Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

High-throughput, non-invasive prenatal testing for fetal rhesus D status in RhD-negative women: a systematic review and meta-analysis.

BACKGROUND: High-throughput non-invasive prenatal testing (NIPT) for fetal Rhesus D (RhD) status could avoid unnecessary treatment with anti-D immunoglobulin for RhD-negative women found to be carrying an RhD-negative fetus. We aimed to assess the diagnostic accuracy of high-throughput NIPT for fetal RhD status in RhD-negative women not known to be sensitized to the RhD antigen, by performing a systematic review and meta-analysis. METHODS: Prospective cohort studies of high-throughput NIPT used to determine fetal RhD status were included. The eligible population were pregnant women who were RhD negative and not known to be sensitized to RhD antigen. The index test was high-throughput, NIPT cell-free fetal DNA tests of maternal plasma used to determine fetal RhD status. The reference standard considered was serologic cord blood testing at birth. Databases including MEDLINE, EMBASE, and Science Citation Index were searched up to February 2016. Two reviewers independently screened titles and abstracts and assessed full texts identified as potentially relevant. Risk of bias was assessed using QUADAS-2. The bivariate and hierarchical summary receiver-operating characteristic (HSROC) models were fitted to calculate summary estimates of sensitivity, specificity, false positive and false negative rates, and the associated 95% confidence intervals (CIs). RESULTS: A total of 3921 references records were identified through electronic searches. Eight studies were included in the systematic review. Six studies were judged to be at low risk of bias. The HSROC models demonstrated high diagnostic performance of high-throughput NIPT testing for women tested at or after 11 weeks gestation. In the primary analysis for diagnostic accuracy, women with an inconclusive test result were treated as having tested positive. The false negative rate (incorrectly classed as RhD negative) was 0.34% (95% CI 0.15 to 0.76) and the false positive rate (incorrectly classed as RhD positive) was 3.86% (95% CI 2.54 to 5.82). There was limited evidence for non-white women and multiple pregnancies. CONCLUSIONS: High-throughput NIPT is sufficiently accurate to detect fetal RhD status in RhD-negative women and would considerably reduce unnecessary treatment with routine anti-D immunoglobulin. The applicability of these findings to non-white women and women with multiple pregnancies is uncertain.

Defining professionalism for mental health services: a rapid systematic review.

Background: Efforts have been made to define professionalism across the professions, yet little attention has been paid to the concept in mental health services, where patients' needs differ to that in other healthcare specialties. Aims: To derive a definition of professionalism for mental health services using the existing literature. Method: A rapid, systematic review was conducted to identify empirical and non-empirical records that described professionalism in a mental health service context from 2006 to 2017. Studies were synthesised narratively using thematic analysis. Results: Seventy records were included in the review. Professionalism was described on two levels; at a societal level, a dynamic social contract between professions and society, and; at an individual level, having intrapersonal, interpersonal, and working professionalism. Utilising emerging themes, an operationalised definition of professionalism, suitable for a mental health service context was derived. Conclusions: Within mental health services, emphasis is placed on the interpersonal aspects of practice such as communication skills, maintaining boundaries and humanity. Themes relating to the vulnerability of patients and the challenge of supporting autonomy and choice whilst maintaining safety and acting in a client's best interest are also evident. 'Practical wisdom' and a flexible approach to working are needed to manage these challenging situations.

Screening for poststroke major depression: a meta-analysis of diagnostic validity studies.

BACKGROUND: Major depression is common in stroke patients and associated with increased rates of disability and mortality. Identifying depression may improve mental and physical health. The aim of this review was to determine the most accurate tool for detecting poststroke depression. METHODS: Seven databases were searched up to November 2012. Two authors selected studies using International Classification of Disease  or Diagnostic and Statistical Manual diagnosis of depression as the reference standard. Two authors extracted data and assessed methodological quality. Included studies were synthesised using meta-analyses. RESULTS: A total of 24 included studies provided data on 2907 participants. The Center of Epidemiological Studies-Depression Scale (CESD) (sensitivity: 0.75; 95% CI 0.60 to 0.85; specificity: 0.88; 95% CI 0.71 to 0.95), the Hamilton Depression Rating Scale (HDRS) (sensitivity: 0.84; 95% CI 0.75 to 0.90; specificity:0.83; 95% CI 0.72 to 0.90) and the Patient Health Questionnaire (PHQ)-9 (sensitivity: 0.86; 95% CI 0.70 to 0.94; specificity: 0.79; 95% CI 0.60 to 0.90) appeared to be the optimal measures for screening measures. However, the clinical utility of all tools was modest for case-finding. INTERPRETATION: There are a number of possible instruments that may help in screening for poststroke depression but none are satisfactory for case-finding. Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options. Although it should be noted such scales should not be used in isolation but followed up with a more detailed clinical assessment. While there is promising data for the PHQ-2 in other populations, it performed less well than other measures.

An international systematic review and meta-analysis of multisession psychosocial interventions compared with educational or minimal interventions on the HIV sex risk behaviors of people who use drugs.

This systematic review and meta-analysis examines the effectiveness of multisession psychosocial interventions compared with educational interventions and minimal interventions in reducing sexual risk in people who use drugs (51 studies; 19,209 participants). We conducted comprehensive searches (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and PsychINFO 1998-2012). Outcomes (unprotected sex, condom use, or a composite outcome) were extracted by two authors and synthesised using meta-analysis. Subgroup analyses and meta-regression were conducted to explore heterogeneity. Multisession psychosocial interventions had modest additional benefits compared to educational interventions (K = 46; OR 0.86; 95% CI 0.77, 0.96), and large positive effects compared to minimal interventions (K = 7; OR 0.60; 95% CI 0.46, 0.78). Comparison with previous meta-analyses suggested limited progress in recent years in developing more effective interventions. Multisession psychosocial and educational interventions provided similar modest sexual risk reduction justifying offering educational interventions in settings with limited exposure to sexual risk reduction interventions, messages, and resources.

Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation.

BACKGROUND: Chronic heart failure is a debilitating condition that accounts for an annual NHS spend of £2.3B. Low levels of endogenous coenzyme Q10 may exacerbate chronic heart failure. Coenzyme Q10 supplements might improve symptoms and slow progression. As statins are thought to block the production of coenzyme Q10, supplementation might be particularly beneficial for patients taking statins. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of coenzyme Q10 in managing chronic heart failure with a reduced ejection fraction. METHODS: A systematic review that included randomised trials comparing coenzyme Q10 plus standard care with standard care alone in chronic heart failure. Trials restricted to chronic heart failure with a preserved ejection fraction were excluded. Databases including MEDLINE, EMBASE and CENTRAL were searched up to March 2020. Risk of bias was assessed using the Cochrane Risk of Bias tool (version 5.2). A planned individual participant data meta-analysis was not possible and meta-analyses were mostly based on aggregate data from publications. Potential effect modification was examined using meta-regression. A Markov model used treatment effects from the meta-analysis and baseline mortality and hospitalisation from an observational UK cohort. Costs were evaluated from an NHS and Personal Social Services perspective and expressed in Great British pounds at a 2019/20 price base. Outcomes were expressed in quality-adjusted life-years. Both costs and outcomes were discounted at a 3.5% annual rate. RESULTS: A total of 26 trials, comprising 2250 participants, were included in the systematic review. Many trials were reported poorly and were rated as having a high or unclear risk of bias in at least one domain. Meta-analysis suggested a possible benefit of coenzyme Q10 on all-cause mortality (seven trials, 1371 participants; relative risk 0.68, 95% confidence interval 0.45 to 1.03). The results for short-term functional outcomes were more modest or unclear. There was no indication of increased adverse events with coenzyme Q10. Meta-regression found no evidence of treatment interaction with statins. The base-case cost-effectiveness analysis produced incremental costs of £4878, incremental quality-adjusted life-years of 1.34 and an incremental cost-effectiveness ratio of £3650. Probabilistic sensitivity analyses showed that at thresholds of £20,000 and £30,000 per quality-adjusted life-year coenzyme Q10 had a high probability (95.2% and 95.8%, respectively) of being more cost-effective than standard care alone. Scenario analyses in which the population and other model assumptions were varied all found coenzyme Q10 to be cost-effective. The expected value of perfect information suggested that a new trial could be valuable. LIMITATIONS: For most outcomes, data were available from few trials and different trials contributed to different outcomes. There were concerns about risk of bias and whether or not the results from included trials were applicable to a typical UK population. A lack of individual participant data meant that planned detailed analyses of effect modifiers were not possible. CONCLUSIONS: Available evidence suggested that, if prescribed, coenzyme Q10 has the potential to be clinically effective and cost-effective for heart failure with a reduced ejection fraction. However, given important concerns about risk of bias, plausibility of effect sizes and applicability of the evidence base, establishing whether or not coenzyme Q10 is genuinely effective in a typical UK population is important, particularly as coenzyme Q10 has not been subject to the scrutiny of drug-licensing processes. Stronger evidence is needed before considering its prescription in the NHS. FUTURE WORK: A new independent, well-designed clinical trial of coenzyme Q10 in a typical UK heart failure with a reduced ejection fraction population may be warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018106189. 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. 26, No. 4. See the NIHR Journals Library website for further project information.

People living with chronic heart failure suffer from shortness of breath, ankle swelling, tiredness, frequent stays in hospital and reduced quality of life and have shorter lives. The NHS spends over £2 billion each year managing chronic heart failure. Coenzyme Q10 is a vitamin-like substance made by the body that helps cells produce energy. Low levels of coenzyme Q10 in heart muscle may lead to, or exacerbate, chronic heart failure. Taking coenzyme Q10 supplements might improve symptoms or slow deterioration. To the best of our knowledge, we found all randomised clinical trials of coenzyme Q10 in patients with the type of chronic heart failure caused by muscle weakness (i.e. heart failure with reduced ejection fraction, where the heart's pumping function is weaker than normal). We asked the research groups responsible for these trials to provide the patient data that they had collected in their trials. Most research groups did not share their data and so we mainly used information from published trial reports. This limited our planned analyses. We found that taking coenzyme Q10 alongside usual treatment for heart failure with reduced ejection fraction potentially reduced deaths by approximately one-third and reduced readmission to hospital by around 40%. However, these results were uncertain. Side effects were not increased. We had some concerns about how reliable the data were, and it is not clear how well the results apply to UK patients. We also worked out what the benefits and costs to the NHS would be if coenzyme Q10 became available on prescription for patients with heart failure with reduced ejection fraction. Our model found that prescription could be worthwhile; however, a new trial is needed first to make sure that coenzyme Q10 improves outcomes for patients. A new trial would be particularly important because coenzyme Q10 has not been assessed in the same way as prescribed medicines. A new trial could make sure that there is better evidence about whether or not prescribing would be a good use of NHS resources.

Promoting the uptake of HIV testing among men who have sex with men: systematic review of effectiveness and cost-effectiveness.

What interventions are effective and cost-effective in increasing the uptake of HIV testing among men who have sex with men (MSM)? A systematic review was conducted of the following databases: AEGIS, ASSIA, BL Direct, BNI, Centre for Reviews and Dissemination, Cochrane Database of Systematic Reviews, CINAHL, Current Contents Connect, EconLit, EMBASE, ERIC, HMIC, Medline, Medline In-Process, NRR, PsychINFO, Scopus, SIGLE, Social Policy and Practice, Web of Science, websites, journal hand-searching, citation chasing and expert recommendations. Prospective studies of the effectiveness or cost-effectiveness of interventions (randomised controlled trial (RCT), controlled trial, one-group or any economic analysis) were included if the intervention aimed to increase the uptake of HIV testing among MSM in a high-income (Organization for Economic Co-operation and Development) country. Quality was assessed and data were extracted using standardised tools. Results were synthesised narratively. Twelve effectiveness studies and one cost-effectiveness study were located, covering a range of intervention types. There is evidence that rapid testing and counselling in community settings (one RCT), and intensive peer counselling (one RCT), can increase the uptake of HIV testing among MSM. There are promising results regarding the introduction of opt-out testing in sexually transmitted infection clinics (two one-group studies). Findings regarding other interventions, including bundling HIV tests with other tests, peer outreach in community settings, and media campaigns, are inconclusive. Findings indicate several promising approaches to increasing HIV testing among MSM. However, there is limited evidence overall, and evidence for the effectiveness of key intervention types (particularly peer outreach and media campaigns) remains lacking.

