Cost-utility analysis of molnupiravir for high-risk, community-based adults with COVID-19: an economic evaluation of the PANORAMIC trial.

BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease.

INTRODUCTION: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. METHODS AND ANALYSIS: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). ELIGIBILITY CRITERIA: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18-49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. ETHICS AND DISSEMINATION: Ethical approval granted by South Central-Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN30448031; EudraCT number: 2021-005748-31.

Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT.

Background: Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives: To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design: Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting: UK general practices. Participants: Children aged 1-12 years with acute uncomplicated lower respiratory tract infections. Outcomes: The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2-4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods: Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results: A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child's cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when 'necessary', and clinicians noted a reduction in parents' expectations for antibiotics. Limitations: The study was underpowered to detect small benefits in key subgroups. Conclusion: Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child's illness and safety-netting. Future work: The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN79914298. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

Children are commonly prescribed antibiotics for chest infections, but such infections are becoming resistant to antibiotics, and it is not clear if antibiotics work in treating them. A total of 432 children who saw their general practitioner with a chest infection were given either an antibiotic (amoxicillin) or a placebo (no antibiotic) for 7 days. Symptom diaries documented the infection's duration and its side effects. Children not in the placebo study were able to participate in another study that documented the same outcomes (an 'observational study'). We interviewed parents, doctors and nurses about their observations and concerns. Our patient and public involvement and engagement work with parents indicated that a 3-day symptom reduction was required to justify giving antibiotics. After seeing the doctor, parents whose children received antibiotics rated infective symptoms as moderately bad or worse for 5 days, and parents whose children received the placebo rated these for 6 days. Side effects and complications were similar in the two groups. Findings were similar when including the results of the observational study, and for children in whose chest the doctor could hear wheeze or rattles; who had fever; who were rated by the doctor as more unwell, who were short of breath, or who had had bacteria detected in the throat. The costs to the NHS per child were similar (antibiotics, £29; placebo, £26), and the wider costs to society were the same (antibiotics, £33; placebo, £33). Parents found it difficult to interpret their child's symptoms, and commonly used the sound of the cough to judge severity. Parents commonly consulted to receive an examination and reassurance, and accepted that antibiotics should be used only when 'necessary'. Clinicians noted a reduction in parents' expectations for antibiotics. Amoxicillin for chest infections in children is unlikely to be effective. General practitioners should support parents to self-manage at home and give clear communication about when and how to seek medical help if they continue to be concerned.

Cost-effectiveness of adding oseltamivir to primary care for influenza-like-illness: economic evaluation alongside the randomised controlled ALIC4E trial in 15 European countries.

BACKGROUND: Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries. METHODS: Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed. RESULTS: The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient). CONCLUSION: Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > €22,459) and cost-saving in adults/adolescents from a societal perspective.

Impact of Adding Oseltamivir to Usual Care on Quality-Adjusted Life-Years During Influenza-Like Illness.

OBJECTIVES: The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). METHODS: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (<13 years old) and adults (≥13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. RESULTS: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged ≥65 years, patients without relevant comorbidities, or patients experiencing symptoms for ≤48 hours. Using VAS and accounting for 28-day follow-up resulted in higher QALY gain. CONCLUSIONS: QALY gain owing to oseltamivir is limited compared with other diseases, and its clinical meaningfulness remains to be determined. Further analysis is needed to evaluate whether QALY gain and its impact on ILI treatment cost render oseltamivir cost-effective.

Direct and Indirect Costs of Influenza-Like Illness Treated with and Without Oseltamivir in 15 European Countries: A Descriptive Analysis Alongside the Randomised Controlled ALIC4E Trial.

BACKGROUND AND OBJECTIVE: Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone. METHODS: Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed. RESULTS: Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: €17 [0-95% Crl: 16-19] vs. €24 [5-100% Crl: 18-29]; healthcare provider: €37 [28-67] vs. €44 [25-55]; healthcare payers: €54 [45-85] vs. €68 [45-81]; and society: €423 [399-478] vs. €451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences. CONCLUSION: The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant.

