The Roles of Unrecognized Mpox Cases, Contact Isolation and Vaccination in Determining Epidemic Size in Belgium: A Modeling Study.

We used a network model to simulate a mpox epidemic among men who have sex with men. Our findings suggest that unrecognized infections have an important impact on the epidemic, and that vaccination of individuals at highest risk of infection reduces epidemic size more than post-exposure vaccination of sexual partners.

Protocol, rationale and design of BE-PEOPLE (Bedaquiline enhanced exposure prophylaxis for LEprosy in the Comoros): a cluster randomized trial on effectiveness of rifampicin and bedaquiline as post-exposure prophylaxis of leprosy contacts.

BACKGROUND: Leprosy is an ancient infectious disease with an annual global incidence of around 200,000 over the past decade. Since 2018, the World Health Organization (WHO) recommends single-dose rifampicin as post-exposure prophylaxis (SDR-PEP) for contacts of leprosy patients. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial evaluated PEP with a double dose of rifampicin in Comoros and Madagascar. Preliminary results of this trial show some reduction in leprosy incidence in intervention villages but a stronger regimen may be beneficial. The objective of the current Bedaquiline Enhanced ExpOsure Prophylaxis for LEprosy trial (BE-PEOPLE) is to explore effectiveness of a combination of bedaquiline and rifampicin as PEP. METHODS: BE-PEOPLE is a cluster-randomized trial in which 44 clusters in Comoros will be randomized to two study arms. Door-to-door screening will be conducted annually during four years, leprosy patients identified will be offered standard of care treatment. Based on study arm, contacts aged five years and above and living within a 100-meter radius of an index case will either receive bedaquiline (400-800 mg) and rifampicin (150-600 mg) or only rifampicin (150-600 mg). Contacts aged two to four years will receive rifampicin only. Household contacts randomized to the bedaquiline plus rifampicin arm will receive a second dose four weeks later. Incidence rate ratios of leprosy comparing contacts who received either of the PEP regimens will be the primary outcome. We will monitor resistance to rifampicin and/or bedaquiline through molecular surveillance in all incident tuberculosis and leprosy patients nationwide. At the end of the study, we will assess anti-M. leprae PGL-I IgM seropositivity as a proxy for the population burden of M. leprae infection in 8 villages (17,000 individuals) that were surveyed earlier as part of the PEOPLE trial. DISCUSSION: The COLEP trial on PEP in Bangladesh documented a reduction of 57% in incidence of leprosy among contacts treated with SDR-PEP after two years, which led to the WHO recommendation of SDR-PEP. Preliminary results of the PEOPLE trial show a lesser reduction in incidence. The BE-PEOPLE trial will explore whether reinforcing SDR-PEP with bedaquiline increases effectiveness and more rapidly reduces the incidence of leprosy, compared to SDR-PEP alone. TRIAL REGISTRATION: NCT05597280. Protocol version 5.0 on 28 October 2022.

Etiological spectrum of persistent fever in the tropics and predictors of ubiquitous infections: a prospective four-country study with pooled analysis.

