasise the importance of adherence counselling to those who continue using PrEP. Trial registration number: NL5413

The impact of COVID-19-related restrictions in 2020 on sexual healthcare use, pre-exposure prophylaxis use, and sexually transmitted infection incidence among men who have sex with men in Amsterdam, the Netherlands

Objectives: We studied the effects of restrictions related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) pandemic on the use of sexual healthcare and pre-exposure prophylaxis (PrEP) and on the incidence of sexually transmitted infections (STIs) among men who have sex with men (MSM) in a prospective, open-label PrEP demonstration study (AMPrEP) in Amsterdam, the Netherlands. Methods: We retrieved data from 2019 to 2020 for participants with one or more study visit in 2019 (n = 305) and from two COVID-19 questionnaires (2020: n = 203; 2021: n = 160). Analyses were stratified for three periods of pandemic-related restrictions (first: 15 March 2020–15 June 2020; second: 16 June 2020–15 September 2020; third: 16 September 2020–31 December 2020 or 1 April 2021 for the COVID-19 questionnaire). Endpoints included returning for care during the pandemic, PrEP use (increased/unchanged vs. deceased/stopped, relative to 2019), and any STI/HIV. We modelled determinants of care and PrEP use via multivariable logistic regression and STI incidence using piecewise Poisson regression, comparing the 2020 and 2019 periods. Results: Of the 305 MSM included in the analysis, 72.8% returned for care during the pandemic, and this was significantly more likely among daily (vs. event-driven) PrEP users (p < 0.001). Increased/unchanged PrEP use ranged from 55.2% to 58.1% across the three pandemic periods and was more likely among those reporting chemsex in the first (p = 0.001) and third (p = 0.020) periods and among those reporting an increased/unchanged number of sex partners during the second period (p = 0.010). STI incidence was significantly lower in 2020 than in 2019 during the first period (incidence rate ratio [IRR] 0.43; 95% confidence interval [CI] 0.28–0.68) and not significantly different during the second (IRR 1.38; 95% CI 0.95–2.00) and third (IRR 1.42; 95% CI 0.86–2.33) periods. No HIV was diagnosed. Conclusion: COVID-19-related restrictions coincided with reduced care and PrEP use. Changes in STI incidence suggest delayed diagnoses. Ways to ensure continued access to sexual healthcare during restrictions are needed

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

Abstract 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

Improving adherence to daily PrEP 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

Adherence to event-driven HIV PrEP among men who have sex with men in Amsterdam, the Netherlands: analysis based on online diary data, 3-monthly questionnaires and intracellular TFV-DP

INTRODUCTION: Event-driven pre-exposure prophylaxis (edPrEP) with oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective for preventing HIV acquisition in men who have sex with men (MSM) and is preferred over daily PrEP by some MSM. However, it is largely unknown how well MSM adhere to edPrEP. We then aimed to assess PrEP protection during CAS among MSM using edPrEP and participating in the Amsterdam PrEP demonstration project (AMPrEP). METHODS: We analysed data from participants enrolled in AMPrEP who were taking edPrEP. We measured adherence through (1) a mobile application in which sexual behaviour and PrEP-use were recorded daily, (2) three-monthly self-completed questionnaires and (3) dried blood spot (DBS) samples collected around six, twelve and twenty-four months after PrEP initiation. We assessed the proportion of days with condomless anal sex (CAS) acts that were protected by PrEP, per partner type (i.e. steady partners, known casual partners, unknown casual partners), and the proportion of three-month periods during which PrEP was correctly used. Intracellular TFV-diphosphate (TFV-DP) concentrations were determined from DBS. Good adherence was defined as at least one tablet before and one tablet within 48 hours after a CAS act. RESULTS: Between 11 September 2015 and 6 October 2019, 182 of 376 MSM (48.4%) used edPrEP for at least one three-month period. Of the 8224 CAS days that were reported in the app during edPrEP-use, we observed good protection for most CAS days involving steady partners (n = 1625/2455, 66.9%), known casual partners (n = 3216/3472, 92.6%) and unknown casual partners (n = 2074/2297, 90.3%). Men reported consistently correct PrEP-use in 851 (81.4%) of the 1046 three-month periods of edPrEP-use. The median TFV-DP concentration was 591 fmol/sample (interquartile range = 270 to 896). CONCLUSIONS: Adherence to edPrEP was high as determined from the online app and questionnaire. DBS measurements were consistent with two to three tablets per week on average

