Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial.

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants.

Study protocol for a randomised controlled trial of a virtual antenatal intervention for improved diet and iron intake in Kapilvastu district, Nepal: VALID.

INTRODUCTION: Despite evidence that iron and folic acid (IFA) supplements can improve anaemia in pregnant women, uptake in Nepal is suboptimal. We hypothesised that providing virtual counselling twice in mid-pregnancy, would increase compliance to IFA tablets during the COVID-19 pandemic compared with antenatal care (ANC alone. METHODS AND ANALYSIS: This non-blinded individually randomised controlled trial in the plains of Nepal has two study arms: (1) control: routine ANC; and (2) 'Virtual' antenatal counselling plus routine ANC. Pregnant women are eligible to enrol if they are married, aged 13-49 years, able to respond to questions, 12-28 weeks' gestation, and plan to reside in Nepal for the next 5 weeks. The intervention comprises two virtual counselling sessions facilitated by auxiliary nurse midwives at least 2 weeks apart in mid-pregnancy. Virtual counselling uses a dialogical problem-solving approach with pregnant women and their families. We randomised 150 pregnant women to each arm, stratifying by primigravida/multigravida and IFA consumption at baseline, providing 80% power to detect a 15% absolute difference in primary outcome assuming 67% prevalence in control arm and 10% loss-to-follow-up. Outcomes are measured 49-70 days after enrolment, or up to delivery otherwise. PRIMARY OUTCOME: consumption of IFA on at least 80% of the previous 14 days. SECONDARY OUTCOMES: dietary diversity, consumption of intervention-promoted foods, practicing ways to enhance bioavailability and knowledge of iron-rich foods. Our mixed-methods process evaluation explores acceptability, fidelity, feasibility, coverage (equity and reach), sustainability and pathways to impact. We estimate costs and cost-effectiveness of the intervention from a provider perspective. Primary analysis is by intention-to-treat, using logistic regression. ETHICS AND DISSEMINATION: We obtained ethical approval from Nepal Health Research Council (570/2021) and UCL ethics committee (14301/001). We will disseminate findings in peer-reviewed journal articles and by engaging policymakers in Nepal. TRIAL REGISTRATION NUMBER: ISRCTN17842200.

How did the COVID-19 pandemic affect access to condoms, chlamydia and HIV testing, and cervical cancer screening at a population level in Britain? (Natsal-COVID).

OBJECTIVES: To investigate how differential access to key interventions to reduce STIs, HIV and their sequelae changed during the COVID-19 pandemic. METHODS: British participants (18-59 years) completed a cross-sectional web survey 1 year (March-April 2021) after the initial lockdown in Britain. Quota-based sampling and weighting resulted in a quasi-representative population sample. We compared Natsal-COVID data with Natsal-3, a household-based probability sample cross-sectional survey (16-74 years) conducted in 2010-2012. Reported unmet need for condoms because of the pandemic and uptake of chlamydia testing/HIV testing/cervical cancer screening were analysed among sexually experienced participants (18-44 years) (n=3869, Natsal-COVID; n=8551, Natsal-3). ORs adjusted for age and other potential confounders describe associations with demographic and behavioural factors. RESULTS: In 2021, 6.9% of women and 16.2% of men reported unmet need for condoms because of the pandemic. This was more likely among participants: aged 18-24 years, of black or black British ethnicity, and reporting same-sex sex (past 5 years) or one or more new relationships (past year). Chlamydia and HIV testing were more commonly reported by younger participants, those reporting condomless sex with new sexual partners and men reporting same-sex partners; a very similar distribution to 10 years previously (Natsal-3). However, there were differences during the pandemic, including stronger associations with chlamydia testing for men reporting same-sex partners; with HIV testing for women reporting new sexual partners and with cervical screening among smokers. CONCLUSIONS: Our study suggests differential access to key primary and secondary STI/HIV prevention interventions continued during the first year of the COVID-19 pandemic. However, there was not strong evidence that differential access has changed during the pandemic when compared with 2010-2012. While the pandemic might not have exacerbated inequalities in access to primary and secondary prevention, it is clear that large inequalities persisted, typically among those at greatest STI/HIV risk.

Comprehensive Anaemia Programme and Personalized Therapies (CAPPT): protocol for a cluster-randomised controlled trial testing the effect women's groups, home counselling and iron supplementation on haemoglobin in pregnancy in southern Nepal.

