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.

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.

Potential cost-effectiveness of community availability of tenofovir, lamivudine, and dolutegravir for HIV prevention and treatment in east, central, southern, and west Africa: a modelling analysis.

BACKGROUND: Post-exposure prophylaxis (PEP) offers protection from HIV after condomless sex, but is not widely available in a timely manner in east, central, southern, and west Africa. To inform the potential pilot implementation of such an approach, we modelled the effect and cost-effectiveness of making PEP consisting of tenofovir, lamivudine, and dolutegravir (TLD) freely and locally available in communities without prescription, with the aim of enabling PEP use within 24 h of condomless sex. Free community availability of TLD (referred to as community TLD) might also result in some use of TLD as pre-exposure prophylaxis (PrEP) and as antiretroviral therapy for people living with HIV. METHODS: Using an existing individual-based model (HIV Synthesis), we explicitly modelled the potential positive and negative effects of community TLD. Through the sampling of parameter values we created 1000 setting-scenarios, reflecting the uncertainty in assumptions and a range of settings similar to those seen in east, central, southern, and west Africa (with a median HIV prevalence of 14·8% in women and 8·1% in men). For each setting scenario, we considered the effects of community TLD. TLD PEP was assumed to have at least 90% efficacy in preventing HIV infection after condomless sex with a person living with HIV. FINDINGS: The modelled effects of community TLD availability based on an assumed high uptake of TLD resulted in a mean reduction in incidence of 31% (90% range over setting scenarios, 6% increase to 57% decrease) over 20 years, with an HIV incidence reduction over 50 years in 91% of the 1000 setting scenarios, deaths averted in 55% of scenarios, reduction in costs in 92% of scenarios, and disability-adjusted life-years averted in 64% of scenarios with community TLD. Community TLD was cost-effective in 90% of setting scenarios and cost-saving (with disability-adjusted life-years averted) in 58% of scenarios. When only examining setting scenarios in which there was lower uptake of community TLD, community TLD is cost-effective in 92% of setting scenarios. INTERPRETATION: The introduction of community TLD, enabling greater PEP access, is a promising approach to consider further in pilot implementation projects. FUNDING: Bill & Melinda Gates Foundation to the HIV Modelling Consortium.

Estimating the hospital costs of care for people living with HIV in England using routinely collected data.

BACKGROUND: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning. METHODS: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations. RESULTS: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions. CONCLUSION: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV-related technologies.

Understanding the Potential Impact of Different Drug Properties on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission and Disease Burden: A Modelling Analysis.

BACKGROUND: The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. METHODS: Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. RESULTS: The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. CONCLUSIONS: Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Deprivation and exposure to public activities during the COVID-19 pandemic in England and Wales.

BACKGROUND: Differential exposure to public activities may contribute to stark deprivation-related inequalities in SARS-CoV-2 infection and outcomes but has not been directly investigated. We set out to investigate whether participants in Virus Watch-a large community cohort study based in England and Wales-reported differential exposure to public activities and non-household contacts during the autumn-winter phase of the COVID-19 pandemic according to postcode-level socioeconomic deprivation. METHODS: Participants (n=20 120-25 228 across surveys) reported their daily activities during 3 weekly periods in late November 2020, late December 2020 and mid-February 2021. Deprivation was quantified based on participants' residential postcode using English or Welsh Index of Multiple Deprivation quintiles. We used Poisson mixed-effect models with robust standard errors to estimate the relationship between deprivation and risk of exposure to public activities during each survey period. RESULTS: Relative to participants in the least deprived areas, participants in the most deprived areas exhibited elevated risk of exposure to vehicle sharing (adjusted risk ratio (aRR) range across time points: 1.73-8.52), public transport (aRR: 3.13-5.73), work or education outside of the household (aRR: 1.09-1.21), essential shops (aRR: 1.09-1.13) and non-household contacts (aRR: 1.15-1.19) across multiple survey periods. CONCLUSION: Differential exposure to essential public activities-such as attending workplaces and visiting essential shops-is likely to contribute to inequalities in infection risk and outcomes. Public health interventions to reduce exposure during essential activities and financial and practical support to enable low-paid workers to stay at home during periods of intense transmission may reduce COVID-related inequalities.

Bayesian inference assessment of protein secondary structure analysis using circular dichroism data - how much structural information is contained in protein circular dichroism spectra?

