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Increased rates of sexually transmitted infections (STIs) are reported among men who have sex with men (MSM) and new interventions are needed. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of chlamydia or syphilis (or both) and whether the meningococcal group B vaccine (4CMenB) could reduce the incidence of gonorrhoea in this population. ANRS 174 DOXYVAC is a multicentre, open-label, randomised trial with a 2 × 2 factorial design conducted at ten hospital sites in Paris, France. Eligible participants were MSM aged 18 years or older, HIV negative, had a history of bacterial STIs within the 12 months before enrolment, and who were already included in the ANRS PREVENIR study (a cohort of MSM using pre-exposure prophylaxis with tenofovir and emtricitabine for HIV prevention). Participants were randomly assigned (2:1) to doxycycline PEP (two pills of 100 mg each orally within 72 h after condomless sex, with no more than three doses of 200 mg per week) or no PEP groups and were also randomly assigned (1:1) to the 4CMenB vaccine (GlaxoSmithKline, Paris, France; two intramuscular injections at enrolment and at 2 months) or no vaccine groups, using a computer-generated randomisation list with a permuted fixed block size of four. Follow-up occurred for at least 12 months (with visits every 3 months) up to 24 months. The coprimary outcomes were the risk of a first episode of chlamydia or syphilis (or both) after the enrolment visit at baseline for the doxycycline intervention and the risk of a first episode of gonorrhoea starting at month 3 (ie, 1 month after the second vaccine dose) for the vaccine intervention, analysed in the modified intention-to-treat population (defined as all randomly assigned participants who had at least one follow-up visit). This trial is registered with ClinicalTrials.gov, NCT04597424 (ongoing). Between Jan 19, 2021, and Sept 19, 2022, 556 participants were randomly assigned. 545 (98%) participants were included in the modified intention-to-treat analysis for the doxycycline PEP and no PEP groups and 544 (98%) were included for the 4CMenB vaccine and no vaccine groups. The median follow-up was 14 months (IQR 9–18). The median age was 40 years (34–48) and all 545 participants were male. There was no interaction between the two interventions (p≥0·1) for the primary outcome. The incidence of a first episode of chlamydia or syphilis (or both) was 8·8 per 100 person-years (35 events in 362 participants) in the doxycycline PEP group and 53·2 per 100 person-years (80 events in 183 participants) in the no PEP group (adjusted hazard ratio [aHR] 0·17 [95% CI 0·12–0·26]; p<0·0001). The incidence of a first episode of gonorrhoea, starting from month 3 was 58·3 per 100 person-years (103 events in 274 participants) in the 4CmenB vaccine group and 77·1 per 100 person-years (122 events in 270 participants) in the no vaccine group (aHR 0·78 [95% CI 0·60–1·01]; p=0·061). There were no deaths during the study. One drug-related serious adverse event (fixed-drug eruption) occurred in the doxycycline PEP group. Six (2%) participants in the doxycycline group discontinued doxycycline PEP because of gastrointestinal adverse events. Doxycycline PEP strongly reduced the incidence of chlamydia and syphilis in MSM, but we did not show efficacy of the 4CmenB vaccine for gonorrhoea. Doxycycline PEP should be assessed in other populations, such as heterosexual men and women, and its effect on antimicrobial resistance carefully monitored. ANRS Maladies Infectieuses Emergentes. For the French translation of the abstract see Supplementary Materials section.

Tens of thousands of people die from dog-mediated rabies annually. Deaths can be prevented through post-exposure prophylaxis for people who have been bitten, and the disease eliminated through dog vaccination. Current post-exposure prophylaxis use saves many lives, but availability remains poor in many rabies-endemic countries due to high costs, poor access, and supply. We developed epidemiological and economic models to investigate the effect of an investment in post-exposure prophylaxis by Gavi, the Vaccine Alliance. We modelled post-exposure prophylaxis use according to the status quo, with improved access using WHO-recommended intradermal vaccination, with and without rabies immunoglobulin, and with and without dog vaccination. We took the health provider perspective, including only direct costs. We predict more than 1 million deaths will occur in the 67 rabies-endemic countries considered from 2020 to 2035, under the status quo. Current post-exposure prophylaxis use prevents approximately 56 000 deaths annually. Expanded access to, and free provision of, post-exposure prophylaxis would prevent an additional 489 000 deaths between 2020 and 2035. Under this switch to efficient intradermal post-exposure prophylaxis regimens, total projected vaccine needs remain similar (about 73 million vials) yet 17·4 million more people are vaccinated, making this an extremely cost-effective method, with costs of US$635 per death averted and $33 per disability-adjusted life-years averted. Scaling up dog vaccination programmes could eliminate dog-mediated rabies over this time period; improved post-exposure prophylaxis access remains cost-effective under this scenario, especially in combination with patient risk assessments to reduce unnecessary post-exposure prophylaxis use. Investing in post-exposure vaccines would be an extremely cost-effective intervention that could substantially reduce disease burden and catalyse dog vaccination efforts to eliminate dog-mediated rabies. World Health Organization.

Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections among men who have sex with men and transgender women. Although poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from the DoxyPEP trial, a randomized clinical trial comparing doxy-PEP use, a one-time doxycycline 200-mg dose taken after condomless sex (DP arm, n  = 100), to standard of care (SOC arm, n  = 50) among men who have sex with men and transgender women. From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data were analyzable from 127 samples derived from 89 participants, and RNA-seq data were analyzable from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. The median number of doxycycline doses taken since enrollment by participants with DNA-seq data was zero (interquartile range (IQR): 0–7 doses) for the SOC arm and 42 (IQR: 27–64 doses) for the DP arm. Tetracycline ARGs were detected in all day-0 DNA-seq samples and in 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46% to 51% in the metagenome ( P  = 2.3 × 10 −2 ) and from 4% to 15% in the metatranscriptome ( P  = 4.5 × 10 −6 ), but no statistically significant increases in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman’s ρ  = 0.23, P  = 9.0 × 10 −3 ) and metatranscriptome (Spearman’s ρ  = 0.55, P  = 3.7 × 10 −8 ). Bacterial microbiome alpha diversity, beta diversity and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome and an increase in the expression of tetracycline ARGs. At 6 months of doxy-PEP use, no residual differences were observed in alpha and beta diversity or taxonomic composition of the gut microbiome. As doxy-PEP is implemented as a public health strategy, further studies and population-level surveillance of doxycycline-resistant pathogens are needed to understand the implications of these findings. ClinicalTrials.gov registration number: NCT03980223 . In participants from a randomized controlled trial, doxy-PEP use over 6 months minimally affected the gut microbiome’s taxonomic composition but increased the abundance and active expression of tetracycline antibiotic resistance genes.

Rabies is almost invariably fatal. A rabies monoclonal antibody (RmAb) was approved in India in 2016 for passive prophylaxis. This post-marketing study aimed to evaluate the long-term safety, immunogenicity, and efficacy of a post-exposure prophylaxis (PEP) regimen containing RmAb. This phase 4, open-label, randomised, active-controlled study was conducted at 15 tertiary care hospitals in India. Patients aged 2 years or older with WHO category 3 rabies exposure by a suspected rabid animal were eligible if the exposure occurred less than 72 h before enrolment, or less than 24 h before enrolment for exposures to the face, neck, hand, or fingers. Participants were randomly assigned (3:1) to receive either RmAb (Rabishield; Serum Institute of India, Pune, India) plus a purified Vero cell rabies vaccine (PVRV; Rabivax-S) or equine rabies immunoglobulin (ERIG; Equirab) plus PVRV as PEP. In each treatment group, patients were further randomly assigned (1:1) to receive PVRV either intradermally or intramuscularly. Study group allocation was done using a permuted block design with random block sizes of eight. A central randomisation list was generated before the study start and randomisation was performed with an interactive web response system. Participants and site personnel were not masked to group assignment. RmAb (3·33 IU/kg) and ERIG (40 IU/kg) were infiltrated into and around the wounds only on day 0 as per WHO 2018 recommendations. PVRV was administered 1·0 mL intramuscularly (days 0, 3, 7, 14, and 28) or 0·1 mL plus 0·1 mL intradermally (days 0, 3, 7, and 28). The primary outcome was treatment-related serious adverse events up to 365 days after immunisation, analysed in the safety analysis set (all participants who received at least one dose of vaccine with treatment). Geometric mean concentrations of rabies virus neutralising antibody were measured in a subset of patients. This study is registered with Clinical Trial Registry–India (CTRI/2019/06/019622) and is completed. 4059 participants were enrolled between Aug 21, 2019, and March 31, 2022, and randomly assigned. A total of 3994 participants (3001 male, 993 female) were treated (2996 RmAb plus PVRV, 998 ERIG plus PVRV), of which 3622 (90·7%) participants completed the 1-year follow-up. 11 adverse events were considered causally related to RmAb plus PVRV and 17 were considered causally related to the ERIG plus PVRV regimen. Most adverse events were mild and transient. Seven serious adverse events occurred in the RmAb group and all were causally unrelated. One causally related serious adverse event was reported in the ERIG group. On day 14, the geometric mean concentrations increased to 16·05 IU/mL (95% CI 13·25–19·44) in the RmAb group and 13·48 IU/mL (9·51–19·11) in the ERIG group (point estimate 1·19 [95% CI 0·82–1·72]). No patient developed rabies during the 1-year follow-up period. RmAb was safe and well tolerated and showed protective efficacy against rabies. A PEP regimen containing RmAb plus PVRV was immunogenic with long-term persistence of immune response. Serum Institute of India.