BACKGROUND: Anaemia in pregnancy remains prevalent in Nepal and causes severe adverse health outcomes. METHODS: This non-blinded cluster-randomised controlled trial in the plains of Nepal has two study arms: (1) Control: routine antenatal care (ANC); (2) Home visiting, iron supplementation, Participatory Learning and Action (PLA) groups, plus routine ANC. Participants, including women in 54 non-contiguous clusters (mean 2582; range 1299-4865 population) in Southern Kapilbastu district, are eligible if they consent to menstrual monitoring, are resident, married, aged 13-49 years and able to respond to questions. After 1-2 missed menses and a positive pregnancy test, consenting women < 20 weeks' gestation, who plan to reside locally for most of the pregnancy, enrol into trial follow-up. Interventions comprise two home-counselling visits (at 12-21 and 22-26 weeks' gestation) with iron folic acid (IFA) supplement dosage tailored to women's haemoglobin concentration, plus monthly PLA women's group meetings using a dialogical problem-solving approach to engage pregnant women and their families. Home visits and PLA meetings will be facilitated by auxiliary nurse midwives. The hypothesis is as follows: Haemoglobin of women at 30 ± 2 weeks' gestation is ≥ 0.4 g/dL higher in the intervention arm than in the control. A sample of 842 women (421 per arm, average 15.6 per cluster) will provide 88% power, assuming SD 1.2, ICC 0.09 and CV of cluster size 0.27. Outcomes are captured at 30 ± 2 weeks gestation. Primary outcome is haemoglobin concentration (g/dL). Secondary outcomes are as follows: anaemia prevalence (%), mid-upper arm circumference (cm), mean probability of micronutrient adequacy (MPA) and number of ANC visits at a health facility. Indicators to assess pathways to impact include number of IFA tablets consumed during pregnancy, intake of energy (kcal/day) and dietary iron (mg/day), a score of bioavailability-enhancing behaviours and recall of one nutrition knowledge indicator. Costs and cost-effectiveness of the intervention will be estimated from a provider perspective. Using constrained randomisation, we allocated clusters to study arms, ensuring similarity with respect to cluster size, ethnicity, religion and distance to a health facility. Analysis is by intention-to-treat at the individual level, using mixed-effects regression. DISCUSSION: Findings will inform Nepal government policy on approaches to increase adherence to IFA, improve diets and reduce anaemia in pregnancy. TRIAL REGISTRATION: ISRCTN 12272130 .

Initial impacts of the COVID-19 pandemic on sexual and reproductive health service use and unmet need in Britain: findings from a quasi-representative survey (Natsal-COVID).

BACKGROUND: The COVID-19 pandemic has affected sexual and reproductive health (SRH) service use and unmet need, but the impact is unknown. We aimed to determine the proportion of participants reporting sexual risk behaviours, SRH service use and unmet need, and to assess remote sexually transmitted infection (STI) testing service use after the first national lockdown in Britain. METHODS: We used data from the National Surveys of Sexual Attitudes and Lifestyles (Natsal)-COVID cross-sectional, quasi-representative web survey (Natsal-COVID Wave 1). Adults aged 18-59 years who resided in England, Scotland, or Wales completed the survey between July 29 and Aug 10, 2020, which included questions about the approximate 4-month period after announcement of the initial lockdown in Britain (March 23, 2020). Quota-based sampling and weighting were used to achieve a quasi-representative population sample. Participants aged 45-59 years were excluded from services analysis due to low rates of SRH service use. Among individuals aged 18-44 years, we estimated reported SRH service use and inability to access, and calculated age-adjusted odds ratios (aORs) among sexually experienced individuals (those reporting any sexual partner in their lifetime) and sexually active individuals (those reporting any sexual partner in the past year). Unweighted denominators and weighted estimates are presented hereafter. FINDINGS: 6654 individuals had complete interviews and were included in the analysis. Among 3758 participants aged 18-44 years, 82·0% reported being sexually experienced, and 73·7% reported being sexually active. 20·8% of sexually experienced participants aged 18-44 years reported using SRH services in the 4-month period. Overall, 9·7% of 3108 participants (9·5% of men; 9·9% of women) reported being unable to use a service they needed, although of the participants who reported trying but not being able to use a SRH service at least once, 76·4% of participants also reported an instance of successful use. 5·9% of 1221 sexually active men and 3·6% of 1560 sexually active women reported use of STI-related services and 14·8% of 1728 sexually experienced women reported use of contraceptive services, with SRH service use highest among individuals aged 18-24 years. Sexually active participants reporting condomless sex with new partners since lockdown were much more likely to report using STI-related services than those who did not report condomless sex (aOR 23·8 [95% CI 11·6-48·9]) for men, 10·5 [3·9-28·2] for women) and, among men, were also more likely to have an unsuccessful attempt at STI-service use (aOR 13·3 [5·3-32·9]). Among 106 individuals who reported using STI testing services, 64·4% accessed services remotely (telephone, video, or online). Among 2581 women aged 25-59 years, 2·4% reported cervical screening compared with an estimated 6% in a comparable 4-month period before the pandemic. INTERPRETATION: Many people accessed SRH care during the initial lockdown; however, young people and those reporting sexual risk behaviours reported difficulties in accessing services and thus such services might need to address a backlog of need. FUNDING: Wellcome Trust, The Economic and Social Research Council, The National Institute for Health Research, Medical Research Council/Chief Scientist Office and Public Health Sciences Unit, and UCL Coronavirus Response Fund.

Risk for development of active tuberculosis in patients with chronic airway disease-a systematic review of evidence.

Reports suggest an increased risk of tuberculosis (TB) in people with chronic airway diseases (CADs) such as chronic obstructive pulmonary disease (COPD), but evidence has not been systematically reviewed. We performed a systematic review by searching MEDLINE and Embase for studies published from 1 January 1993 to 15 January 2021 reporting the association between the incident risk of TB in people with CADs (asthma, COPD and bronchiectasis). Two reviewers independently assessed the quality of individual studies. We included nine studies, with two from low-income high TB burden countries. Three cohort studies reported a statistically significant independent association between COPD and the risk of TB in high-income countries (n=711 389). Hazard ratios for incident TB ranged from 1.44 to 3.14 adjusted for multiple confounders including age, sex and comorbidity. There was large between-study heterogeneity (I2=97.0%) across studies. The direction of effect on the TB risk from asthma was inconsistent. Chronic bronchitis or bronchiectasis studies were limited. The small number of available studies demonstrated an increased risk of TB in people with COPD; however, the magnitude of the increase varies by setting and population. Data in high TB burden countries and for other CADs are limited.

