Impact case study database

Evidence from the UCL-led PROUD and START studies (the latter co-led with four other universities) have led to changes in clinical guidelines in the UK and internationally, preventing thousands of new infections and transforming the futures of millions more people living with HIV.

UK clinical guideline changes as a direct result of the UCL work

The British HIV Association (BHIVA) updated its treatment guidelines in 2015 (co-authored by UCL’s Professor Andrew Phillips), to recommend that people diagnosed with HIV should ‘begin ART immediately, regardless of CD4 count’ in both chronic HIV and in primary treatment of HIV [S1], underpinned by the START findings [R1]. BHIVA published the PrEP guidelines in 2018, together with the British Association of Sexual Health and HIV [S2]. UCL’s Dr Valentina Cambiano and Professor Sheena McCormack were among the co-authors of the guideline and PROUD findings are embedded throughout the recommendations as key evidence. This includes citation of [R2] as underpinning evidence to recommend that PrEP should be offered to MSM and trans women at high risk of HIV infection, on PrEP dosing schedules and lead-in times, and contributed to the guidance on adherence to PrEP including support and education, and the settings and context for administering PrEP [S2].

Following the change in treatment guidelines, based on the START trial, the proportion of MSM with HIV who have undetectable viral load (meaning their infection is fully controlled and they are not sexually infectious) was estimated by Public Health England (PHE) to have increased from 48% in 2011 to 87% in 2017 in their report ‘Progress towards ending the HIV epidemic in the UK’ [S3]. Changes to clinical practice as a result of the START and PROUD findings feature prominently in this report, which states: “The progressive implementation of combination HIV prevention is the principal explanation for the fall in HIV incidence in gay and bisexual men since 2012… Current key components of combination HIV prevention in the UK include: condom provision, pre-exposure prophylaxis (PrEP), expanded HIV testing and prompt initiation of antiretroviral therapy (ART) after diagnosis.” [S3].

UK roll-out of PrEP: Early use of PrEP was almost entirely confined to those individuals enrolled in the UCL-led PROUD trial itself. From 2017, PrEP has been available for free through the PrEP Impact Study, which includes UCL’s Dr Richard Gilson and Professor Sheena McCormack among its co-investigators, and which has informed planning of the PrEP programme in England. In March 2020, the Department of Health and Social Care announced that PrEP would be provided by the NHS: “Local authorities will receive GBP16m in 2020 to 2021 to deliver the preventative HIV treatment PrEP. The funding from the Department of Health and Social Care will ensure anyone who is at a high risk of contracting HIV will receive PrEP from their local sexual health clinic to reduce their risk of getting the virus.” In October 2020, the English Department of Health made available a PrEP grant to support local authorities in England to deliver routine commissioning of PrEP in 2020 to 2021. PrEP has been available as part of a trial since 2017 and on NHS prescription (generic versions of the drug) in Wales since 2018 according to Public Health Wales; as part of a pilot trial in Northern Ireland since 2018 overseen by Health and Social Care in Northern Ireland; and has been prescribed to anyone at high risk of HIV infection by the NHS in Scotland since 2017 [S4]. In December 2020, the AIDS Vaccine Advocacy Coalition (AVAC)’s PrEP Watch Initiative estimated that between 17,500 and 18,500 people are now receiving PrEP in the UK [S4].

Dramatic reduction of new diagnoses in MSM observed in the UK: The UCL-led team estimated, through modelling, that the number of incident cases of HIV in MSM in England and Wales was approximately 3,500 in 2015, although PHE had slightly lower estimates of 2,500 from a separate modelling exercise. Using the more conservative figure from the latter approach, the combined impact of ART for prevention and PrEP have resulted in an 71% reduction in HIV incidence among MSM to 800 cases, as stated in PHE’s 2019 report ‘HIV in the United Kingdom: Towards Zero HIV transmissions by 2030’: “ Evidence from a series of randomised-controlled trials, including the jointly PHE-sponsored and partially PHE-funded PROUD Trial, showed that when PrEP is taken consistently, it is highly effective at protecting people who are at a high risk of acquiring HIV.” [S5].

Various clinic-based studies have documented declines of up to 80% in new HIV diagnoses since 2015, including a 2017 study published in Eurosurveillance of HIV diagnoses in MSM following adoption of the new guidelines. This reported a 32% annual fall in diagnoses in selected London clinics in 2015 to 2016 compared with 2014 to 2015. This fall coincided with higher HIV testing and rapid initiation of treatment. The authors conclude: “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.” [S6].

No studies have suggested that condom use has increased during this period, or that any other prevention mechanisms might have operated. While the relative impact of ART for prevention and PrEP is uncertain, it is clear that PROUD and START have contributed substantially to changes in policy and practice that have resulted in more than a 50% reduction in the number of new infections in MSM in the UK [S3], [S5], [S6], [S7].

International guideline changes and global uptake of PrEP

START and PROUD have also influenced World Health Organization’s ‘Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV’ (2015), which states: “The PROUD study, conducted in the United Kingdom and designed to mimic real-life settings, demonstrated that PrEP is feasible and effective and is not associated with significant changes in behavioural risk.” [S8]. The studies also influenced a 2017 update to the United States Centers for Disease Control (CDC) guideline on PrEP for the prevention of HIV infection, which cites PROUD as a key piece of evidence for the safety and efficacy of antiretroviral prophylaxis [S9]. Both studies led to changes in guidelines, respectively to initiate ART immediately in all people with HIV diagnosed and to recommend PrEP use in HIV negative MSM to prevent HIV.

PrEP first became available through self-purchase online from global pharmacies, and clinics began to actively promote and support use from September 2015, working closely with community organisations. Data collected by the World Health Organization, published in July 2019, for 194 WHO Member States – including 137 low- and middle-income countries (LMICs) – estimated that, by the end of 2020, 95% of all LMICs would have adopted the policy of treating everyone diagnosed with HIV, 115 (84%) LMICs had already put the ‘treat all’ policy fully into practice and five (4%) LMICs would have implemented this policy in the majority of treatment sites [S10]. The 'treat all' policy has been adopted globally and affects 99% of people living with HIV. According to UNAIDS, “In 2019, 25.4 million [24.5 million–25.6 million] people were accessing antiretroviral therapy, up from 6.4 million [5.9 million–6.4 million] in 2009.” [S11]. The guideline change as a result of the START trial made a significant contribution to this increase.

Summary: Through two ground-breaking randomised studies, UCL researchers have proven that PrEP is highly effective in reducing the incidence of HIV among MSM, and that starting ART in HIV-positive people at an earlier stage (when their immune systems are relatively preserved) can halve their later risk of dying or developing serious disease. These two findings have had a direct and powerful influence on clinical guidelines across the world and have changed the futures of millions of people who would otherwise have become infected with HIV, lived shorter lives or developed serious diseases.

Cardiovascular diseases are the most common cause of death worldwide, responsible for an estimated 31% of all deaths, according to the World Health Organization. UCL research between 2014 and 2020, led by Professor Hemingway, has made novel use of large-scale health records data to gain several important insights into the diagnosis and treatment of the most common cardiovascular diseases: high blood pressure, coronary disease, heart attack and atrial fibrillation. His insights have challenged the status quo, shaped policy, and informed improvements in care for millions of patients worldwide.

The impacts started with a radical change in the standard method for diagnosis of coronary disease, in people with stable (non-emergency) chest pain . Research [R1] led by Hemingway and colleagues at QMUL was cited 16 times in the NICE Guidelines Committee on Chest pain (CG95) [S1], which recommended that exercise ECG should no longer be the standard diagnostic procedure. Hemingway was a member of this NICE guideline committee. Each year since 2014, approximately 100,000 new patients are seen in the NHS with suspected stable coronary disease. Subsequent near-complete abandonment of exercise ECG has allowed an estimated 15,000 more people per year to be diagnosed with coronary disease - earlier and with greater accuracy - by CT angiography. This, in turn, enables sooner treatment with secondary preventative medication (such as aspirin, statins or beta blockers), which is estimated to have averted 1,100 fatal and non-fatal cardiovascular events per year.

Hemingway’s UCL hypertension research was cited as observational evidence informing the decision to make one of the most significant changes in the international clinical guidelines [S2, S3], for blood pressure management in recent years: lowering the blood pressure thresholds at which hypertension is diagnosed from ≥140 systolic or ≥90mmHg diastolic to ≥130 systolic or ≥80mmHg diastolic [R2]. As a result, a larger proportion of the general population are now eligible for drug and other interventions to reduce risks of heart attack and stroke which are caused by high blood pressure. Health care professionals have benefitted from new, clear guidance on how to manage such patients. This major change in clinical guidelines has been estimated to increase by 4,200,000 the number of US adults now diagnosed and recommended for blood pressure-lowering medication, compared with the previous guidelines in 2003 [S4].

