HIV pre-exposure prophylaxis and its implementation in the PrEP Impact Trial in England: a pragmatic health technology assessment.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV acquisition. To enable routine commissioning of PrEP in England, we aimed to establish population need, duration of need, PrEP uptake, and duration of use in attendees of sexual health services (SHS) in England. METHODS: The Impact Trial was a prospective, open-label, single-arm, multicentre trial conducted at 157 SHS across England between Oct 13, 2017, and July 12, 2020. Clinicians assessed HIV-negative attendees for their risk of HIV acquisition to identify those who were eligible to participate and receive either daily or event-based oral PrEP (tenofovir disoproxil maleate with emtricitabine), as appropriate. Eligible participants were aged 16 years or older, considered HIV-negative on the day of enrolment, and willing to adhere to the trial procedures. Non-trial attendees are mutually exclusive of trial participants and included SHS attendees who were not recruited to the Impact Trial at any point. They include HIV-negative individuals aged 16 years or older who attended a participating SHS at least once after recruitment at that SHS had begun and before Feb 29, 2020. The main outcomes assessed were PrEP need, uptake, and use, and HIV and sexually transmitted infection (STI) incidence. Data are presented up to Feb 29, 2020, before the introduction of COVID-19 control measures. The study is registered with ClinicalTrials.gov, NCT03253757. FINDINGS: In this analysis, we include 21 356 of 24 268 participants enrolled before Feb 29, 2020. 20 403 participants (95·5%) were men who have sex with men (MSM). Uptake of PrEP among SHS attendees clinically assessed and coded as eligible was 21 292 (57·1%) of 37 289. 18 400 trial participants had at least one post-enrolment visit and a median of 361 days of follow-up (IQR 143-638); 14 039 (75·9%) of these had enough PrEP prescribed to provide protection for 75% of their follow-up time. Among MSM, HIV incidence was 0·13 (95% CI 0·08-0·19) per 100 person-years in trial participants (27 seroconversions) and 0·95 (95% CI 0·88-1·03) per 100 person-years in non-trial attendees (587 seroconversions; proportionate reduction of 86·8%, 95% CI 80·2-91·6). 18 607 bacterial STIs were recorded (incidence 68·1 per 100 person-years in trial participants who were MSM). 4343 (24·4%) MSM participants were diagnosed with two or more STIs, accounting for 14 800 (79·5%) of all 18 607 diagnoses. INTERPRETATION: PrEP need was higher than initially estimated by an expert stakeholder group. The high proportion of follow-up time protected by PrEP suggests that the need for protection persisted throughout trial participation for most participants. HIV incidence among MSM trial participants was low. The large unmet need for PrEP suggests that greater provision is required to maximise the potential of a national programme. The high incidence of bacterial STIs among participants, concentrated within a subgroup of PrEP users, presents an opportunity for tailored STI control measures. FUNDING: NHS England.

Prevalence and risk factors of bacterial enteric pathogens in men who have sex with men: A cross-sectional study at the UK's largest sexual health service.

OBJECTIVES: Outbreaks of bacterial enteric pathogens (BEPs) in men who have sex with men (MSM) associated with antimicrobial resistance are a public health concern. We investigated the prevalence and risk factors of BEPs in MSM to inform infection control. METHODS: We conducted a cross-sectional study at a London sexual health clinic between 20/12/2017 and 06/02/2018. Residual rectal swabs from MSM attending for sexually transmitted infection (STI) testing were anonymously tested for a range of BEPs using real-time PCR. A sub-set of samples were tested for the mphA gene (a marker of azithromycin resistance). Results were linked to electronic health records. RESULTS: BEPs were detected in 207 of 2116 participants, giving an overall prevalence of 9.8% (95% CI 8.5%-11.1%) ranging from 0.8% (0.4%-1.2%) for Shigella to 4.9% (4.0%-5.9%) for Enteroaggregative E. coli. MSM with BEPs were more likely to have a history of bacterial STIs (p = 0.010), to report more sexual partners (p<0.001), and among HIV-negative MSM, to report current HIV pre-exposure prophylaxis use (p<0.001). Gastrointestinal symptoms were rare (1.7%) and not associated with BEPs. 41.3% of MSM with BEPs and 14.1% of those without BEPs carried mphA (p<0.001). Among the former, this was associated with a history of bacterial STIs (51.5% vs 31.1%, p = 0.003). CONCLUSIONS: One in ten MSM had a BEP detected and most did not report symptoms. MphA carriage was common, particularly among those with BEPs. Bacterial STI treatment might contribute to selection of resistant gut organisms, emphasising the need for better antimicrobial stewardship.

