The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis.

Background: Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Objectives: Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Design, participants, main outcome measures, data sources: Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). Results: CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Limitations: Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Conclusions: Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. Study registration: This study is registered as PROSPERO CRD42021249959. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Before offering a medicine to prevent disease, prescribers must expect it to do more good than harm. This balance depends on how likely it is that the person will develop the disease we want to prevent. But people might first die for other reasons. We call this a 'competing risk'. In most cases, the mathematical tools we use to estimate the chance of developing a disease do not account for competing risks. Another problem is that, when weighing up the benefits and harms of medicines, we ignore the hassle they cause patients, even when they do not cause side effects. We used two examples: statins to prevent heart disease and bisphosphonates to prevent fractures. First, we assessed if existing tools get predictions wrong by not accounting for competing risks. We found that they exaggerate the chance of heart attacks and strokes. However, the exaggeration is greatest among people who would clearly benefit from preventative treatment. So it may not change treatment decisions much. The fracture prediction tool we studied was very inaccurate, exaggerating risk among older people, but underestimating risk among younger people. We made a new fracture risk prediction tool. It gave better predictions, but it was still inaccurate for people aged > 85 years and those with several health problems. Next, we asked people questions designed to put a number on the hassle that statins and bisphosphonates cause. Most people thought that taking either is inconvenient, but the hassle factor for bisphosphonates is bigger. Finally, we updated the mathematical models that the National Institute for Health and Care Excellence used when recommending statins and bisphosphonates. We worked out if competing risks and the hassle of taking medicines make a difference to results. Statins remain a good idea for almost everyone, unless they really hate the idea of taking them. But bisphosphonates would do more harm than good for anyone who agrees with the hassle factor we found.

International Systematic Review of Utility Values Associated with Cardiovascular Disease and Reflections on Selecting Evidence for a UK Decision-Analytic Model.

PURPOSE: Evaluating interventions for cardiovascular disease (CVD) requires estimates of its effect on utility. We aimed to 1) systematically review utility estimates for CVDs published since 2013 and 2) critically appraise UK-relevant estimates and calculate corresponding baseline utility multipliers. METHODS: We searched MEDLINE and Embase (April 22, 2021) using CVD and utility terms. We screened results for primary studies reporting utility distributions for people with experience of heart failure, myocardial infarction, peripheral arterial disease, stable angina, stroke, transient ischemic attack, or unstable angina. We extracted characteristics from studies included. For UK estimates based on the EuroQoL 5-dimension (EQ-5D) measure, we assessed risk of bias and applicability to a decision-analytic model, pooled arms/time points as appropriate, and estimated baseline utility multipliers using predicted utility for age- and sex- matched populations without CVD. We sought utility sources from directly applicable studies with low risk of bias, prioritizing plausibility of severity ordering in our base-case model and highest population ascertainment in a sensitivity analysis. RESULTS: Most of the 403 studies identified used EQ-5D (n = 217) and most assessed Organisation for Economic Co-operation and Development populations (n = 262), although measures and countries varied widely. UK studies using EQ-5D (n = 29) produced very heterogeneous baseline utility multipliers for each type of CVD, precluding meta-analysis and implying different possible severity orderings. We could find sources that provided a plausible ordering of utilities while adequately representing health states. CONCLUSIONS: We cataloged international CVD utility estimates and calculated UK-relevant baseline utility multipliers. Modelers should consider unreported sources of heterogeneity, such as population differences, when selecting utility evidence from reviews. HIGHLIGHTS: Published systematic reviews have summarized estimates of utility associated with cardiovascular disease published up to 2013.We 1) reviewed utility estimates for 7 types of cardiovascular disease published since 2013, 2) critically appraised UK-relevant studies, and 3) estimated the effect of each cardiovascular disease on baseline utility.Our review 1) recommends a consistent and reliable set of baseline utility multipliers for 7 types of cardiovascular disease and 2) provides systematically identified reference information for researchers seeking utility evidence for their own context.

Expanding health technology assessment towards broader value: Ireland as a case study.

