Human papillomavirus infection among adolescents living with HIV: a focus on prevention.

PURPOSE OF REVIEW: To highlight recent data on HPV infection and cervical precancerous lesions in adolescents with HIV, and priorities for primary and secondary HPV prevention. RECENT FINDINGS: Incident and persistent high-risk HPV infections and cervical abnormalities are higher among young women with perinatally acquired HIV compared to their HIV-negative peers; data on HPV among males with perinatally acquired HIV are scarce. HPV vaccination is highly effective in preventing HPV-related disease, but antibody titers may decline in people with HIV. It remains unclear if emerging recommendations to reduce vaccine schedules from three doses to two or one dose are appropriate for children and adolescents with perinatally acquired HIV. Due to higher risks of HPV-related cancers, screening guidelines for cervical cancer differ in their frequency and age at initiation for women with HIV, but there are no recommendations for women with perinatally acquired HIV; nor for anal cancer screening for men with perinatally acquired HIV. SUMMARY: Data on the effectiveness of reduced HPV vaccine schedules in children and adolescents with HIV are needed. Implementation research to guide strategies for vaccination, screening, and treatment should include children, adolescents, and young adults with perinatally acquired HIV to ensure they are not left behind.

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.

Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion.

Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < -1.64 for forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) and/or FEV1/FVC), plethysmography (total lung capacity (TLC) < 80% of predicted, residual volume over TLC of >45%) and/or diffusion capacity (DLCO z-score < -1.64). Findings: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls. Interpretation: Adolescents with tuberculosis have impaired lung function even after treatment completion. It is crucial to include adolescents in trials on the prevention and treatment of tuberculosis-associated respiratory morbidity. Funding: EDCTP, National Institute of Health, Medical Research Council, BMBF.

What determines mpox vaccination uptake? Assessing the effect of intent-to-vaccinate versus other determinants among men who have sex with men.

BACKGROUND: In response to the mpox outbreak, vaccination was offered in the Netherlands to men who have sex with men (MSM) at increased risk for mpox. Successful vaccination campaigns are leveraged by high intent-to-vaccinate, yet intent might not always lead to uptake. Therefore, we assessed the impact of intent-to-vaccinate and other factors on vaccination uptake among participants of the Amsterdam Cohort Studies (ACS). METHOD: In July 2022, prior to the mpox vaccination campaign, we distributed an online survey regarding mpox intent-to-vaccinate, as well as e.g. beliefs, attitude, subjective norms, and perception of risk among ACS participants (all MSM). Vaccination uptake was self-reported during study visits after August 2022. The association between vaccination intent and uptake, and determinants of intent, was jointly assessed using a structural equation model (SEM) based on components of the Theory of Planned Behavior (TPB). In a second SEM, determinants of intent were allowed to have a direct effect on vaccination uptake. RESULTS: 492 MSM (median age = 46 years) were included in analyses. 380 (77%) had high intent-to-vaccinate and 238 (48%) received at least one vaccine dose. In the first model with a direct relation between intent and uptake only, TBP components predicted intent as expected, and high intent-to-vaccinate was significantly associated with getting vaccinated (ß = 1.1, 95%CI = 0.6-1.5). However, 175/380 (46%) participants with high intent-to-vaccinate did not get vaccinated. The second model had an improved model fit compared to the first model. The effect of intent on uptake was non-significant, and only perceiving to be at higher risk of infection significantly increased vaccination uptake later on (ß = 0.42, 95%CI = 0.26-0.59). Having a steady relationship decreased the probability of vaccination (ß = -0.59, 95%CI = -1.0- -0.18). CONCLUSIONS: While intent-to-vaccinate for mpox was high among MSM, high intent did not necessarily result in vaccine uptake. Mpox risk perception might have played a more pivotal role in getting vaccinated, which may be related to the evolution of vaccination eligibility criteria and accessibility to the vaccine.

Sexual Distancing During 5 Periods Around and During the COVID-19 Pandemic, Amsterdam, the Netherlands.