Further research from UCL in 2016 has challenged the status quo of ‘gender blind’ treatment of the most common heart rhythm disorder, atrial fibrillation. This evidence on safe targeting of oral anticoagulants in women with atrial fibrillation [R3] was solely responsible for changing major international clinical guidelines [S5, S6]. The 2012 guidelines did not offer sex-specific thresholds of risk in the prescribing of anti-coagulants for preventing stroke; but it was known that men are at greater risk of stroke than women. Based on new UCL evidence, the 2016 European guidelines were then changed to explicitly recommend anti-coagulation to women with a score of ≥2. There are an estimated 5 million women with atrial fibrillation in Europe, about 7.4% (370,000) of whom have a CHA2DS2-VASC score of 2, and in whom anti-coagulation confers net clinical benefit. Hemingway and colleagues estimate that - even assuming only 50% of women in this group are anticoagulated - this prevents up to 1,900 fatal and non-fatal strokes each year. Such prevention is particularly important given the high levels of disability and health care use associated with stroke.

Research on unmet need and real-world effectiveness of the blood-thinning drug ticagrelor [R4], published by the UCL team in 2016, was cited in the NICE regulatory approval (TA420) [S7] for ticagrelor use for preventing atherothrombotic events after myocardial infarction. This changed clinical practice to address the very high risk of major cardiovascular events in heart attacks survivors, demonstrated by the UCL research. NICE approved the use of prolonged (effectively lifelong) medication with dual anti-platelet therapy (i.e. aspirin and ticagrelor). Previously, only certain sub-groups of patients were prescribed ticagrelor and ticagrelor was stopped within one year after heart attack. This research helps to show how the risk of further heart attacks in such patients can be further reduced. The British Heart Foundation estimates that there are 1,300,000 survivors of acute myocardial infarction, most of whom now are recommended for prolonged dual anti-platelet therapy with ticagrelor. Hemingway and colleagues’ research [R4] is based on unselected clinical populations, which provides a more real-world estimate of risks of cardiovascular events (compared to the lower risks estimated in healthier populations selected into trials). Using the real-world risks, and assuming only half of eligible patients receive dual anti-platelet treatment, an estimated 6,500 cardiovascular deaths, non-fatal myocardial infarction or strokes are prevented every year in the UK.

The UCL research demonstrating the ‘international mortality gap’ between the UK and Sweden [R5] among heart attack patients has had impacts beyond stimulating cardiologists to provide better care and close the mortality gap; it informed amendments to the Health and Social Care Act. The research was published on 23 January 2014 amidst public concerns that the government may sell NHS data to insurance companies in the ‘care.data’ programme. The widespread TV and print media coverage of the research (with headlines such as ‘Second rate care’ - Sky) ensured that the research was used in discussions with the Secretary of State for Health [S8] about the value of health data. On 12 February 2014, Secretary of State for Health, Jeremy Hunt, called a meeting with Chair of the UK Academy of Medical Royal Colleges, among others. An email from the Chair about the meeting describes how the UCL findings had shaped the Health and Social Care Act: “I used your [UCL] examples of linking datasets to improve quality of care now and the Swedish comparison. The latter seemed to make a big impact. The immediate result is Jeremy Hunt made an amendment to the [Heath and Social] Care Act the same day to ensure the public that care.data will not be available to insurance companies, mortgage lenders etc.” [S8]

The research rapidly became an influential example of public good arising from public sector access to health record data, with appropriate information governance. The amendments were passed in the Care Act 2014, to allow data release only: “for the purposes of—the provision of health care or adult social care, or the promotion of health.” This stimulated professional societies to understand care and outcomes from NHS care [S9] .

Docetaxel chemotherapy improves survival

NHS England’s Clinical Commissioning Policy statement, commissioning docetaxel for men with metastatic, hormone-sensitive prostate cancer, was published in early 2016 [S1], just four weeks after STAMPEDE and STOPCAP’s results were published. This recognised that when “men who are diagnosed with metastatic prostate cancer are given docetaxel at the same time as ADT [androgen deprivation therapy] they have an improved overall survival benefit of up to 15 months longer, when compared to current practice” The four-week turnaround was uncommonly fast, since the process usually takes months, if not years, signalling the strength of evidence provided by STAMPEDE and STOPCAP. The statement continues: “NHS England has reviewed the evidence and concluded that it is sufficient to enable docetaxel to be routinely funded for the treatment of newly-diagnosed hormone naïve metastatic prostate cancer, where treatment with docetaxel is started within 12 weeks of commencing treatment with ADT.” Subsequently, STAMPEDE and STOPCAP papers [R1], [R2] have been globally cited in at least 20 international, national and regional key clinical care guidelines [S2]. These include the widely influential US National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO) and the European Association of Urology (EAU)-led consortium, all recommending the use of upfront docetaxel alongside hormone therapy for the treatment of metastatic prostate cancer.

Whilst the patent for docetaxel, held by manufacturer Sanofi-Aventis, expired around the time of STAMPEDE’s results, the company commissioned and submitted a report on STAMPEDE’s results to successfully extend its license in 2019 across Europe, Russia, Pakistan and Colombia. Sanofi’s statement confirms: “[STAMPEDE] data, along with … contributions of Eastern Cooperative Oncology Group [USA] … and Unicancer [France], supported Sanofi’s submission of the registration dossier to EMA. In December 2019, Taxotere in combination with androgen deprivation therapy (with or without prednisone or prednisone), was officially approved for the treatment of men with mHSPC [metastatic hormone-sensitive prostate cancer] ” [S3]. The EMA license, in particular, will further encourage uptake in countries where it is difficult to use drugs for indications beyond those for which they are explicitly licensed. For example, licensing applications were ongoing in Brazil in 2020.

The National Prostate Cancer Audit of England and Wales introduced the proportion of metastatic patients receiving docetaxel treatment as a performance indicator in 2019. The proportion rose from 27% in the 2019 report (April 2017 to March 2018 diagnoses) to 36% in the 2020 report (April 2018 to March 2019 diagnoses), although the authors note that the proportion “seems quite low” [S4]. Currently, approximately 7,000 people are diagnosed with metastatic prostate cancer in the UK each year. Assuming docetaxel rates are similar across the UK and the clinical benefit is consistent, approximately 2,500 of those people should receive primary docetaxel. This can be extrapolated to a gain of 31,250 extra life-years over the next decade in the UK, assuming the proportion of men treated with docetaxel remains the same. The proportion of people treated with up-front docetaxel on the findings of STAMPEDE and STOPCAP is likely to further increase.

New health economic data from STAMPEDE in 2018 showed that adding docetaxel was cost-effective in the long run in both metastatic and non-metastatic patients [S5]. The model, based on STAMPEDE trial data, projected that docetaxel would be cost-effective in both metastatic prostate cancer (incremental cost-effectiveness ratio GBP5,514 per quality-adjusted life-year (QALY) compared with standard of care) and nonmetastatic prostate cancer (higher QALYs, lower costs versus standard of care). Docetaxel remained cost-effective in non-metastatic prostate cancer when the assumption of no survival advantage was modelled [S6]. NICE Guideline ‘NG131: Prostate cancer: diagnosis and management’ was published in 2019, extending docetaxel as a treatment option to men with high-risk non-metastatic disease [R1]. This recommendation, based on data from the only UK trial considered (STAMPEDE), advised that the option of docetaxel chemotherapy should be discussed with people who have newly diagnosed non-metastatic prostate cancer, who are starting long-term ADT [S7]. Further, there was worldwide consensus among 60 key opinion leaders at the Advanced Prostate Cancer Consensus Conference (2017) in St Gallen, that docetaxel should be used as standard care in metastatic, hormone-sensitive, prostate cancer [S8]. This was corroborated at the following conference in 2019 [S8], giving a global consensus on treatment pathways with the aim of helping clinicians across the world discuss innovative new therapies with patients.

Abiraterone changing international policy and practice for patient benefits

Whilst in the UK docetaxel is more readily available to patients through the NHS and administered similarly to other intravenous chemotherapy drugs, abiraterone is not yet NICE-approved for men with hormone-sensitive disease. However, as a tablet-based treatment that would allow patients to control their medication at home, there has been wide enthusiasm for access to abiraterone based on STAMPEDE and STOPCAP papers [R3], [R4] for patients with advanced prostate cancer. Results are cited in at least 10 key international and national care and clinical guidance documents for metastatic prostate cancer [S2], including: the NCCN, ASCO, ESMO, Canadian Urological Association (CUA) and EAU. For example, the EAU Oncology guidelines state: “Based on these data, upfront abiraterone acetate plus prednisone combined with ADT should be considered as a standard in men presenting with metastases at first presentation, provided they are fit enough to receive the drug” [S2]. To set standards, the STAMPEDE team adapted the protocol to allow abiraterone as an amended standard-of-care in ongoing comparisons where abiraterone was available.