Healthcare innovations often represent important improvements in population welfare, but at what cost, and to whom? Health technology assessment (HTA) is a multidisciplinary process to inform resource allocation. HTA is conventionally anchored on health maximization as the only relevant output of health services. If we accept the proposition that health technologies can generate value outside the healthcare system, resource allocation decisions could be suboptimal from a societal perspective. Incorporating "broader value" in HTA as derived from social values and patient experience could provide a richer evaluative space for informing resource allocation decisions. This article considers how HTA is practiced and what its current context implies for adopting "broader value" to evaluating health technologies. Methodological challenges are highlighted, as is a future research agenda. Ireland serves as an example of a healthcare system that both has an explicit role for HTA and is evolving under a current program of reform to offer universal, single-tier access to public services. There are various ways in which HTA processes could move beyond health, including considering the processes of care delivery and/or expanding the evaluative space to some broader concept of well-being. Methods to facilitate the latter exist, but their adaptation to HTA is still emerging. We recommend a multi-stakeholder working group to develop and advance an international agenda for HTA that captures welfare/benefit beyond health.

Assessment of a primary care e-support package of automated case finding, simplified treatment algorithm and decision support to increase hepatitis B treatment uptake in primary care clinics in Australia (SIMPLY-B Study): protocol for a pilot evaluation.

INTRODUCTION: Despite the availability of effective, subsidised hepatitis B treatment, linkage to care and treatment rates remain very low globally. In Australia, specially trained primary care physicians (general practitioner, GPs) can prescribe hepatitis B treatment, however, most hepatitis B care occurs in specialist clinics. Increasing hepatitis B management by GPs in primary care clinics is essential to achieve national hepatitis B linkage to care and treatment targets by 2030.This pilot study determines the feasibility, acceptability and effectiveness of Simply B, a novel GP hepatitis B e-support package designed to increase hepatitis B management by GPs in primary care clinics. METHODS AND ANALYSIS: This study will be conducted in three parts:Part A: A prospective open-label pilot intervention study, comparing the proportion of people with hepatitis B who are managed by their GP in primary care clinics before, 12 months and 24 months after implementation of the Simply B electronic hepatitis B support package.Part B: A nested qualitative health services feasibility study using semistructured interviews and thematic analysisPart C: Cost-effectiveness analysis. ETHICS AND DISSEMINATION: This study has received ethics approval by St Vincent's Hospital. Data management and analysis will be centralised through the Department of Gastroenterology, St Vincent's Hospital. TRIAL REGISTRATION NUMBER: NCT05614466.

The cost-effectiveness of universal hepatitis B screening for reaching WHO diagnosis targets in Australia by 2030.

OBJECTIVES: To assess the impact on diagnosis targets, cost, and cost-effectiveness of universal hepatitis B screening in Australia. DESIGN: Markov model simulation of disease and care cascade progression for people with chronic hepatitis B in Australia. SETTING: Three scenarios were compared: 1. no change to current hepatitis B virus (HBV) testing practice; 2. universal screening strategy, with the aim of achieving the WHO diagnosis target by 2030 (90% of people with chronic hepatitis B diagnosed), based on opportunistic (general practitioner-initiated) screening for HBsAg; 3. universal screening strategy, and also ensuring that 50% of people with chronic hepatitis B are receiving appropriate clinical management by 2030. MAIN OUTCOME MEASURES: Projected care cascade for people with chronic hepatitis B, cumulative number of HBV-related deaths, intervention costs, and health utility (quality-adjusted life-years [QALYs] gained during 2020-2030). An incremental cost-effectiveness ratio (ICER) threshold (v scenario 1) of $50 000 per QALY gained was applied. RESULTS: Compared with scenario 1, 80 HBV-related deaths (interquartile range [IQR], 41-127 deaths) were averted during 2020-2030 in scenario 2, 315 HBV-related deaths (IQR, 211-454 deaths) in scenario 3. Scenario 2 cost $84 million (IQR, $41-106 million) more than scenario 1 during 2020-2030 (+8%), yielding an ICER of $104 921 (IQR, $49 587-107 952) per QALY gained. Scenario 3 cost $263 million (IQR, $214-316 million) more than scenario 1 during 2020-2030 (+24%), yielding an ICER of $47 341 (IQR, $32 643-58 200) per QALY gained. Scenario 3 remained cost-effective if the test positivity rate was higher than 0.35% or the additional costs per person tested did not exceed $4.02. CONCLUSIONS: Universal screening for hepatitis B will be cost-effective only if the cost of testing is kept low and people receive appropriate clinical management.

Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

PURPOSE: To determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking. METHODS: We developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed. RESULTS: In the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI -£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs -£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI -£4202 to £2652). CONCLUSION: Annual CERMRI in HLRCC is cost-effective across age groups modelled.