HIV testing among men who have sex with men (MSM): systematic review of qualitative evidence.

We conducted a systematic review of qualitative evidence relating to the views and attitudes of men who have sex with men (MSM) concerning testing for HIV. Studies conducted in high-income countries (Organisation for Economic Co-operation and Development members) since 1996 were included. Seventeen studies were identified, most of gay or bisexual men. Data were analysed using a thematic analysis methodology. The uncertainty of unknown HIV status is an important motive for testing; however, denial is also a common response to uncertainty. Fear of the consequences of a positive HIV test is widespread and may take several forms. A sense of responsibility towards oneself or one's partner may be a motive for testing. The perception of stigma, from other gay men or from the wider culture, is a barrier to testing. Gay and other MSM have clear preferences regarding testing services, particularly for those that are community based, include non-judgemental and gay-positive service providers, and offer a high degree of confidentiality.

Exploring Heterogeneity in Histology-Independent Technologies and the Implications for Cost-Effectiveness.

BACKGROUND: The National Institute for Health and Care Excellence and a number of international health technology assessment agencies have recently undertaken appraisals of histology-independent technologies (HITs). A strong and untested assumption inherent in the submissions included identical clinical response across all tumour histologies, including new histologies unrepresented in the trial. Challenging this assumption and exploring the potential for heterogeneity has the potential to impact upon cost-effectiveness. METHOD: Using published response data for a HIT, a Bayesian hierarchical model (BHM) was used to identify heterogeneity in response and to estimate the probability of response for each histology included in single-arm studies, which informed the submission for the HIT, larotrectinib. The probability of response for a new histology was estimated. Results were inputted into a simplified response-based economic model using hypothetical parameters. Histology-independent and histology-specific incremental cost-effectiveness ratios accounting for heterogeneity were generated. RESULTS: The results of the BHM show considerable heterogeneity in response rates across histologies. The predicted probability of response estimated by the BHM is 60.9% (95% credible interval 16.0; 91.8%), lower than the naively pooled probability of 74.5%. A mean response probability of 56.9% (0.2; 99.9%) is predicted for an unrepresented histology. Based on the economic analysis, the probability of the hypothetical HIT being cost-effective under the assumption of identical response is 78%. Allowing for heterogeneity, the probability of various approval decisions being cost-effective ranges from 93% to 11%. CONCLUSIONS: Central to the challenge of reimbursement of HITs is the potential for heterogeneity. This study illustrates how heterogeneity in clinical effectiveness can result in highly variable and uncertain estimates of cost-effectiveness. This analysis can help improve understanding of the consequences of histology-independent versus histology-specific decisions.

Non-invasive imaging software to assess the functional significance of coronary stenoses: a systematic review and economic evaluation.

BACKGROUND: QAngio® XA 3D/QFR® (three-dimensional/quantitative flow ratio) imaging software (Medis Medical Imaging Systems BV, Leiden, the Netherlands) and CAAS® vFFR® (vessel fractional flow reserve) imaging software (Pie Medical Imaging BV, Maastricht, the Netherlands) are non-invasive technologies to assess the functional significance of coronary stenoses, which can be alternatives to invasive fractional flow reserve assessment. OBJECTIVES: The objectives were to determine the clinical effectiveness and cost-effectiveness of QAngio XA 3D/QFR and CAAS vFFR. METHODS: We performed a systematic review of all evidence on QAngio XA 3D/QFR and CAAS vFFR, including diagnostic accuracy, clinical effectiveness, implementation and economic analyses. We searched MEDLINE and other databases to January 2020 for studies where either technology was used and compared with fractional flow reserve in patients with intermediate stenosis. The risk of bias was assessed with quality assessment of diagnostic accuracy studies. Meta-analyses of diagnostic accuracy were performed. Clinical and implementation outcomes were synthesised narratively. A simulation study investigated the clinical impact of using QAngio XA 3D/QFR. We developed a de novo decision-analytic model to estimate the cost-effectiveness of QAngio XA 3D/QFR and CAAS vFFR relative to invasive fractional flow reserve or invasive coronary angiography alone. Scenario analyses were undertaken to explore the robustness of the results to variation in the sources of data used to populate the model and alternative assumptions. RESULTS: Thirty-nine studies (5440 patients) of QAngio XA 3D/QFR and three studies (500 patients) of CAAS vFFR were included. QAngio XA 3D/QFR had good diagnostic accuracy to predict functionally significant fractional flow reserve (≤ 0.80 cut-off point); contrast-flow quantitative flow ratio had a sensitivity of 85% (95% confidence interval 78% to 90%) and a specificity of 91% (95% confidence interval 85% to 95%). A total of 95% of quantitative flow ratio measurements were within 0.14 of the fractional flow reserve. Data on the diagnostic accuracy of CAAS vFFR were limited and a full meta-analysis was not feasible. There were very few data on clinical and implementation outcomes. The simulation found that quantitative flow ratio slightly increased the revascularisation rate when compared with fractional flow reserve, from 40.2% to 42.0%. Quantitative flow ratio and fractional flow reserve resulted in similar numbers of subsequent coronary events. The base-case cost-effectiveness results showed that the test strategy with the highest net benefit was invasive coronary angiography with confirmatory fractional flow reserve. The next best strategies were QAngio XA 3D/QFR and CAAS vFFR (without fractional flow reserve). However, the difference in net benefit between this best strategy and the next best was small, ranging from 0.007 to 0.012 quality-adjusted life-years (or equivalently £140-240) per patient diagnosed at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. LIMITATIONS: Diagnostic accuracy evidence on CAAS vFFR, and evidence on the clinical impact of QAngio XA 3D/QFR, were limited. CONCLUSIONS: Quantitative flow ratio as measured by QAngio XA 3D/QFR has good agreement and diagnostic accuracy compared with fractional flow reserve and is preferable to standard invasive coronary angiography alone. It appears to have very similar cost-effectiveness to fractional flow reserve and, therefore, pending further evidence on general clinical benefits and specific subgroups, could be a reasonable alternative. The clinical effectiveness and cost-effectiveness of CAAS vFFR are uncertain. Randomised controlled trial evidence evaluating the effect of quantitative flow ratio on clinical and patient-centred outcomes is needed. FUTURE WORK: Studies are required to assess the diagnostic accuracy and clinical feasibility of CAAS vFFR. Large ongoing randomised trials will hopefully inform the clinical value of QAngio XA 3D/QFR. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019154575. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 56. See the NIHR Journals Library website for further project information.