Testing approaches to sharing trial results with participants: The Show RESPECT cluster randomised, factorial, mixed methods trial.

BACKGROUND: Sharing trial results with participants is an ethical imperative but often does not happen. We tested an Enhanced Webpage versus a Basic Webpage, Mailed Printed Summary versus no Mailed Printed Summary, and Email List Invitation versus no Email List Invitation to see which approach resulted in the highest patient satisfaction with how the results were communicated. METHODS AND FINDINGS: We carried out a cluster randomised, 2 by 2 by 2 factorial, nonblinded study within a trial, with semistructured qualitative interviews with some patients (ISRCTN96189403). Each cluster was a UK hospital participating in the ICON8 ovarian cancer trial. Interventions were shared with 384 ICON8 participants who were alive and considered well enough to be contacted, at 43 hospitals. Hospitals were allocated to share results with participants through one of the 8 intervention combinations based on random permutation within blocks of 8, stratified by number of participants. All interventions contained a written plain English summary of the results. The Enhanced Webpage also contained a short video. Both the Enhanced Webpage and Email contained links to further information and support. The Mailed Printed Summary was opt-out. Follow-up questionnaires were sent 1 month after patients had been offered the interventions. Patients' reported satisfaction was measured using a 5-point scale, analysed by ordinal logistic regression estimating main effects for all 3 interventions, with random effects for site, restricted to those who reported receiving the results and assuming no interaction. Data collection took place in 2018 to 2019. Questionnaires were sent to 275/384 randomly selected participants and returned by 180: 90/142 allocated Basic Webpage, 90/133 Enhanced Webpage; 91/141 no Mailed Printed Summary, 89/134 Mailed Printed Summary; 82/129 no Email List Invitation, 98/146 Email List Invitation. Only 3 patients opted out of receiving the Mailed Printed Summary; no patients signed up to the email list. Patients' satisfaction was greater at sites allocated the Mailed Printed Summary, where 65/81 (80%) were quite or very satisfied compared to sites with no Mailed Printed Summary 39/64 (61%), ordinal odds ratio (OR) = 3.15 (1.66 to 5.98, p < 0.001). We found no effect on patient satisfaction from the Enhanced Webpage, OR = 1.47 (0.78 to 2.76, p = 0.235) or Email List Invitation, OR = 1.38 (0.72 to 2.63, p = 0.327). Interviewees described the results as interesting, important, and disappointing (the ICON8 trial found no benefit). Finding out the results made some feel their trial participation had been more worthwhile. Regardless of allocated group, patients who received results generally reported that the information was easy to understand and find, were glad and did not regret finding out the results. The main limitation of our study is the 65% response rate. CONCLUSIONS: Nearly all respondents wanted to know the results and were glad to receive them. Adding an opt-out Mailed Printed Summary alongside a webpage yielded the highest reported satisfaction. This study provides evidence on how to share results with other similar trial populations. Further research is needed to look at different results scenarios and patient populations. TRIAL REGISTRATION: ISRCTN: ISRCTN96189403.

An evaluation of whether propensity score adjustment can remove the self-selection bias inherent to web panel surveys addressing sensitive health behaviours.

BACKGROUND: In health research, population estimates are generally obtained from probability-based surveys. In market research surveys are frequently conducted from volunteer web panels. Propensity score adjustment (PSA) is often used at analysis to try to remove bias in the web survey, but empirical evidence of its effectiveness is mixed. We assess the ability of PSA to remove bias in the context of sensitive sexual health research and the potential of web panel surveys to replace or supplement probability surveys. METHODS: Four web panel surveys asked a subset of questions from the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Five propensity scores were generated for each web survey. The scores were developed from progressively larger sets of variables, beginning with demographic variables only and ending with demographic, sexual identity, lifestyle, attitudinal and sexual behaviour variables together. The surveys were weighted to match Natsal-3 based on propensity score quintiles. The performance of each survey and weighting was assessed by calculating the average 'absolute' odds ratio (inverse of the odds ratio if less than 1) across 22 pre-specified sexual behaviour outcomes of interest comparing the weighted web survey with Natsal-3. The average standard error across odds ratios was examined to assess the impact of weighting upon variance. RESULTS: Propensity weighting reduced bias relative to Natsal-3 as more variables were added for males, but had little effect for females, and variance increased for some surveys. Surveys with more biased estimates before propensity weighting showed greater reduction in bias from adjustment. Inconsistencies in performance were evident across surveys and outcomes. For most surveys and outcomes any reduction in bias was only partial and for some outcomes the bias increased. CONCLUSIONS: Even after propensity weighting using a rich range of information, including some sexual behaviour variables, some bias remained and variance increased for some web surveys. Whilst our findings support the use of PSA for web panel surveys, the reduction in bias is likely to be partial and unpredictable, consistent with the findings from market research. Our results do not support the use of volunteer web panels to generate unbiased population health estimates.

Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT.