Janssen submitted for and obtained a license for use only in patients with ‘high volume’ metastatic disease. Despite this, the international clinical community widely encourages use for patients with newly diagnosed metastatic prostate cancer [S2]. Whilst not yet recommended, during COVID-19 NICE have allowed treatment using abiraterone as an alternative to docetaxel because docetaxel causes transient immune suppression and requires more frequent hospital visits.

Radiotherapy improves survival in metastatic disease

In 2018, findings from [R5] and [R6] indicated that radiotherapy can help some men to live longer with metastatic prostate cancer. By the end of 2020, this had already been cited in eight major international guidelines and clinical care documents, encouraging radiotherapy for low metastatic burden prostate cancer [S2]. These include the US NCCN and the ESMO. The EAU Oncology Guidelines for Prostate Cancer, published in 2020, refer to STOPCAP, saying: “the authors found that, overall, there was no evidence that the addition of prostate RT to ADT improved survival in unselected patients. However, there was a clear difference in the effect of metastatic burden on survival, with an absolute improvement of 7% in three-year survival in men who had four or fewer bone metastases.” [S9]. The Association used this to justify its recommendation to offer radiotherapy to men with ‘low volume’ metastatic disease. The radiotherapy schedule used is simple to plan and cheap to deliver, so it has potential be used in middle income countries (LMICs) as much as higher income countries. Prostate Cancer UK stated: “The breadth of STAMPEDE and its applicability to everyday practice in the NHS mean that Prostate Cancer UK has been able to use this robust evidence to influence for access to life extending treatments for men that previously had few options available to them.” [S10]. A leading oncologist and research at Canadian Cancer Trials Group said: “Thanks to these data, there’ll be men dancing at their daughter’s weddings who wouldn’t otherwise have been there.”

Lives saved from smoking cessation: Tobacco smoking is estimated to lead to the premature death of approximately 8 million people worldwide and 80,000 people in the UK each year. These premature deaths each typically represent 10 years of life years lost. Smoking cessation is a function of two processes: making an attempt to stop; and succeeding in that attempt. Novel mass media campaigns can stimulate quit attempts and UTARG’s research and theory was pivotal in influencing the design of ‘Stoptober’, a novel mass media smoking cessation campaign run by the Department of Health since 2012 and PHE (from 2013).

The influence of four key themes of UTARG research on the design of ‘Stoptober’ is summarised in [R2], which was co-authored by Matthew Walmsley at Department of Health and states: “The English Department of Health with input from an academic partner (RW) designed a campaign called ‘Stoptober’.” These themes have been central to each subsequent iteration of ‘Stoptober’ between October 2013 to 2020 and their ongoing influence on campaign designs is clear in PHE’s Social Marketing Strategy 2014 – 2017 [S1], which states, in relation to utilising evidence-based approaches in public health marketing: “We use Prime Theory in tobacco control… we have collaborated with… Professor Robert West and his team at University College London (UCL) on a wide range of projects”. These collaborations include frequent contact between UTARG and PHE on tobacco control monitoring, assessment, and strategies, and participation in implementation boards and expert roundtables on tobacco control policy at the Department of Health. The NHS SmokeFree website, which delivered the digital components of the ‘Stoptober’ campaign, publicly acknowledged UCL’s input until April 2020: “ Our thanks in particular go to Professor Robert West for providing data and analysis from the Smoking Toolkit Study and supporting our campaign and product development with insight and advice” [S2].

A UTARG evaluation [R2] estimated that ‘Stoptober’ led more than a third of a million smokers to try to quit in October 2012 than would otherwise have done (quit attempts are a commonly used metric in tobacco cessation research, being on the causal pathway to quitting). Assuming these effects extended from 2013 to 2020, then ‘Stoptober’ saved an estimated 83,200 DLY at a cost to government of GBP414.26 per DLY in the modal age group. This UCL evaluation was also later identified as just one of eleven appropriate studies in a 2015 independent review of economic evaluations of tobacco mass media campaigns, published in Tobacco Control. The authors concluded that the UCL study was among the higher quality evaluations (scoring 7/10 on their quality checklist) and was an important part of the evidence that led to the conclusion: “the cost effectiveness of tobacco control mass media campaigns is limited, but of acceptable quality and consistently suggests that they offer good value for money.” [S3]

Shaping national commissioning decisions: The original UTARG evaluation of the first year of operation was critical in the commissioning of ‘Stoptober’ in subsequent years [R2]. In an article published in the leading French epidemiology and public health journal Bulletin épidémiologique hebdomadaire, Professor Kevin Fenton, then the National Director of Health and Wellbeing at PHE, described the UTARG study results and consequences: “ A study published in 2014 to evaluate how effective and cost-effective ‘Stoptober’ was in 2012 – the first year of the campaign – found that ‘designing a national public health campaign with a clear behavioural target using key psychological principles can yield substantial behaviour change and public health impact’…” [S4]. There is continuing reference to ongoing evaluation in the STS, led by West and Brown, in PHE press releases on ‘Stoptober’, e.g., “And according to UCL’s Smoking Toolkit Study, smoking rates are continuing to fall in 2014” [S6]. The UTARG evaluation is the second reference in the Welcome in PHE’s 2017 to 2020 social marketing strategy and is listed as evidence that “ Marketing…can encourage behaviours that lead to longer lives, and it can give people the confidence to make healthier choices (Brown et al, 2014)” [S1]. Three UTARG publications are also listed the strategy’s section on recognition of PHE’s work.

Informing political debate on smoking cessation campaigns: UTARG evidence on the impact of smoking cessation public campaigns, and the argument for continued spending on them, has been raised in parliament through political debate. UTARG research on the value of tobacco control spending was referenced by Labour MP Sir Kevin Barron’s opening speech of a House of Commons debate on a new Tobacco Control Strategy in December 2015: “ The cut in spending [on mass media campaigns] *is already having an impact. An early indicator of the effects of reductions in spending on tobacco control is given by the smoking toolkit study run by Professor Robert West, from UCL. Results for 2015 show that smoking prevalence has stopped declining and is beginning to go back up again for the first time in many years.*” [S5].

This political and policy debate continued into 2020 as a cross-party issue. In a parliamentary debate on ‘Smokefree England 2030’ in November 2020, Conservative MP and ex-Public Health Minister Steve Brine noted: “ The UCL smoking toolkit [R1], [R2], [R6] indicates that the pandemic has been a driver of quitting among smokers across all social groups, with the highest rate of people stopping smoking seen in the past 30 years. However...there are worrying signs among the 18 to 24-year-old group that smoking rates may be increasing” [S5]. In December 2020, Public Health Minister Jo Churchill responded: “ The Department, working with PHE, will develop and publish a new Tobacco Control Plan to deliver its ‘Smokefree 2030’ ambition” [S5].

UTARG research was also published to coincide with the start of ‘Stoptober’ 2020: a government press release reported that “ New data from the UCL Smoking Toolkit Study show that in England in 2020 there has been an increase of nearly a quarter (22%) in quit attempts compared to 2019 and an increase of almost two-thirds in the quitting success rate from 14% to 23%, the highest since at least 2007” and included quotes from Jo Churchill, and UTARG’s Professor Jamie Brown, who acted as a media spokesperson for the 2020 campaign [S6].

Engagement with the media has been important in communicating this message to the public, politicians and policymakers and reinforcing the message that investment in public health campaigns for smoking cessation is cost-effective. An ITV report from 2018 included results from UTARG research, mentioning the additional 350,000 quit attempts [S6] while various online media outlets quoted the study team, including the Daily Mail and GP online: “Lead author Dr Jamie Brown said: ‘The data clearly show ‘Stoptober’ resulted in a large increase in the number of people stopping smoking in England. The GBP5.8m spent on the campaign by the DH appears to have been an excellent investment.’” [S6] .

International commissioning decisions:

France: The success of ‘Stoptober’ has led to it being adopted in France. A case study by Public Health France (Santé publique France) directly cited [R2] and reported “ France decided to import the UK campaign ‘Stoptober’ because it was effective in increasing quit attempt rates.” [S7]. Furthermore, an editorial by Executive Director of France’s National Institute for Prevention and Health Education (INPES) cites the UTARG evaluation (google translate): “ The positive evaluation of the ‘Stoptober’ 2012 campaign led to the renewal of the campaign in 2013 and 2014… Inpes, in conjunction with the Alliance against Tobacco, is considering adapting this system to French territory” [S8]. UTARG hosted a delegation from INPES to plan the French initiative and to ensure robust evaluation plans were in place, with one French delegate stating: “ we often present it ( **[R2]**) to our partners as a positive argument in favour of the French adaptation of ‘Stoptober’.” The first iteration was launched in 2016, continuing to 2020, and has generated an estimated 380,000 quit attempts, according to an evaluation [S7].