BACKGROUND: Persistent fever, defined as fever lasting for 7 days or more at first medical evaluation, has been hardly investigated as a separate clinical entity in the tropics. This study aimed at exploring the frequencies and diagnostic predictors of the ubiquitous priority (i.e., severe and treatable) infections causing persistent fever in the tropics. METHODS: In six different health settings across four countries in Africa and Asia (Sudan, Democratic Republic of Congo [DRC], Nepal, and Cambodia), consecutive patients aged 5 years or older with persistent fever were prospectively recruited from January 2013 to October 2014. Participants underwent a reference diagnostic workup targeting a pre-established list of 12 epidemiologically relevant priority infections (i.e., malaria, tuberculosis, HIV, enteric fever, leptospirosis, rickettsiosis, brucellosis, melioidosis, relapsing fever, visceral leishmaniasis, human African trypanosomiasis, amebic liver abscess). The likelihood ratios (LRs) of clinical and basic laboratory features were determined by pooling all cases of each identified ubiquitous infection (i.e., found in all countries). In addition, we assessed the diagnostic accuracy of five antibody-based rapid diagnostic tests (RDTs): Typhidot Rapid IgM, Test-itTM Typhoid IgM Lateral Flow Assay, and SD Bioline Salmonella typhi IgG/IgM for Salmonella Typhi infection, and Test-itTM Leptospira IgM Lateral Flow Assay and SD Bioline Leptospira IgG/IgM for leptospirosis. RESULTS: A total of 1922 patients (median age: 35 years; female: 51%) were enrolled (Sudan, n = 667; DRC, n = 300; Nepal, n = 577; Cambodia, n = 378). Ubiquitous priority infections were diagnosed in 452 (23.5%) participants and included malaria 8.0% (n = 154), tuberculosis 6.7% (n = 129), leptospirosis 4.0% (n = 77), rickettsiosis 2.3% (n = 44), enteric fever 1.8% (n = 34), and new HIV diagnosis 0.7% (n = 14). The other priority infections were limited to one or two countries. The only features with a positive LR ≥ 3 were diarrhea for enteric fever and elevated alanine aminotransferase level for enteric fever and rickettsiosis. Sensitivities ranged from 29 to 67% for the three RDTs targeting S. Typhi and were 9% and 16% for the two RDTs targeting leptospirosis. Specificities ranged from 86 to 99% for S. Typhi detecting RDTs and were 96% and 97% for leptospirosis RDTs. CONCLUSIONS: Leptospirosis, rickettsiosis, and enteric fever accounted each for a substantial proportion of the persistent fever caseload across all tropical areas, in addition to malaria, tuberculosis, and HIV. Very few discriminative features were however identified, and RDTs for leptospirosis and Salmonella Typhi infection performed poorly. Improved field diagnostics are urgently needed for these challenging infections. TRIAL REGISTRATION: NCT01766830 at ClinicalTrials.gov.

Chlorhexidine Mouthwash Fails to Eradicate Oropharyngeal Gonorrhea in a Clinical Pilot Trial (MoNg).

ABSTRACT: This single-arm open-label pilot trial in Antwerp, Belgium, was ended early in accordance with the protocol because twice-daily gargling with chlorhexidine 0.2% for 6 days failed to eradicate Neisseria gonorrhoeae from the oropharynx of asymptomatic men who have sex with men (n = 3; efficacy of 0%; 95% confidence interval, 0%-56.1%).

Preexposure Intradermal Rabies Vaccination: A Noninferiority Trial in Healthy Adults on Shortening the Vaccination Schedule From 28 to 7 Days.

Background: The existing 4-week preexposure rabies vaccination schedule is costly and often not practicable. Shorter effective schedules would result in wider acceptance. Methods: We conducted a noninferiority trial in 500 healthy adults comparing the safety and immunogenicity of a 2-visit (days 0 and 7) intradermal (ID) primary vaccination (2 doses of 0.1 mL ID of the human diploid cell culture rabies vaccine [HDCV] at days 0 and 7) vs a standard 3-visit schedule (single dose of 0.1 mL ID at days 0, 7, and 28). One year to 3 years after primary vaccination, a single booster dose of 0.1 mL ID of HDCV was given to evaluate the anamnestic rabies antibody response. The primary endpoint for immunogenicity was the percentage of subjects with an adequate antibody level >0.5 IU/mL 7 days after the booster injection. The safety endpoint was the proportion of participants developing adverse reactions following the primary vaccination and/or booster dose. Results: All subjects in both study groups possessed a rabies antibody titer >0.5 IU/mL on day 7 following the booster dose. Following the booster dose, subjects exposed to the double-dose 2-visit ID schedule had a geometric mean titer of 37 IU/mL, compared with 25 IU/mL for the single-dose 3-visit schedule (P < .001). Local reactions at the injection site following primary vaccination were mild and transient. Conclusions: In healthy adults, ID administration of a double dose of 0.1 mL of HDCV over 2 visits (days 0 and 7) was safe and not inferior to the single-dose 3-visit schedule. Clinical Trials Registration: NCT01388985, EudraCT 2011-001612-62.