BACKGROUND: The comparative efficacy, and cost-effectiveness, of imiquimod or podophyllotoxin cream, either alone or in combination with the quadrivalent HPV vaccine (Gardasil®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) in the treatment and prevention of recurrence of anogenital warts is not known. OBJECTIVE: The objective was to compare the efficacy of imiquimod and podophyllotoxin creams to treat anogenital warts and to assess whether or not the addition of quadrivalent human papillomavirus vaccine increases wart clearance or prevention of recurrence. DESIGN: A randomised, controlled, multicentre, partially blinded factorial trial. Participants were randomised equally to four groups, combining either topical treatment with quadrivalent human papillomavirus vaccine or placebo. Randomisation was stratified by gender, a history of previous warts and human immunodeficiency virus status. There was an accompanying economic evaluation, conducted from the provider perspective over the trial duration. SETTING: The setting was 22 sexual health clinics in England and Wales. PARTICIPANTS: Participants were patients with a first or repeat episode of anogenital warts who had not been treated in the previous 3 months and had not previously received quadrivalent human papillomavirus vaccine. INTERVENTIONS: Participants were randomised to 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Takeley, UK) for up to 16 weeks or 0.15% podophyllotoxin cream (Warticon®; GlaxoSmithKlein plc, Brentford, UK) for 4 weeks, which was extended to up to 16 weeks if warts persisted. Participants were simultaneously randomised to quadrivalent human papillomavirus vaccine (Gardasil) or saline control at 0, 8 and 24 weeks. Cryotherapy was permitted after week 4 at the discretion of the investigator. MAIN OUTCOME MEASURES: The main outcome measures were a combined primary outcome of wart clearance at week 16 and remaining wart free at week 48. Efficacy analysis was by logistic regression with multiple imputation for missing follow-up values; economic evaluation considered the costs per quality-adjusted life-year. RESULTS: A total of 503 participants were enrolled and attended at least one follow-up visit. The mean age was 31 years, 66% of participants were male (24% of males were men who have sex with men), 50% had a previous history of warts and 2% were living with human immunodeficiency virus. For the primary outcome, the adjusted odds ratio for imiquimod cream versus podophyllotoxin cream was 0.81 (95% confidence interval 0.54 to 1.23), and for quadrivalent human papillomavirus vaccine versus placebo, the adjusted odds ratio was 1.46 (95% confidence interval 0.97 to 2.20). For the components of the primary outcome, the adjusted odds ratio for wart free at week 16 for imiquimod versus podophyllotoxin was 0.77 (95% confidence interval 0.52 to 1.14) and for quadrivalent human papillomavirus vaccine versus placebo was 1.30 (95% confidence interval 0.89 to 1.91). The adjusted odds ratio for remaining wart free at 48 weeks (in those who were wart free at week 16) for imiquimod versus podophyllotoxin was 0.98 (95% confidence interval 0.54 to 1.78) and for quadrivalent human papillomavirus vaccine versus placebo was 1.39 (95% confidence interval 0.73 to 2.63). Podophyllotoxin plus quadrivalent human papillomavirus vaccine had inconclusive cost-effectiveness compared with podophyllotoxin alone. LIMITATIONS: Hepatitis A vaccine as control was replaced by a saline placebo in a non-identical syringe, administered by someone outside the research team, for logistical reasons. Sample size was reduced from 1000 to 500 because of slow recruitment and other delays. CONCLUSIONS: A benefit of the vaccine was not demonstrated in this trial. The odds of clearance at week 16 and remaining clear at week 48 were 46% higher with vaccine, and consistent effects were seen for both wart clearance and recurrence separately, but these differences were not statistically significant. Imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, but with a wide confidence interval. The trial results do not support earlier evidence of a lower recurrence with use of imiquimod than with use of podophyllotoxin. Podophyllotoxin without quadrivalent human papillomavirus vaccine is the most cost-effective strategy at the current vaccine list price. A further larger trial is needed to definitively investigate the effect of the vaccine; studies of the immune response in vaccine recipients are needed to investigate the mechanism of action. TRIAL REGISTRATION: Current Controlled Trials. Current Controlled Trials ISRCTN32729817 and EudraCT 2013-002951-14. 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. 24, No. 47. See the NIHR Journals Library website for further project information.

The HIPvac [Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts] trial compared two commonly used creams to treat genital warts: 0.15% podophyllotoxin cream (Warticon^®; GlaxoSmithKlein plc, Brentford, UK) and 5% imiquimod cream (Aldara^®; Meda Pharmaceuticals, Takeley, UK). It also investigated whether or not a vaccine used to prevent human papillomavirus infection, quadrivalent human papillomavirus vaccine (Gardasil^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA), could help treat warts or prevent them from coming back in patients whose warts had been cleared. The HIPvac trial was a randomised controlled trial involving 503 patients with warts attending sexual health clinics in England and Wales. The creams and the vaccine were well tolerated; there was some soreness where the cream was applied, but no unexpected side effects. When deciding which treatment was better, we looked at whether or not the warts had cleared by 16 weeks after starting treatment and, if cleared, whether or not they returned by 48 weeks. We compared the creams against each other, and the addition of vaccine against no vaccine (a placebo injection). Patients were allowed to have cryotherapy (freezing treatment) as well, if the investigator advised this. We also calculated the value for money of each type of treatment. The two creams were very similar in how well they worked to clear the warts. One difference was that podophyllotoxin cream worked slightly quicker. The number of patients given cryotherapy was about the same for both types of cream. We had expected that recurrence of warts after treatment with imiquimod cream might be less than after treatment with podophyllotoxin cream, but, in fact, the two creams were similar. Quadrivalent human papillomavirus vaccine did not improve clearance of warts or reduce the chance of recurrence, but the result remains inconclusive. If we had been able to recuit 1000 participants as originally planned, we might have been able to be more certain about whether there was any benefit of vaccination. Further research would be needed to investigate any possible effect. The two creams offered similar value for money in treating warts. Giving patients the vaccine in addition to the cream is not good value for money at its current list price, given the uncertainty about the benefit it offers.