Circular dichroism spectroscopy is an important tool for determining the structural characteristics of biomolecules, particularly the secondary structure of proteins. In this paper we propose a Bayesian model that estimates the covariance structure within a measured spectrum and quantifies the uncertainty associated with the inferred secondary structures and characteristic spectra associated with each secondary structure type. Furthermore, we used tools from Bayesian model selection to determine the best secondary structure classification scheme and illustrate a technique for comparing whether or not two or more measured protein spectra share the same secondary structure. Our findings suggest that it is not possible to identify more than 3 distinct secondary structure classes from CD spectra above 175 nm. The inclusion of data from wavelengths between 175 and 200 nm did not substantially affect the ability to determine secondary structure fractions.

Pilot phase of an internet-based RCT of HIVST targeting MSM and transgender people in England and Wales: advertising strategies and acceptability of the intervention.

BACKGROUND: The SELPHI study (An HIV Self-Testing Public Health Intervention) is an online randomised controlled trial (RCT) of HIV self-testing (HIVST). The aim of this study was to assess the feasibility of recruiting UK men who have sex with men (cis and trans) and trans women who have sex with men to the SELPHI pilot, and the acceptability of the HIVST intervention used among those randomised to receive a kit. METHODS: A mixed-methods approach to assessing trial feasibility and intervention acceptability was taken, using quantitative data from advertising sources and RCT surveys alongside qualitative data from a nested sub-study. RESULTS: Online recruitment and intervention delivery was feasible. The recruitment strategy led to the registration of 1370 participants of whom 76% (1035) successfully enrolled and were randomised 60/40 to baseline testing vs no baseline testing. Advertising platforms performed variably. Reported HIVST kit use increased from 83% at two weeks to 96% at three months. Acceptability was very high across all quantitative measures. Participants described the instructions as easy to use, and the testing process as simple. The support structures in SELPHI were felt to be adequate. Described emotional responses to HIVST varied. CONCLUSIONS: Recruiting to a modest sized HIVST pilot RCT is feasible, and the recruitment, intervention and HIVST kit were acceptable. Research on support needs of individuals with reactive results is warranted.

Sexual risk reduction interventions for patients attending sexual health clinics: a mixed-methods feasibility study.

BACKGROUND: Sexually transmitted infections (STIs) continue to represent a major public health challenge. There is evidence that behavioural interventions to reduce risky sexual behaviours can reduce STI rates in patients attending sexual health (SH) services. However, it is not known if these interventions are effective when implemented at scale in SH settings in England. OBJECTIVES: The study (Santé) had two main objectives - (1) to develop and pilot a package of evidence-based sexual risk reduction interventions that can be delivered through SH services and (2) to assess the feasibility of conducting a randomised controlled trial (RCT) to determine effectiveness against usual care. DESIGN: The project was a multistage, mixed-methods study, with developmental and pilot RCT phases. Preparatory work included a systematic review, an analysis of national surveillance data, the development of a triage algorithm, and interviews and surveys with SH staff and patients to identify, select and adapt interventions. A pilot cluster RCT was planned for eight SH clinics; the intervention would be offered in four clinics, with qualitative and process evaluation to assess feasibility and acceptability. Four clinics acted as controls; in all clinics, participants would be consented to a 6-week follow-up STI screen. SETTING: SH clinics in England. PARTICIPANTS: Young people (aged 16-25 years), and men who have sex with men. INTERVENTION: A three-part intervention package - (1) a triage tool to score patients as being at high or low risk of STI using routine data, (2) a study-designed web page with tailored SH information for all patients, regardless of risk and (3) a brief one-to-one session based on motivational interviewing for high-risk patients. MAIN OUTCOME MEASURES: The three outcomes were (1) the acceptability of the intervention to patients and SH providers, (2) the feasibility of delivering the interventions within existing resources and (3) the feasibility of obtaining follow-up data on STI diagnoses (primary outcome in a full trial). RESULTS: We identified 33 relevant trials from the systematic review, including videos, peer support, digital and brief one-to-one sessions. Patients and SH providers showed preferences for one-to-one and digital interventions, and providers indicated that these intervention types could feasibly be implemented in their settings. There were no appropriate digital interventions that could be adapted in time for the pilot; therefore, we created a placeholder for the purposes of the pilot. The intervention package was piloted in two SH settings, rather than the planned four. Several barriers were found to intervention implementation, including a lack of trained staff time and clinic space. The intervention package was theoretically acceptable, but we observed poor engagement. We recruited patients from six clinics for the follow-up, rather than eight. The completion rate for follow-up was lower than anticipated (16% vs. 46%). LIMITATIONS: Fewer clinics were included in the pilot than planned, limiting the ability to make strong conclusions on the feasibility of the RCT. CONCLUSION: We were unable to conclude whether or not a definitive RCT would be feasible because of challenges in implementation of a pilot, but have laid the groundwork for future research in the area. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16738765. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 12. See the NIHR Journals Library website for further project information.

Reducing sexually transmitted infections (STIs) is a public health priority. Those most likely to be diagnosed with a STI are young people (aged 16­25 years) and men who have sex with men. Studies in other countries have shown that interventions aimed at changing sexual behaviour (e.g. increasing condom use) can reduce the chance of getting new STIs in patients attending sexual health (SH) clinics. However, it is not clear if these interventions will work in English sexual health clinics, or if they could be implemented within existing resources. This study aimed to find out if effective interventions could be adapted to an English setting and tested this in a randomised trial. The scientific literature was searched for potential interventions and 33 trials were found. Effective methods included videos, digital web-based interventions, self-testing kits and talking sessions (e.g. counselling). Patients and providers were asked which interventions were acceptable and preferences for digital and one-to-one talking interventions were found. Providers suggested that these were feasible to deliver. Data routinely collected from patients (e.g. number of partners) were used to select patients at a higher risk of having a STI, a computerised risk score calculation was developed, and the highest risk group was directed to a one-to-one counselling intervention. There were no appropriate digital interventions available; therefore, a stand-in web page was created to signpost users to appropriate SH resources. This was offered to all patients. The intervention package was piloted in two SH settings rather than the planned four because of a lack of clinic staff time and space. It was planned to follow up a subset of patients from all eight clinics 6 weeks after their visit to collect information on STI diagnoses. Patients were recruited from six clinics, but only 16% of patients completed the survey and returned a sample. It was not possible to conclude definitively whether or not a randomised trial is feasible because of challenges in implementation and recruitment.

Getting the balance right-tackling the obesogenic environment by reducing unhealthy options in a hospital shop without affecting profit.

Background: UK hospitals have been criticized for fuelling obesity by allowing contracts with food retailers selling high fat and high-sugar products on hospital premises. Methods: We assessed the impact for a major retailer of increasing healthy food choices at their Royal Free London NHS Foundation Trust outlet. To assess the impact on sales, profit and acceptability to customers, a multi-component intervention based on behavioural insights theory was enacted over 2 months (November-December 2014) at the Royal Free site WHSmith. Sales data on all food and drink were assessed over three time periods: (i) 2 months immediately prior to, and (ii) immediately after the intervention, and (iii) the equivalent period 10 months later. Acceptability to customers was assessed via questionnaires, and profit assessed as a proxy for retailer satisfaction. Results: Compared to the pre-intervention period, total sales increased immediately after the intervention, and again 10 months after the intervention. Sales of healthier options increased as a proportion of total sales following the intervention, sales of sweets and chocolates decreased, while the relative sales of other items remained similar. Conclusions: We demonstrated that healthier alternatives could be provided in a hospital retail premises without negatively affecting total sales, retailer or customer satisfaction.

Cost-effectiveness of pre-exposure prophylaxis for HIV prevention in men who have sex with men in the UK: a modelling study and health economic evaluation.

BACKGROUND: In the UK, HIV incidence among men who have sex with men (MSM) has remained high for several years, despite widespread use of antiretroviral therapy and high rates of virological suppression. Pre-exposure prophylaxis (PrEP) has been shown to be highly effective in preventing further infections in MSM, but its cost-effectiveness is uncertain. METHODS: In this modelling study and economic evaluation, we calibrated a dynamic, individual-based stochastic model, the HIV Synthesis Model, to multiple data sources (surveillance data provided by Public Health England and data from a large, nationally representative survey, Natsal-3) on HIV among MSM in the UK. We did a probabilistic sensitivity analysis (sampling 22 key parameters) along with a range of univariate sensitivity analyses to evaluate the introduction of a PrEP programme with sexual event-based use of emtricitabine and tenofovir for MSM who had condomless anal sexual intercourse in the previous 3 months, a negative HIV test at baseline, and a negative HIV test in the preceding year. The main model outcomes were the number of HIV infections, quality-adjusted life-years (QALYs), and costs. FINDINGS: Introduction of such a PrEP programme, with around 4000 MSM initiated on PrEP by the end of the first year and almost 40 000 by the end of the 15th year, would result in a total cost saving (£1·0 billion discounted), avert 25% of HIV infections (42% of which would be directly because of PrEP), and lead to a gain of 40 000 discounted QALYs over an 80-year time horizon. This result was particularly sensitive to the time horizon chosen, the cost of antiretroviral drugs (for treatment and PrEP), and the underlying trend in condomless sex. INTERPRETATION: This analysis suggests that the introduction of a PrEP programme for MSM in the UK is cost-effective and possibly cost-saving in the long term. A reduction in the cost of antiretroviral drugs (including the drugs used for PrEP) would substantially shorten the time for cost savings to be realised. FUNDING: National Institute for Health Research.