D-MannosE to prevent Recurrent urinary tract InfecTions (MERIT): protocol for a randomised controlled trial.

INTRODUCTION: Recurrent urinary tract infections (RUTIs) have a significant negative impact on quality of life and healthcare costs. To date, daily prophylactic antibiotics are the only treatment which have been shown to help prevent RUTIs. D-mannose is a type of sugar which is believed to inhibit bacterial adherence to uroepithelial cells, and is already being used by some women in an attempt to prevent RUTIs. There is currently insufficient rigorous evidence on which to base decisions about its use. The D-mannose to prevent recurrent urinary tract infections (MERIT) study will evaluate whether D-mannose is clinically and cost-effective in reducing frequency of infection and symptom burden for women presenting to UK primary care with RUTI. METHODS AND ANALYSIS: MERIT will be a two-arm, individually randomised, double blind placebo controlled, pragmatic trial. Participants will be randomised to take D-mannose powder or placebo powder daily for 6 months. The primary outcome will be the number of medical attendances attributable to symptoms of RUTI. With 508 participants we will have 90% power to detect a 50% reduction in the chance of a further clinically suspected UTI, assuming 20% lost to follow-up. Secondary outcomes will include: number of days of moderately bad symptoms of UTI; time to next consultation; number of clinically suspected UTIs; number of microbiologically proven UTIs; number of antibiotic courses for UTI; quality of life and healthcare utilisation related to UTI. A within trial economic evaluation will be conducted to examine cost-effectiveness of D-mannose in comparison with placebo. A nested qualitative study will explore participants' experiences and perceptions of recruitment to, and participation in a study requiring a daily treatment. ETHICS AND DISSEMINATION: Ethical approval has been obtained from South West-Central Bristol Research Ethics Committee. Publication of the MERIT study is anticipated to occur in 2021. TRIAL REGISTRATION NUMBER: ISRCTN 13283516.

Social and Contextual Influences on Antibiotic Prescribing and Antimicrobial Stewardship: A Qualitative Study with Clinical Commissioning Group and General Practice Professionals.

Antibiotic prescribing in England varies considerably between Clinical Commissioning Groups (CCGs) and general practices. We aimed to assess social and contextual factors affecting antibiotic prescribing and engagement with antimicrobial stewardship (AMS) initiatives. Semi-structured telephone interviews were conducted with 22 CCG professionals and 19 general practice professionals. Interviews were audio-recorded, transcribed, and analyzed thematically. Social/contextual influences were grouped into the following four categories: (1) Immediate context, i.e., patients' social characteristics (e.g., deprivation and culture), clinical factors, and practice and clinician characteristics (e.g., "struggling" with staff shortage/turnover) were linked to higher prescribing. (2) Wider context, i.e., pressures on the healthcare system, limited resources, and competing priorities were seen to reduce engagement with AMS. (3) Collaborative and whole system approaches, i.e., communication, multidisciplinary networks, leadership, and teamwork facilitated prioritizing AMS, learning, and consistency. (4) Relativity of appropriate prescribing, i.e., "high" or "appropriate" prescribing was perceived as relative, depending on comparators, and disregarding different contexts, but social norms around antibiotic use among professionals and patients seemed to be changing. Further optimization of antibiotic prescribing would benefit from addressing social/contextual factors and addressing wider health inequalities, not only targeting individual clinicians. Tailoring and adapting to local contexts and constraints, ensuring adequate time and resources for AMS, and collaborative, whole system approaches to promote consistency may help promote AMS.

Vaccine effectiveness of live attenuated and trivalent inactivated influenza vaccination in 2010/11 to 2015/16: the SIVE II record linkage study.