Comparative Immunogenicity and Safety Trial of 2 Different Schedules of Single-visit Intradermal Rabies Postexposure Vaccination.

BACKGROUND: Effective and safe single-visit rabies vaccination for pre- and postexposure prophylaxis (PrEP and PEP) could substantially simplify rabies prevention and therefore increase compliance. METHODS: In a comparative trial, 303 healthy adults received a primary vaccination that consisted of 2 intradermal (ID) doses of 0.1 mL of the purified chicken embryo cell vaccine (PCEV) during a single visit. One year later, participants were randomly assigned to receive either 4 or 2 ID PEP booster doses of 0.1 mL PCEV during a single visit. The primary endpoint for immunogenicity was the percentage of participants with an adequate antibody level (>0.5 IU/mL) 7 days after the booster doses. The safety endpoint was the proportion of participants who developed adverse events (AEs) following primary and/or booster vaccination. RESULTS: All participants, except 1 (99.3%) in each study group, had a rabies antibody titer >0.5 IU/mL on day 7 following the booster schedules. Participants exposed to the 4-dose PEP schedule had a geometric mean titer of 20 IU/mL vs 14 IU/mL for the 2-dose PEP schedule (P = .0228). Local reactions at the injection site following PrEP and PEP were mild and transient and only seen in 14.9% and 49.6%-53% of the participants, respectively. No serious AEs were reported. CONCLUSIONS: In healthy adults, a 2-dose (2 × 0.1 mL) single-visit ID PEP schedule was as immunologically adequate and safe as a 4-dose (4 × 0.1 mL) single-visit PEP schedule 7 to 28 months following a 2-dose (2 × 0.1 mL) single-visit ID PREP. CLINICAL TRIALS REGISTRATION: EudraCT 2014-00183612.

Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial.

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation. Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/µL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis. Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period. Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined. Clinical Trials Registration: NCT01360762.

Repeat syphilis has a different immune response compared with initial syphilis: an analysis of biomarker kinetics in two cohorts.

OBJECTIVE: We aimed to asses if there are differences in the clinical presentation and immune response of repeat as compared with initial syphilis. METHODS: Prospective study: we prospectively recruited all patients with a new diagnosis of syphilis and tested their plasma for a range of cytochemokines and rapid plasma reagin (RPR) at baseline pretreatment and 6 months following therapy. Retrospective study: we compared RPR assay response kinetics between initial and repeat syphilis in persons attending our HIV/STI clinic from 1993 to 2016. RESULTS: Prospective study: a total of 91 individuals, 36 with initial syphilis and 55 with repeat syphilis, were included in the study. At baseline visit, those with initial syphilis were more likely to be symptomatic and have higher levels of interleukin-10 than repeaters. At baseline, median RPR titres were higher in the repeat than the initial infection groups. Repeaters were less likely than those with initial infections to serorevert to a negative RPR and be serofast (<4-fold RPR titre decline) at 6 months.Retrospective study: syphilis was diagnosed in 1027/43 870 individuals tested. At diagnosis, repeaters had higher RPR titres and a stepwise increase in RPR titre with number of syphilis episodes. They had a different RPR test response kinetic: they were less likely to be serofast and to serorevert than initial syphilis at 6 and 12 months. No individuals with four or more previous episodes of syphilis seroreverted. CONCLUSION: Repeat syphilis has a different clinical presentation and immunological response to initial infection.

Is Screening for Chlamydia and Gonorrhea in Men Who Have Sex With Men Associated With Reduction of the Prevalence of these Infections? A Systematic Review of Observational Studies.