Intravenous or oral antibiotic treatment in adults and children with cystic fibrosis and Pseudomonas aeruginosa infection: the TORPEDO-CF RCT.

BACKGROUND: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. OBJECTIVE: To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. DESIGN: This was a Phase IV, multicentre, parallel-group, randomised controlled trial. SETTING: Seventy UK and two Italian cystic fibrosis centres. PARTICIPANTS: Participants were individuals with cystic fibrosis aged > 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. INTERVENTIONS: Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1 : 1 ratio using simple block randomisation with random variable block length. MAIN OUTCOME MEASURES: The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. RESULTS: Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to -£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. LIMITATIONS: Only 15 out of the 286 participants recruited were adults - partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. CONCLUSIONS: Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. FUTURE WORK: Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10. 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. 25, No. 65. See the NIHR Journals Library website for further project information.

Cystic fibrosis is a genetic condition that affects mucous glands, causing sticky mucus in the lungs and digestive system. People with cystic fibrosis are prone to lung infection with a bacterium called Pseudomonas aeruginosa, which can lead to serious long-term complications and death. It is possible to eradicate P. aeruginosa if antibiotics are started promptly and taken for several months. The Trial of Optimal TheRapy for Pseudomonas EraDicatiOn in Cystic Fibrosis (TORPEDO-CF) was designed to find out if intravenous ceftazidime and tobramycin were better at eradicating P. aeruginosa than oral ciprofloxacin. A total of 286 children, young people and adults with cystic fibrosis joined the study from 70 UK and two Italian centres. Approximately half of the participants received treatment with intravenous antibiotics and half with oral antibiotics. All participants received inhaled colistin for 3 months and were followed up for a minimum of 15 months. We studied whether or not either treatment eradicated P. aeruginosa, and if reinfection happened during follow-up. We also collected data on lung function, other chest infections and hospital admissions, and examined whether or not one treatment was more cost-effective than the other. In total, 15 adults joined TORPEDO-CF, so the study population may not totally match the wider cystic fibrosis population; however, in TORPEDO-CF, we found that intravenous antibiotics did not achieve persistent eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. We also found that oral antibiotics were more cost-effective than intravenous antibiotics. The intravenous antibiotics group had fewer hospital admissions during follow-up, but, as they were usually admitted for their initial treatment, this was not considered an advantage over the oral antibiotics group. The TORPEDO-CF results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis and, when the findings of this trial are applied in routine clinical practice in the NHS, patients will most likely receive oral treatment as an outpatient, avoiding the need for hospital admission.

A costing analysis of a state-wide, nurse-led hepatitis C treatment model in prison.

BACKGROUND: Hepatitis C is highly prevalent among prisoners. The simplicity of direct-acting antiviral (DAA) treatment for hepatitis C makes it possible to use novel models of care to increase treatment uptake within prisons. We estimate the average non-drug cost of initiating a prisoner on treatment using real world data from the State-wide Hepatitis Program (SHP) in Victoria, Australia - a coordinated nurse-led model of care. METHODS: Data were considered from prisoners presenting to the SHP (following antibody-positive diagnosis) during the evaluation period, November 2015 to December 2016. All costs associated with the SHP were estimated, including staffing salaries, medical tests, pharmacy costs and overhead costs. DAA costs were excluded as in Australia an unlimited number are available, covered by a federal government risk-sharing agreement with pharmaceutical companies. The average non-drug cost of treatment initiation through the SHP was compared to equivalent costs from primary and hospital-based models of care in the community. RESULTS: The total non-drug cost accumulated by prisoners in the SHP was AUD$749,470 (uncertainty range: AUD$728,905-794,111). 659/803 were PCR positive, 424/659 had sentences long enough to be eligible for treatment, and 416/424 were initiated on treatment, resulting in an average non-drug cost of AUD$1,802 (95% CI: AUD$1799-1841) per prisoner initiated. A protocol change allowing prisoners with short sentences to start treatment reduced the average non-drug cost to AUD$1263 (95% CI: AUD$1263-1287) per prisoner initiating treatment - 11% and 56% cheaper than estimated equivalent costs in primary (AUD$1654) and hospital-based (AUD$2847) models of care in the community, respectively. CONCLUSION: Delivering hepatitis C treatment in prison using a nurse-led model of care is cheaper than delivering treatment in the community. These findings provide an economic rationale for implementing coordinated prison-based hepatitis C treatment programs.

A global investment framework for the elimination of hepatitis B.

BACKGROUND & AIMS: More than 292 million people are living with hepatitis B worldwide and are at risk of death from cirrhosis and liver cancer. The World Health Organization (WHO) has set global targets for the elimination of viral hepatitis as a public health threat by 2030. However, current levels of global investment in viral hepatitis elimination programmes are insufficient to achieve these goals. METHODS: To catalyse political commitment and to encourage domestic and international financing, we used published modelling data and key stakeholder interviews to develop an investment framework to demonstrate the return on investment for viral hepatitis elimination. RESULTS: The framework utilises a public health approach to identify evidence-based national activities that reduce viral hepatitis-related morbidity and mortality, as well as international activities and critical enablers that allow countries to achieve maximum impact on health outcomes from their investments - in the context of the WHO's 2030 viral elimination targets. CONCLUSION: Focusing on hepatitis B, this health policy paper employs the investment framework to estimate the substantial economic benefits of investing in the elimination of hepatitis B and demonstrates how such investments could be cost saving by 2030. LAY SUMMARY: Hepatitis B infection is a major cause of death from liver disease and liver cancer globally. To reduce deaths from hepatitis B infection, we need more people to be tested and treated for hepatitis B. In this paper, we outline a framework of activities to reduce hepatitis B-related deaths and discuss ways in which governments could pay for them.

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

BACKGROUND: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. METHODS: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. FINDINGS: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. INTERPRETATION: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

A model of the economic benefits of global hepatitis C elimination: an investment case.

Major gains in reducing the burden of hepatitis C are now possible because of the discovery of a cure. The prevention of premature deaths and increased workforce participation among people who are cured are likely to provide substantial indirect economic benefits. We developed an investment case for hepatitis C for the six WHO world regions, which, to our knowledge, is the first to consider both indirect and direct economic benefits in this context. Scaling up of testing and treatment to reach the 2030 WHO hepatitis C elimination targets was estimated to prevent 2·1 million (95% credible interval 1·3-3·2 million) hepatitis C-related deaths and 10 million (4-14 million) new hepatitis C virus infections globally between 2018 and 2030. This elimination strategy was estimated to cost US$41·5 billion (33·1-48·7 billion) in testing, treatment, and health care between 2018 and 2030 ($23·4 billion more than the status quo scenario of no testing or treatment scale up), with a global average of $885 (654-1189) per disability-adjusted life-year averted at 2030. Compared with the status quo scenario, the elimination scenario generated $46·1 billion (35·9-53·8 billion) in cumulative productivity gains by 2030. These indirect costs made elimination cost-saving by 2027, with a net economic benefit of $22·7 billion (17·1-27·9 billion) by 2030. This model shows that countries might be underestimating the true burden of hepatitis C and will benefit from investing in elimination.

Enhancing the hepatitis B care cascade in Australia: A cost-effectiveness model.

If Australia is to successfully eliminate hepatitis B as a public health threat, it will need to enhance the chronic hepatitis B (CHB) care cascade. This study used a Markov model to assess the impact, cost and cost-effectiveness of scaling up CHB diagnosis, linkage to care and treatment to reach national and international elimination targets for hepatitis B in Australia. Compared to continued current trends, the model calculated the difference in care cascade projection, disability-adjusted life years (DALYs), costs and the incremental cost-effectiveness ratio (ICER), of scaling up CHB diagnosis, linkage to care and treatment to reach: (a) Australia's 2022 national targets and (b) the WHO's 2030 global targets. Achieving the national and WHO targets had ICERs of A$13 435 (A$10 236-A$21 165) and A$14 482 (A$13 031-A$25 641) per DALY averted between 2016 and 2030 in Australia, respectively. However, this excluded implementation and demand generation costs. The ICER for the National Strategy and WHO Strategy remained under A$50 000 per DALY averted if Australia spent up to A$328 or A$538 million, respectively, per annum (for 2016-2030) on implementation and demand generation activities. Sensitivity analysis showed that cost-effectiveness was predominately driven by the cost of CHB treatment and influenced by disease progression rates. Hence for Australia to reach the National Hepatitis B Strategy 2022 targets and WHO Strategy 2030 targets, it requires an improvement in the CHB care cascade. We estimated it is cost-effective to spend up to A$328 million or A$538 million per year to reach the National and WHO Strategy targets, respectively.