Stable angina is a type of chest pain; left untreated, it can lead to heart failure, heart attack and sudden death. To avoid these outcomes, patients may require surgical intervention to open obstructed arteries, known as 'revascularisation'. Patients who might need revascularisation undergo tests to identify blocked arteries. The last line of testing is called invasive fractional flow reserve assessment. This is an invasive measurement of blood flow that involves inserting a wire into an artery after the patient has taken drugs to dilate the artery. It carries some risks and may have side effects. Non-invasive tests have been proposed to precede or replace invasive fractional flow reserve assessments. These include QAngio^® XA 3D/QFR^® (three-dimensional/quantitative flow ratio) (Medis Medical Imaging Systems BV, Leiden, the Netherlands) and CAAS^® vFFR^® (vessel fractional flow reserve) (Pie Medical Imaging BV, Maastricht, the Netherlands) imaging software. This project investigated whether or not these technologies can provide accurate assessments of blood pressure, and if they are a reasonable use of NHS resources. A thorough review of all the literature on the technologies was performed. All data were combined and re-analysed to determine whether or not the tests accurately predict the need for revascularisation and to consider their clinical benefits. An economic analysis was conducted to investigate whether or not using either of these technologies is economically viable. The project found that QAngio XA 3D/QFR can accurately measure blood flow, may be a reasonable alternative to fractional flow reserve, pending more evidence on benefits to patients' health, and is a reasonable use of NHS resources. The current evidence for CAAS vFFR is too limited to draw any firm conclusions.

Cost-effectiveness of point-of-care creatinine testing to assess kidney function prior to contrast-enhanced computed tomography imaging.

BACKGROUND: Patients undergoing contrast-enhanced computed tomography (CECT) imaging in a non-emergency outpatient setting often lack a recent estimated Glomerular Filtration Rate measurement. This may lead to inefficiencies in the CECT pathway. The use of point-of-care (POC) creatinine tests to evaluate kidney function in these patients may provide a safe and cost-effective alternative to current practice, as these can provide results within the same CECT appointment. METHODS: A decision tree model was developed to characterise the diagnostic pathway and patient management (e.g., intravenous hydration) and link these to adverse renal events associated with intravenous contrast media. Twelve diagnostic strategies including three POC devices (i-STAT, ABL800 Flex and StatSensor), risk factor screening and laboratory testing were compared with current practice. The diagnostic accuracy of POC devices was derived from a systematic review and meta-analysis; relevant literature sources and databases informed other parameters. The cost-effective strategy from a health care perspective was identified based on highest net health benefit (NHB) which were expressed in quality-adjusted life years (QALYs) at £20,000/QALY. RESULTS: The cost-effective strategy, with a NHB of 9.98 QALYs and a probability of being cost-effective of 79.3%, was identified in our analysis to be a testing sequence involving screening all individuals for risk factors, POC testing (with i-STAT) on those screening positive, and performing a confirmatory laboratory test for individuals with a positive POC result. The incremental NHB of this strategy compared to current practice, confirmatory laboratory test, is 0.004 QALYs. Results were generally robust to scenario analysis. CONCLUSIONS: A testing sequence combining a risk factor questionnaire, POC test and confirmatory laboratory testing appears to be cost-effective compared to current practice. The cost-effectiveness of POC testing appears to be driven by reduced delays within the CECT pathway. The contribution of intravenous contrast media to acute kidney injury, and the benefits and harms of intravenous hydration remain uncertain.

Imaging for detection of osteomyelitis in people with diabetic foot ulcers: A systematic review and meta-analysis.

BACKGROUND: Osteomyelitis is an infection of the bone which can occur in people with diabetic foot ulcers. It can be diagnosed using X-rays, ultrasound, scintigraphy, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). OBJECTIVES: To review the evidence on the diagnostic accuracy of imaging tests to diagnose osteomyelitis in people with diabetic foot ulcers. METHODS: We conducted a systematic review and meta-analysis. MEDLINE, EMBASE and other databases were searched to July 2018. Risk of bias was evaluated. Diagnostic accuracy was estimated using bivariate meta-analyses. RESULTS: Thirty-six studies were included in the meta-analysis. Eight studies were at high risk of bias MRI had high diagnostic accuracy (22 studies: 96.4 % sensitivity (95 % CI 90.7-98.7); 83.8 % specificity (76.0-89.5)). PET scans also had high accuracy (6 studies: 84.3 % sensitivity (52.8-96.3); 92.8 % specificity (75.7-98.2)), and possibly also SPECT, but with few studies (3 studies: 95.6 % sensitivity (76.0-99.3); 55.1 % specificity (19.3-86.3)). Scintigraphy (17 studies: 84.2 % sensitivity (76.8-89.6); 67.7 % specificity (56.2-77.4)), and X-rays (16 studies: 61.9 % sensitivity (50.5-72.1); 78.3 % specificity (62.9-88.5)) had generally inferior diagnostic accuracy. CONCLUSIONS: MRI and PET both reliably diagnose osteomyelitis in diabetic foot ulcer patients. SPECT may also have good diagnostic accuracy, although evidence is limited. This review confirms most current guidelines, showing that MRI may be the preferable test in most cases, given its wider availability and the lack of potentially harmful ionising radiation.