BACKGROUND: There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged ≥ 65 years and for those aged < 65 years who are at an increased risk of complications from influenza infection (e.g. people with asthma). OBJECTIVE: To examine the vaccine effectiveness of LAIV and TIV. DESIGN: Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. SETTING: A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. PARTICIPANTS: A total of 1,250,000 people. INTERVENTIONS: LAIV for 2- to 11-year-olds and TIV for older people (aged ≥ 65 years) and those aged < 65 years who are at risk of diseases, from 2010/11 to 2015/16. MAIN OUTCOME MEASURES: The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. RESULTS: Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2-11 years) for preventing RT-PCR laboratory-confirmed influenza was 21% (95% CI -19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged ≥ 65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). CONCLUSIONS: The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged ≥ 65 years (although this was significant in only one season). FUTURE WORK: The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged ≥ 65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88072400. 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. 67. See the NIHR Journals Library website for further project information.

In Scotland, a new type of influenza vaccine (live attenuated influenza vaccine), administered via the nose, was introduced in 2014/15 for all children aged between 2 and 11 years. It can be difficult to evaluate any changes in health as a result of new immunisation programmes, given that randomised controlled trials of vaccines are impractical and can also be seen as unethical. These changes are therefore typically not evaluated, making it difficult to inform future policy in this field. Observational studies can be used to assess the effects of health-care interventions without influencing the care that is provided or affecting the people who receive it. An evaluation (effectiveness and safety) of this change in the immunisation programme was conducted. The vaccine programme, an inactivated vaccine administered as an injection, for other groups for whom the evidence available is limited was also evaluated [i.e. for people aged ≥ 65 years and people aged < 65 years who have a medical condition (e.g. asthma) that puts them at risk of severe illness from influenza]. The findings support the view that the intranasal vaccine is effective and safe in preventing influenza in children. The injectable vaccine in people aged < 65 years who are more at risk of complications from flu was safe and effective. Lower effectiveness was found in people aged ≥ 65 years. Both the injectable vaccine and the intranasal vaccine have high levels of uptake in the population offered vaccination. When considering these results, the important limitation of bias in observational study designs should be noted [for instance, residual confounding, whereby it is not possible to measure a characteristic of those people receiving the vaccine (e.g. being healthier)], and this is accounted for in this analysis.

How did a Quality Premium financial incentive influence antibiotic prescribing in primary care? Views of Clinical Commissioning Group and general practice professionals.

BACKGROUND: The Quality Premium (QP) was introduced for Clinical Commissioning Groups (CCGs) in England to optimize antibiotic prescribing, but it remains unclear how it was implemented. OBJECTIVES: To understand responses to the QP and how it was perceived to influence antibiotic prescribing. METHODS: Semi-structured telephone interviews were conducted with 22 CCG and 19 general practice professionals. Interviews were analysed thematically. RESULTS: The findings were organized into four categories. (i) Communication: this was perceived as unstructured and infrequent, and CCG professionals were unsure whether they received QP funding. (ii) Implementation: this was influenced by available local resources and competing priorities, with multifaceted and tailored strategies seen as most helpful for engaging general practices. Many antimicrobial stewardship (AMS) strategies were implemented independently from the QP, motivated by quality improvement. (iii) Mechanisms: the QP raised the priority of AMS nationally and locally, and provided prescribing targets to aim for and benchmark against, but money was not seen as reinvested into AMS. (iv) Impact and sustainability: the QP was perceived as successful, but targets were considered challenging for a minority of CCGs and practices due to contextual factors (e.g. deprivation, understaffing). CCG professionals were concerned with potential discontinuation of the QP and prescribing rates levelling off. CONCLUSIONS: CCG and practice professionals expressed positive views of the QP and associated prescribing targets and feedback. The QP helped influence change mainly by raising the priority of AMS and defining change targets rather than providing additional funding. To maximize impact, behavioural mechanisms of financial incentives should be considered pre-implementation.

Understanding how community antiretroviral delivery influences engagement in HIV care: a qualitative assessment of the Centralised Chronic Medication Dispensing and Distribution programme in South Africa.