BACKGROUND: Social and sexual distancing (ie, abstaining from sex with persons outside one's household) was important in the control of the COVID-19 pandemic. Compliance to distancing measures can change over time. We assessed changes in compliance to the sexual distancing measures during five periods of the COVID-19 pandemic in the Netherlands. METHODS: Between November 2021 and March 2022, we used a structured questionnaire containing questions about sexual behavior and factors that could have influenced compliance with sexual distancing. Variables related to sexual behavior were measured for 5 periods, before and during the pandemic, delineated by imposement and relaxation of lockdown measures. RESULTS: Eight hundred seventy participants (predominantly MSM) completed the questionnaire. We found that compliance to the sexual distancing measures decreased over time. The number of casual partners was highest after the lockdown measures were relaxed for the second time (April 2021 to March 2022), and even higher than before the first lockdown. Factors positively associated with sexual distancing compliance were: having confidence in the information provided by the government and experiencing less or similar need for physical contact compared with before the pandemic. Factors that lowered compliance over time were: previously having had COVID-19, perceiving the lockdown measures as overstated, having sex with casual partners and similar drug use during the pandemic as before. CONCLUSIONS: Our findings suggest that sexual distancing measures are difficult to maintain for a long period. Other measures, such as confinement to a small network of known partners, might be more effective for longer pandemics in minimizing the spread of infectious diseases.

Online-Mediated HIV Pre-exposure Prophylaxis Care and Reduced Monitoring Frequency for Men Who Have Sex With Men: Protocol for a Randomized Controlled Noninferiority Trial (EZI-PrEP Study).

BACKGROUND: Daily and event-driven HIV pre-exposure prophylaxis (PrEP) with oral tenofovir-emtricitabine is highly effective to prevent HIV in men who have sex with men (MSM). PrEP care generally consists of in-clinic monitoring every 3 months that includes PrEP dispensing, counseling, and screening for HIV and sexually transmitted infections (STIs). However, the optimal frequency for monitoring remains undetermined. Attending a clinic every 3 months for monitoring may be a barrier for PrEP. Online-mediated PrEP care and reduced frequency of monitoring may lower this barrier. OBJECTIVE: The primary objective of this study is to establish the noninferiority of online PrEP care (vs in-clinic care) and monitoring every 6 months (vs every 3 months). The secondary objectives are to (1) examine differences between PrEP care modalities regarding incidences of STIs, HIV infection, and hepatitis C virus infection; retention in PrEP care; intracellular tenofovir-diphosphate concentration; and satisfaction, usability, and acceptability of PrEP care modalities; and (2) evaluate associations of these study outcomes with sociodemographic, behavioral, and psychological characteristics. METHODS: This study is a 2×2 factorial, 4-arm, open-label, multi-center, randomized, controlled, noninferiority trial. The 4 arms are (1) in-clinic monitoring every 3 months, (2) in-clinic monitoring every 6 months, (3) online monitoring every 3 months, and (4) online monitoring every 6 months. The primary outcome is a condomless anal sex act with a casual partner not covered or insufficiently covered by PrEP (ie, "unprotected act") as a proxy for HIV infection risk. Eligible individuals are MSM, and transgender and gender diverse people aged ≥18 years who are eligible for PrEP care at 1 of 4 participating sexual health centers in the Netherlands. The required sample size is 442 participants, and the planned observation time is 24 months. All study participants will receive access to a smartphone app, which contains a diary. Participants are requested to complete the diary on a daily basis during the first 18 months of participation. Participants will complete questionnaires at baseline and 6, 12, 18, and 24 months. Dried blood spots will be collected at 6 and 12 months for assessment of intracellular tenofovir-diphosphate concentration. Incidence rates of unprotected acts will be compared between the online and in-clinic arms, and between the 6-month and 3-month arms. Noninferiority will be concluded if the upper limit of the 2-sided 97.5% CI of the incidence rate ratio is <1.8. RESULTS: The results of the main analysis are expected in 2024. CONCLUSIONS: This trial will demonstrate whether online PrEP care and monitoring every 6 months is noninferior to standard PrEP care in terms of PrEP adherence. If noninferiority is established, these modalities may lower barriers for initiating and continuing PrEP use and potentially reduce the systemic burden for PrEP providers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05093036; https://tinyurl.com/28b8ndvj. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51023.

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<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.