An interactive website for informed contraception choice: randomised evaluation of Contraception Choices.

OBJECTIVE: Improving use of effective contraception to prevent unintended pregnancy is a global priority, but misperceptions and concerns about contraception are common. Our objective was to evaluate an interactive website to aid informed choice of contraception. METHODS: The Contraception Choices website is an interactive digital intervention which offers tailored advice to aid contraception decision-making (www.contraceptionchoices.org). In a parallel single-blind trial, we randomised 927 women aged 15-30 years from six clinic settings to access the intervention website (n = 464) or to a waiting-list control group (n = 463). The study was initially a feasibility trial, evolving into an evaluation of efficacy, with two primary outcomes at six months: long-acting reversible contraception (LARC) use, and satisfaction with contraceptive method. Secondary outcomes included self-reported pregnancy and sexually transmitted infection diagnoses. Free-text comments on the 3 and 6 month outcome surveys were analysed thematically. FINDINGS: There was no significant difference between intervention and control groups in the proportion of women using LARC [30.4% intervention versus 31.0% control; adjusted odds ratio 0.87 (95% confidence interval 0.60 to 1.28)]; satisfaction with contraceptive method [82.6% versus 82.1%; adjusted ordinal odds ratio 0.93 (95% CI 0.69 to 1.25)]; self-reported pregnancy [3.3% versus 4.1%; adjusted odds ratio 0.90 (95% CI 0.45 to 1.79)] nor sexually transmitted infection [5.3% versus 4.7%; adjusted odds ratio 0.72 (95% CI 0.55 to 2.36)]. Highly positive free-text comments from intervention participants indicated that the website facilitates contraception choice and can help women feel better prepared before consultation with healthcare providers. INTERPRETATION: The Contraception Choices website was popular for its design, trustworthy information and decision aids but it was not associated with significant differences in use of LARC or satisfaction with contraceptive method. An interactive website can aid contraception choice, but interventions that address factors beyond women's control, such as access to services, and partner, family or community influences are needed to complement this approach. RESEARCH IN CONTEXT: Preventing unintended pregnancy through effective use of contraception is essential for women's health, but choosing between different contraceptive methods can be challenging, and the opportunity for adequate discussion during routine consultations is often constrained. EVIDENCE BEFORE THIS STUDY: We conducted two systematic literature reviews: 1) Factors influencing contraception choice, uptake and use: a meta-synthesis of systematic reviews; and 2) Effectiveness of interactive digital interventions (IDI) for contraception choice, uptake and use. For the first review we searched PubMed, CDSR, Epistemonikos, DoPHER, DARE, NHS Economic Evaluation Database, Campbell Library, NIHR Health Technology Assessment, and Health Evidence Canada databases for systematic reviews which addressed contraceptive choice, uptake or use, from 2000 to 2017. PROSPERO registration number: CRD42017081521 https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=81521. We synthesised the findings of 18 systematic reviews of mostly moderate or high quality. They highlighted the importance of women's knowledge, beliefs, perceptions of side effects and health risks, as well as relationship status, social network, economic and healthcare factors on contraception choice and use. For the second review, we searched 23 electronic databases, trials registers and reference lists for randomised controlled trials of IDI for contraception, including CENTRAL, MEDLINE, EMBASE, CINAHL, ERIC, ASSIA and PsycINFO, from start date to June 2017. PROSPERO registration number: CRD42017081636. We found only five randomised trials of IDI, all from the USA. Risk of bias prevented synthesis of results. www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=81636. ADDED VALUE OF THIS STUDY: Women's common concerns about contraception - fear of hormones, weight gain, cancer, infertility, mood changes, breaks from contraception and changes in bleeding patterns - underpinned development of a new interactive website (www.contraceptionchoices.org). Contraception Choices addresses women's concerns through succinct text; Q and A format (Frequently Asked Questions, Did you Know?; videos of women and health professionals); an effectiveness infographic, and an interactive decision aid (What's right for me?).In an online randomised trial with 927 women attending clinics, we found no association of the Contraception Choices intervention with the primary outcomes - satisfaction with contraceptive method and uptake of long-acting reversible methods at 6 months. Nor did we find an association with secondary adverse outcomes - sexually transmitted infections or pregnancy. Comments from women indicated that the website can meet young women's need for information on the benefits and drawbacks of contraception, help them to make informed decisions, and feel better prepared before healthcare consultations. Contraception Choices is now available on the NHS website: www.nhs.uk/conditions/contraception/which-method-suits-me. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: Interactive digital interventions (websites) can aid contraception choice, but other intervention research is needed to address wider influences on unintended pregnancy, including partner views, friends, family, the media, wider society and experiences with healthcare professionals. Future research could examine the impact of the website in different settings, e.g. schools or different countries. We hypothesise that use of the website during contraceptive consultations might improve the efficiency or quality of consultation, for both patients and healthcare providers. Appropriate methodology and time-scale for evaluating digital health interventions remains a key question.