Netherlands: The evaluation of the original campaign in England was an influence in the launch of the Dutch ‘Stoptober’, in 2014, as indicated on the ‘Stoptober Nederlands’ launch website: “ After the great success in England, the Netherlands also embraces 'Stoptober' this year”. The influence of the underpinning research by UTARG can be seen in the public description of the campaign, which uses the same concept: “’ Stoptober’ encourages every step you take towards a non-smoking life through the free app that supports you personally. …Through social media you encourage each other to keep it going for 28 days.” Subsequent evaluations of ‘Stoptober’ show the influence of UTARG research in the campaign design and estimate that 50,000 people have participated each year, with evidence that “an abstinence campaign with a wide reach in a national population may be effective in decreasing smoking prevalence and cigarette consumption among a broad range of participants” [S9] .

New Zealand: A ‘Stoptober’ campaign was also launched and run in New Zealand between 2014 and 2016 by Smoke Free New Zealand, with clear links to the evidence behind the English version of the campaign; an online presentation by the organisation references both the study design by England’s Department of Health and Brown and West’s PRIME theory [S10]. Results from the end of the first year of the campaign estimated that “5,200 smokers signed up to ‘Stoptober’ NZ 2014” and that 55% of those successfully completed the programme with 82% being motivated by ‘Stoptober’ to stop smoking by “a lot to a fair amount” and 80% of participants confident in their ability to stop smoking [S10].

This research has contributed to further centralisation and the lives of more stroke patients being saved in Greater Manchester (GM). Furthermore, it has supported sustained effectiveness of the London stroke care system; helped shape national policy in England, Scotland and Northern Ireland; and has been cited in documents making the case for regional stroke service reorganisations.

Driving improvements in care delivery and outcomes in Greater Manchester

Between 2012 and 2014, GM hospitals had attempted to centralise their stroke services, but changes were delayed, as a result of national reorganisations of governance and commissioning of healthcare, and local challenges with governance and service provision. UCL evidence [R1], [R2] on patient mortality was pivotal in driving further change in GM. The researchers shared their findings with senior members of the GM Stroke Network in February 2014 at the project steering committee meeting. At GM stakeholders’ request, in May 2014, the UCL team calculated the potential impact of further reorganisation and estimated that an additional 50 lives per year could be saved by doing this. GM stroke leaders used this figure to argue against any further delays. One senior stroke physician stated: “ being able to go to meetings and say to people ‘We’re looking at fifty excess deaths a year …’ because it was a paper and it was a medical journal, not just another audit report or just another internal report, I think that has had a significant impact.” [R1]

Supporting local buy-in: The argument that further change would increase access to evidence-based care, also saving 50 additional lives per year, was central to a large regional publicity campaign, gaining support for the new system from the public, local authorities, commissioners, and providers in GM. This included tweets from local providers and commissioners, an infographic (see below) and a briefing, which stated: “ if a similar approach is taken in GM it could result in 50 fewer deaths each year. The changes we are introducing in GM are based on a strong evidence base that it works”.

**Fewer deaths from stroke: Findings [R1], [R5] showed that, following further centralisation, 86% of GM stroke patients were treated in a HASU, resulting in an estimated 68 fewer deaths per year than if GM had reduced mortality at the same rate as other large urban areas in England (improvements in other large urban areas are likely to have been achieved through wider efforts to achieve national quality standards combined with public health interventions). National stroke audit data from July to September 2020 [S1] confirm that GM stroke services remain among the highest performing in England, with all routinely-admitting stroke services regularly achieving ‘A’ or ‘B’ national audit ratings – classified as indicating world-class stroke care as defined by the Royal College of Physicians.

Providing evidence to sustain centralised stroke services in London

Fulop and colleagues presented their clinical outcomes findings to London’s stroke clinical leaders in November 2014. From December 2014, these findings were cited in London’s Stroke acute commissioning and tariff guidance, published by the NHS Strategic Clinical Network. The guidance presents the clinical standards used to assess London stroke services [S2] and cites the finding from [R2] that: “reconfiguration resulted in a significant decline in risk-adjusted mortality, with approximately 168 lives saved at 90 days after admission, and a 7% reduction in length of stay in the first 21 months”. Senior management and frontline clinicians have said that the UCL research on outcomes has played an important part in sustaining the London system. For example, a representative of NHS England in London described making the case to commissioners to continue funding the London system:

“The team bringing their findings to the Stroke Clinical Leadership Group was really valuable […] it gave us a really good understanding of the research. This ‘heads up’ was crucial in helping clinical leads understand and share the main messages more widely. Your evidence was instrumental in addressing pushback from local commissioners and trusts [...] the fact that we could point to impartial research showing the London system had saved lives and reduced length of stay really swayed CCGs to support the tariff. Your work has also helped London to be seen as an aspirational model or ‘gold standard’ at regional and national level” [S2].

The research team’s follow-up analysis [R5] suggests that, from April 2013 to March 2016, London patients were significantly more likely to receive evidence-based care than patients elsewhere, and the impact on patient mortality was sustained. National stroke audit data from July to September 2020 [S1] suggest that London remains a high-performing system. Like GM, London is amongst the only areas in the English NHS where all routinely admitting stroke services regularly achieve ‘A’ or ‘B’ ratings, which indicate world class stroke care.

Influencing national policy and regional planning

National and regional leadership have used UCL’s work on impact of centralisation of stroke services on patient outcomes [R2], [R5] and quality of care [R3], [R5] as key evidence in their recommendations to centralise hospital stroke services. Findings on the impact on stroke patient outcomes [R2] have been cited in NHS England’s ‘Five Year Forward View’ [S3], the Scottish Government’s ‘National Clinical Strategy for Scotland’ [S4], NHS England’s ‘Configuration support guide for stroke services’ (2015) and proposals to reorganise stroke services in Northern Ireland [S5]. Fulop and colleagues’ findings of impact on stroke care delivery [R3] are cited in England’s ‘National Clinical Guidelines for Stroke’ [S6]. UCL’s work on both implementation and impact of change [R2], [R3], [R6] was cited in the Stroke Association’s position paper on stroke service reorganisation [S7], and 15 ‘case for change’ documents across the English NHS, of which three stroke service centralisations – in South Yorkshire and Bassetlaw; West Yorkshire and Harrogate; and North Cumbria – have been implemented [S8]. Finally, the UCL findings of lives saved per year in London [R2], and Greater Manchester [R5], were cited by change leaders in Kent and Medway in their submission to a judicial review of their proposal to centralise local stroke services into three HASUs; the judicial review ruled in favour of the changes in early 2020 [S9].

Shaping the ‘NHS Long Term Plan’: UCL’s 2014 research on stroke outcomes was one of just 11 documents cited in an internal paper resulting in stroke’s inclusion as a priority in the ‘NHS Long Term Plan’ [S10]. This followed considerable engagement activity carried out through an NIHR Knowledge mobilisation Fellowship held by Ramsay, who, for example, presented key findings at national workshops for development of the ‘NHS Long Term Plan’. A representative of the team leading its development stated: “ *The research was clearly presented in initial publication, ensuring it was accessible to less academic audiences, with clear messages more easily translated into policy initiatives. This led us to highlight the work as one of a small number of key references within our internal proposal for ‘NHS Long Term Plan’ prioritisation. The research clearly strengthened our case, and helped support its ultimate success. We have subsequently continued to refer back to this research and to reference within further documentation.*”- Team member, ‘NHS England Long Term Plan’ [S10].

Prioritisation in the ‘NHS Long Term Plan’ has resulted in additional resources for development of stroke services across England, including the new Integrated Stroke Delivery Networks, which will reshape organisation and delivery of stroke care across the whole of the English NHS over the coming years.

Evidence and advocacy for Everyone In, the UK national response to supporting the homeless community during COVID-19

Hayward and Story’s plenary presentation at the Homeless and Inclusion Health Conference in London on 12 March 2020 presented their research showing extreme clinical vulnerability and high risk of outbreaks, warned of the need for immediate action and outlined their proposed “Test-Triage-Cohort-Care” approach to attendees, including senior government advisors and NHS decision-makers [S1].

The following day, they were invited to present their findings and recommendations to the Greater London Authority’s Head of Health and began drafting the Homeless Sector COVID-19 plan [S2] in collaboration with NHS England, Public Health England, the GLA and the Ministry for Housing, Communities and Local Government (MCLG). This plan strongly recommended closing shared airspace communal night shelters, providing safe single-room, ensuite accommodation, prioritised to the clinically vulnerable, where they could receive specialist health and care support (COVID-PROTECT), and a comprehensive active surveillance, testing and TRIAGE programme across homeless venues, with isolation of suspected or confirmed cases in dedicated medical care facilities (COVID-CARE) [S3].