BACKGROUND: Neisseria gonorrhoeae (gonorrhea) could become untreatable in the near future. Indeed, while the treatment of symptomatic gonorrhea in core groups, such men who have sex with men (MSM), is crucial for gonorrhea control programs, screening for and treating asymptomatic gonorrhea/Chlamydia trachomatis(chlamydia) in MSM may contribute to antibiotic resistance in gonorrhea. In this systematic review, we aim to assess if there is evidence that screening MSM for gonorrhea/chlamydia is associated with a decline in the prevalence of these infections. METHODS: We conducted a systematic review in PubMed and Web of Science for relevant studies including uncontrolled observational studies and reported the results following the PRISMA guidelines. The change in estimated prevalences for chlamydia and gonorrhea across the different time points for 3 anatomical sites (oral, urethral and anal) were collected and examined. RESULTS: Twelve studies met our entry criteria. We were able to statistically assess the change in prevalence in 10 of 12 studies. In 3 studies, there was a significant increase in chlamydia prevalence, whereas for gonorrhea, 2 studies reported a significant increase and 2 others a decrease. Our review provides little evidence that screening for gonorrhea and chlamydia in MSM has an effect on the prevalence of these infections. No evidence was found that more frequent screening reduces prevalence more effectively than annual screening. CONCLUSIONS: Our study was not able to provide evidence that screening for chlamydia and gonorrhea lowers the prevalence of these infections in MSM. Randomized controlled trials are required to assess the risks and benefits of gonorrhea/chlamydia screening in high- and low-risk MSM.

Lymphogranuloma venereum is on the rise in Belgium among HIV negative men who have sex with men: surveillance data from 2011 until the end of June 2017.

BACKGROUND: The number of cases of Lymphogranuloma venereum (LGV) is increasing in Europe. The described epidemic is mostly confined to HIV positive men who have sex with men (MSM). However, dissemination of LGV from HIV positive to HIV negative MSM could take place due to the implementation of pre-exposure prophylaxis (PrEP) and subsequent possible decrease in condom use. We describe here the LGV epidemiology in Belgium before the PrEP-era, starting from 2011 up to the end of the first half of 2017. METHODS: A descriptive analysis of the socio-demographic and clinical characteristics of all LGV cases was performed. Fisher's exact test was used to compare symptomatic to asymptomatic patients. Logistic regression models were used to check for trends over time for: number of LGV cases, HIV status and symptoms. RESULTS: The number of LGV cases rose by a factor four, from 21 in 2011 to 88 in 2016, and regression models showed a positive trend estimate of 14% increase per half year (p < 0.001). LGV decreased among HIV positive cases (odds ratio (OR): 0.79, p < 0.001) and increased among HIV negative cases (OR: 1.27, p < 0.001). In addition, a rise in the number of asymptomatic LGV cases (6.7%) was observed (OR:1.39, p = 0.047). Asymptomatic cases were also less likely to be HIV (p = 0.046) or Hepatitis C positive (p = 0.027). CONCLUSIONS: The rise of LGV in HIV negative MSM has now been documented. If we aim to halt the epidemic in HIV negative MSM, future public health strategies should include LGV testing of all Chlamydia trachomatis positive samples from MSM.

The Risk and Predictors of Visceral Leishmaniasis Relapse in Human Immunodeficiency Virus-Coinfected Patients in Ethiopia: A Retrospective Cohort Study.

BACKGROUND: East Africa, where Leishmania donovani is prevalent, faces the highest burden world-wide of visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) coinfection. However, data on the risk and predictors of VL relapse are scarce. Such information is vital to target medical follow-up and interventions to those at highest risk. METHODS: We conducted a retrospective cohort study at a Médecins Sans Frontières-supported health center in northwest Ethiopia. We included adult VL-HIV coinfected patients treated for VL and discharged cured between February 2008 and February 2013. The risk of relapse was calculated using Kaplan-Meier methods, and predictors were determined using Cox regression models. RESULTS: Of the 146 patients included, 140 (96%) were male and the median age was 31 years. At the index VL diagnosis, 110 (75%) had primary VL, 57 (40%) were on antiretroviral therapy (ART), and the median CD4 count was 149 cells/µL. The median follow-up time after cure was 11 months, during which 44 (30%) patients relapsed. The risk of relapse was 15% at 6 months, 26% at 12 months, and 35% at 24 months. Predictors of relapse were: not being on ART at VL diagnosis, ART not initiated during VL treatment, and high tissue parasite load (parasite grade 6+) at VL diagnosis. CONCLUSIONS: The risk of VL relapse in coinfected patients was high, particularly in those not on ART or presenting with a high tissue parasite load. These patients should be preferentially targeted for secondary prophylaxis and/or regular medical follow-up. Timely ART initiation in all coinfected patients is crucial.