Introduction Post‐exposure prophylaxis (PEP) remains underutilized despite being the only prevention option currently available that covers risk after an exposure. We sought to evaluate uptake and patterns of use of PEP among men and women in rural Uganda and Kenya. Methods We analysed PEP uptake from three randomized trials enrolling persons aged ≥15 years with HIV risk from antenatal clinics, outpatient departments and community settings from April through August 2021 (NCT04810650). In each trial, participants were randomized to a person‐centred, dynamic choice HIV prevention (DCP) model or standard‐of‐care (SoC) arm. DCP offered choice of biomedical product (oral pre‐exposure prophylaxis [PrEP] or PEP) with an option to switch over time; service location (clinic vs. out‐of‐clinic); testing option (rapid blood‐based test or oral HIV self‐test). The SoC offered HIV prevention services as per in‐country guidelines. In both arms, PEP comprised a 28‐day oral Tenofovir/Lamivudine/Dolutegravir course with HIV testing at start and end of the 28‐day period. We described patterns of and predictors of self‐reported PEP use over the 12 months of follow‐up. Results A total of 1232 participants were enrolled, balanced by arm and country. Of the 1147 (93%) who completed at least one survey on self‐reported use of biomedical prevention, the median follow‐up time was 12 months [IQR: 11, 12]. Overall, a total of 104 courses of PEP were dispensed to 59 participants. PEP use was significantly higher among persons enrolled in the DCP arm (relative risk [RR] = 3.30; 95% CI: 1.58−6.91), from Uganda (RR = 3.17; 95% CI: 1.53−6.59), reporting alcohol use (RR = 2.20; 95% CI: 1.30−3.72) and men (RR = 2.08; 95% CI: 1.11−3.91). Of the 59 PEP users, 14 (24%) transitioned to PrEP and 28(47%) used PEP on more than one occasion. Multiple uses of PEP were more common among persons from Uganda versus Kenya (RR = 4.43; 95% CI: 1.10−17.80) and persons enrolled from the community (RR = 4.45; 95% CI: 1.89−10.45) versus clinic. There were no seroconversions reported among PEP users. No serious adverse events were reported. Conclusions PEP reaches groups such as men and those who use alcohol who are more likely to benefit from this short‐term prevention modality than PrEP. There is a need to make PEP accessible within a context of person‐centred delivery to optimize its benefits.

To evaluate the safety, immunogenicity and immune persistence of a lyophilized purified human diploid cells rabies vaccine in healthy and previously unvaccinated people in a simulated rabies post-exposure prophylaxis, by traditional 5-dose Essen regimen and abbreviated 4-dose Zagreb regimen. A cohort of 1800 healthy participants aged 10–60 years old were randomized into three groups: 5-dose test group (T5, Essen regimen), 5-dose control group (C5, Essen regimen) and 4-dose test group (T4, Zagreb regimen) according to the ratio of 1:1:1, and inoculated with trial vaccine or control vaccine separately to analyze the safety of vaccine as well as rabies antibody levels before and after vaccination. Adverse reactions (AEs) mainly occurred after the initial dose of immunization, which were mostly mild (grade 1) in severity. The incidence of total AEs in T4 (38 %) was lower than that in C5 (45 %) (P = 0.02) from the initial dose to 28 days after the final dose; fever rate in T5 (12 %, P = 0.01) and T4 (13 %, P = 0.03) was lower than that in C5 (17 %). No vaccine-related serious AEs (SAEs) were observed. Seroconversion rates reached 100 % in all three groups 14 days following the first dose. Moreover, the seroconversion rate was 98 %, 96 % and 98 % 12 months following the first dose in T5, C5 and T4, respectively. Both T5 and T4 displayed higher neutralizing antibodies geometric mean concentration (GMC) and geometric mean increase (GMI) compared to those in C5 on day 7, day 14, and 12 months after the first dose, as well as on day 14 after the last dose. There were no significant differences in the incidence of AEs, seroconversion rate, GMC and GMI between T5 and T4. The trial vaccine administered following both Essen regimen and Zagreb regimen shows good safety, immunogenicity and immune persistence, and the trial vaccine is not inferior to the control vaccine. Clinical Trials Registration:NCT03971370.