The government’s lead for rough sleeping Dame (now Baroness) Louise Casey attended the plenary presentation on 12^th March and met with Hayward and Story on 23^rd March. Baroness Casey said, “[Prof Hayward and Dr Story’s] use of emerging information on the transmission of COVID-19 in communal facilities helped me to make the case that everybody needed an opportunity to self-isolate from the virus.  Their research therefore helped to make a convincing case for the need for an urgent housing and health response” [S2]. On 26^th March the UK Government announced the Everyone In campaign, which brought together the key agencies and services to provide a single, unified response to supporting people experiencing homelessness during lockdown. The Minister’s letter to local authorities was circulated with advice on triage and cohorting as per the Hayward and Story UK Homeless Sector Clinical Plan [S4].

Everyone In was the largest single homelessness and rough sleeping initiative ever implemented in the UK. By mid-April 2020, 5,400 people had been offered emergency accommodation (90% of those on the street and in shelters at that time) [S2]. By the end of November 2020, 33,139 people were provided with accommodation through Everyone In (including hotels and more settled accommodation) [S5]. The campaign was highly successful in controlling the spread of COVID. During the first wave of the pandemic the UK recorded only 16 homeless COVID-19 deaths and a UCL model estimated that Everyone In prevented 20,000 COVID-19 infections and 266 deaths of homeless people [R6]. Hayward and Story used this model to advocate to prevent reopening of communal airspace shelters in the second wave [S6]. An NHS Strategy Unit report acknowledges that “this strategy, and the subsequent response from professionals across the homelessness sector, was significantly informed by members of the University College London’s (UCL) Institute of Epidemiology and Health Care” [S7].

According to Baroness Casey, “Professor Hayward and Dr Story’s work not only saved lives but has shown us what is now possible in terms of ending rough sleeping, especially the importance of including integrated accommodation and health responses” [S2]. A Local Government Association report about the lessons learnt by local authorities from implementing Everyone In reported that it had prompted rapid and beneficial changes to the way homeless support services were delivered across England, noting “the Everyone In response has had a profound short-term effect on homelessness services… To reduce street homelessness by 90% in one week is something which many would have thought impossible, but which was accomplished” [S7]. The report noted the transformative effect of hotel accommodation on homeless people’s sense of safety and dignity, and highlighted practices local authorities identified as crucial to their successful response, including; the systematic use of comprehensive needs assessments; multi-agency teams coming to accommodation facilities and directly encouraging engagement with their services; and the importance of rapid response to accommodating rough sleepers, including those not normally eligible (e.g. due to immigration status).

Everyone In was influential internationally. For example, in Ireland UCL work influenced a similar approach leading to lower levels of COVID-19 than in the general population in stark contrast to high levels of infection in countries that did not adopt the approach [S8].

Surveillance and clinical guidance for the London homelessness sector response

Hayward and Story acted as Academic and Clinical Advisors to the London Homeless Health Emergency Planning Group (EPG). They conducted an Online Preparedness Survey of 173 Homeless Hostels across London published as a real-time online dashboard [S9]. The Healthy London Partnership COVID-19 Homeless Resource Page provided extensive links to guidance, training and policy addressing gaps identified in the preparedness survey [S10]. CCIH conducted modelling of the accommodation and care requirements [R5] supporting the HLP EPG’s role as a strategic multi-agency coordinating hub. CCIH carried out daily active surveillance (April-July 2021) of suspected COVID-19 cases across London homeless venues allowing Find&Treat teams of nurses and homeless health peers led by Dr Sultan to outreach testing to suspected cases and contacts [S8]. As of September 2020 approximately 2000 swabs for PCR tests were taken by Find&Treat across London homeless venues [S8] and 48 suspected or positive cases were referred to the London COVID-CARE hotel (April-June 2020) [S11].

COVID-CARE was clinically managed by Find&Treat and staffed in partnership with Medicins Sans Frontières (their first deployment in the UK). The MSF UK Director explained the unprecedented intervention: “We have decades of experience in working during outbreaks… Here in the UK, the homeless community are among the most marginalised and are more likely to be at risk because of pre-existing health conditions” [S11].

From June the CHRISP Health Needs Assessment tool [S12] developed by Hayward, Story and Sultan based on previous survey tools [R3] underpinned the HLP/ GLA’s onward housing placements, registration with primary care and engagement with physical and mental health and addiction services. Over 1500 in-depth surveys have been completed to date [S12]. CHRISP screening showed 20% of people assessed were not registered with a GP and were subsequently registered; a blood-borne virus test administered as part of CHRISP showed an HIV prevalence of 3%, significantly higher than in the general population, and only 55% of those with HIV were receiving antiretroviral therapy. Following assessment 89% entered treatment [S12].

The HLP Director of Transformation, Health Inequalities and Inclusion said, “The strong academic/service partnership that has been developed between CCIH and the pan London Find&Treat Service was critical for the success of the [EPG] response” [S8]. The Director of Public Health for NHS London said, “I want to place on record my thanks to you [Professor Hayward], your team and your colleagues in the Find and Treat team in UCLH, for the work that you have done throughout the COVID-19 pandemic. I know that your work and advice on containing infections and outbreaks, as well as on testing and screening, is really valued and recognised across London - here at PHE regional level, in the GLA and across our boroughs” [S8].

In March 2021 Healthy London Partnership and the GLA’s London Homeless Health Response to COVID-19 won the 2020 Health Service Journal Health and Local Government Partnership Award.

There are approximately 410,000 older people (>65) resident in UK care homes, all of whom are significantly vulnerable due to mental and/ or physical ill-health. They are cared for by a residential adult care sector that is diverse and complex: there are 11,300 care homes for the elderly alone, 95% of which are independent providers and 80% of which operate only one site.

Initial UK Government COVID-19 guidance for the adult care sector stated that no special measures need be taken, and that “it is very unlikely that anyone in a care home will be infected” [S1]. By the beginning of April 2020, modelling from the University of Manchester and DHSC based on early care home COVID-19 infections showed this assumption to likely be unsound: a prevalence of 75% was projected if policy remained unchanged. On the basis of her earlier research, Shallcross was asked in early May 2020 to work with NHS England, the Office for National Statistics (ONS) and DHSC to set up the VIVALDI-1 study and provide a robust evidence base with which to plan a response to protect this large, varied and highly vulnerable care sector and its residents. Shallcross’ research was initiated explicitly to supply the critical epidemiological data needed to identify the likely most effective policy measures for protecting care home residents and staff [ S2].

Shallcross presented the study’s findings [R4], [R5] and their implications to the government’s Scientific Advisory Group for Emergencies (SAGE) Social Care working group in June 2020. These findings were provided directly to senior UK decision makers in the Department of Health and Social Care, SAGE, and 10 Downing Street, thus delivering crucial insights into the risk factors driving the first wave of the pandemic. The Chair of the UK Government Social Care Sector COVID-19 Support Taskforce writes in a letter that: “ *this research influenced my views on how to protect care home staff and residents from COVID-19. The research findings informed recommendations that were published in the Social Care Sector Taskforce’s report, and subsequently largely accepted by Government and translated into practice through the Adult Social Care COVID-19 Winter Plan.*” [ S2]

Referring to the early policy influence of VIVALDI-1, UK Government Chief Scientific Adviser Sir Patrick Vallance wrote in a testimonial letter to the Provost of UCL: “This work informed key policy decisions in June/July 2020 regarding the frequency of care home testing, and strategies to reduce the spread of infection as detailed below:

• Whether limited testing capacity should be used for staff or residents, and which care homes to prioritise for testing. VIVALDI-1 showed that per capita people in small care homes were equally as vulnerable [as those in large ones] and this changed the proposed testing strategy so that all care homes were tested, not just large care homes, as testing capacity increased.

• Limiting movement of staff between care homes. VIVALDI-1 […] results had a major impact on policy decisions/discussions with the care sector about how to ensure sufficient staffing ratios whilst limiting the number of staff who work across multiple sites.

• Payment of staff sickness pay to ensure that staff could self-isolate when unwell. Findings from VIVALDI-1 supported the decision to establish the Infection Control Fund (ICF)… This has led to a substantial increase in the proportion of care homes that report paying sickness pay to their staff.” [S3]

Implementing the recommendations of the VIVALDI-1 report: impacts of testing, staffing and sick pay in the adult residential care sector.

Testing strategy in care homes: Shallcross’ research directly informed the current approach of mass weekly testing for all staff in all homes (currently hundreds of thousands of tests a week). Each of the [TEXT REDACTED FOR PUBLICATION] positive tests between 29 June and 31 December 2021 among care home staff and residents represented a case that could have led to a dangerous outbreak in at least one residential care setting, in every instance infecting many of the UK’s most vulnerable people, placing extra burden on healthcare systems and potentially resulting in deaths, as shown in UK national COVID-19 Pillar 1 and 2 test results [S4].