Effect of weighting for sampling and non-response on estimates of STI prevalence in the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

OBJECTIVES: In addition to researcher-designed sampling biases, population-representative surveys for biomarker measurement of STIs often have substantial missingness due to non-contact, non-consent and other study-implementation issues. STI prevalence estimates may be biased if this missingness is related to STI risk. We investigated how accounting for sampling, interview non-response and non-provision of biological samples affects prevalence estimates in the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). METHODS: Natsal-3 was a multistage, clustered and stratified probability sample of 16-74 year-olds conducted between 2010 and 2012. Individuals were sampled from all private residential addresses in Britain; respondents aged 16-44 were further sampled to provide a urine specimen based on characteristics including self-reported sexual behaviours. We generated prevalence estimates and confidence intervals for six STIs in five stages: first without accounting for sampling or non-response, then applying inverse-probability weights cumulatively accounting for interview sampling, interview non-response, urine sampling and urine non-response. RESULTS: Interview non-completion occurred for 42.3% of interview-sampled individuals; urine non-completion occurred for 43.5% of urine-sampled individuals. Interview-sampled individuals, interview respondents, those selected for urine samples and those providing urine samples were each in turn slightly more at-risk for most STIs, leading to lower prevalence estimates after incorporating each set of weights. Researcher-controlled sampling had more impact than respondent-controlled response. CONCLUSIONS: Accounting for both sampling structures and willingness to interview or provide urine specimens can affect national STI prevalence estimates. Using both types of weights, as was done in Natsal-3, is important in reporting on population-based biomarker surveys.

Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis.

BACKGROUND: Multiple blood transcriptional signatures have been proposed for identification of active and incipient tuberculosis. We aimed to compare the performance of systematically identified candidate signatures for incipient tuberculosis and to benchmark these against WHO targets. METHODS: We did a systematic review and individual participant data meta-analysis. We searched Medline and Embase for candidate whole blood mRNA signatures discovered with the primary objective of diagnosis of active or incipient tuberculosis, compared with controls who were healthy or had latent tuberculosis infection. We tested the performance of eligible signatures in whole blood transcriptomic datasets, in which sampling before tuberculosis diagnosis was done and time to disease was available. Culture-confirmed and clinically or radiologically diagnosed pulmonary or extrapulmonary tuberculosis cases were included. Non-progressor (individuals who remained tuberculosis-free during follow-up) samples with less than 6 months of follow-up from the date of sample collection were excluded, as were participants with prevalent tuberculosis and those who received preventive therapy. Scores were calculated for candidate signatures for each participant in the pooled dataset. Receiver operating characteristic curves, sensitivities, and specificities were examined using prespecified intervals to tuberculosis (<3 months, <6 months, <1 year, and <2 years) from sample collection. This study is registered with PROSPERO, number CRD42019135618. RESULTS: We tested 17 candidate mRNA signatures in a pooled dataset from four eligible studies comprising 1126 samples. This dataset included 183 samples from 127 incipient tuberculosis cases in South Africa, Ethiopia, The Gambia, and the UK. Eight signatures (comprising 1-25 transcripts) that predominantly reflect interferon and tumour necrosis factor-inducible gene expression, had equivalent diagnostic accuracy for incipient tuberculosis over a 2-year period with areas under the receiver operating characteristic curves ranging from 0·70 (95% CI 0·64-0·76) to 0·77 (0·71-0·82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two SDs above the mean of uninfected controls to prioritise specificity and positive-predictive value, the eight signatures achieved sensitivities of 24·7-39·9% over 24 months and of 47·1-81·0% over 3 months, with corresponding specificities of more than 90%. Based on pre-test probability of 2%, the eight signatures achieved positive-predictive values ranging from 6·8-9·4% over 24 months and 11·2-14·4% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum WHO target product profile parameters for incipient tuberculosis biomarkers over a 2-year period. INTERPRETATION: Blood transcriptional biomarkers reflect short-term risk of tuberculosis and only exceed WHO benchmarks if applied to 3-6-month intervals. Serial testing among carefully selected target groups might be required for optimal implementation of these biomarkers. FUNDING: Wellcome Trust and National Institute for Health Research.

Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial).

BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013).

Prospective observational study to evaluate the performance of the BioSure HIV Self-Test in the hands of lay users.

OBJECTIVES: In order to assess whether the BioSure HIV Self-Test could be reliably performed by users at home and to determine whether they were able to perform and correctly interpret the test, we carried out an evaluation study among attendees at a sexual health service. METHODS: A prospective observational study of clinic attendees to determine their ability to follow the instructions, complete the test on themselves and correctly interpret the results. The evaluation included interpretation of three dummy (contrived) devices, chosen at random from a sample of 12 devices, to ensure that a sufficient number of all possible test outcomes were included. RESULTS: Two hundred participants were recruited. 97.0% (95% CI 93.5 to 98.9) conducted the test so as to achieve a valid result. 99.5% correctly identified the test result. Participants correctly interpreted the result of 94.0% (95% CI 91.4 to 95.9) of 586 contrived devices. CONCLUSIONS: The majority of participants were able to follow the instructions and perform the test in order to get a valid result. Interpretation of the test results was good and the majority of participants were able to correctly read the result of their own and contrived tests. The availability of HIV self-tests will provide another option to increase access to testing particularly for those who may not wish or are unable to access clinical services.