Point-of-care creatinine tests to assess kidney function for outpatients requiring contrast-enhanced CT imaging: systematic reviews and economic evaluation.

BACKGROUND: Patients with low estimated glomerular filtration rates may be at higher risk of post-contrast acute kidney injury following contrast-enhanced computed tomography imaging. Point-of-care devices allow rapid measurement of estimated glomerular filtration rates for patients referred without a recent estimated glomerular filtration rate result. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of point-of-care creatinine tests for outpatients without a recent estimated glomerular filtration rate measurement who need contrast-enhanced computed tomography imaging. METHODS: Three systematic reviews of test accuracy, implementation and clinical outcomes, and economic analyses were carried out. Bibliographic databases were searched from inception to November 2018. Studies comparing the accuracy of point-of-care creatinine tests with laboratory reference tests to assess kidney function in adults in a non-emergency setting and studies reporting implementation and clinical outcomes were included. Risk of bias of diagnostic accuracy studies was assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Probabilities of individuals having their estimated glomerular filtration rates correctly classified were estimated within a Bayesian framework and pooled using a fixed-effects model. A de novo probabilistic decision tree cohort model was developed to characterise the decision problem from an NHS and a Personal Social Services perspective. A range of alternative point-of-care testing approaches were considered. Scenario analyses were conducted. RESULTS: Fifty-four studies were included in the clinical reviews. Twelve studies reported diagnostic accuracy for estimated glomerular filtration rates; half were rated as being at low risk of bias, but there were applicability concerns for most. i-STAT (Abbott Point of Care, Inc., Princeton, NJ, USA) and ABL (Radiometer Ltd, Crawley, UK) devices had higher probabilities of correctly classifying individuals in the same estimated glomerular filtration rate categories as the reference laboratory test than StatSensor® devices (Nova Biomedical, Runcorn, UK). There was limited evidence for epoc® (Siemens Healthineers AG, Erlangen, Germany) and Piccolo Xpress® (Abaxis, Inc., Union City, CA, USA) devices and no studies of DRI-CHEM NX 500 (Fujifilm Corporation, Tokyo, Japan). The review of implementation and clinical outcomes included six studies showing practice variation in the management decisions when a point-of-care device indicated an abnormal estimated glomerular filtration rate. The review of cost-effectiveness evidence identified no relevant studies. The de novo decision model that was developed included a total of 14 strategies. Owing to limited data, the model included only i-STAT, ABL800 FLEX and StatSensor. In the base-case analysis, the cost-effective strategy appeared to be a three-step testing sequence involving initially screening all individuals for risk factors, point-of-care testing for those individuals with at least one risk factor, and including a final confirmatory laboratory test for individuals with a point-of-care-positive test result. Within this testing approach, the specific point-of-care device with the highest net benefit was i-STAT, although differences in net benefit with StatSensor were very small. LIMITATIONS: There was insufficient evidence for patients with estimated glomerular filtration rates < 30 ml/minute/1.73 m2, and on the full potential health impact of delayed or rescheduled computed tomography scans or the use of alternative imaging modalities. CONCLUSIONS: A three-step testing sequence combining a risk factor questionnaire with a point-of-care test and confirmatory laboratory testing appears to be a cost-effective use of NHS resources compared with current practice. The risk of contrast causing acute kidney injury to patients with an estimated glomerular filtration rate of < 30 ml/minute/1.73 m2 is uncertain. Cost-effectiveness of point-of-care testing appears largely driven by the potential of point-of-care tests to minimise delays within the current computed tomography pathway. FUTURE WORK: Studies evaluating the impact of risk-stratifying questionnaires on workflow outcomes in computed tomography patients without recent estimated glomerular filtration rate results are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018115818. 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. 39. See the NIHR Journals Library website for further project information.

Before computed tomography scans are done, a contrast agent is usually needed to improve the visibility of internal body structures. After receiving a contrast agent (through a vein), some patients' kidneys may be affected, especially if their kidneys already do not work well. A blood test can identify these patients before a computed tomography scan, to reduce the risk of kidney harm. The blood test measures creatinine, which is a marker of how well the kidneys work. Before a contrast-enhanced computed tomography scan, some patients have a recent creatinine result from an earlier blood test. Blood tests are normally done in a central laboratory, and usually take at least 1 hour. Other patients do not have a recent creatinine result, so their computed tomography scan may be delayed or rearranged. Sometimes, to avoid risking kidney harm, patients may have scans without contrast. 'Point-of-care' (handheld, tabletop or portable) devices can quickly measure creatinine (usually in patients with risk factors), often from a finger-prick blood sample. Many point-of-care devices are available but they may not be as exact as laboratory tests, so their benefit is unclear. This study reviewed all available evidence on the benefits and harms of point-of-care creatinine tests before computed tomography scans and assessed whether or not they are a cost-effective use of NHS resources. The study found that some devices [i.e. i-STAT (Abbott Point of Care, Inc., Princeton, NJ, USA) and ABL (Radiometer Ltd, Crawley, UK)] were more accurate than others [i.e. StatSensor^® (Nova Biomedical, Runcorn, UK)]. There was insufficient evidence for other devices. The study found that, for outpatients, doing a point-of-care test in patients who are at a higher risk of kidney harm (according to a questionnaire) and then confirming this with a laboratory test appeared to be a cost-effective use of NHS resources. The study found that the risk of kidney harm as a result of contrast agents appears very low. The main benefit of point-of-care testing may be to reduce needless delays or rearranged computed tomography scan appointments.