Estimating Partnership Duration among MSM in Belgium-A Modeling Study.

Mathematical modeling is widely used for describing infection transmission and evaluating interventions. The lack of reliable social parameters in the literature has been mentioned by many modeling studies, leading to limitations in the validity and interpretation of the results. Using data from the European MSM Internet survey 2017, we developed a network model to describe sex acts among MSM in Belgium. The model simulates daily sex acts among steady, persistent casual and one-off partners in a population of 10,000 MSM, grouped as low- or high-activity by using three different definitions. Model calibration was used to estimate partnership duration and homophily rates to match the distribution of cumulative sex partners over 12 months. We estimated an average duration between 1065 and 1409 days for steady partnerships, 4-6 and 251-299 days for assortative high- and low-activity individuals and 8-13 days for disassortative persistent casual partnerships, respectively, varying across the three definitions. High-quality data on social network and behavioral parameters are scarce in the literature. Our study addresses this lack of information by providing a method to estimate crucial parameters for network specification.

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate-mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6-14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg-1 single dose; n = 364) or to artesunate-mefloquine (antimalarial dosage: artesunate 4 mg kg-1 and mefloquine 8 mg kg-1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate-mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate-mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of -2.5% (95% confidence interval (CI) -9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate-mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate-mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

Effect of screening for Neisseria gonorrhoeae and Chlamydia trachomatis on incidence of these infections in men who have sex with men and transgender women taking HIV pre-exposure prophylaxis (the Gonoscreen study): results from a randomised, multicentre, controlled trial.

BACKGROUND: Guidelines recommend screening for Neisseria gonorrhoeae and Chlamydia trachomatis at three anatomical sites (urethra, anus, and pharynx) every 3 months (3 × 3) in men who have sex with men (MSM) and transgender women taking HIV pre-exposure prophylaxis (PrEP). We present the first randomised controlled trial to compare the effect of screening versus non-screening for N gonorrhoeae and C trachomatis on the incidence of these infections in MSM and transgender women taking PrEP. METHODS: A multicentre, randomised, controlled trial of 3 × 3 screening for N gonorrhoeae and C trachomatis versus non-screening was done among MSM and transgender women taking PrEP in five HIV reference centers in Belgium. Participants attended the PrEP clinics quarterly for 12 months. N gonorrhoeae and C trachomatis was tested at each visit in both arms, but results were not provided to the non-screening arm, if asymptomatic. The primary outcome was incidence rate of N gonorrhoeae and C trachomatis infections in each arm, assessed in the per-protocol population. Non-inferiority of the non-screening arm was proven if the upper limit of the 95% CI of the incidence rate ratio (IRR) was lower than 1·25. This trial is registered with ClinicalTrials.gov, NCT04269434, and is completed. FINDINGS: Between Sept 21, 2020, and June 4, 2021, 506 participants were randomly assigned to the 3 × 3 screening arm and 508 to the non-screening arm. The overall incidence rate of N gonorrhoeae and C trachomatis was 0·155 cases per 100 person-days (95% CI 0·128-0·186) in the 3 × 3 screening arm and 0·205 (95% CI 0·171-0·246) in the non-screening arm. The incidence rate was significantly higher in the non-screening arm (IRR 1·318, 95% CI 1·068-1·627). Participants in the non-screening arm had a higher incidence of C trachomatis infections and symptomatic C trachomatis infections. There were no significant differences in N gonorrhoeae infections. Participants in the non-screening arm consumed significantly fewer antimicrobial drugs. No serious adverse events were reported. INTERPRETATION: We failed to show that non-screening for N gonorrhoeae and C trachomatis is non-inferior to 3 × 3 screening in MSM and transgender women taking PrEP in Belgium. However, screening was associated with higher antibiotic consumption and had no effect on the incidence of N gonorrhoeae. Further research is needed to assess the benefits and harms of N gonorrhoeae and C trachomatis screening in this population. FUNDING: Belgian Health Care Knowledge Centre.