A cost-effectiveness analysis of primary versus hospital-based specialist care for direct acting antiviral hepatitis C treatment.

BACKGROUND: Hepatitis C virus elimination may be possible by scaling up direct-acting antiviral (DAA) treatment. Due to the safety and simplicity of DAA treatment, primary care-based treatment delivery is now feasible, efficacious and may be cheaper than hospital-based specialist care. In this paper, we use Prime Study data - a randomised controlled trial comparing the uptake of DAA treatment between primary and hospital-based care settings amongst people who inject drugs (PWID) - to estimate the cost of initiating treatment for PWID diagnosed with hepatitis C in primary care compared to hospital-based care. METHODS: The total economic costs associated with delivering DAA treatment (post hepatitis C diagnosis) within the Prime study - including health provider time/training, medical tests, equipment, logistics and pharmacy costs - were collected. Appointment data were used to estimate the number/type of appointments required to initiate treatment in each case, or the stage at which loss to follow up occurred. RESULTS: Among the hepatitis C patients randomised to be treated within primary care, 43/57 (75%) commenced treatment at a mean cost of A$885 (95% CI: A$850-938) per patient initiating treatment. In hospital-based care, 18/53 hepatitis C patients (34%) commenced treatment at a mean cost of A$2078 (range: A$2052-2394) per patient initiating treatment - more than twice as high as primary care. The lower cost in the primary care arm was predominantly the result of increased retention in care compared to the hospital-based arm. CONCLUSIONS: Compared to hospital-based care, providing hepatitis C services for PWID in primary care can improve treatment uptake and approximately halve the average cost of treatment initiation. To improve treatment uptake and cure, countries should consider primary care as the main model for hepatitis C treatment scale-up.

The case for a universal hepatitis C vaccine to achieve hepatitis C elimination.

BACKGROUND: The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. METHODS: The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018-2030. RESULTS: The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15-113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6-8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7-10.8) billion cost reduction across 78 countries (47%). CONCLUSIONS: These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.

Defining Optimal Care for Functional Gut Disorders - Multi-Disciplinary Versus Standard Care: A Randomized Controlled Trial Protocol.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are the commonest reason for gastroenterological consultation, with patients usually seen by a specialist working in isolation. There is a wealth of evidence testifying to the benefit provided by dieticians, behavioral therapists, hypnotherapists and psychotherapists in treating these conditions, yet they rarely form a part of the therapeutic team, and these treatment modalities are rarely offered as part of the therapeutic management. There has been little examination of different models of care for FGIDs. We hypothesize that multi-disciplinary integrated care is superior to standard specialist-based care in the treatment of functional gut disorders. METHODS: The "MANTRA" (Multidisciplinary Treatment for Functional Gut Disorders) study compares comprehensive multi-disciplinary outpatient care with standard hospital outpatient care. Consecutive new referrals to the gastroenterology and colorectal outpatient clinics of a single secondary and tertiary care hospital of patients with an FGID, defined by the Rome IV criteria, will be included. Patients will be prospectively randomized 2:1 to multi-disciplinary (gastroenterologist, gut-hypnotherapist, psychiatrist, behavioral therapist ('biofeedback') and dietician) or standard care (gastroenterologist or colorectal surgeon). Patients are assessed up to 12 months after completing treatment. The primary outcome is an improvement on a global assessment scale at the end of treatment. Symptoms, quality of life, psychological well-being, and healthcare costs are secondary outcome measures. DISCUSSION: There have been few studies examining how best to deliver care for functional gut disorders. The MANTRA study will define the clinical and cost benefits of two different models of care for these highly prevalent disorders. TRIAL REGISTRATION NUMBER: Clinicaltrials.govNCT03078634 Registered on Clinicaltrials.gov, completed recruitment, registered on March 13th 2017. Ethics and Dissemination: Ethical approval has been received by the St Vincent's Hospital Melbourne human research ethics committee (HREC-A 138/16). The results will be disseminated in peer-reviewed journals and presented at international conferences. Protocol version 1.2.

Estimating Joint Health Condition Utility Values.