INTRODUCTION: Providing antiretroviral therapy (ART) for millions of people living with HIV requires efficient, client-centred models of differentiated ART delivery. In South Africa, the Centralised Chronic Medication Dispensing and Distribution (CCMDD) programme allows over 1 million people to collect chronic medication, including ART, from community pick-up points. We aimed to explore how CCMDD influences engagement in HIV care. METHODS: We performed in-depth interviews and focus group discussions with clients receiving ART and healthcare workers in Durban, South Africa. We analysed transcripts using deductive thematic analysis, with a framework informed by 'theories of practice', which highlights the materialities, competencies, meanings and other life practices that underpin clients' engagement in HIV care. RESULTS: Between March 2018 to August 2018 we undertook 25 interviews and four focus groups with a total of 55 clients, and interviewed eight healthcare workers. The material challenges of standard clinic-based ART provision included long waiting times, poor confidentiality and restricted opening hours, which discouraged clients from engagement. In contrast, CCMDD allowed quicker and more convenient ART collection in the community. This required the development of new competencies around accessing care, and helped change the meanings associated with HIV, by normalising treatment collection. CCMDD was seen as a reward by clients for taking ART well, and helped reduce disruption to other life practices such as employment. At private pharmacies, some clients reported receiving inferior care compared with paying customers, and some worried about inadvertently revealing their HIV status. Clients and healthcare workers had to negotiate problems with CCMDD implementation, including some pharmacies reaching capacity or only allowing ART collection at restricted times. CONCLUSIONS: In South Africa, CCMDD overcame material barriers to attending clinics, changed the meanings associated with collecting ART and was less disruptive to other social practices in clients' lives. Expansion of community-based ART delivery programmes may help to facilitate engagement in HIV care. TRIAL REGISTRATION NUMBER: STREAM study clinical trial registration: NCT03066128, registered February 2017.

C-reactive protein point-of-care testing for safely reducing antibiotics for acute exacerbations of chronic obstructive pulmonary disease: the PACE RCT.

BACKGROUND: Most patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in primary care are prescribed antibiotics, but these may not be beneficial, and they can cause side effects and increase the risk of subsequent resistant infections. Point-of-care tests (POCTs) could safely reduce inappropriate antibiotic prescribing and antimicrobial resistance. OBJECTIVE: To determine whether or not the use of a C-reactive protein (CRP) POCT to guide prescribing decisions for AECOPD reduces antibiotic consumption without having a negative impact on chronic obstructive pulmonary disease (COPD) health status and is cost-effective. DESIGN: A multicentre, parallel-arm, randomised controlled open trial with an embedded process, and a health economic evaluation. SETTING: General practices in Wales and England. A UK NHS perspective was used for the economic analysis. PARTICIPANTS: Adults (aged ≥ 40 years) with a primary care diagnosis of COPD, presenting with an AECOPD (with at least one of increased dyspnoea, increased sputum volume and increased sputum purulence) of between 24 hours' and 21 days' duration. INTERVENTION: CRP POCTs to guide antibiotic prescribing decisions for AECOPD, compared with usual care (no CRP POCT), using remote online randomisation. MAIN OUTCOME MEASURES: Patient-reported antibiotic consumption for AECOPD within 4 weeks post randomisation and COPD health status as measured with the Clinical COPD Questionnaire (CCQ) at 2 weeks. For the economic evaluation, patient-reported resource use and the EuroQol-5 Dimensions were included. RESULTS: In total, 653 participants were randomised from 86 general practices. Three withdrew consent and one was randomised in error, leaving 324 participants in the usual-care arm and 325 participants in the CRP POCT arm. Antibiotics were consumed for AECOPD by 212 out of 274 participants (77.4%) and 150 out of 263 participants (57.0%) in the usual-care and CRP POCT arm, respectively [adjusted odds ratio 0.31, 95% confidence interval (CI) 0.20 to 0.47]. The CCQ analysis comprised 282 and 281 participants in the usual-care and CRP POCT arms, respectively, and the adjusted mean CCQ score difference at 2 weeks was 0.19 points (two-sided 90% CI -0.33 to -0.05 points). The upper limit of the CI did not contain the prespecified non-inferiority margin of 0.3. The total cost from a NHS perspective at 4 weeks was £17.59 per patient higher in the CRP POCT arm (95% CI -£34.80 to £69.98; p = 0.408). The mean incremental cost-effectiveness ratios were £222 per 1% reduction in antibiotic consumption compared with usual care at 4 weeks and £15,251 per quality-adjusted life-year gained at 6 months with no significant changes in sensitivity analyses. Patients and clinicians were generally supportive of including CRP POCT in the assessment of AECOPD. CONCLUSIONS: A CRP POCT diagnostic strategy achieved meaningful reductions in patient-reported antibiotic consumption without impairing COPD health status or increasing costs. There were no associated harms and both patients and clinicians valued the diagnostic strategy. FUTURE WORK: Implementation studies that also build on our qualitative findings could help determine the effect of this intervention over the longer term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24346473. 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. 15. See the NIHR Journals Library website for further project information.