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 (β = -0.36; 95% CI = -0.72 to 0.00) but not with SPs and KCPs. Condom use during sex decreased with KCPs (β = -0.36; 95% CI = -0.67 to 0.04) and UCPs (β = -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

Trajectories of PrEP use among men who have sex with men:a pooled analysis of two prospective, observational cohort studies

Introduction: Daily and event-driven oral pre-exposure prophylaxis (PrEP) reduce the risk of HIV acquisition. PrEP use can vary over time, yet little is known about the trajectories of PrEP use irrespective of the chosen PrEP regimens among men who have sex with men (MSM). Methods: Using data from a mobile, web-based diary application collected daily from 17 August 2015 until 6 May 2018, we analysed PrEP use and sexual behaviour in two large cohorts, AMPrEP (Amsterdam, the Netherlands) and Be-PrEP-ared (Antwerp, Belgium). In both cohorts, participants could choose between daily and event-driven oral PrEP every 3 months. We used group-based trajectory modelling to identify trajectories of PrEP use over time and their determinants. In addition, we estimated the incidence rate of chlamydia, gonorrhoea and syphilis within these trajectories. Results: We included 516 MSM (n = 322 AMPrEP; n = 194 Be-PrEP-ared), of whom 24% chose event-driven PrEP at PrEP initiation. Participants contributed 225,015 days of follow-up (median = 508 days [IQR = 429−511]). Four distinct PrEP use trajectories were identified: ≤2 tablets per week (“low frequency,” 12% of the total population), 4 tablets per week (“variable,” 17%), “almost daily” (31%) and “always daily” (41%). Compared to participants with “low frequency” PrEP use, participants with “variable” (odds ratio [OR] = 2.18, 95% confidence interval [CI] = 1.04−4.60) and “almost daily” PrEP use were more often AMPrEP participants (OR = 2.64, 95% CI = 1.27−5.49). “Almost daily” PrEP users were more often employed (OR = 6.76, 95% CI = 2.10−21.75) and were younger compared to participants with “low frequency” PrEP use. In addition, the number of days on which anal sex occurred was lower among participants with “low frequency” PrEP use compared to the other groups (all p&lt;0.001). Compared to “low frequency” PrEP users, the incidence rates of chlamydia and gonorrhoea were higher for participants with “almost daily” and “always daily” PrEP use. Conclusions: We uncovered four distinct PrEP use trajectories, pointing to different patterns of PrEP use in practice beyond the two-regimen dichotomy. These trajectories were related to sexual behaviour and rates of sexually transmitted infection. Tailoring PrEP care according to different PrEP use patterns could be an important strategy to improve efficient PrEP delivery.</p

Constructing mixed density functionals for describing dissociative chemisorption on metal surfaces : basic principles

Abstract: The production of a majority of chemicals involves heterogeneous catalysis at some stage, and the rates of many heterogeneously catalyzed processes are governed by transition states for dissociative chemisorption on metals. Accurate values of barrier heights for dissociative chemisorption on metals are therefore important to benchmarking electronic structure theory in general and density functionals in particular. Such accurate barriers can be obtained using the semiempirical specific reaction parameter (SRP) approach to density functional theory. However, this approach has thus far been rather ad hoc in its choice of the generic expression of the SRP functional to be used, and there is a need for better heuristic approaches to determining the mixing parameters contained in such expressions. Here we address these two issues. We investigate the ability of several mixed, parametrized density functional expressions combining exchange at the generalized gradient approximation (GGA) level with either GGA or nonlocal correlation to reproduce barrier heights for dissociative chemisorption on metal surfaces. For this, seven expressions of such mixed density functionals are tested on a database consisting of results for 16 systems taken from a recently published slightly larger database called SBH17. Three expressions are derived that exhibit high tunability and use correlation functionals that are either of the PBE GGA form or of one of two limiting nonlocal forms also describing the attractive van der Waals interaction in an approximate way. We also find that, for mixed density functionals incorporating GGA correlation, the optimum fraction of repulsive RPBE GGA exchange obtained with a specific GGA density functional is correlated with the charge-transfer parameter, which is equal to the difference in the work function of the metal surface and the electron affinity of the molecule. However, the correlation is generally not large and not large enough to obtain accurate guesses of the mixing parameter for the systems considered, suggesting that it does not give rise to a very effective search strategy