Bacterial sexually transmitted infections are concentrated in subpopulations of men who have sex with men using HIV pre-exposure prophylaxis.

OBJECTIVE: Studies have shown varying trends in incidence of sexually transmitted infections (STIs) among individuals using HIV pre-exposure prophylaxis (PrEP). Characterization of individuals at increased risk for STIs may offer an opportunity for targeted STI screening. DESIGN: Group-based trajectory modeling. METHODS: We screened participants from the AMPrEP demonstration project (2015-2020) for urogenital, anal, and pharyngeal chlamydia and gonorrhea, and syphilis every 3 months and when needed. We identified trajectories of STI incidence within individuals over time and determinants of belonging to a trajectory group. We calculated cumulative proportions of STIs within STI trajectory groups. RESULTS: Three hundred and sixty-six participants with baseline and at least one screening visit during follow-up were included (median follow-up time = 3.7 years [interquartile range, IQR = 3.5-3.7]). We identified three trajectories of STI incidence: participants with a mean of approximately 0.1 STIs per 3 months ('low overall', 52% of the population), participants with a mean 0.4 STI per 3 months ('medium overall', 43%), and participants with high and fluctuating (between 0.3 and 1 STIs per 3 months) STI incidence ('high and fluctuating', 5%). Participants in the 'low overall' trajectory were significantly older, and reported less chemsex and condomless anal sex with casual partners than participants in the other trajectories. Participants in the 'high and fluctuating' and 'medium overall' groups accounted for respectively 23 and 64% of all STIs observed during follow-up. CONCLUSIONS: STI incidence was concentrated in subpopulations of PrEP users who were younger, had more chemsex and condomless anal sex. Screening frequency for STIs could be reduced for subpopulations with low risk for incident STIs.

Sexualized drug use and STD and HIV incidence among men who have sex with men in Amsterdam, the Netherlands.

BACKGROUND: We assessed the association between sexualized drug use (SDU), and incident sexually transmitted diseases (STDs) and human immunodeficiency virus (HIV) infections among men who have sex with men (MSM). METHODS: We used data from the MS2 cohort study, conducted at the STI Outpatient Clinic of the Public Health Service of Amsterdam, the Netherlands, in 2014-2019. Eligible participants were adult HIV-negative MSM with ≥2 STDs in the preceding year and MSM living with HIV and ≥1 STD. Participation encompassed 3-monthly visits including STD screening and questionnaires on drug use. Primary outcomes were incident HIV, anal chlamydia/gonorrhoea, and syphilis. We studied the association between SDU of individual drugs and incident HIV and STDs, using Poisson regression. Analyses were adjusted for age and HIV-status. RESULTS: 131 HIV-negative MSM and 173 MSM living with HIV were included for analysis. SDU with GHB/GBL (aIRR = 7.2, 95% CI = 1.4-35.5) in the 3 months before testing was associated with incident HIV. SDU with GHB/GBL (aIRR = 1.2, 95% CI = 1.0-1.4), ketamine (aIRR = 1.3, 95% CI = 1.0-1.6) or methamphetamine (aIRR = 1.3, 95% CI = 1.0-1.6) was associated with incident anal chlamydia/gonorrhoea. We found no association between SDU with specific drug types and syphilis incidence. CONCLUSIONS: SDU with GHB/GBL, ketamine and methamphetamine among MSM was associated with incident HIV and anal chlamydia/gonorrhoea. HIV-negative MSM engaging in SDU should be advised to use HIV pre-exposure prophylaxis, and all MSM engaging in SDU should be advised to have STD screening regularly. We suggest counselling on STDs among MSM engaging in SDU.

Can we screen less frequently for STI among PrEP users? Assessing the effect of biannual STI screening on timing of diagnosis and transmission risk in the AMPrEP Study.