Post-exposure prophylaxis in leprosy (PEOPLE): a cluster randomised trial.

BACKGROUND: Post-exposure prophylaxis (PEP) using single-dose rifampicin reduces progression from infection with Mycobacterium leprae to leprosy disease. We compared effectiveness of different administration modalities, using a higher (20 mg/kg) dose of rifampicin-single double-dose rifampicin (SDDR)-PEP. METHODS: We did a cluster randomised study in 16 villages in Madagascar and 48 villages in Comoros. Villages were randomly assigned to four study arms and inhabitants were screened once a year for leprosy, for 4 consecutive years. All permanent residents (no age restriction) were eligible to participate and all identified patients with leprosy were treated with multidrug therapy (SDDR-PEP was provided to asymptomatic contacts aged ≥2 years). Arm 1 was the comparator arm, in which no PEP was provided. In arm 2, SDDR-PEP was provided to household contacts of patients with leprosy, whereas arm 3 extended SDDR-PEP to anyone living within 100 m. In arm 4, SDDR-PEP was offered to household contacts and to anyone living within 100 m and testing positive to anti-phenolic glycolipid-I. The main outcome was the incidence rate ratio (IRR) of leprosy between the comparator arm and each of the intervention arms. We also assessed the individual protective effect of SDDR-PEP and explored spatial associations. This trial is registered with ClinicalTrials.gov, NCT03662022, and is completed. FINDINGS: Between Jan 11, 2019, and Jan 16, 2023, we enrolled 109 436 individuals, of whom 95 762 had evaluable follow-up data. Our primary analysis showed a non-significant reduction in leprosy incidence in arm 2 (IRR 0·95), arm 3 (IRR 0·80), and arm 4 (IRR 0·58). After controlling for baseline prevalence, the reduction in arm 3 became stronger and significant (IRR 0·56, p=0·0030). At an individual level SDDR-PEP was also protective with an IRR of 0·55 (p=0·0050). Risk of leprosy was two to four times higher for those living within 75 m of an index patient at baseline. INTERPRETATION: SDDR-PEP appears to protect against leprosy but less than anticipated. Strong spatial associations were observed within 75 m of index patients. Targeted door-to-door screening around index patients complemented by a blanket SDDR-PEP approach will probably have a substantial effect on transmission. FUNDING: European and Developing Countries Clinical Trials Partnership. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Rethinking Screening Intensity in Terms of Reducing Prevalence or Increasing Selection Pressure for the Emergence of Resistant Gonorrhea: A Modeling Study of Men Who Have Sex With Men in Belgium.

Background: Neisseria gonorrhoeae (NG) has developed antimicrobial resistance (AMR) to multiple classes of antibiotics. While treatment of symptomatic NG in groups, such as men who have sex with men (MSM), is crucial, screening programs targeting asymptomatic NG cases may contribute to excessive antibiotic exposure of the population and thus to the emergence of gonococcal AMR. Our primary aim was to assess if intense screening could promote AMR in NG. Methods: We built a network-based model of NG transmission dynamics among MSM in Belgium to estimate the prevalence of NG in the population and the risk of AMR. The model simulates daily transmission of NG among 3 anatomical sites in a population of 10 000 MSM, grouped as low risk or high risk, over 10 years. The effect of group-wise variation in treatment efficacy levels and screening intensities on NG prevalence and cumulative risk of AMR emergence was evaluated. Results: Increasing screening intensity in the low-risk MSM had little effect on NG prevalence. An inverse correlation between screening intensity in the high-risk group and both NG prevalence and the risk for azithromycin resistance was observed, irrespective of the screening intensity in the low-risk group. High-risk MSM were at higher risk for azithromycin-resistant NG in all screening intensity and treatment efficacy scenarios, compared to low-risk MSM. Conclusions: Our results suggest that intensive screening in the low-risk population has little impact on prevalence but may increase the probability of AMR emerging. In contrast, intensive screening in the high-risk population reduces both the prevalence of NG and macrolide resistance.