Imaging tests for the detection of osteomyelitis: a systematic review.

BACKGROUND: Osteomyelitis is an infection of the bone. Medical imaging tests, such as radiography, ultrasound, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET), are often used to diagnose osteomyelitis. OBJECTIVES: To systematically review the evidence on the diagnostic accuracy, inter-rater reliability and implementation of imaging tests to diagnose osteomyelitis. DATA SOURCES: We conducted a systematic review of imaging tests to diagnose osteomyelitis. We searched MEDLINE and other databases from inception to July 2018. REVIEW METHODS: Risk of bias was assessed with QUADAS-2 [quality assessment of diagnostic accuracy studies (version 2)]. Diagnostic accuracy was assessed using bivariate regression models. Imaging tests were compared. Subgroup analyses were performed based on the location and nature of the suspected osteomyelitis. Studies of children, inter-rater reliability and implementation outcomes were synthesised narratively. RESULTS: Eighty-one studies were included (diagnostic accuracy: 77 studies; inter-rater reliability: 11 studies; implementation: one study; some studies were included in two reviews). One-quarter of diagnostic accuracy studies were rated as being at a high risk of bias. In adults, MRI had high diagnostic accuracy [95.6% sensitivity, 95% confidence interval (CI) 92.4% to 97.5%; 80.7% specificity, 95% CI 70.8% to 87.8%]. PET also had high accuracy (85.1% sensitivity, 95% CI 71.5% to 92.9%; 92.8% specificity, 95% CI 83.0% to 97.1%), as did SPECT (95.1% sensitivity, 95% CI 87.8% to 98.1%; 82.0% specificity, 95% CI 61.5% to 92.8%). There was similar diagnostic performance with MRI, PET and SPECT. Scintigraphy (83.6% sensitivity, 95% CI 71.8% to 91.1%; 70.6% specificity, 57.7% to 80.8%), computed tomography (69.7% sensitivity, 95% CI 40.1% to 88.7%; 90.2% specificity, 95% CI 57.6% to 98.4%) and radiography (70.4% sensitivity, 95% CI 61.6% to 77.8%; 81.5% specificity, 95% CI 69.6% to 89.5%) all had generally inferior diagnostic accuracy. Technetium-99m hexamethylpropyleneamine oxime white blood cell scintigraphy (87.3% sensitivity, 95% CI 75.1% to 94.0%; 94.7% specificity, 95% CI 84.9% to 98.3%) had higher diagnostic accuracy, similar to that of PET or MRI. There was no evidence that diagnostic accuracy varied by scan location or cause of osteomyelitis, although data on many scan locations were limited. Diagnostic accuracy in diabetic foot patients was similar to the overall results. Only three studies in children were identified; results were too limited to draw any conclusions. Eleven studies evaluated inter-rater reliability. MRI had acceptable inter-rater reliability. We found only one study on test implementation and no evidence on patient preferences or cost-effectiveness of imaging tests for osteomyelitis. LIMITATIONS: Most studies included < 50 participants and were poorly reported. There was limited evidence for children, ultrasonography and on clinical factors other than diagnostic accuracy. CONCLUSIONS: Osteomyelitis is reliably diagnosed by MRI, PET and SPECT. No clear reason to prefer one test over the other in terms of diagnostic accuracy was identified. The wider availability of MRI machines, and the fact that MRI does not expose patients to harmful ionising radiation, may mean that MRI is preferable in most cases. Diagnostic accuracy does not appear to vary with the potential cause of osteomyelitis or with the body part scanned. Considerable uncertainty remains over the diagnostic accuracy of imaging tests in children. Studies of diagnostic accuracy in children, particularly using MRI and ultrasound, are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017068511. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 61. See the NIHR Journals Library website for further project information.

Osteomyelitis is an infection of the bone and is treated with antibiotics. Left untreated, it can cause permanent damage and can lead to amputation. The best method to diagnose osteomyelitis is to take a bone sample (bone biopsy) but this is invasive and painful. Imaging may help target the best locations for biopsies or remove the need for a biopsy entirely. Several methods are available, including radiography, ultrasound, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). This project systematically reviewed the relevant literature to determine which tests are the most accurate and relevant for clinical practice. All types of patients and all types of osteomyelitis were reviewed. Studies were pooled using statistical methods (meta-analyses) to estimate the overall accuracy of the imaging tests. The review identified 81 studies and concluded that MRI, PET and SPECT all had similar accuracy, correctly identifying over 85% of people who did have osteomyelitis and over 80% of people who did not have osteomyelitis. Radiography and computed tomography were less accurate. Modern forms of scintigraphy have accuracy similar to PET or MRI. There was no evidence that the accuracy of the imaging tests was different depending on the cause of osteomyelitis or which body part was affected. In particular, diagnostic accuracy in people with diabetic foot ulcers was similar to other types of osteomyelitis in adults. There was not enough evidence about which tests are most accurate in children, so further studies in children are needed.

Adjunctive colposcopy technologies for assessing suspected cervical abnormalities: systematic reviews and economic evaluation.