Take up of Infection Control Fund (ICF) support for the residential care sector and workforce: The ICF is a GBP6m fund to support adult social care providers, to reduce transmission within the sector and increase workforce resilience [S5]. The ICF was targeted at two of the VIVALDI-1 recommendations to minimise COVID-19 transmission in residential adult care: that movement of care workers between sites should cease, and that worker sick pay should be topped up by government. It was deployed in two tranches: the first (of GBP300m) ran until 23 July 2020, and the second half of the funding was released on 24 July 2020. In the period to 23 July 2020, GBP257,601,441 had been allocated by English local authorities to 14,156 residential care providers, and of that figure 24.7% (across 8,411 providers) had been spent on limiting worker movement between sites. A further 18.72% (across 7,898 providers) had been used to pay staff full wages following a positive COVID-19 test [S6]. As noted by several of the corroborating sources here, without Shallcross’ research and the VIVALDI-1 project neither of these factors in COVID-19 transmission in care homes would have been identified and prioritised, and the scale of the problem (as evidenced by the majority of care providers making use of the ICF for these purposes) would not have been apparent. On 18 September 2020, the UK Government published the ‘Adult Social Coronavirus Winter Care Plan 2020-2021’, in which the ICF was extended until March 2021, with an extra GBP546m available [S1].

Ongoing impacts of VIVALDI-1 on DHSC’s response to COVID-19

In addition to providing an evidence base for key policy decisions, the VIVALDI-1 study also contributed improved data-gathering and reporting mechanisms around COVID-19 testing in care homes. VIVALDI-1 linked information derived from care homes to the UK national COVID-19 testing Pillar 2 results that were being collected through the national care home testing programme. Shallcross and her colleagues were the only team who were accessing and analysing Pillar 2 data in this way. In mid-2020, Shallcross realised the potential of this data, which could be used to monitor SARS-CoV-2 prevalence in care home staff and residents by region and over time. She started producing short reports based on the dashboard for DSHC. These reports were presented to the DHSC Adult Social Care team and to Ministers via the Data Debrief Group, chaired by the DHSC Director of COVID-19 Response. The interactive dashboard was being used up to the end of the REF 2021 period and beyond by DHSC to monitor the burden of infection in care homes, explore factors associated with outbreaks and mortality, and is shared with local directors of public health. The Director of the Adult Social Care Team at DHSC states: [TEXT REDACTED FOR PUBLICATION] [S7].

The insights into COVID-19 infection in care homes have also directly informed vaccination policy and shaped the recommendations of the Joint Committee on Vaccination and Immunisation in December 2020 to prioritise the vaccination of care home residents and residential care home staff [S8]. In November 2020, the government further recognised the importance of the VIVALDI-1 project by announcing plans to expand the study and provide an even more detailed picture of COVID-19 infection in care homes [S9].

The Director of Strategy for Private Testing, DHSC, concludes: “As a direct result of [Dr Shallcross’s] findings, and thanks to intelligent and diplomatic pressure from [her], SAGE and DHSC changed their advice, and rolled out mass repeat weekly testing of staff across all care homes for the >65s in England. […] Motivated by public service, [Dr Shallcross] showed real intellectual and moral bravery in her approach, and it is increasingly clear that her actions are likely to have contributed to saving many hundreds of lives.” [S10]

The impact of the VIVALDI-1 study – the speed with which it was established and its effectiveness in shaping and informing policy – has been recognised in its 2021 nomination for a Civil Service Award.

Natsal is the primary source of information about sexual behaviour and sexual health service use in Britain, and has influenced the design and delivery of other national sex surveys, including those in Ireland, Germany, Slovenia, Australia, New Zealand, and the US. Natsal’s international impact has been recognised by its choice as an example in the World Health Organization’s development of a standardised, population-representative sexual health survey instrument [S1].

In Britain, Natsal is used widely by policymakers, clinicians and service planners to design, deliver and monitor a number of sexual and reproductive health strategies. For example, Natsal was recognised in the House of Commons’ Health and Social Care Committee’s Inquiry into Sexual Health in 2019, which sought to identify priority areas for the next national strategy to help both providers and commissioners deliver sexual health services to a high quality and consistent level [S2]. Natsal’s submission cited evidence from 37 peer-reviewed articles (including [R1] to **[R7]**) to inform this prioritisation exercise. Impacts since 2013 include:

Evidence to inform HPV vaccination policy: As the world-leading research resource on sexual health, due to its unique size, detail and quality, Natsal provides the underlying population behavioural and biological parameters (e.g. sexual mixing patterns by age and gender at a population level) that are essential for transmission models of the impact and cost-effectiveness of HPV vaccination programmes in the UK and internationally. These are repeatedly used by the Department of Health’s Joint Committee on Vaccination and Immunisation’s (JCVI) to model effectiveness and cost-effectiveness and recommend (i) extending vaccination to men who have sex with men (MSM) in JCVI’s 2015 statement on HPV vaccination in MSM [S3], and (ii) in its July 2018 statement recommending extending the HPV vaccination programme to adolescent boys [S3]. The reach of this impact extends to a number of countries that use these parameters to inform decision-making, for example 2016 research led by the International Agency for Research on Cancer used Natsal’s HPV transmission model to show links between age-specific sexual patterns and HPV vaccination effectiveness, considering rural India and the USA as examples of two heterosexual populations with tradition and gender-similar age-specific sexual behaviour [S4].

Contributing to the National Chlamydia Screening Programme (NCSP): Public Health England (PHE) delivers the NCSP and relies on Natsal to understand the risk of chlamydia infection within the general population; co-infection with other STIs; knowledge of risk; and the factors associated with risk; as described in its 2017 evidence pack for external peer reviewers [S5]. This intelligence has contributed, for example to the 2020 ‘State of the nation’ report by the Terrence Higgins Trust, which cites Natsal evidence alongside its recommendations to reduce societal inequalities in levels of chlamydia infection: “ research using the Natsal-3 survey highlighted the potential impact of poverty. It found higher prevalence of chlamydia among women living in deprived areas despite testing rates not being any higher” [S6].

Shaping screening and clinical guidelines for (other) STIs and sexual health service delivery: Importantly, Natsal captures those who do - as well as those who do not - attend services, which is especially important as STIs can be asymptomatic and stigmatised. For cases diagnosed in sexual health clinics, Natsal provides the population-based perspective and informs appropriate screening strategies. For example, the low prevalence of gonorrhoea in the general population raises the issue of false positives, as outlined in PHE’s national guidance on the management of gonorrhoea (2014): “A recent population-based survey [Natsal] detected gonorrhoea only in those aged 20-24 years; in this age group the prevalence was 0.1% in men and 0.2% in women…..despite excellent specificity, high rates of false positive tests can occur due to low gonorrhoea prevalence in the population tested and the potential for cross reaction with non-gonococcal neisseria species” [S7]. Also, Natsal’s evidence that there are differences in the age- and sex-specific prevalences of chlamydia and M. Genitalium (MGen), with higher prevalence in older age groups than those targeted in the NCSP, has formed the basis for the BASHH’s 2018 national guidelines for the management of infection with MGen, which recommends the management of patients who are symptomatic and attend services, rather than a population-based MGen screening programme in young people [S7].

Impact on HIV prevention, control and service provision: Natsal data are essential for use in mathematical models used by PHE for estimating the national burden of HIV. The models combine anonymous prevalence surveillance data with Natsal’s estimates of the size of the population at risk to estimate the number infected and the proportion who remain undiagnosed [S8]. In addition, Natsal parameters and data have been used to evaluate the cost-effectiveness of key interventions, including the roll-out of pre-exposure prophylaxis (PrEP) for HIV, as described in an NIHR-funded analysis published in Lancet Infectious Diseases which showed that introduction of PrEP could result in a GBP1bn cost saving and prevent 25% of HIV infections within 15 years [S8]. Natsal also continues to inform national HIV prevention efforts by providing robust underpinning evidence, for example those run by charity the National AIDS Trust in its 2015 report ‘Preventing HIV in the UK heterosexual population’: “HIV transmission studies and prevention interventions for heterosexuals are mainly built on an assumption of vaginal sex as the primary route of transmission. The most recent Natsal survey has found an increase in the number of respondents reporting anal sex. In 2010-12, 15% of women reported anal sex, compared with 11% in 1999-2001…HIV prevention efforts should consider specific behavioural risks and prevention needs of heterosexuals, for example anal sex and partner numbers, just as we do for MSM.” [R7], [S8].

Evidence to address health inequalities: Natsal-3 demonstrated how MSM are disproportionately affected by a range of harmful health behaviours and poor health outcomes, and this contributed to the evidence base informing national guidelines to identify problematic recreational drug and alcohol use among MSM as a marker for increased STI risk [S9]. Similarly, Natsal-3’s evidence of a greater burden of poor sexual health among ethnic minorities is recognised by BASHH and the Terrence Higgins Trust in their 2020 ‘State of the Nation’ report, leading them to call commissioners to translate the evidence into effective targeted prevention interventions as part of their provision of sexual health services [S6].