Effect of non-monetary incentives on uptake of couples' counselling and testing among clients attending mobile HIV services in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Couples' HIV testing and counselling (CHTC) is associated with greater engagement with HIV prevention and care than individual testing and is cost-effective, but uptake remains suboptimal. Initiating discussion of CHTC might result in distrust between partners. Offering incentives for CHTC could change the focus of the pre-test discussion. We aimed to determine the impact of incentives for CHTC on uptake of couples testing and HIV case diagnosis in rural Zimbabwe. METHODS: In this cluster-randomised trial, 68 rural communities (the clusters) in four districts receiving mobile HIV testing services were randomly assigned (1:1) to incentives for CHTC or not. Allocation was not masked to participants and researchers. Randomisation was stratified by district and proximity to a health facility. Within each stratum random permutation was done to allocate clusters to the study groups. In intervention communities, residents were informed that couples who tested together could select one of three grocery items worth US$1·50. Standard mobilisation for testing was done in comparison communities. The primary outcome was the proportion of individuals testing with a partner. Analysis was by intention to treat. 3 months after CHTC, couple-testers from four communities per group individually completed a telephone survey to evaluate any social harms resulting from incentives or CHTC. The effect of incentives on CHTC was estimated using logistic regression with random effects adjusting for clustering. The trial was registered with the Pan African Clinical Trial Registry, number PACTR201606001630356. FINDINGS: From May 26, 2015, to Jan 29, 2016, of 24 679 participants counselled with data recorded, 14 099 (57·1%) were in the intervention group and 10 580 (42·9%) in the comparison group. 7852 (55·7%) testers in the intervention group versus 1062 (10·0%) in the comparison group tested with a partner (adjusted odds ratio 13·5 [95% CI 10·5-17·4]). Among 427 (83·7%) of 510 eligible participants who completed the telephone survey, 11 (2·6%) reported that they were pressured or themselves pressured their partner to test together; none regretted couples' testing. Relationship unrest was reported by eight individuals (1·9%), although none attributed this to incentives. INTERPRETATION: Small non-monetary incentives, which are potentially scalable, were associated with significantly increased CHTC and HIV case diagnosis. Incentives did not increase social harms beyond the few typically encountered with CHTC without incentives. The intervention could help achieve UNAIDS 90-90-90 targets. FUNDING: The study was funded by the UK Department for International Development, Irish AID, and Swedish SIDA, through Population Services International Zimbabwe under the Integrated Support Program.

Is "Sexual Competence" at First Heterosexual Intercourse Associated With Subsequent Sexual Health Status?

The timing of first sexual intercourse is often defined in terms of chronological age, with particular focus on "early" first sex. Arguments can be made for a more nuanced concept of readiness and appropriateness of timing of first intercourse. Using data from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), conducted in 2010-2012, this study examined whether a context-based measure of first intercourse-termed sexual competence-was associated with subsequent sexual health in a population-based sample of 17-to 24-year-olds residing in Britain (n = 2,784). Participants were classified as "sexually competent" at first intercourse if they reported the following four criteria: contraceptive protection, autonomy of decision (not due to external influences), that both partners were "equally willing," and that it happened at the "right time." A lack of sexual competence at first intercourse was independently associated with testing positive for human papillomavirus (HPV) at interview; low sexual function in the past year; and among women only, reported sexually transmitted infection (STI) diagnosis ever; unplanned pregnancy in the past year; and having ever experienced nonvolitional sex. These findings provide empirical support for defining the nature of first intercourse with reference to contextual aspects of the experience, as opposed to a sole focus on chronological age at occurrence.

Sexual behaviours, HIV testing, and the proportion of men at risk of transmitting and acquiring HIV in London, UK, 2000-13: a serial cross-sectional study.