Effects of COVID-19 Pandemic Response on Service Provision for Sexually Transmitted Infections, HIV, and Viral Hepatitis, England.

Since the coronavirus disease pandemic response began in March 2020, tests, vaccinations, diagnoses, and treatment initiations for sexual health, HIV, and viral hepatitis in England have declined. The shift towards online and outreach services happened rapidly during 2020 and highlights the need to evaluate the effects of these strategies on health inequalities.

Linkage of Whole Genome Sequencing, Epidemiological, and Clinical Data to Understand the Genetic Diversity and Clinical Outcomes of Shigella flexneri among Men Who Have Sex with Men in England.

The public health value of whole genome sequencing (WGS) for Shigella spp. in England has been limited by a lack of information on sexual identity and behavior. We combined WGS data with other data sources to better understand Shigella flexneri transmission in men who have sex with men (MSM). WGS data for all S. flexneri isolates referred to the national reference laboratory were linked to i) clinical and behavioral data collected in seven of 21 health regions in England using a standardized exposure questionnaire and, ii) national HIV surveillance data. We included 926 S. flexneri isolates, of which 43.0% (n = 398) fell phylogenetically within two domestically circulating clades associated with genotypic markers of azithromycin resistance. Approximately one third of isolates in these clades were from people living with HIV, primarily acquired through sex between men. 182 (19.7%) isolates had linked questionnaire data; 88% (84/95) of MSM isolates fell phylogenetically within the domestically circulating clades, while 92% (72/78) of isolates from other cases fell within lineages linked with travel to high-risk regions. There was no evidence of sustained transmission between networks of MSM and the wider community. MSM were more likely to be admitted to hospital and receive antimicrobials. Our study emphasizes the importance of sex between men as a major route of transmission for S. flexneri. Combined WGS, epidemiological and clinical data provide unique insights that can inform contact tracing, clinical management and the delivery of targeted prevention activities. Future studies should investigate why MSM experience more severe clinical outcomes. IMPORTANCE Within the last 2 decades there have been an increasing number of Shigella spp. outbreaks among men who have sex with men (MSM) worldwide. In 2015, Public Health England (PHE) introduced routine whole genome sequencing (WGS) for the national surveillance of Shigella spp. However, the lack of information on sexual identity and behavior has hindered interpretation. Our study illustrates the power of linking WGS data with epidemiological, behavioral, and clinical data. We provide unique population-level insights into different transmission networks that can inform the delivery of appropriate public health interventions and patient management. Furthermore, we describe and compare clinical characteristics and outcomes of S. flexneri infection in MSM and other exposure groups. We found that MSM were more likely to be admitted to hospital and receive antimicrobials, indicating that their infections were potentially more severe. The exact reasons for this are unclear and require further exploration.

What Do Diagnoses of Pelvic Inflammatory Disease in Specialist Sexual Health Services in England Tell Us About Chlamydia Control?

BACKGROUND: Pelvic inflammatory disease (PID) is an outcome measure for the evaluation of chlamydia screening programs. We explore PID diagnoses in specialist sexual health services (SSHSs) in England to inform the evaluation of the National Chlamydia Screening Programme, which was implemented nationally in 2008. METHODS: We conducted descriptive analyses using data on diagnoses of PID-with and without Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC)-by age and year of birth, in SSHSs between 2009 and 2019 from the GUMCAD STI Surveillance System database. Rates were calculated per 100 000 females residing in England. RESULTS: CT screening activity peaked in 2010. The rates of all PID diagnoses decreased between 2009 and 2019 by 39%. CT-associated PID (CT-PID) declined by 58%, and nonspecific PID declined by 37%. GC-PID increased by 34%. CT-PID decreased across all age groups with the highest observed decline, 71%, in 15- to 19-year-olds. A dose-response relationship was observed between CT-PID rates and screening, with rates lowest in those with the greatest exposure to screening. CONCLUSIONS: There was a marked decline in diagnoses of CT-PID, and nonspecific PID, at SSHSs after the introduction of widespread chlamydia screening, whereas GC-PID diagnoses increased. This ecological trend was broadly consistent with what we would have expected to see if widespread screening reduced the incidence of chlamydia-associated PID (and of nonspecific PID), as has been observed in randomized controlled trials of screening.