People with chronic obstructive pulmonary disease (COPD) often experience flare-ups known as acute exacerbations of chronic obstructive pulmonary disease. Antibiotics are prescribed for most flare-ups, but they do not always benefit patients and may cause harm, such as side effects or subsequent infections that are resistant. Rapid point-of-care tests (POCTs) can be used to help determine when antibiotics are more likely to be needed. C-reactive protein (CRP) is a marker of inflammation that can be measured with a POCT. Patients with flare-ups and a low CRP value are less likely to benefit from antibiotics. The PACE trial asked whether or not measuring CRP with a POCT could lead to fewer antibiotics being consumed for flare-ups, without having negative effects for patients. We aimed to recruit 650 patients with a COPD flare-up from primary care. Patients were randomly assigned to either (1) usual care with the addition of a CRP POCT, or (2) usual care without the addition of the test. Antibiotic use over the first 4 weeks and patients' self-assessment of their health 2 weeks after enrolment were measured in both groups. Patients in the CRP test group used fewer antibiotics than those managed as usual, and had improved patient-reported outcomes. Costs were a little higher in the CRP POCT group. Interviews with patients and clinicians found that they appreciated the CRP test being included in the decision-making process.

C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations.

BACKGROUND: Point-of-care testing of C-reactive protein (CRP) may be a way to reduce unnecessary use of antibiotics without harming patients who have acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: We performed a multicenter, open-label, randomized, controlled trial involving patients with a diagnosis of COPD in their primary care clinical record who consulted a clinician at 1 of 86 general medical practices in England and Wales for an acute exacerbation of COPD. The patients were assigned to receive usual care guided by CRP point-of-care testing (CRP-guided group) or usual care alone (usual-care group). The primary outcomes were patient-reported use of antibiotics for acute exacerbations of COPD within 4 weeks after randomization (to show superiority) and COPD-related health status at 2 weeks after randomization, as measured by the Clinical COPD Questionnaire, a 10-item scale with scores ranging from 0 (very good COPD health status) to 6 (extremely poor COPD health status) (to show noninferiority). RESULTS: A total of 653 patients underwent randomization. Fewer patients in the CRP-guided group reported antibiotic use than in the usual-care group (57.0% vs. 77.4%; adjusted odds ratio, 0.31; 95% confidence interval [CI], 0.20 to 0.47). The adjusted mean difference in the total score on the Clinical COPD Questionnaire at 2 weeks was -0.19 points (two-sided 90% CI, -0.33 to -0.05) in favor of the CRP-guided group. The antibiotic prescribing decisions made by clinicians at the initial consultation were ascertained for all but 1 patient, and antibiotic prescriptions issued over the first 4 weeks of follow-up were ascertained for 96.9% of the patients. A lower percentage of patients in the CRP-guided group than in the usual-care group received an antibiotic prescription at the initial consultation (47.7% vs. 69.7%, for a difference of 22.0 percentage points; adjusted odds ratio, 0.31; 95% CI, 0.21 to 0.45) and during the first 4 weeks of follow-up (59.1% vs. 79.7%, for a difference of 20.6 percentage points; adjusted odds ratio, 0.30; 95% CI, 0.20 to 0.46). Two patients in the usual-care group died within 4 weeks after randomization from causes considered by the investigators to be unrelated to trial participation. CONCLUSIONS: CRP-guided prescribing of antibiotics for exacerbations of COPD in primary care clinics resulted in a lower percentage of patients who reported antibiotic use and who received antibiotic prescriptions from clinicians, with no evidence of harm. (Funded by the National Institute for Health Research Health Technology Assessment Program; PACE Current Controlled Trials number, ISRCTN24346473.).