BACKGROUND: In many countries, HIV pre-exposure prophylaxis (PrEP) users are screened quarterly for STIs. We assessed the consequences of less frequent STI testing. We also assessed determinants of asymptomatic STI and potential for onward transmission. METHODS: Using data from the AMPrEP study, we assessed the proportion of syphilis, and genital, anal, and pharyngeal chlamydia and gonorrhoea diagnoses which would have been delayed with biannual versus quarterly screening. We assessed the potential for onward transmission by examining reported condomless anal sex (CAS) in periods after to-be-omitted visits when screening biannually. We assessed determinants of incident asymptomatic STIs using Poisson regression and calculated individual risk scores on the basis of the coefficients from this model. RESULTS: We included 366 participants. Median follow-up was 47 months (IQR 43-50). 1,183STIs were diagnosed, of which 932(79%) asymptomatic. With biannual screening, 483 asymptomatic STIs (52%) diagnoses would have been delayed at 364 study visits. Of these visits, 129 (35%), 240 (66%) and 265 (73%) were followed by periods of CAS with steady, known casual or unknown casual partners, respectively. Older participants had a lower risk of asymptomatic STI (incidence rate ratio (IRR) 0.86/10-year increase, 95% CI 0.80 to 0.92), while CAS with known (IRR 1.36, 95% CI 1.10 to 1.68) and unknown (IRR 1.86, 95% CI 1.48 to 2.34) casual partners and chemsex (IRR 1.51, 95% CI 1.28 to 1.78) increased the risk. The individual risk scores had limited predictive value (sensitivity=0.70 (95% CI 0.66 to 0.74), specificity=0.50 (95% CI 0.48 to 0.51)). CONCLUSION: Reducing the STI screening frequency to biannually among PrEP users will likely result in delayed diagnoses, potentially driving onward transmission. Although determinants for asymptomatic STIs were identified, predictive power was low.

Approaches to Estimating Clearance Rates for Human Papillomavirus Groupings: A Systematic Review and Real Data Examples.

INTRODUCTION: Approaches to estimating clearance rates, an important metric of human papillomavirus (HPV) clearance, for HPV groupings differ between studies. We aimed to identify the approaches used in the literature for estimating grouped HPV clearance rates. We investigated whether these approaches resulted in different estimations, using data from existing studies. METHODS: In this systematic review, we included articles that reported clearance rates of HPV groupings. We identified approaches to data in the HAVANA cohort, comprising adolescent girls, and the H2M cohort, comprising men who have sex with men. We estimated clearance rates for six HPV groupings (bivalent-, quadrivalent- and nonavalent vaccine-related, and low-risk, high-risk, and any HPV). RESULTS: From 26 articles, we identified 54 theoretically possible approaches to estimating clearance rates. These approaches varied regarding definitions of clearance events and person-time, and prevalence or incidence of infections included in the analysis. Applying the nine most-used approaches to the HAVANA ( n = 1,394) and H2M ( n = 745) cohorts demonstrated strong variation in clearance rate estimates depending on the approach used. For example, for grouped high-risk HPV in the H2M cohort, clearance rates ranged from 52.4 to 120.0 clearances/1000 person-months. Clearance rates also varied in the HAVANA cohort, but differences were less pronounced, ranging from 24.1 to 57.7 clearances/1000 person-months. CONCLUSIONS: Varied approaches from the literature for estimating clearance rates of HPV groupings yielded different clearance rate estimates in our data examples. Estimates also varied between study populations. We advise clear reporting of methodology and urge caution in comparing clearance rates between studies.

Efficacy of ertapenem, gentamicin, fosfomycin, and ceftriaxone for the treatment of anogenital gonorrhoea (NABOGO): a randomised, non-inferiority trial.

BACKGROUND: Neisseria gonorrhoeae causes gonorrhoea, a common sexually transmitted infection. Emerging strains resistant to first-line ceftriaxone threaten N gonorrhoeae management. Hence, alternative treatments are needed. We aimed to evaluate the efficacy of ertapenem, gentamicin, and fosfomycin as alternative treatments for anogenital N gonorrhoeae. METHODS: In a randomised, controlled, double-blind, non-inferiority trial (three experimental groups and one control group) at the Centre for Sexual Health in Amsterdam, Netherlands, we included adults aged 18 years or older, with anorectal or urogenital gonorrhoea. With random permuted blocks, participants were randomly assigned (1:1:1:1) to receive intramuscular 500 mg ceftriaxone (control group), intramuscular 1000 mg ertapenem, intramuscular 5 mg/kg gentamicin (maximum 400 mg), or oral 6 g fosfomycin. The primary outcome was the proportion of participants with a negative nucleic acid amplification test of the predefined primary infected site, 7-14 days after treatment. The primary analysis was per protocol (ie, excluding those lost to follow-up). The modified intention-to-treat analysis included all randomly assigned patients with anogenital gonorrhoea considering those lost-to-follow-up as treatment failure. Non-inferiority was established if the lower Hochberg-corrected 95% CI for difference between the experimental and control groups was greater than -10%. For the analysis of adverse events, we included all participants who received medication. The trial was registered at ClinicalTrials.gov (NCT03294395) and is complete. FINDINGS: Between Sept 18, 2017, and June 5, 2020, from 2160 patients invited to participate, we assigned 346 (16%) participants to receive either ceftriaxone (n=103), ertapenem (n=103), gentamicin (n=102), or fosfomycin (n=38). The fosfomycin group was terminated early after interim analysis revealed less than 60% efficacy. In the primary per-protocol analysis, 93 (100%) of 93 patients in the ceftriaxone group, 86 (99%) of 87 patients in the ertapenem group, 79 (93%) of 85 patients in the gentamicin group, and four (12%) of 33 patients in the fosfomycin group cleared N gonorrhoeae (risk difference vs ceftriaxone -0·01 [95% CI -0·08 to 0·05] for ertapenem and -0·07 [-0·16 to -0·01] for gentamicin). Thus, ertapenem proved non-inferior to ceftriaxone. In mITT analysis, risk differences versus ceftriaxone were -0·08 (-0·17 to 0·003) for ertapenem and -0·11 (-0·21 to -0·04) for gentamicin. We observed a higher proportion of patients with at least one adverse event in the ertapenem group (58 [56%] of 103) and fosfomycin group (36 [95%] of 38) versus the ceftriaxone group (24 [23%] of 103). INTERPRETATION: Single-dose 1000 mg ertapenem is non-inferior to single-dose 500 mg ceftriaxone in gonorrhoea treatment. Yet, 5 mg/kg gentamicin (maximum 400 mg) is not non-inferior to ceftriaxone. Ertapenem is a potential effective alternative for anogenital N gonorrhoeae infections and merits evaluation for ceftriaxone-resistant infections. FUNDING: ZonMw and GGD-Amsterdam. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Choosing event-driven and daily HIV pre-exposure prophylaxis - data from two European PrEP demonstration projects among men who have sex with men.

INTRODUCTION: Daily and event-driven PrEP are both efficacious in reducing the risk for HIV infection. However, the practice of event-driven PrEP (edPrEP) is less well studied, in particular when provided as an alternative to daily PrEP. We studied regimen preferences and switches, and sexually transmitted infection (STI) incidence. METHODS: We analysed pooled data from two prospective cohort studies among MSM: Be-PrEP-ared, Belgium and AMPrEP, the Netherlands. In both projects, participants could choose between daily and edPrEP at three-monthly study visits, when they were also screened for sexually transmitted infections including hepatitis C (HCV). We assessed the proportion choosing each regimen, and the determinants of choosing edPrEP at baseline. Additionally, we compared the incidence rates (IRs) of HCV, syphilis and chlamydia or gonorrhoea between regimens using Poisson regression. The study period was from 3 August 2015 until 24 September 2018. RESULTS AND DISCUSSION: We included 571 MSM, of whom 148 (25.9%) chose edPrEP at baseline. 31.7% of participants switched regimen at least once. After 28 months, 23.5% used edPrEP. Older participants (adjusted odds ratio (aOR) = 1.38 per 10 years, 95% confidence interval (CI) = 1.15 to 1.64) and those unemployed (aOR = 1.68, 95% CI = 1.03 to 1.75) were more likely to initially choose edPrEP. IR of HCV and syphilis did not differ between regimens, but the IR of chlamydia/gonorrhoea was higher among daily users (adjusted incidence rate ratio = 1.61, 95% CI = 1.35 to 1.94). CONCLUSIONS: A quarter of participants chose edPrEP at baseline and at 28 months this proportion was similar. Although the IR of HCV and syphilis were similar in the two regimens, the lower incidence of chlamydia and gonorrhoea among edPrEP users may suggest that less frequent STI testing of this group could be considered.