Persistent Transmission of Shigellosis in England Is Associated with a Recently Emerged Multidrug-Resistant Strain of Shigella sonnei.

Whole-genome sequencing has enhanced surveillance and facilitated detailed monitoring of the transmission of Shigella species in England. We undertook an epidemiological and phylogenetic analysis of isolates from all cases of shigellosis referred to Public Health England between 2015 and 2018 to explore recent strain characteristics and the transmission dynamics of Shigella species. Of the 4,950 confirmed cases of shigellosis identified during this period, the highest proportion of isolates was Shigella sonnei (54.4%), followed by S. flexneri (39.2%), S. boydii (4.1%), and S. dysenteriae (2.2%). Most cases were adults (82.9%) and male (59.5%), and 34.9% cases reported recent travel outside the United Kingdom. Throughout the study period, diagnoses of S. flexneri and S. sonnei infections were most common in men with no history of recent travel abroad. The species prevalence was not static, with cases of S. flexneri infection in men decreasing between 2015 and 2016 and the number of cases of S. sonnei infection increasing from 2017. Phylogenetic analysis showed this recent increase in S. sonnei infections was attributed to a novel clade that emerged from a Central Asia sublineage exhibiting resistance to ciprofloxacin and azithromycin. Despite changes in species prevalence, diagnoses of Shigella infections in England are persistently most common in adult males without a reported travel history, consistent with sexual transmission among men who have sex with men. The trend toward increasing rates of ciprofloxacin resistance in S. sonnei, in addition to plasmid-mediated azithromycin resistance, is of significant public health concern with respect to the transmission of multidrug-resistant gastrointestinal pathogens and the risk of treatment failures.

Use of whole-genome sequencing to identify clusters of Shigella flexneri associated with sexual transmission in men who have sex with men in England: a validation study using linked behavioural data.

Since the 1970s, shigellosis has been reported as a sexually transmissible infection, and in recent years, genomic data have revealed the breadth of Shigella spp. transmission among global networks of men who have sex with men (MSM). In 2015, Public Health England (PHE) introduced routine whole-genome sequencing (WGS) of Shigella spp. to identify transmission clusters. However, limited behavioural information for the cases hampers interpretation. We investigated whether WGS can distinguish between clusters representing sexual transmission in MSM and clusters representing community (non-sexual) transmission to inform infection control. WGS data for Shigella flexneri from August 2015 to July 2017 were aggregated into single linkage clusters based on SNP typing using a range of SNP distances (the standard for Shigella surveillance at PHE is 10 SNPs). Clusters were classified as 'adult male', 'household', 'travel-associated' or 'community' using routine demographic data submitted alongside laboratory cultures. From August 2015 to March 2017, PHE contacted those with shigellosis as part of routine public-health follow-up and collected exposure data on a structured questionnaire, which for the first time included questions about sexual identity and behaviour. The questionnaire data were used to determine whether clusters classified as 'adult male' represented likely sexual transmission between men, thereby validating the use of the SNP clustering tool for informing appropriate public-health responses. Overall, 1006 S. flexneri cases were reported, of which 563 clustered with at least one other case (10-SNP threshold). Linked questionnaire data were available for 106 clustered cases, of which 84.0 % belonged to an 'adult male' cluster. At the 10-SNP threshold, 95.1 % [95 % confidence interval (CI) 88.0-98.1%] of MSM belonged to an 'adult male' cluster, while 73.2 % (95 % CI 49.1-87.5%) of non-MSM belonged to a 'community' or 'travel-associated' cluster. At the 25-SNP threshold, all MSM (95 % CI 96.0-100%) belonged to an 'adult male' cluster and 77.8 % (95 % CI 59.2-89.4%) of non-MSM belonged to a 'community' or 'travel-associated' cluster. Within one phylogenetic clade of S. flexneri, 9 clusters were identified (7 'adult male'; 2 'community') using a 10-SNP threshold, while a single 'adult male' cluster was identified using a 25-SNP threshold. Genotypic markers of azithromycin resistance were detected in 84.5 % (294/348) of 'adult male' cases and 20.9 % (9/43) of cases in other clusters (10-SNP threshold), the latter of which contained gay-identifying men who reported recent same-sex sexual contact. Our study suggests that SNP clustering can be used to identify Shigella clusters representing likely sexual transmission in MSM to inform infection control. Defining clusters requires a flexible approach in terms of genetic relatedness to ensure a clear understanding of underlying transmission networks.

Preparing for PrEP: estimating the size of the population eligible for HIV pre-exposure prophylaxis among men who have sex with men in England.

OBJECTIVES: The size of the population of men who have sex with men (MSM) who may be eligible for HIV pre-exposure prophylaxis (HIV-PrEP) in England remains unknown. To plan for a national PrEP implementation trial, we estimated the number of MSM attending sexual health clinics (SHCs) that may be eligible for HIV-PrEP in England. METHODS: Sexually transmitted infection (STI) surveillance data from 2010 to 2015 from the GUMCAD surveillance system were used to estimate the annual number of HIV-negative MSM who may be eligible for HIV-PrEP in England. Based on national eligibility criteria, we identified HIV-negative MSM attending SHCs with a HIV-negative test in the past year and used diagnosed bacterial STI (past year) in this group as a proxy for condomless sex and eligibility for HIV-PrEP. We estimated HIV incidence per 100 person-years (py) in these groups in 2014. RESULTS: During 2010-2015, the number of HIV-negative MSM attending SHCs with a HIV-negative test in the past year doubled from 14 643 to 29 023, and HIV incidence in this group was 1.9 (95% CI 1.6 to 2.2) per 100 py in 2014. In the same period, the subgroup with a bacterial STI diagnosis (past year), and therefore considered potentially eligible for HIV-PrEP in this analysis, increased from 4365 (30%) to 10 276 (35%). HIV incidence in this subgroup was 3.3 (95% CI 2.7 to 4.0) per 100 py in 2014. CONCLUSIONS: In 2015, approximately 10 000 HIV-negative MSM were considered potentially eligible for HIV-PrEP based on clinic history in GUMCAD. These data were used to inform the initial recruitment target for the PrEP Impact Trial and will inform future evaluations at a population level.

Association between STI and child sexual exploitation in children under 16 years old attending sexual health clinics in England: findings from a case-control study.

OBJECTIVE: Child sexual exploitation (CSE) can be difficult to identify, as there may be few reliable indicators. Although they may be used in decision-making, there is no evidence that STIs are predictors of CSE. We investigated the relationship between STI presentation at sexual health clinics (SHCs) and CSE. METHODS: SHCs with 18 or more children aged 13-15 years old with STI diagnoses in 2012 were identified using the Genitourinary Medicine Clinic Activity Data Set STI Surveillance System. Cases with confirmed bacterial or protozoal STIs were matched by age, gender and clinic with non-STI controls. Lead clinicians were asked to complete an online questionnaire on CSE-related risk factors of cases and controls irrespective of STI presence. Associations between STI outcome and CSE-related risk factors were analysed using conditional logistic regression. RESULTS: Data were provided on 466 children aged 13-15 years old; 414 (89%) were female, 340 (80%) were aged 15, 108 (23%) were aged 14, and 18 (3.9%) were aged 13 years. In matched univariate analysis, an STI diagnosis was significantly associated with 'highly-likely/confirmed' CSE (OR 3.87, p=0.017) and safeguarding concerns (OR 1.94, p=0.022). Evidence of an association between STI diagnosis and 'highly-likely/confirmed' CSE persisted after adjustment for partner numbers and prior clinic attendance (OR 3.85, p=0.053). CONCLUSION: Presentation with bacterial or protozoal STIs in children aged 13-15 years old at SHCs may be considered a potential marker for CSE. It would be prudent to consider CSE, indepth assessment and potential referral for any children under 16 years old presenting with a bacterial or protozoal STI.