Impact of antibiotic treatment duration on outcomes in older men with suspected urinary tract infection: Retrospective cohort study.

PURPOSE: Clinical guidelines recommend at least 7 days of antibiotic treatment for older men with urinary tract infection (UTI). There may be potential benefits for patients, health services, and antimicrobial stewardship if shorter antibiotic treatment resulted in similar outcomes. We aimed to determine if treatment duration could be reduced by estimating risk of adverse outcomes according to different prescription durations. METHODS: This retrospective cohort study included men aged greater than or equal to 65 years old with a suspected UTI. We compared outcomes in men prescribed 3, 5, 7, and 8 to 14 days of antibiotic treatment in a multivariable logistic regression analysis and 3 versus 7 days in a propensity-score matched analysis. Our outcomes were reconsultation and represcription (proxy for treatment failure), hospitalisation for UTI, sepsis, or acute kidney injury (AKI), and death. RESULTS: Of 360 640 men aged greater than or equal to 65 years, 33 745 (9.4%) had a UTI. Compared with 7 days, men prescribed 3-day treatment had greater odds of reconsultation and represcription (adjusted OR 1.48; 95% CI, 1.25-1.74) but lower odds of AKI hospitalisation (adjusted OR 0.66; 95% CI, 0.45-0.97). We estimated that treating 150 older men with 3 days instead of 7 days of antibiotics could result in four extra reconsultation and represcriptions and one less AKI hospitalisation. We estimated annual prescription cost savings at around £2.2 million. CONCLUSIONS: Antibiotic treatment for older men with suspected UTI could be reduced to 3 days, albeit with a small increase in risk of treatment failure. A definitive randomised trial is urgently needed.

The challenge of antimicrobial resistance: What economics can contribute.

As antibiotic consumption grows, bacteria are becoming increasingly resistant to treatment. Antibiotic resistance undermines much of modern health care, which relies on access to effective antibiotics to prevent and treat infections associated with routine medical procedures. The resulting challenges have much in common with those posed by climate change, which economists have responded to with research that has informed and shaped public policy. Drawing on economic concepts such as externalities and the principal-agent relationship, we suggest how economics can help to solve the challenges arising from increasing resistance to antibiotics. We discuss solutions to the key economic issues, from incentivizing the development of effective new antibiotics to improving antibiotic stewardship through financial mechanisms and regulation.

Oral steroids for hearing loss associated with otitis media with effusion in children aged 2-8 years: the OSTRICH RCT.