Impact on Sex and Relationship Education (SRE): Natsal informs the content and delivery of evidence-based SRE, including in public-facing resources disseminated by sexual health charities e.g. Brook , Relate, PSHE Association, and the Sex Education Forum (SEF). According to SEF’s Director, Lucy Emmerson: “[we] quote [Natsal] [in everything we do and we have made it accessible for approximately 100 partner organisations and network of hundreds of schools” [S10]. In November 2014, Natsal collaborated with the SEF to deliver ‘SRE: Coming of Age’, a conference to pre-release Natsal-3’s SRE-related findings to those involved with the (then) Education Select Committee Inquiry into SRE, and those working in local authorities who received SEF’s ‘A briefing for local councillors on Relationships and Sex Education’. This included bespoke infographics created from Natsal-3 data to share with and inform their Directors of Public Health. According to the SEF, Natsal research played a key part in the Education Select Committee concluding that SRE should be statutory [S10].

Contribution to public engagement activities on sexual health: Natsal has played a key role in contributing to public conversations about sex (for example Mercer’s 2014 TEDx talk about the realities of people’s sex lives; >250,000 views; 1,700 likes **[S11]**) and promoting the public’s understanding of sex research. Natsal was the inspiration for the Wellcome Collection’s highly successful ‘Institute of Sexology’ exhibition in 2015, which was accompanied by 117 live events and 82 workshops, attended by 8,600 participants. This was accompanied by a book named after the exhibition, and also Professor Sir David Spiegelhalter’s book ‘Sex by numbers’, that showcased Natsal as one of the few examples of high-quality research into sexual behaviour.

Informing global strategies and guidelines to end the HIV epidemic

Interim PARTNER1 data [R3] indicated that among 548 serodifferent heterosexual and 340 gay couples, there were no documented cases of within-couple HIV transmission despite 58,000 condomless sex acts. These results were shown to have an immediate global impact. These results were cited as evidence in the role of viral suppression via antiretroviral therapy (ART) in preventing HIV transmission in the UNAIDS 90-90-90 Strategy ‘Ambitious Treatment Targets: Writing the Final Chapter of the Aids Epidemic (2017)’, which aimed to have 90% of people living with HIV diagnosed, 90% on treatment and 90% living with viral suppression by 2020 [S1]. PARTNER was also a key evidence source (and the only data for gay men) in the 2016 World Health Organization Guidelines [S2] ‘The Use of Antiretroviral Drugs for Treating and Preventing HIV’, as the official recommendation for global public health approaches to HIV. Citing [R3] and [R4] as a key research findings within the report’s clinical guidelines, the WHO recommended “ Initiating ART at any CD4 cell count[…]in order to reduce mortality, morbidity and HIV transmission outcomes […]substantially reducing transmission to HIV-negative sexual partners among homosexual couples”, reflecting the studies’ findings and recommendations. In monitoring the implementation of these WHO HIV ‘treat all (patients)’ policies, low/middle-income countries adopting WHO guidance rose from 33% (2016) to 93% (2018) as the transmission benefits of ART demonstrated in the UCL research became official WHO policy [S2].

In the UK, HIV positive gay men with an undetectable viral load increased from 48% in 2011 (pre-PARTNER1) to 87% in 2017 (post-PARTNER1) [S3]. Rodgers et al. estimated, through modelling, that the number of incident cases of HIV in England and Wales in men who have sex with men (MSM) fell 71% from 3,500 in 2015 to 800 in 2018 [S3], demonstrating the significant reduction in HIV transmissions through universal roll-out of ART in policy and practice, which resulted in the large reduction in new UK infections in MSM. PARTNER1 has also been shown to alter treatment plans for those exposed to HIV. Based on [R3] and [R4], findings in the absence of transmission in condomless acts between serodifferent partners, UK post-exposure prophylaxis for sexual exposure (PEPSE) guidelines were updated by the British Association for Sexual Health and HIV (BASHH) and the British HIV Association (BHIVA) in 2015. These guidelines recommended that Post-exposure prophylaxis (PEP) treatment was now not necessary, in the circumstances that the HIV positive person was known to be taking ART with a confirmed and sustained HIV viral load <200 copies/ml [S3], switching from their previous recommendation to prescribe PEP. This would save their sexual partner potentially from having to take the 28-day treatment course of PEP, as well as the additional HIV testing and counselling.

National US HIV treatment guidelines were updated using both PARTNER 1 and PARTNER2 data in December 2019 by the US Department of Health and Human Services (DHHS) and National Institute of Health, who strongly recommend that: “All PLWH should be informed that HIV viral load <200 copies/mL prevents sexual transmission of HIV” [S4]. Based on these findings, the DHHS went on to make further recommendations that PLWH should use another form of prevention with sexual partners for at least six months from starting ART, until a viral load of <200 copies/mL has been documented, with patients explicitly told that by not adhering to ART, their viral load will increase rapidly and increasing their risk to transmission. DHHS also recommended further support through counselling should be given to maintain suppression through ART adherence, which could be challenging for a number of social groups such as adolescents or homeless people.

Launched in 2019, PARTNER data also underpins the current US national HIV/AIDS strategy ‘Ending the HIV Epidemic ’ [S4] *, which aims to reduce new infections of HIV by 75% by 2025, and 90% by 2030. A 2019 position paper by the US Assistant Secretary for Health, Admiral Brett Giroir, entitled ‘The Time is Now to End the HIV Epidemic’, stated: “ recent data *[R6] from multiple long-term, well-controlled studies have established that people with HIV who take HIV medication daily as prescribed, and maintain an undetectable viral load, have effectively zero risk of sexually transmitting HIV. The profound prevention benefit of treatment is the foundation for a community-led campaign known as Undetectable = Untransmittable (U = U), which is also a key strategic advantage for our initiative”. The level of confidence enabled by PARTNER 1 and PARTNER2 data - that taking ART daily maintains viral suppression and eliminates HIV sexual transmission - was also recognised by unprecedented changes in the US Centers for Disease Control and Prevention (CDC) recommendations (2019). After citing [R4] and [R6], the CDC stated: “ ART is 100% effective to prevent sexual transmission in heterosexuals and gay men” [S4] as part of a calculation of the effectiveness of prevention strategies for acquiring or transmitting HIV. As Dr Anthony Fauci, Director of the US National Institute for Allergy and Infectious Diseases stated at the 2019 International AIDS Society Conference on HIV Science: “ Treatment as Prevention, or U=U, is the hallmark of what we [NIAID] are doing…the concept of U=U is the foundation of being able to end the epidemic” [S4].

Addressing criminalisation of PLWH

Criminalizing PLWH undermines epidemic control efforts, promotes stigma, discourages testing and treatment and stigmatizes vulnerable populations. PARTNER results [R4] and [R5] underpin the International AIDS Society (IAS) consensus statement (2018), to combat criminalization laws that imprison hundreds of people based on assumptions of risk that the PARTNER results disprove. The Consensus statement extensively references PARTNER data, using UCL’s up-to-date scientific evidence to limit unjust criminal prosecutions, calling for “ correct and complete understanding of current scientific knowledge to inform any application of the criminal law in cases related to HIV” [S5]. PARTNER data has led to modernisation/repeal of HIV-specific laws, including in the US, Malawi, Canada, the DRC, Brazil and Belarus, as outlined in the HIV Justice Network report in 2019 [S5].

Underpinning the U=U consensus statement

PARTNER data was pivotal for underpinning the definition of the 2016 treatment as prevention statement Undetectable=Untransmittable (U=U): “A person living with HIV who has undetectable viral load does not transmit HIV to their partners” [S6]. In 2016, the founder of U=U, health equality initiative Prevention Access, contacted the PARTNER study group about transmission risks of HIV, looking to use data to transform the social, sexual, and reproductive lives of PLWH. Together with multiple citations from NAM (AIDS charity) AidsMap, the organisations utilised the UCL groups’ research to cement the message that HIV is not transmittable with viral suppression on ART. After this, ‘U=U’ was launched. Advocating for favourable health outcomes, including ART adherence, optimal health and disclosure of HIV status, the influential U=U statement was initiated following PARTNER1 interim results [R3] and publication [R4], and is now endorsed by >1000 organisations in 100 countries, including Elton John Aids Foundation and the Africa Centre for Health Policy [S6].