The SYN023–006 study was conducted in WHO Category III rabies-exposed patient populations to assess the safety and efficacy of post-exposure prophylaxis that included either the monoclonal antibody mixture SYN023 or human rabies immunoglobulin (HRIG). This phase 3, double-blind, randomized, controlled trial was conducted at multiple clinical disease control sites in China. Patients were randomized 3:1 (stratified by study site) to wound infiltration with 0.3 mg/kg SYN023 or 20 IU/kg HRIG. All patients received thorough wound washing and 5 doses intramuscular Vero cell rabies vaccine. The composite primary study objective was to demonstrate: 1) superiority of Day 8 geometric mean (GM) concentration of serum rabies virus neutralizing antibodies (RVNA) with SYN023 versus HRIG (protocol-defined superiority margin: GM RVNA ratio 95 % confidence interval [CI] lower limit >1.2) and 2) no rabies in SYN023 recipients. Efficacy was evaluated in the Per-Protocol population. Safety endpoints included solicited and unsolicited adverse events (AEs) analyzed in all patients receiving any study treatment. Trial registration: ClinicalTrials.govNCT04644484. From 23 September 2020 to 26 June 2021, 537 male and 463 female patients were randomized (n = 750 SYN023, n = 250 HRIG). Day 8 GM RVNA was 4.339 IU/mL (standard error [SE]: 1.035) with SYN023 and 0.232 IU/mL (SE: 1.060) with HRIG. The SYN023:HRIG GM RVNA ratio was 18.695 (95 % CI: 16.440, 21.260) indicating superior RVNA with SYN023. No suspected rabies cases or deaths occurred. AEs were generally similar between treatment groups except greater local solicited AEs frequencies with HRIG (SYN023: 165/750 patients [22.0 %]; HRIG: 97/250 [38.8 %]). This study indicates that SYN023, a monoclonal antibody product, may be used as part of rabies post-exposure prophylaxis and provides superior protection sooner after exposure than HRIG.

To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. ClinicalTrials.gov NCT05406479.

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety. Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events. In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis.

•SYN023-004: a large, one-year, randomized, double blind, controlled, rabies PEP study in Category III patients.•SYN023 is comprised of two humanized monoclonals against non-overlapping rabies virus epitopes.•SYN023 produces rapid and higher RVNA during the 2-week period after administration.•SYN023 safety profile appears similar to human rabies immunoglobulin. SYN023 is an anti-rabies monoclonal antibody mixture administered as part of post-exposure prophylaxis regimens. The rabies virus neutralizing antibody (RVNA) concentration generally accepted as an adequate immune response to vaccination is ≥ 0.5 IU/mL. Within 54 h of potential rabies exposure, 448 patients in two risk substrata of WHO Category III exposure were randomized to receive either 0.3 mg/kg SYN023 or 0.133 mL/kg human rabies immunoglobulin (HRIG) injected in and around the wound site(s) plus a course of rabies vaccination. Patients were followed for safety and absence of rabies for ≥ 365 days. GMT RVNA was higher with SYN023 throughout the 2-week post-treatment period. In the primary analysis group (n = 368), 99.4 % of SYN023 recipients versus 4.5 % of HRIG recipients had protective RVNA levels on Day 4. On Day 8, 98.1 % SYN023 versus 12.2 % HRIG recipients were protected. The SYN023:HRIG ratio of geometric mean titer of RVNA (RVNA GMTs) on Day 8 (19.42) exceeded the 10 % superiority margin (P < 0.0001) indicating higher Day 8 RVNA with SYN023. On Day 99, the SYN023:HRIG RVNA GMT ratio (0.66) was below the non-inferiority margin of 20 % (P = 0.9485) suggesting some moderation of vaccine immune response by SYN023 relative to HRIG. The ratio of percent SYN023:HRIG recipients achieving RVNA ≥ 0.5 IU/mL on Day 99 (0.98) met the non-inferiority margin of 20 % (P = 0.013) indicating anti-rabies immune response with SYN023 was non-inferior to HRIG despite this effect. There were no probable/confirmed rabies cases in any patient. Study regimens were well tolerated. SYN023 provided higher RVNA than HRIG soon after rabies exposure. By Day 99 post-treatment, GM RVNA with SYN023 was lower than HRIG, however, the percent of SYN023 recipients with a protective response was not inferior at this time point. No rabies cases were reported in the study. The SYN023 safety profile was acceptable. ClinicalTrials.gov ID: NCT03961555.