BACKGROUND: Children with hearing loss associated with otitis media with effusion (OME) are commonly managed through surgical intervention, hearing aids or watchful waiting. A safe, inexpensive, effective medical treatment would enhance treatment options. Small, poorly conducted trials have found a short-term benefit from oral steroids. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of a 7-day course of oral steroids in improving hearing at 5 weeks in children with persistent OME symptoms and current bilateral OME and hearing loss demonstrated by audiometry. DESIGN: Double-blind, individually randomised, placebo-controlled trial. SETTING: Ear, nose and throat outpatient or paediatric audiology and audiovestibular medicine clinics in Wales and England. PARTICIPANTS: Children aged 2-8 years, with symptoms of hearing loss attributable to OME for at least 3 months, a diagnosis of bilateral OME made on the day of recruitment and audiometry-confirmed hearing loss. INTERVENTIONS: A 7-day course of oral soluble prednisolone, as a single daily dose of 20 mg for children aged 2-5 years or 30 mg for 6- to 8-year-olds, or matched placebo. MAIN OUTCOME MEASURES: Acceptable hearing at 5 weeks from randomisation. Secondary outcomes comprised acceptable hearing at 6 and 12 months, tympanometry, otoscopic findings, health-care consultations related to OME and other resource use, proportion of children who had ventilation tube (grommet) surgery at 6 and 12 months, adverse effects, symptoms, functional health status, health-related quality of life, short- and longer-term cost-effectiveness. RESULTS: A total of 389 children were randomised. Satisfactory hearing at 5 weeks was achieved by 39.9% and 32.8% in the oral steroid and placebo groups, respectively (absolute difference of 7.1%, 95% confidence interval -2.8% to 16.8%; number needed to treat = 14). This difference was not statistically significant. The secondary outcomes were consistent with the picture of a small or no benefit, and we found no subgroups that achieved a meaningful benefit from oral steroids. The economic analysis showed that treatment with oral steroids was more expensive and accrued fewer quality-adjusted life-years than treatment as usual. However, the differences were small and not statistically significant, and the sensitivity analyses demonstrated large variation in the results. CONCLUSIONS: OME in children with documented hearing loss and attributable symptoms for at least 3 months has a high rate of spontaneous resolution. Discussions about watchful waiting and other interventions will be enhanced by this evidence. The findings of this study suggest that any benefit from a short course of oral steroids for OME is likely to be small and of questionable clinical significance, and that the treatment is unlikely to be cost-effective and, therefore, their use cannot be recommended. FUTURE WORK: Studies exploring optimal approaches to sharing natural history data and enhancing shared decision-making are needed for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49798431 and EudraCT 2012-005123-32. 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. 22, No. 61. See the NIHR Journals Library website for further project information.

Oral steroids for resolution of otitis media with effusion in children (OSTRICH): a double-blinded, placebo-controlled randomised trial.

BACKGROUND: Children with persistent hearing loss due to otitis media with effusion are commonly managed by surgical intervention. A safe, cheap, and effective medical treatment would enhance treatment options. Underpowered, poor-quality trials have found short-term benefit from oral steroids. We aimed to investigate whether a short course of oral steroids would achieve acceptable hearing in children with persistent otitis media with effusion and hearing loss. METHODS: In this individually randomised, parallel, double-blinded, placebo-controlled trial we recruited children aged 2-8 years with symptoms attributable to otitis media with effusion for at least 3 months and with confirmed bilateral hearing loss. Participants were recruited from 20 ear, nose, and throat (ENT), paediatric audiology, and audiovestibular medicine outpatient departments in England and Wales. Participants were randomly allocated (1:1) to sequentially numbered identical prednisolone (oral steroid) or placebo packs by use of computer-generated random permuted block sizes stratified by site and child's age. The primary outcome was audiometry-confirmed acceptable hearing at 5 weeks. All analyses were by intention to treat. This trial is registered with the ISRCTN Registry, number ISRCTN49798431. FINDINGS: Between March 20, 2014, and April 5, 2016, 1018 children were screened, of whom 389 were randomised. 200 were assigned to receive oral steroids and 189 to receive placebo. Hearing at 5 weeks was assessed in 183 children in the oral steroid group and in 180 in the placebo group. Acceptable hearing was observed in 73 (40%) children in the oral steroid group and in 59 (33%) in the placebo group (absolute difference 7% [95% CI -3 to 17], number needed to treat 14; adjusted odds ratio 1·36 [95% CI 0·88-2·11]; p=0·16). There was no evidence of any significant differences in adverse events or quality-of-life measures between the groups. INTERPRETATION: Otitis media with effusion in children with documented hearing loss and attributable symptoms for at least 3 months has a high rate of spontaneous resolution. A short course of oral prednisolone is not an effective treatment for most children aged 2-8 years with persistent otitis media with effusion, but is well tolerated. One in 14 children might achieve improved hearing but not quality of life. Discussions about watchful waiting and other interventions will be supported by this evidence. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Cost-effectiveness of internet-based training for primary care clinicians on antibiotic prescribing for acute respiratory tract infections in Europe.