BACKGROUND: Dynamic Spectral Imaging System (DySIS)map (DySIS Medical Ltd, Edinburgh, UK) and ZedScan (Zilico Limited, Manchester, UK) can be used adjunctively with conventional colposcopy, which may improve the detection of cervical intraepithelial neoplasia (CIN) and cancer. OBJECTIVES: To systematically review the evidence on the diagnostic accuracy, clinical effectiveness and implementation of DySISmap and ZedScan as adjuncts to standard colposcopy, and to develop a cost-effectiveness model. METHODS: Four parallel systematic reviews were performed on diagnostic accuracy, clinical effectiveness issues, implementation and economic analyses. In January 2017 we searched databases (including MEDLINE and EMBASE) for studies in which DySISmap or ZedScan was used adjunctively with standard colposcopy to detect CIN or cancer in women referred to colposcopy. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. Summary estimates of diagnostic accuracy were calculated using bivariate and other regression models when appropriate. Other outcomes were synthesised narratively. A patient-level state-transition model was developed to evaluate the cost-effectiveness of DySISmap and ZedScan under either human papillomavirus (HPV) triage or the HPV primary screening algorithm. The model included two types of clinics ['see and treat' and 'watchful waiting' (i.e. treat later after confirmatory biopsy)], as well as the reason for referral (low-grade or high-grade cytological smear). Sensitivity and scenario analyses were undertaken. RESULTS: Eleven studies were included in the diagnostic review (nine of DySISmap and two of ZedScan), three were included in the clinical effectiveness review (two of DySISmap and one of ZedScan) and five were included in the implementation review (four of DySISmap and one of ZedScan). Adjunctive DySISmap use was found to have a higher sensitivity for detecting CIN grade 2+ (CIN 2+) lesions [81.25%, 95% confidence interval (CI) 72.2% to 87.9%] than standard colposcopy alone (57.91%, 95% CI 47.2% to 67.9%), but with a lower specificity (70.40%, 95% CI 59.4% to 79.5%) than colposcopy (87.41%, 95% CI 81.7% to 91.5%). (Confidential information has been removed.) The base-case cost-effectiveness results showed that adjunctive DySISmap routinely dominated standard colposcopy (it was less costly and more effective). The only exception was for high-grade referrals in a watchful-waiting clinic setting. The incremental cost-effectiveness ratio for ZedScan varied between £272 and £4922 per quality-adjusted life-year. ZedScan also dominated colposcopy alone for high-grade referrals in see-and-treat clinics. These findings appeared to be robust to a wide range of sensitivity and scenario analyses. LIMITATIONS: All but one study was rated as being at a high risk of bias. There was no evidence directly comparing ZedScan with standard colposcopy. No studies directly compared DySIS and ZedScan. CONCLUSIONS: The use of adjunctive DySIS increases the sensitivity for detecting CIN 2+, so it increases the number of high-grade CIN cases that are detected. However, it also reduces specificity, so that more women with no or low-grade CIN will be incorrectly judged as possibly having high-grade CIN. The evidence for ZedScan was limited, but it appears to increase sensitivity and decrease specificity compared with colposcopy alone. The cost-effectiveness of both adjunctive technologies compared with standard colposcopy, under both the HPV triage and primary screening algorithms, appears to be favourable when compared with the conventional thresholds used to determine value in the NHS. FUTURE WORK: More diagnostic accuracy studies of ZedScan are needed, as are studies assessing the diagnostic accuracy for women referred to colposcopy as part of the HPV primary screening programme. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017054515. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

High-throughput non-invasive prenatal testing for fetal rhesus D status in RhD-negative women not known to be sensitised to the RhD antigen: a systematic review and economic evaluation.

BACKGROUND: High-throughput non-invasive prenatal testing (NIPT) for fetal rhesus (D antigen) (RhD) status could avoid unnecessary treatment with routine anti-D immunoglobulin for RhD-negative women carrying a RhD-negative fetus, although this may lead to an increased risk of RhD sensitisations. OBJECTIVES: To systematically review the evidence on the diagnostic accuracy, clinical effectiveness and implementation of high-throughput NIPT and to develop a cost-effectiveness model. METHODS: We searched MEDLINE and other databases, from inception to February 2016, for studies of high-throughput NIPT free-cell fetal deoxyribonucleic acid (DNA) tests of maternal plasma to determine fetal RhD status in RhD-negative pregnant women who were not known to be sensitised to the RhD antigen. Study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) and A Cochrane Risk of Bias Assessment Tool: for Non-Randomised Studies of Interventions (ACROBAT-NRSI). Summary estimates of false-positive rates (FPRs) and false-negative rates (FNRs) were calculated using bivariate models. Clinical effectiveness evidence was used to conduct a simulation study. We developed a de novo probabilistic decision tree-based cohort model that considered four alternative ways in which the results of NIPT could guide the use of anti-D immunoglobulin antenatally and post partum. Sensitivity analyses (SAs) were conducted to address key uncertainties and model assumptions. RESULTS: Eight studies were included in the diagnostic accuracy review, seven studies were included in the clinical effectiveness review and 12 studies were included in the review of implementation. Meta-analyses included women mostly at or post 11 weeks' gestation. The pooled FNR (women at risk of sensitisation) was 0.34% [95% confidence interval (CI) 0.15% to 0.76%] and the pooled FPR (women needlessly receiving anti-D) was 3.86% (95% CI 2.54% to 5.82%). SAs did not materially alter the overall results. Data on clinical outcomes, including sensitisation rates, were limited. Our simulation suggests that NIPT could substantially reduce unnecessary use of antenatal anti-D with only a small increase in the risk of sensitisation. All large implementation studies suggested that large-scale implementation of high-throughput NIPT was feasible. Seven cost-effectiveness studies were included in the review, which found that the potential for the use of NIPT to produce cost savings was dependent on the cost of the test. Our de novo model suggested that high-throughput NIPT is likely to be cost saving compared with the current practice of providing routine antenatal anti-D prophylaxis to all women who are RhD negative. The extent of the cost saving appeared to be sufficient to outweigh the small increase in sensitisations. However, the magnitude of the cost saving is highly sensitive to the cost of NIPT itself. LIMITATIONS: There was very limited evidence relating to the clinical effectiveness of high-throughput NIPT, with no evidence on potential adverse effects. The generalisability of the findings to non-white women and multiple pregnancies is unclear. CONCLUSIONS: High-throughput NIPT is sufficiently accurate to detect fetal RhD status in RhD-negative women from 11 weeks' gestation and would considerably reduce unnecessary treatment with routine anti-D immunoglobulin, potentially resulting in cost savings of between £485,000 and £671,000 per 100,000 pregnancies if the cost of implementing NIPT is in line with that reflected in this evaluation. FUTURE WORK: Further research on the diagnostic accuracy of NIPT in non-white women is needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029497. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol.