OBJECTIVES: To predict health state utility values (HSUVs) for individuals with up to 4 conditions simultaneously. METHODS: Person-level data were taken from the General Practice Patient Survey, a national survey of adult patients registered with general practices in England. Individuals reported whether they had any 1 of 16 chronic conditions and completed the 3-level EuroQol 5-dimensional questionnaire. Four nonparametric methods (additive, multiplicative, minimum, and the adjusted decrement estimator) and 1 parametric estimator (the linear index) were used to predict HSUVs for individuals with a joint health condition (JHC). Predicted and actual utility scores were compared for precision using root mean square error and mean absolute error. Bias was assessed using mean error. RESULTS: The analysis included 929,565 individuals, of which 30.5% had at least 2 conditions. Of the nonparametric estimators, the multiplicative approach produced estimates with the lowest bias and most precision for 2 JHCs. For populations with a long-term mental health condition within the JHC, the multiplicative approach overestimated utility scores. All nonparametric methods produced biased results when estimating HSUVs for 3 or 4 JHCs. The linear index generally produced unbiased results with the highest precision. CONCLUSIONS: The multiplicative approach was the best nonparametric estimator when estimating HSUVs for 2 JHCs. None of the nonparametric approaches for estimating HSUVs can be recommended with more than 2 JHCs. The linear index was found to have good predictive properties but needs external validation before being recommended for routine use.

Eliminating hepatitis C: The importance of frequent testing of people who inject drugs in high-prevalence settings.

Modelling suggests that more frequent screening of people who inject drugs (PWID) and an improved care cascade are required to achieve the WHO hepatitis C virus (HCV) elimination target of an 80% reduction in incidence by 2030. We determined the testing frequencies (2-yearly, annually, 6-monthly and 3-monthly) and retention in care required among PWID to achieve the HCV incidence reduction target through treatment as prevention in low (25%), medium (50%) and high (75%) chronic HCV prevalence settings. Mathematical modelling of HCV transmission among PWID, capturing testing, treatment and other features of the care cascade were employed. In low-prevalence settings, 2-yearly antibody testing of PWID was estimated to reach the elimination target by 2027-2030 depending on retention in care, with annual testing reducing the time by up to 3 years. In medium-prevalence settings, if close to 90% testing coverage were achieved, then annual antibody testing of PWID would be sufficient. If testing coverage were lower (80%), 6-monthly antibody testing with at least 70% retention in care or annual HCV RNA/cAg testing would be required. In high-prevalence settings, even 3-monthly HCV RNA/cAg testing of PWID was unable to achieve the incidence reduction target. Thus, for geographical areas or subpopulations with high prevalence, WHO incidence targets are unlikely to be met without 3-monthly RNA/cAg testing accompanied by other prevention measures. Novel testing strategies, such as rapid point-of-care antibody testing or replacing antibody testing with RNA/cAg tests as a screening tool, can provide additional population-level impacts to compensate for imperfect follow-up or testing coverage.

The economic case for precision medicine.

Introduction: The advancement of precision medicine into routine clinical practice has been highlighted as an agenda for national and international health care policy. A principle barrier to this advancement is in meeting requirements of the payer or reimbursement agency for health care. This special report aims to explain the economic case for precision medicine, by accounting for the explicit objectives defined by decision-makers responsible for the allocation of limited health care resources. Areas covered: The framework of cost-effectiveness analysis, a method of economic evaluation, is used to describe how precision medicine can, in theory, exploit identifiable patient-level heterogeneity to improve population health outcomes and the relative cost-effectiveness of health care. Four case studies are used to illustrate potential challenges when demonstrating the economic case for a precision medicine in practice. Expert commentary: The economic case for a precision medicine should be considered at an early stage during its research and development phase. Clinical and economic evidence can be generated iteratively and should be in alignment with the objectives and requirements of decision-makers. Programmes of further research, to demonstrate the economic case of a precision medicine, can be prioritized by the extent that they reduce the uncertainty expressed by decision-makers.

Cost-effectiveness analyses of genetic and genomic diagnostic tests.

Developments in next-generation sequencing technologies have driven the clinical application of diagnostic tests that interrogate the whole genome, which offer the chance to diagnose rare inherited diseases or inform the targeting of therapies. New genomic diagnostic tests compete with traditional approaches to diagnosis, including the genetic testing of single genes and other clinical strategies, for finite health-care budgets. In this context, decision analytic model-based cost-effectiveness analysis is a useful method to help evaluate the costs versus consequences of introducing new health-care interventions. This Perspective presents key methodological, technical, practical and organizational challenges that must be considered by decision-makers responsible for the allocation of health-care resources to obtain robust and timely information about the relative cost-effectiveness of the increasing numbers of emerging genomic tests.