Liver test abnormalities in patients with HIV mono-infection: assessment with simple noninvasive fibrosis markers.

BACKGROUND: Patients with HIV mono-infection may develop chronic liver disease due to a number of factors including hepatic steatosis. We estimated the prevalence and predictors of hepatic steatosis and fibrosis in a cohort of HIV-mono-infected patients with persistently deranged liver function tests. METHODS: Of 2398 consecutive patients at one UK clinical center, 156 (6.5%) had persistently abnormal transaminases in at least two measurements six months apart. We used APRI and FIB4 scores to determine the presence of significant and/or advanced fibrosis in this group as well as its potential associations. RESULTS: Mean age was 47.5±8.5 years and 91% (142/156) were males. Diabetes mellitus was present in 11% of patients; hypertension in 18%; and dyslipidemia in 52%. Almost all were on antiretroviral therapy (ART) (97%) and most were virologically suppressed (94%). Steatosis was detected by ultrasound in 71% of patients. The prevalence of FIB4≤1.45, 1.46-3.24 and >3.25 was 67%, 29% and 4%, respectively, and that of APRI≤0.5, 0.51-1.49 and >1.5 was 52%, 45% and 3% respectively. In multivariate analysis, only cumulative ART exposure was associated with FIB4>1.45 (odds ratio [OR] 1.008, 95% confidence interval [CI] 1.000-1.016), while APRI>0.5 was associated with higher alanine aminotransferase levels (OR 1.033, 95%CI 1.015-1.510). Twenty patients had a liver biopsy, of whom 13 had non-alcoholic fatty liver disease (NAFLD). CONCLUSIONS: Elevated transaminases are often present in HIV-mono-infected patients and this may be associated with NAFLD and/or ART. Non-invasive screening for the presence of NAFLD and fibrosis in all HIV-mono-infected patients as part of their routine clinical management should be further explored.

UK guideline for the use of HIV Post-Exposure Prophylaxis Following Sexual Exposure, 2015.

We present the updated British Association for Sexual Health and HIV guidelines for HIV post-exposure prophylaxis following sexual exposure (PEPSE). This document includes a review of the current data to support the use of PEPSE, considers how to calculate the risks of infection after a potential exposure, and provides recommendations on when PEPSE should and should not be considered. We also review which medications to use for PEPSE, provide a checklist for initial assessment, and make recommendations for monitoring individuals receiving PEPSE. Special scenarios, cost-effectiveness of PEPSE, and issues relating to service provision are also discussed. Throughout the document, the place of PEPSE within the broader context of other HIV prevention strategies is considered.

Potential impact on HIV incidence of higher HIV testing rates and earlier antiretroviral therapy initiation in MSM.

BACKGROUND: Increased rates of testing, with early antiretroviral therapy (ART) initiation, represent a key potential HIV-prevention approach. Currently, in MSM in the United Kingdom, it is estimated that 36% are diagnosed by 1 year from infection, and the ART initiation threshold is at CD4 cell count 350/µl. We investigated what would be required to reduce HIV incidence in MSM to below 1 per 1000 person-years (i.e. <535 new infections per year) by 2030, and whether this is likely to be cost-effective. METHODS: A dynamic, individual-based simulation model was calibrated to multiple data sources on HIV in MSM in the United Kingdom. Outcomes were projected according to future alternative HIV testing and ART initiation scenarios to 2030, considering also potential changes in levels of condomless sex. RESULTS: For ART use to result in an incidence of close to 1/1000 person-years requires the proportion of all HIV-positive MSM with viral suppression to increase from below 60% currently to 90%, assuming no rise in levels of condomless sex. Substantial increases in HIV testing, such that over 90% of men are diagnosed within a year of infection, would increase the proportion of HIV-positive men with viral suppression to 80%, and it would be 90%, if ART is initiated at diagnosis. The scenarios required for such a policy to be cost-effective are presented. CONCLUSION: This analysis provides targets for the proportion of all HIV-positive MSM with viral suppression required to achieve substantial reductions in HIV incidence.

Socio-economic factors and virological suppression among people diagnosed with HIV in the United Kingdom: results from the ASTRA study.

INTRODUCTION: In the United Kingdom, rates of virological suppression on antiretroviral therapy (ART) are very high, but there remain a small but significant number of people on ART with detectable viraemia. The impact of socio-economic factors on virological suppression has been little studied. MATERIALS AND METHODS: We used data from ASTRA, a cross-sectional, questionnaire study of >3000 individuals from 8 clinics in the United Kingdom in 2011-2012, linked to clinical records to address this question. Included participants had received ART for >6 months with a recorded current viral load (VL) (latest at the time of questionnaire). Participants provided data on demographic factors: gender, sexual orientation, ethnicity and age; and socio-economic factors: UK birth/English reading ability, employment, housing, education and financial hardship. To assess non-adherence, participants were asked if in the past 3 months, they had missed ART for ≥2 days at a time. Virological suppression was defined as VL≤50 cps/mL. For each socio-economic factor, we calculated prevalence ratios using modified Poisson regression, first adjusting for demographic factors, then also for non-adherence. RESULTS: A total of 2445 people fulfilled the inclusion criteria (80% male, 69% MSM, median age: 46 years, median CD4 count: 556 cells/mm(3)); 10% (234/2445) had VL>50 cps/mL. After adjusting for demographic factors, non-fluent English, not being employed, not home owning, education below university level and increasing financial hardship were each associated with higher prevalence of VL>50 cps/mL. Additional adjustment for non-adherence largely attenuated each association, but did not fully explain them (see Table 1). After adjustment for non-adherence and demographic factors, younger age was also associated with VL>50 cps/mL: for each additional 10 years an individual was 0.80 (95% CI 0.70-0.92) times as likely to have VL>50 cps/mL (p=0.0019). Adjusted prevalence ratios for VL>50cps/mL were 0.91 (0.62-1.34) for women and 1.25 (0.85-1.84) for non-MSM men versus MSM, and 1.29 (0.92-1.80) for white versus non-white people. CONCLUSIONS: Among people on ART in the United Kingdom, the proportion with detectable VL is low. Poorer socio-economic status is associated with increased probability of virological non-suppression. It is likely that much of this association is mediated through difficulties in taking ART. Emphasis should be put on aiding the adherence of people in these higher risk groups.

Partners of people on ART - a New Evaluation of the Risks (The PARTNER study): design and methods.

BACKGROUND: It is known that being on antiretroviral therapy reduces the risk of HIV transmission through sex. However it remains unknown what the absolute level of risk of transmission is in a person on ART with most recent measured HIV plasma viral load<50 c/mL in the absence of condom use. There are no data on risk of transmission for anal sex in MSM when the index partner is on ART. METHODS/DESIGN: The PARTNER study is an international, observational multi-centre study, taking place from 2010 to 2014 in which HIV serodifferent partnerships who at enrolment reported recently having had condom-less vaginal or anal sexual intercourse are followed over time, with 46 monthly reporting of transmission risk behaviour through a confidential self completed risk behaviour questionnaire and with 46 monthly HIV testing for the HIV negative partner. The objective is to study (i) the risk of HIV transmission to partners, in particular in partnerships that continue not to use condoms consistently and the HIV-positive partner is on therapy with a viral load<50 copies/mL and (ii) why some partnerships do not use condoms, to describe the proportion who begin to adopt consistent condom use, and factors associated with this. For any negative partner who becomes infected phylogenetic analysis will be used following anonymisation of the samples to assess if transmission had been from the HIV infected partner. DISCUSSION: This observational study will provide missing information on the absolute risk of HIV transmission for both vaginal and anal sex when the index case is on ART with a VL<50 copies/mL in the absence of condom use.

Probing the structure of long DNA molecules in solution using synchrotron radiation linear dichroism.

Linear dichroism (LD), a spectroscopic method for aligned samples, has been used with a synchrotron radiation source to reveal insights into the structure and stability of DNA with increasing salt concentrations (thus stabilizing the base pairing) and increasing temperature while remaining below the melting point (thus destabilizing the base pairing). Measurements have been made from 350 nm to 182 nm, and the spectral changes observed quantified using a Bayesian Markov chain Monte Carlo (MCMC) algorithm, which uses statistical methods to fit to experimental data. Based on literature H-D exchange experiments, we surmise that the cause of the spectral variations is the induction of transient single stranding of tracts in the DNA polymer, particularly those with significant content of the weaker AT base pairs. More detailed analysis of the LD data will require better nucleotide transition polarization assignments.