Objectives: Overprescribing of antibiotics by general practitioners (GPs) is seen as a major driver of antibiotic resistance. Training in communication skills and C-reactive protein (CRP) testing both appear effective in reducing such prescribing. This study assesses the cost-effectiveness (compared with usual care) of: (i) training GPs in the use of CRP testing; (ii) training GPs in communication skills; and (iii) training GPs in both CRP testing and communication skills. Methods: Economic analyses [cost-utility analysis (CUA) accounting for the cost of antibiotic resistance and cost-effectiveness analysis (CEA)] were both conducted from a healthcare perspective with a time horizon of 28 days alongside a multinational, cluster, randomized, factorial controlled trial in patients with respiratory tract infections in five European countries. The primary outcome measures were QALYs and percentage reduction in antibiotic prescribing. Hierarchical modelling was used to estimate an incremental cost per QALY gained and an incremental cost per percentage reduction in antibiotic prescribing. Results: Overall, the results of both the CUA and CEA showed that training in communication skills is the most cost-effective option. However, excluding the cost of antibiotic resistance in the CUA resulted in usual care being the most cost-effective option. Country-specific results from the CUA showed that training in communication skills was cost-effective in Belgium, UK and Netherlands whilst training in CRP was cost-effective in Poland. Conclusions: Internet-based training in communication skills is a cost-effective intervention to reduce antibiotic prescribing for respiratory tract infections in primary care if the cost of antibiotic resistance is accounted for.

Antivirals for influenza-Like Illness? A randomised Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4 E): the ALIC4 E protocol.

INTRODUCTION: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. METHODS AND ANALYSIS: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (<12, 12-64 and >64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. ETHICS AND DISSEMINATION: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN27908921; Pre-results.

Reducing demand for antibiotic prescriptions: evidence from an online survey of the general public on the interaction between preferences, beliefs and information, United Kingdom, 2015.

BACKGROUND: Antimicrobial resistance (AMR), a major public health threat, is strongly associated with human antibiotic consumption. Influenza-like illnesses (ILI) account for substantial inappropriate antibiotic use; patient understanding and expectations probably play an important role. AIM: This study aimed to investigate what drives patient expectations of antibiotics for ILI and particularly whether AMR awareness, risk preferences (attitudes to taking risks with health) or time preferences (the extent to which people prioritise good health today over good health in the future) play a role. METHODS: In 2015, a representative online panel survey of 2,064 adults in the United Kingdom was asked about antibiotic use and effectiveness for ILI. Explanatory variables in multivariable regression included AMR awareness, risk and time preferences and covariates. RESULTS: The tendency not to prioritise immediate gain over later reward was independently strongly associated with greater awareness that antibiotics are inappropriate for ILI. Independently, believing antibiotics were effective for ILI and low AMR awareness significantly predicted reported antibiotic use. However, 272 (39%) of those with low AMR awareness said that the AMR information we provided would lead them to ask a doctor for antibiotics more often, significantly more than would do so less often, and in contrast to those with high AMR awareness (p < 0.0001). CONCLUSION: Information campaigns to reduce AMR may risk a paradoxical consequence of actually increasing public demand for antibiotics. Public antibiotic stewardship campaigns should be tested on a small scale before wider adoption.