The effect of the PARTNER studies are felt across the landscape of health service users - from policy makers to PLWH. PARTNER research has also helped fight stigma that is repeatedly recognized as a major barrier to HIV testing and treatment, providing the scientific evidence to place U=U at the heart of HIV prevention policy and efforts to destigmatise HIV. This effort was summed up by one PLWH in 2018, who said: " It was like the sky opened. There's, like, zero risk? I don't feel I'm a threat anymore. I don't feel I'm dirty. I don't feel I'm dangerous." [S7]

In 2018, PARTNER2 results [R5], [R6], finally provided scientific evidence for transmission risk of zero with suppressive ART in gay men. The author of the U=U, Bruce Richman, stated: “Something shifted in 2018. We’re tremendously grateful to the groundbreaking PARTNER2 researchers for the unequivocal final chapter confirming U=U. PARTNER2 has forever changed what it means to live and love with HIV around the world” [S8]. The PARTNER study team has always engaged with the HIV community to help rapid dissemination and trust in study results: Bruce Richman said, in 2018: “ Alison Rodger did something so unusual and wonderful, she confirmed the research supports U=U and acknowledged Prevention Access Campaign for our work to ensure evidence reaches the public. It was so respectful. I’m so grateful to her.” [S8] Matthew Hodson (Executive Director of AIDSMAP), commented on the confidence PARTNER2 data gave the U=U movement: “ IAS2018 will forever be remembered as the conference when ‘U=U’ moved from an activist rallying cry to the scientifically established position.” [S8]

By leading the first randomised, controlled trial showing the superiority of VOT over DOT in terms of user engagement, retention, outcomes and reduced costs, UCL research has driven the rapid translation of this work into service provision, both nationally and internationally. Through UCL’s engagement with the WHO and national health commissioners, VOT is now in widespread use in the US and England and is increasingly being used around the world to improve management of TB.

Evidence of VOT’s effectiveness to change NHS England and WHO policy and guidelines:

VOT is recommended by NHS England as a key tool to reduce health inequalities, particularly for TB patients with complex social needs and those with MDRTB. The guidance specifically recommends the UCLH ‘Find&Treat’ model, citing Story and colleagues’ UCL initial 2007 clinical trial and subsequent papers on the effectiveness of the SureAdhere app used in the trial, along with multiple studies applying the UCLH VOT in several other countries and with Inclusion Health groups. It concludes by assessing and recommending SureAdhere specifically, citing its high standards of governance as well as its clinical effectiveness [S1]. In 2019, NIHR created an ‘NIHR Signal’ based on the UCL SureAdhere clinical trial which highlights impactful studies for decision makers in the NHS, public health and social care [S2].

By engaging key decision-makers and thematic leads with emerging findings from UCL VOT clinical trials, UCL researchers have had a major influence on WHO strategy and recommendations around TB, and in particular treating vulnerable or marginalised TB patients or those with MDRTB, who require lengthy treatment plans. In 2014, the WHO developed the ‘End TB Strategy’ with the aim of ending the global TB epidemic by 2035 and in the following year it launched the Global Taskforce for Digital Health and TB, of which Story was a member. Hayward and Story contributed research insights and evidence to both areas of WHO activity.

The UCL VOT studies contributed to the 2015 WHO report ‘Digital Health for the End TB Strategy: An agenda for action ’ [S3]. Hayward, Story and colleagues presented the preliminary results of the UK studies at a series of WHO meetings, including the technical consultation on the role of e/mHealth in tuberculosis and tobacco control from 25 to 27 February 2015; the launch of the Global Taskforce on Digital Health for TB in April 2015; and a subsequent International collaborative group on VOT for TB on 14 July 2015.

The invitations to the UCL team were issued by the WHO because this work was one of the few health interventions whose effectiveness was backed by field studies, and eventually the first RCT that was completed, in this domain. The Digital Lead for the WHO Global TB Programme says: “At that time there was no evidence from randomised controlled trials and no evidence of effectiveness within socially complex groups. It was therefore extremely helpful to have trial-based evidence, showing the higher degree of acceptability, increased levels of observation and lower costs compared to traditional DOT. […] The UCL research was a very important part of the evidence that led to the development of a series of [WHO] policy and guideline documents promoting increased use of VOT and wider promotion of Digital Adherence Technologies” [S4].

In the subsequent 2015 WHO report titled ‘Digital Health for the End TB Strategy: An agenda for action’, VOT is identified as a key emerging technology and clinical tool to tackle TB health inclusion challenges and health inequalities within and between countries more broadly, noting the increasing availability of internet-enabled smartphones in higher and lower income health settings, and the flexibility of the intervention compared to DOT. It also notes the broad applicability of VOT to other sorts of social-determined health inequalities, for example smoking cessation. It emphasises the patient-centred principles underpinning VOT, and its relationship to UN Sustainability Goals: specifically, that the often lengthy treatment process for TB should accommodate the patient’s needs and commitments, and that it should place as little burden and stigma upon them as possible [S3].

Following this, in 2017 the WHO published a ‘Handbook for the use of digital technologies to support tuberculosis medication adherence ’, including technical specifications for commissioning VOT platforms and guidance on establishing national digital health strategies [S5]. The WHO quotes Story’s 2019 paper [R3] in support of the specifications for VOT, as one of three digital technologies identified in the handbook. In 2020, in the WHO/EUR ‘Quick guide to video-supported treatment of tuberculosis’ , SureAdhere is listed as one of the products employed in the field to deliver VOT (in Ukraine). UCL research is also cited in the Stop TB ‘Partnership guidance on Technologies for Improving TB Medication Adherence and Treatment Outcomes’, as evidence for the WHO 2017 recommendations on the use of VOT for improving adherence in TB medication [S6]. Stop TB is an INGO (international NGO) with over 1,700 partners dedicated to the eradication of TB by influencing international policy and treatment guidelines.

Improved outcomes for TB service users in the UK and other countries:

In 2017, Hayward presented the results of the clinical trial of SureAdhere (prior to final publication) to the London TB board and other commissioners of TB services across England [S7]. The Chair of the London TB Board at the time said: “ The trial was already supporting a high proportion of the most socially complex cases and most of the multidrug resistant cases in London, so we saw a clear need to urgently translate this NIHR research investment into a commissioned service based on the strong evidence of acceptability, effectiveness and cost effectiveness provided by the study […] I can say with confidence that the VOT service only exists because of the research conducted in partnership between UCL, UCLH and TB clinics across the country” [S7].

TB services differ considerably in their structure across England, as do concentrations of need. By engaging with key decision-makers during the conclusion of the clinical trial, the UCL team facilitated the rapid scale-up and expansion of the service nationally as appropriate evidence-based action could now be taken, and secured a seamless transition from trial to real-world adoption. VOT is now commissioned as an England-wide TB treatment service delivered from UCLH through the ‘Find&Treat’ service. ‘Find&Treat’ is led by Story, and the national VOT service within it is now led by one of the UCL research team. Most of the MDRTB patients in England are now treated with VOT along with a high proportion of socially complex patients. On average, around 75 to 80% of MDRTB London patients are referred to VOT (in some London TB Services it could be as many as 90% of MDRTB patients). Around 55 to 60% of patients on VOT have at least one social risk factor and around 60% will have had previous treatment episodes or experience previous non-adherence [S8].

The use of VOT increased substantially during the 2020 COVID-19 pandemic, as face-to-face DOT became unfeasible. The service is commissioned across London and also provides VOT on an ad hoc basis outside of London. Including clinical trials, since 2014 ‘Find&Treat’ VOT services have treated a total of 531 TB patients, including a high proportion of the most vulnerable eligible TB patients in England [S8].

UCL worked with the University of California (San Diego) to evaluate and refine the SureAdhere app. Both UCL and UCSD have gone on to work with health services in the UK, US and other countries to implement VOT TB treatment using SureAdhere, which is now a commercially available platform. VOT is now being used to treat TB widely across the US and increasingly in a wide range of other countries. In addition to TB, it is also being used for HIV and Hepatitis C treatment and Opioid Substitution Therapy. SureAdhere is now used across several US State TB control programmes (Arkansas, California, Colorado, New York, Texas, Vermont, Washington) and is being used in some high incidence countries, including Mexico, Vietnam and Uganda [S9].

UCL researchers including Hayward and Story advised the UK Behavioural Insights Team on the setup of a trial of VOT in Moldova, which showed similar effectiveness to the original UK study. VOT is now part of the national programme [S10]. UCL VOT research has also influenced TB treatment in Belarus. In 2015, the Ministry of Health of Belarus, with support from the WHO Global TB Programme Medical Officer (who had also led on the TB Digital Strategy work developed with Story), implemented its first VOT intervention at Minsk Tuberculosis Dispensary number 2, a major TB clinic in the capital city with around 26, 000 outpatient consultations per year and approximately 85 TB patients attending for observed treatment every day. Staff at the dispensary volunteered to introduce VOT as an additional option to support their patients. This pilot showed that VOT was well accepted by patients and underpinned the roll-out of a larger programme by the Belarus Red Cross across 450 treatment centres in 2018, with the support of the Global Fund to Fight AIDS, Malaria and TB [S11].