Measuring the prevalence of autistic traits in a cohort of adults living with HIV or taking HIV pre-exposure prophylaxis and mapping safer-sex barriers and facilitators: a study protocol.

INTRODUCTION: Autistic individuals identify with a wider range of sexual orientations than non-autistic individuals, including higher rates of bisexual orientation in autistic men. Gay, bisexual and other men who have sex with men are at greater risk for HIV. Prevalence data of autistic traits in people living with HIV or using Pre-Exposure Prophylaxis (PrEP) for HIV are lacking so far. Such data, combined with insights in barriers and facilitators for safer sex in autistic people living with HIV or using PrEP, are a first step to improve health support for autistic people in HIV clinics. This support is crucial since autistic individuals have worse physical and mental health outcomes. The objective of this research is to determine the prevalence of autistic traits within the group of people living with HIV or using PrEP in Belgium and to describe specific facilitators and barriers for sexual safer behaviour in people living with HIV and PrEP users with autistic traits. METHODS AND ANALYSIS: The research is a cross-sectional, observational and multicentre study with recruitment of individual participants. The research consists of two phases. In phase 1, adults coming for HIV/AIDS care or HIV PrEP in participating Belgian HIV Reference Centres will be invited to fill in the validated Autism Spectrum Quotient questionnaire. In phase 2, participants with a score above the predefined cut-off for autistic traits (>26), who agreed to be informed about this score, will be invited to complete an additional survey, inquiring facilitators and barriers for sexual safer behaviour. ETHICS AND DISSEMINATION OF RESULTS: Institutional Review Board Institute of Tropical Medicine Antwerp, 25 July 2022, REF 1601/22 and University Hospital of Antwerp, 12 September 2022, Project ID 3679: BUN B3002022000111. Study results will be published in peer-reviewed journals and presented to Belgian HIV Reference Centres and at conferences.

High rate of adverse drug reactions with a novel tuberculosis re-treatment regimen combining triple doses of both isoniazid and rifampicin.

OBJECTIVES: High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB). DESIGN/METHODS: TRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial. RESULTS: Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% [95% confidence interval: 1.0,14.3]). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis. CONCLUSION: We show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.

Five accelerated schedules for the tick-borne encephalitis vaccine FSME-Immun® in last-minute travellers: an open-label, single-Centre, randomized controlled pilot trial.

BACKGROUND: The purpose of this exploratory study was to evaluate different accelerated tick-borne encephalitis (TBE) vaccine schedules for last-minute travellers. METHODS: In a single-centre, open-label pilot study, 77 TBE-naïve Belgian soldiers were randomized to one of the following five schedules with FSME-Immun®: group 1 ('classical accelerated' schedule) received one intramuscular (IM) dose at day 0 and day 14, group 2 two IM doses at day 0, group 3 two intradermal (ID) doses at day 0, group 4 two ID doses at day 0 and day 7, group 5 two ID doses at day 0 and day 14. The last dose(s) of the primary vaccination scheme were given after one year: IM (1 dose) or ID (2 doses). TBE virus neutralizing antibodies were measured in a plaque reduction neutralization test (PRNT90 and 50) at day 0, 14, 21, 28, month 3, 6, 12, and 12 + 21 days. Seropositivity was defined as neutralizing antibody titres ≥10. RESULTS: The median age was 19-19.5 years in each group. Median time-to-seropositivity up to day 28 was shortest for PRNT90 in ID-group 4 and for PRNT50 in all ID groups. Seroconversion until day 28 peaked highest for PRNT90 in ID-group 4 (79%) and for PRNT50 in ID-groups 4 and 5 (both 100%). Seropositivity after the last vaccination after 12 months was high in all groups. Previous yellow fever vaccination was reported in 16% and associated with lower GMTs of TBE-specific antibodies at all time points. The vaccine was generally well tolerated. However, mild to moderate local reactions occurred in 73-100% of ID compared to 0-38% of IM vaccinations, persistent discolouration was observed in nine ID vaccinated individuals. CONCLUSION: The accelerated two-visit ID schedules might offer a better immunological alternative to the recommended classical accelerated IM schedule but an aluminium-free vaccine would preferable.