BACKGROUND: HIV incidence in men who have sex with men (MSM) in the UK has remained unchanged over the past decade despite increases in HIV testing and antiretroviral therapy (ART) coverage. In this study, we examine trends in sexual behaviours and HIV testing in MSM and explore the risk of transmitting and acquiring HIV. METHODS: In this serial cross-sectional study, we obtained data from ten cross-sectional surveys done between 2000 and 2013, consisting of anonymous self-administered questionnaires and oral HIV antibody testing in MSM recruited in gay social venues in London, UK. Data were collected between October and January for all survey years up to 2008 and between February and August thereafter. All men older than 16 years were eligible to take part and fieldworkers attempted to approach all MSM in each venue and recorded refusal rates. Data were collected on demographic and sexual behavioural characteristics. We analysed trends over time using linear, logistic, and quantile regression. FINDINGS: Of 13 861 questionnaires collected between 2000 and 2013, we excluded 1985 (124 had completed the survey previously or were heterosexual reporting no anal intercourse in the past year, and 1861 did not provide samples for antibody testing). Of the 11 876 eligible MSM recruited, 1512 (13%) were HIV positive, with no significant trend in HIV positivity over time. 35% (531 of 1505) of HIV-positive MSM had undiagnosed infection, which decreased non-linearly over time from 34% (45 of 131) to 24% (25 of 106; p=0·01), while recent HIV testing (ie, in the past year) increased from 26% (263 of 997) to 60% (467 of 777; p<0·0001). The increase in recent testing in undiagnosed men (from 29% to 67%, p<0·0001) and HIV-negative men (from 26% to 62%, p<0·0001) suggests that undiagnosed infection might increasingly be recently acquired infection. The proportion of MSM reporting unprotected anal intercourse (UAI) in the past year increased from 43% (513 of 1187) to 53% (394 of 749; p<0·0001) and serosorting (exclusively) increased from 18% (207 of 1132) to 28% (177 of 6369; p<0·0001). 268 (2%) of 11 570 participants had undiagnosed HIV and reported UAI in the past year were at risk of transmitting HIV. Additionally 259 (2%) had diagnosed infection and reported UAI and non-exclusive serosorting in the past year. Although we did not collect data on antiretroviral therapy or viral load, surveillance data suggests that a small proportion of men with diagnosed infection will have detectable viral load and hence might also be at risk of transmitting HIV. 2633 (25%) of 10 364 participants were at high risk of acquiring HIV (defined as HIV-negative MSM either reporting one or more casual UAI partners in the past year or not exclusively serosorting). The proportions of MSM at risk of transmission or acquisition changed little over time (p=0·96 for MSM potentially at risk of transmission and p=0·275 for MSM at high risk of acquiring HIV). Undiagnosed men reporting UAI and diagnosed men not exclusively serosorting had consistently higher partner numbers than did other MSM over the period (median ranged from one to three across surveys in undiagnosed men reporting UAI, two to ten in diagnosed men not exclusively serosorting, and none to two in other men). INTERPRETATION: An increasing proportion of undiagnosed HIV infections in MSM in London might have been recently acquired, which is when people are likely to be most infectious. High UAI partner numbers of MSM at risk of transmitting HIV and the absence of a significant decrease in the proportion of men at high risk of acquiring the infection might explain the sustained HIV incidence. Implementation of combination prevention interventions comprising both behavioural and biological interventions to reduce community-wide risk is crucial to move towards eradication of HIV. FUNDING: Public Health England.

Oral Human Papillomavirus Infection in Men Who Have Sex with Men: A Systematic Review and Meta-Analysis.

BACKGROUND: The epidemiology of oral human papillomavirus (HPV) infection in men who have sex with men (MSM) differs from anogenital HPV infection. The impact of HPV vaccination has, to date, largely focussed on anogenital outcomes. Vaccination of MSM in the UK has been recommended and, if implemented, baseline estimates of oral HPV prevalence will be useful. METHODS: We searched Medline, Embase and psycINFO databases for studies reporting prevalence, incidence, and clearance of oral HPV infection in MSM. We performed a random-effects meta-analysis and meta-regression on prevalence estimates and summarised within-study risk factors for oral HPV DNA detection and incidence/clearance rates. We also performed a meta-analysis of the effect of MSM on oral HPV prevalence compared to heterosexual men. RESULTS: 26 publications were identified. The pooled prevalence of oral HPV16 from twelve estimates was 3.0% (95%CI 0.5-5.5) in HIV-negative and 4.7% (95%CI 2.1-7.3) in HIV-positive MSM. Median age of study participants explained 38% of heterogeneity (p<0.01) in HPV prevalence estimates (pooled = 17% and 29% in HIV-negative and HIV-positive, respectively; 22 estimates). Nine studies compared MSM to heterosexual men and found no difference in oral HPV prevalence (pooled OR 1.07 (95%CI 0.65-1.74)). The clearance rate was higher than incidence within studies. Type-specific concordance between oral and anogenital sites was rare. CONCLUSION: There was substantial heterogeneity between estimates of oral HPV prevalence in MSM populations that was partly explained by HIV status and median age.

Medicated sex in Britain: evidence from the third National Survey of Sexual Attitudes and Lifestyles.

OBJECTIVES: To describe the prevalence of medication use to assist sexual performance in Britain and to identify associated factors. METHODS: Cross-sectional probability sample, undertaken in 2010-2012, of 15 162 people aged 16-74 years, resident in Britain, of whom, 5617 men and 8095 women reported sexual experience (ever) and 4817 men were sexually-active (reported sex in the last year). RESULTS: Ever use of medication to assist sexual performance (medicated sex) was more commonly reported by men than women (12.9% (95% CI 11.9% to 13.9%) vs 1.9% (95% CI 1.7% to 2.3%)) and associated with older age in men and younger age in women. It was associated with reporting smoking, and use of alcohol and recreational drugs, as well as unsafe sex (≥2 partners and no condom use in the last year) in both men and women. Among men, the proportion reporting medicated sex in the last year was higher among those reporting erectile difficulties (ED) than those not doing so (28.4% (95% CI 24.4% to 32.8%) vs 4.1% (95% CI 3.4% to 4.9%)). In all men, medicated sex was associated with more frequent sexual activity, meeting a partner on the internet, unsafe sex and recent sexually transmitted infections diagnosis; associations that persisted after adjusting for same-sex behaviour and ED. However, there were significant interactions with reporting ED, indicating that among men with ED, medicated sex is not associated with same-sex behaviour and ever use of recreational drugs. CONCLUSIONS: A substantial minority of people in Britain report medicated sex, and the association between medicated sex and risky sexual behaviour is not confined to high-risk groups.