BACKGROUND: Preterm birth is the most common cause of death and harm to newborn babies. Babies that are born early may have difficulties at birth and experience health problems during early childhood. Despite extensive study, there is still uncertainty about the effectiveness of progestogen (medications that are similar to the natural hormone progesterone) in preventing or delaying preterm birth, and in improving birth outcomes. The Evaluating Progestogen for Prevention of Preterm birth International Collaborative (EPPPIC) project aims to reduce uncertainty about the specific conditions in which progestogen may (or may not) be effective in preventing or delaying preterm birth and improving birth outcomes. METHODS: The design of the study involves international collaborative individual participant data meta-analysis comprising systematic review, re-analysis, and synthesis of trial datasets. Inclusion criteria are as follows: randomized controlled trials comparing progestogen versus placebo or non-intervention, or comparing different types of progestogen, in asymptomatic women at risk of preterm birth. Main outcomes are as follows; fetal/infant death, preterm birth or fetal death (<=37 weeks, <=34 weeks, <= 28 weeks), serious neonatal complications or fetal/infant death, neurosensory disability (measured at 18 months or later) or infant/child death, important maternal morbidity, or maternal death. In statistical methods, IPD will be synthesized across trials using meta-analysis. Both 'two-stage' models (where effect estimates are calculated for each trial and subsequently pooled in a meta-analysis) and 'one-stage' models (where all IPD from all trials are analyzed in one step, while accounting for the clustering of participants within trials) will be used. If sufficient suitable data are available, a network meta-analysis will compare all types of progesterone and routes of administration extending the one-stage models to include multiple treatment arms. DISCUSSION: EPPPIC is an international collaborative project being conducted by the forming EPPPIC group, which includes trial investigators, an international secretariat, and the research project team. Results, which are intended to contribute to improvements in maternal and child health, are expected to be publicly available in mid 2018. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017068299.

Interventions for hyperhidrosis in secondary care: a systematic review and value-of-information analysis.

BACKGROUND: Hyperhidrosis is uncontrollable excessive sweating that occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. The management of hyperhidrosis is uncertain and variable. OBJECTIVE: To establish the expected value of undertaking additional research to determine the most effective interventions for the management of refractory primary hyperhidrosis in secondary care. METHODS: A systematic review and economic model, including a value-of-information (VOI) analysis. Treatments to be prescribed by dermatologists and minor surgical treatments for hyperhidrosis of the hands, feet and axillae were reviewed; as endoscopic thoracic sympathectomy (ETS) is incontestably an end-of-line treatment, it was not reviewed further. Fifteen databases (e.g. CENTRAL, PubMed and PsycINFO), conference proceedings and trial registers were searched from inception to July 2016. Systematic review methods were followed. Pairwise meta-analyses were conducted for comparisons between botulinum toxin (BTX) injections and placebo for axillary hyperhidrosis, but otherwise, owing to evidence limitations, data were synthesised narratively. A decision-analytic model assessed the cost-effectiveness and VOI of five treatments (iontophoresis, medication, BTX, curettage, ETS) in 64 different sequences for axillary hyperhidrosis only. RESULTS AND CONCLUSIONS: Fifty studies were included in the effectiveness review: 32 randomised controlled trials (RCTs), 17 non-RCTs and one large prospective case series. Most studies were small, rated as having a high risk of bias and poorly reported. The interventions assessed in the review were iontophoresis, BTX, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland (e.g. laser, microwave). There is moderate-quality evidence of a large statistically significant effect of BTX on axillary hyperhidrosis symptoms, compared with placebo. There was weak but consistent evidence for iontophoresis for palmar hyperhidrosis. Evidence for other interventions was of low or very low quality. For axillary hyperhidrosis cost-effectiveness results indicated that iontophoresis, BTX, medication, curettage and ETS was the most cost-effective sequence (probability 0.8), with an incremental cost-effectiveness ratio of £9304 per quality-adjusted life-year. Uncertainty associated with study bias was not reflected in the economic results. Patients and clinicians attending an end-of-project workshop were satisfied with the sequence of treatments for axillary hyperhidrosis identified as being cost-effective. All patient advisors considered that the Hyperhidrosis Quality of Life Index was superior to other tools commonly used in hyperhidrosis research for assessing quality of life. LIMITATIONS: The evidence for the clinical effectiveness and safety of second-line treatments for primary hyperhidrosis is limited. This meant that there was insufficient evidence to draw conclusions for most interventions assessed and the cost-effectiveness analysis was restricted to hyperhidrosis of the axilla. FUTURE WORK: Based on anecdotal evidence and inference from evidence for the axillae, participants agreed that a trial of BTX (with anaesthesia) compared with iontophoresis for palmar hyperhidrosis would be most useful. The VOI analysis indicates that further research into the effectiveness of existing medications might be worthwhile, but it is unclear that such trials are of clinical importance. Research that established a robust estimate of the annual incidence of axillary hyperhidrosis in the UK population would reduce the uncertainty in future VOI analyses. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027803. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Antiretroviral therapy and liver disease progression in HIV and hepatitis C co-infected patients: a systematic review and meta-analysis.

BACKGROUND: HIV co-infection exacerbates hepatitis C disease, increasing the risk of cirrhosis and hepatitis C-related mortality. Combination antiretroviral therapy (cART) is the current standard treatment for co-infected individuals, but the impact of cART and antiretroviral (ARV) monotherapy on liver disease in this population is unclear. We aimed to assess the effect of cART and ARV monotherapy on liver disease progression and liver-related mortality in individuals co-infected with HIV and chronic hepatitis C. METHODS: A systematic review with meta-analyses was conducted. MEDLINE and EMBASE bibliographic databases were searched up to September 2015. