Association between rectal gonorrhoea and HIV incidence in men who have sex with men: a meta-analysis.

BACKGROUND: Incidence of rectal gonorrhoea (GC) has been hypothesised as a correlate of HIV exposure in prevention trials of men who have sex with men (MSM). High rectal GC incidence in MSM trials of new biomedical prevention drugs may provide supportive evidence for ongoing HIV risk. Empirical evidence of correlation between rectal GC and HIV incidence is needed to assess whether high rectal GC rates reliably correlate with high risk of HIV. METHODS: Rectal GC and HIV are routinely tested in sexual health clinics (SHCs) throughout England. Through routine surveillance data collected at visits to SHCs, we assessed HIV incidence and new rectal GC diagnoses in repeat visits by HIV-negative MSM between 2011 and 2018, predating widespread roll-out of pre-exposure prophylaxis. Meta-analysis regression assessed population-level association between HIV and rectal GC incidence over time. FINDINGS: Between 2011 and 2018, HIV and rectal GC incidence was assessed in 541 056 HIV-negative MSM attending SHCs in England. HIV incidence among MSM attending SHCs fell from 1.26/100 person-years (PYs) in 2011 to 0.28/100 PYs in 2018. Rectal GC rates increased from 3.5/100 PYs to 11.1/100 PYs over the same period. The rate of HIV incidence decreased by 22.3% for each percent increase in rectal GC (95% CI -30.8 to -14.7, p<0.001). INTERPRETATION: Among the population of MSM attending SHCs in England, rectal GC rates increased substantially while HIV incidence rates decreased between 2011 and 2018. HIV incidence likely decreased through expanded HIV testing, prompt antiretroviral treatment (ART) initiation and increased viral suppression in persons living with HIV, interventions that did not decrease rectal GC. Rectal GC may not be an ideal proxy for HIV incidence in trials, as HIV exposure risk is complex and context dependent, given effective HIV prevention interventions in MSM.

Differential impact of quarantine policies for recovered COVID-19 cases in England: a case cohort study of surveillance data, June to December 2020.

BACKGROUND: From 12th March 2020, individuals in England were advised to quarantine in their home if a household member tested positive for SARS-CoV-2. A mandatory isolation period of 10 days was introduced on 28th September 2020 and applied to all individuals with COVID-19. We assessed the frequency, timing, and characteristics of recovered COVID-19 cases requiring subsequent quarantine episodes due to household re-exposure. METHODS: In this case cohort study, all laboratory-confirmed COVID-19 cases notified in England (29th June to 28th December 2020) were analysed to identify consecutive household case(s). Multivariable logistic regression was used to determine associations between case characteristics and need to quarantine following recent infection (within 28 days of diagnosis). RESULTS: Among 1,651,550 cases resident in private dwellings and Houses of Multiple Occupancy (HMOs), 744,548 (45.1%) were the only case in their home and 56,179 (3.4%) were succeeded by further household cases diagnosed within 11-28 days of their diagnosis. Of 1,641,412 cases arising in private homes, the likelihood of further household cases was highest for Bangladeshi (aOR = 2.20, 95% CI = 2.10-2.31) and Pakistani (aOR = 2.15, 95% CI = 2.08-2.22) individuals compared to White British, as well as among young people (17-24y vs. 25-64y; aOR = 1.19, 95% CI = 1.16-1.22), men (vs. women; aOR = 1.06, 95% CI = 1.04-1.08), London residents (vs. Yorkshire and Humber; aOR = 1.57, 95% CI = 1.52-1.63) and areas of high deprivation (IMD 1 vs. 10; aOR = 1.13, 95% CI = 1.09-1.19). CONCLUSION: Policies requiring quarantine on re-exposure differentially impact some of the most disadvantaged populations. Quarantine exemption for recently recovered individuals could mitigate the socioeconomic impact of responses to COVID-19 or similar infectious disease outbreaks.

Minimum dataset for monitoring national human immunodeficiency virus pre-exposure prophylaxis (HIV PrEP) programmes: a five-nation consensus, 2019.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP), the use of antiretroviral medication to prevent HIV acquisition, is a highly effective biomedical prevention tool. The World Health Organization (WHO) recommends PrEP for people at substantial risk of HIV infection, as part of combination prevention, and highlights the need for robust evaluation of PrEP programmes. Based on suggested WHO core indicators, we created a concise set of HIV PrEP-related dataset variables, to harmonise the monitoring and evaluation of PrEP programmes across five closely related nations (England, Northern Ireland, Ireland, Scotland and Wales). The dataset is based on the PrEP cascade and is intended to represent the minimum variables needed for reporting and comparison of meaningful data at national and multinational level. The dataset can be modified for settings with different health and surveillance systems. It is intended for public health, academic, clinical and health planning, and public audiences. Here we describe the dataset and illustrate its use with data from the first year of the Scottish National PrEP programme.

Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic.

Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s.

Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction.

BACKGROUND: Drug-resistant minority variants (DRMinVs) detected in patients who recently acquired human immunodeficiency virus type 1 (HIV-1) can be transmitted, generated de novo through virus replication, or technical errors. The first form is likely to persist and result in treatment failure, while the latter two could be stochastic and transient. METHODS: Ultradeep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the United Kingdom was performed to detect DRMinVs at a mutation frequency between 2% and 20%. Sequence alignments including >110 000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD), linked to epidemiological and clinical data from the HIV and AIDS Reporting System, were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events. RESULTS: Drug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n = 48; 72.7%) and DRMinV (n = 63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harbored the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (P < .00001, Fisher exact test). Evidence of likely direct transmission of DRMajVs was observed for 25/66 (37.9%), whereas none were observed for the DRMinVs (P < .00001). CONCLUSIONS: Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals.

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.

Current experiences of accessing and using HIV pre-exposure prophylaxis (PrEP) in the United Kingdom: a cross-sectional online survey, May to July 2019.

The 2019 online pre-exposure prophylaxis (PrEP) user survey in the United Kingdom was conducted to assess HIV PrEP access, and user characteristics. One in five respondents continued experiencing difficulties accessing PrEP; users were almost exclusively gay or bisexual men at high risk of HIV. The majority obtained PrEP through health service clinics and rated PrEP positively. High STI rates were reported among users. Renal and sexual health checks are advised for those sourcing PrEP privately.

Prevalence of new variants of Chlamydia trachomatis escaping detection by the Aptima Combo 2 assay, England, June to August 2019.

We identified two new Chlamydia trachomatis (CT) variants escaping Aptima Combo 2 (AC2) assay detection, in clinical specimens of two patients. One had a C1514T mutation the other a G1523A mutation, both within the AC2 23S rRNA target region. The prevalence of such variants among persons tested for CT in England was estimated to be fewer than 0.003%.

Extending Bayesian back-calculation to estimate age and time specific HIV incidence.

CD4-based multi-state back-calculation methods are key for monitoring the HIV epidemic, providing estimates of HIV incidence and diagnosis rates by disentangling their inter-related contribution to the observed surveillance data. This paper, extends existing approaches to age-specific settings, permitting the joint estimation of age- and time-specific incidence and diagnosis rates and the derivation of other epidemiological quantities of interest. This allows the identification of specific age-groups at higher risk of infection, which is crucial in directing public health interventions. We investigate, through simulation studies, the suitability of various bivariate splines for the non-parametric modelling of the latent age- and time-specific incidence and illustrate our method on routinely collected data from the HIV epidemic among gay and bisexual men in England and Wales.

Enhanced surveillance of HIV-1 drug resistance in recently infected MSM in the UK.

OBJECTIVES: To determine the prevalence of inferred low-frequency HIV-1 transmitted drug resistance (TDR) in MSM in the UK and its predicted effect on first-line therapy. METHODS: The HIV-1 pol gene was amplified from 442 newly diagnosed MSM identified as likely recently infected by serological avidity testing in 2011-13. The PCR products were sequenced by next-generation sequencing with a mutation frequency threshold of >2% and TDR mutations defined according to the 2009 WHO surveillance drug resistance mutations list. RESULTS: The majority (75.6%) were infected with subtype B and 6.6% with rare complex or unique recombinant forms. At a mutation frequency threshold of >20%, 7.2% (95% CI 5.0%-10.1%) of the sequences had TDR and this doubled to 15.8% (95% CI 12.6%-19.6%) at >2% mutation frequency (P < 0.0001). The majority (26/42, 62%) of low-frequency variants were against PIs. The most common mutations detected at >20% and 2%-20% mutation frequency differed for each drug class, these respectively being: L90M (n = 7) and M46IL (n = 10) for PIs; T215rev (n = 9) and D67GN (n = 4) for NRTIs; and K103N (n = 5) and G190E (n = 2) for NNRTIs. Combined TDR was more frequent in subtype B than non-B (OR = 0.38; 95% CI = 0.17-0.88; P = 0.024) and had minimal predicted effect on recommended first-line therapies. CONCLUSIONS: The data suggest differences in the types of low-frequency compared with majority TDR variants that require a better understanding of the origins and clinical significance of low-frequency variants. This will better inform diagnostic and treatment strategies.

Fall in new HIV diagnoses among men who have sex with men (MSM) at selected London sexual health clinics since early 2015: testing or treatment or pre-exposure prophylaxis (PrEP)?

Since October 2015 up to September 2016, HIV diagnoses fell by 32% compared with October 2014-September 2015 among men who have sex with men (MSM) attending selected London sexual health clinics. This coincided with high HIV testing volumes and rapid initiation of treatment on diagnosis. The fall was most apparent in new HIV testers. Intensified testing of high-risk populations, combined with immediately received anti-retroviral therapy and a pre-exposure prophylaxis (PrEP) programme, may make elimination of HIV achievable.

Can we use postal surveys with anonymous testing to monitor chlamydia prevalence in young women in England? Pilot study incorporating randomised controlled trial of recruitment methods.

OBJECTIVES: Chlamydia prevalence in the general population is a potential outcome measure for the evaluation of chlamydia control programmes. We carried out a pilot study to determine the feasibility of using a postal survey for population-based chlamydia prevalence monitoring. METHODS: Postal invitations were sent to a random sample of 2000 17-year-old to 18-year-old women registered with a general practitioner in two pilot areas in England. Recipients were randomised to receive either a self-sampling kit (n=1000), a self-sampling kit and offer of £5 voucher on return of sample (n=500) or a self-sampling kit on request (n=500). Participants returned a questionnaire and self-taken vulvovaginal swab sample for unlinked anonymous Chlamydia trachomatis testing. Non-responders were sent a reminder letter 3 weeks after initial invitation. We calculated the participation rate (number of samples returned/number of invitations sent) and cost per sample returned (including cost of consumables and postage) in each group. RESULTS: A total of 155/2000 (7.8%) samples were returned with consent for testing. Participation rates varied by invitation group: 7.8% in the group who were provided with a self-sampling kit, 14% in the group who were also offered a voucher and 1.0% in the group who were not sent a kit. The cost per sample received was lowest (£36) in the group who were offered both a kit and a voucher. CONCLUSIONS: The piloted survey methodology achieved low participation rates. This approach is not suitable for population-based monitoring of chlamydia prevalence among young women in England. STUDY REGISTRATION NUMBER: (UKCRN ID 10913).

Declining genital Warts in young women in england associated with HPV 16/18 vaccination: an ecological study.

BACKGROUND: Diagnoses of genital warts (GW) in genitourinary medicine (GUM) clinics have been increasing in England for many years. In 2008, an HPV immunization program began with a bivalent vaccine (Cervarix). This was expected to markedly reduce infections and disease due to human papillomavirus (HPV) 16/18 but not HPV 6/11 infections or disease. However, from 2009 to 2011 there were decreases in reported diagnoses of GW in young females at GUM clinics. METHODS: Using data from GUM clinics and a sample of general practices (GPs) throughout England, we analyzed rates of GW diagnoses by age, year of diagnosis, and estimated immunization coverage. RESULTS: The overall reduction in GW diagnoses at GUM clinics between 2008 and 2011 was 13.3% among 16- to 19-year-old females, with the greatest decline of 20.8% in 17-year-olds. Declines were positively associated with estimated immunization coverage. A similar pattern was seen in GP diagnoses, but not among older women, and for other GUM consultations. CONCLUSIONS: Several factors might contribute to declines in GW. However, the size and pattern of the declines strongly suggest that we are observing an unexpected, moderately protective effect of HPV 16/18 vaccination against GW.

Repeat genital Chlamydia trachomatis testing rates in young adults in England, 2010.

OBJECTIVES: To explore patterns of repeat chlamydia testing among young people in England and factors associated with testing positive at repeat test. METHODS: We analysed chlamydia testing among 15 to 24-year-olds in England in a single calendar year (2010) using data from the genitourinary medicine clinic activity dataset (GUMCAD) and tests reported through the National Chlamydia Screening Programme (NCSP). Case records were linked using patient clinic numbers (GUMCAD), or by matching date of birth, gender and postcode (NCSP). Individuals could not be linked between datasets. The incidence of repeat testing was estimated using survival analysis. Risk factors for testing positive at repeat test were explored using multivariable logistic regression. RESULTS: 1 235 058 tests in the NCSP dataset and 502 095 in GUMCAD were included. The incidence of repeat testing was 18.4 and 26.1 per 100 person years in the NCSP dataset and GUMCAD respectively. Among NCSP repeat tests, the proportion testing positive was higher in those reporting recent change of sexual partner (adjusted OR males 1.44; females 1.52), and among those with a positive compared to a negative baseline test (adjusted OR males 2.57; females 1.95). CONCLUSIONS: We observed moderate levels of repeat testing within a year. Considering the frequency of partner change among young people, more could be done to encourage re-testing upon change of sexual partner. Increasing re-testing following a positive test could probably identify unresolved or repeat infections that may otherwise go untreated. Work to establish the optimum approach to repeat testing in England is now warranted.

Non-disclosure of HIV status in UK sexual health clinics--a pilot study to identify non-disclosure within a national unlinked anonymous seroprevalence survey.

OBJECTIVES: To identify if HIV-infected individuals attending genitourinary clinics in the UK are not disclosing their HIV status, and to examine the potential utility of drug detection as a method to indicate non-disclosure. METHODS: HIV-positive samples from the unlinked anonymous seroprevalence survey from one London centre in 2009 had viral load (VL) assays performed to identify samples with VL below the level of detection (50 copies/ml, VLBLD) or <1000 copies/ml. After data matching, known HIV positives were excluded and the remaining samples analysed for the presence of a panel of antiretroviral drugs. RESULTS: Of 130 HIV-positive samples with sufficient clinical information and not undergoing an HIV test, 18 were classified as remaining undiagnosed after the clinic visit. Thirteen (72%, 95% CI: 47% to 90%) had a VLBLD (n=11) or VL <1000 copies/ml (n=2). Eight had sufficient volume to undergo ARV testing, and all were positive for the presence of drug; all with therapeutic levels of clinically appropriate combinations. CONCLUSIONS: Non-disclosure of HIV status occurs among individuals attending sexual health services in the UK. This study demonstrates the feasibility and utility of using both VL and ARV assays in serum samples. Furthermore, the close correlation of detection of ARV with VLBLD suggests drug detection would be a useful tool to monitor non-disclosure prospectively, thus enabling the use of stored serum samples in future studies. The extent to which these findings can be extrapolated to other settings, and the potential impact of non-disclosure on undiagnosed estimates warrants urgent prospective study.

Audit of HIV testing frequency and behavioural interventions for men who have sex with men: policy and practice in sexual health clinics in England.

BACKGROUND: National guidance recommends targeted behavioural interventions and frequent HIV testing for men who have sex with men (MSM). We reviewed current policy and practice for HIV testing and behavioural interventions (BI) in England to determine adherence to guidance. METHODS: 25 sexual health clinics were surveyed using a semistructured audit asking about risk ascertainment for MSM, HIV testing and behavioural intervention policies. Practice was assessed by reviewing the notes of the first 40 HIV-negative MSM aged over 16 who attended from 1 June 2010, in a subset of 15 clinics. RESULTS: 24 clinics completed the survey: 18 (75%) defined risk for MSM and 17 used unprotected anal intercourse (UAI) as an indication of high risk. 21 (88%) offered one or more structured BI. Of 598 notes reviewed, 199 (33%) MSM reported any UAI. BI, including safer sex advice, was offered to and accepted by 251/598 (42%) men. A low proportion of all MSM (52/251: 21%) accepted a structured one-to-one BI as recommended by national guidance and uptake was still low among higher risk MSM (29/107: 27%). 92% (552/598) of men had one or more HIV test over a 1-year period. CONCLUSIONS: In 2010, the number of HIV tests performed met the national minimum standard but structured behavioural interventions were being offered to and accepted by only a small proportion of MSM, including those at a higher risk of infection. Reasons for not offering behavioural interventions to higher risk MSM, whether due to patient choice, a lack of staff training or resource shortage, need to be investigated and addressed.

The effect of combination prevention strategies on HIV incidence among gay and bisexual men who have sex with men in the UK: a model-based analysis.

BACKGROUND: In the UK, the number of new HIV diagnoses among gay and bisexual men who have sex with men (GBMSM) has decreased substantially. We aimed to understand the contribution of different interventions in reducing HIV incidence so far; to estimate future HIV incidence with continuation of current policies and with further scaling up of current interventions; and to estimate the maximum additional annual cost that should be spent towards these interventions for them to offer value for money. METHODS: We calibrated a dynamic, individual-based, stochastic simulation model, the HIV Synthesis Model, to multiple sources of data on HIV among GBMSM aged 15 years or older in the UK. Primarily these were routine HIV surveillance data collected by the UK Health Security Agency. We compared HIV incidence in 2022 with the counterfactual incidence: if HIV testing rates stopped increasing in 2012 and the policy of antiretroviral therapy (ART) at diagnosis was not introduced in mid-2015; if pre-exposure prophylaxis (PrEP) was not introduced; if condom use was low from 2012 in all GBMSM, at levels similar to those observed in 1980; and in the first and second scenario combined. We also projected future outcomes under the assumption of continuation of current policies and considering increases in PrEP and HIV testing uptake and a decrease in condomless sex. FINDINGS: Our model estimated a 77% (90% uncertainty interval [UI] 61-88) decline in HIV incidence since around 2014, with an estimated 597 infections ([90% UI 312-956]; 1·1 per 1000 person-years [90% UI 0·6-1·8]) in men aged 15-64 years in 2022. Both PrEP introduction and increased HIV testing with ART initiation at diagnosis each had a substantial effect on HIV incidence. Without PrEP introduction, we estimate there would have been 2·16 times the number of infections that actually occurred (90% UI 1·06-3·75) between 2012 and 2022; without increased HIV testing and ART initiation at diagnosis there would have been 2·18 times the number of infections that actually occurred (1·18-3·60), and if condomless sex was at the levels before the HIV epidemic, there would have been 2·27 times the number of infections that actually occurred (0·9-5·4). If rates of testing, ART use, and PrEP use remain as they are currently, there is a predicted decline in incidence to 388 HIV infections in 2025 (90% UI 226-650) and to 263 (137-433) in 2030. Increases in HIV testing and PrEP use were predicted to accelerate the decline in HIV incidence. Given the quality-adjusted life-year (QALY) benefit and a cost-effectiveness threshold of £30 000 per QALY gained, in order to be cost-effective an additional £1·62 million could be spent per year to increase testing levels by 34% (90% UI 25-46) and PrEP use by 55% (10-107). To achieve that, a 16% reduction in the cost of delivery of testing and PrEP would be required. INTERPRETATION: Combination prevention, including a PrEP strategy, played a major role in the reduction in HIV incidence observed so far in the UK among GBMSM. Continuation of current activities should lead to a continued decline; however, it is unlikely to lead to reaching the target of fewer than 50 HIV infections per year among GBMSM by 2030. It will be important to reduce costs for testing and PrEP for their continued expansion to be cost-effective. FUNDING: National Institute for Health Research under its Programme Grants for Applied Research Programme and Medical Research Council-UK Research and Innovation.

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.

Large-scale immunohistochemical examination for lymphoreticular prion protein in tonsil specimens collected in Britain.

There have been 173 cases of variant Creutzfeldt-Jakob disease (vCJD) in the UK, as of 5 July 2010, as a result of the bovine spongiform encephalopathy epidemic. The number of individuals subclinically infected with vCJD, and thus the eventual number of cases, remains, however, uncertain. In an attempt to address this problem, 63,007 tonsil tissue specimens were previously tested by enzyme immunoassay (EIA) for the presence of disease-related prion protein (PrP(res)) and found to be negative. To confirm the reliability of this result, all those in the birth cohort most at risk (1961-1985) and a few others, including controls, have now been tested by immunohistochemistry (IHC). Histological slides were prepared from 10,075 anonymized formalin-fixed, paraffin-embedded tissues and examined for PrP(res) with two anti-prion protein antibodies, ICMS35 and KG9. One specimen showed a single strongly positive follicle with both antibodies, on two slides from adjacent sections. As this specimen was negative when it was further investigated by EIA, IHC, and immunoblotting, it is unclear whether the patient from whom the tonsil came will go on to develop vCJD. If, however, this is the case, then a finding of 1 out of 9160 gives a prevalence of disease-related prion protein in the British population of 109 per million, with a 95% confidence interval (CI) of 3-608 per million, which is not statistically different (exact p = 0.63) from population prevalence estimates based on finding three positives out of 10 278 in a previous IHC study of appendix tissue. If this is not the case, a finding of 0 out of 9160 gives a prevalence of 0-403 per million (95% CI) for the 1961-1985 cohort, which is also not different (exact p = 0.25) from previous population prevalence estimates. Therefore, the results of this work could be summarized as finding, by IHC, no or one vCJD-positive individual.