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.

HPV vaccination to prevent recurrence of anal intraepithelial neoplasia in HIV+ MSM.

OBJECTIVE: Anal cancer precursor lesions high-grade anal intraepithelial neoplasia (HGAIN) are highly prevalent among HIV+ MSM. Treatment of HGAIN is frustrated by high recurrence rates. We investigated the efficacy of the quadrivalent human papillomavirus (qHPV) vaccine as posttreatment adjuvant in preventing HGAIN recurrence in HIV+ MSM. DESIGN: Randomized, double-blind, placebo-controlled, multicentre trial. SETTING: Three HIV outpatient clinics in Amsterdam, the Netherlands. SUBJECTS: HIV+ MSM with CD4+ cell count more than 350 cells/µl, biopsy-proven intra-anal HGAIN successfully treated in the past year, and lesions still in remission at enrolment, as assessed by high-resolution anoscopy (HRA). INTERVENTION: Participants were randomized to three doses of qHPV (Gardasil-4, MSD) or placebo with vaccinations at 0, 2, and 6 months. HRA was repeated at 6, 12, and 18 months. MAIN OUTCOME MEASURE: The primary outcome was cumulative, biopsy-proven HGAIN recurrence rate at 18 months, evaluated in an intention-to-treat (ITT) (received all vaccinations) and per-protocol analysis (all vaccinations and complete follow-up). RESULTS: We randomized 126 participants of which 64 (50.8%) received qHPV and 62 (49.2%) placebo. All participants received three vaccinations, and in both groups for two participants follow-up was incomplete. We found no difference (P = 0.38) in cumulative HGAIN recurrence rates between the qHPV (44/64, 68.8%) and placebo group (38/62, 61.3%) in the ITT analysis [absolute risk reduction -7.5 (95% confidence interval (CI) -24.1 to 9.2)]. This was similar in the per-protocol analysis. CONCLUSION: Despite adequate serological responses to qHPV vaccination, short-term recurrence of HGAIN was not prevented. These findings do not support qHPV vaccination as a treatment adjuvant to prevent HGAIN recurrence in HIV+ MSM.

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.

Incidence and risk factors of C. trachomatis and N. gonorrhoeae among young women from the Western Cape, South Africa: The EVRI study.

OBJECTIVE: Young women in South Africa are highly affected by sexually transmitted infections (STI), like C. trachomatis (CT) and N. gonorrhoeae (NG). We aimed to estimate the incidence of CT and NG, and its determinants, among young women from the Western Cape, South Africa, participating in an HPV vaccine trial (the EVRI study). METHODS: HIV-negative women aged 16-24 years were enrolled between October 2012 and July 2013. At enrolment and month 6 participants were screened for CT and NG (Anyplex CT/NG real-time detection method). A questionnaire on demographic and sexual history characteristics was completed at enrolment and month 7. Treatment for CT and/or NG was offered to infected participants. Incidence rates (IR) of CT and NG were estimated. Determinants of incident CT and NG infections were assessed using Poisson regression. RESULTS: 365 women were tested for CT and/or NG at least twice. Prevalence of CT and NG at baseline was 33.7% and 10.4%, respectively. Prevalence of co-infection with CT and NG was 7.1%. During 113.3 person-years (py), 48 incident CT infections were diagnosed (IR = 42.4 per 100 py, 95% confidence interval (CI) 31.9-56.2). Twenty-nine incident NG were diagnosed during 139.3 py (IR = 20.8 per 100 py, 95%CI 14.5-29.9). Prevalent CT infection at baseline was associated with incident CT (adjusted incidence rate ratio (aIRR) 5.8, 95%CI 3.0-11.23. More than three lifetime sex partners increased the risk for incident NG (3-4 partners aIRR = 7.3, 95%CI 2.1-26.0; ≥5 partners aIRR = 4.3, 95%CI 1.1-17.5). CONCLUSIONS: The IR of bacterial STIs among young women in the Western Cape is very high. Besides being previously infected and a higher lifetime number of sex partners, no other risk factors were found for CT and NG, suggesting that the majority of these women were at risk. This indicates the need for intensified prevention of STIs as well as screening and treatment programs to increase sexual health in this region.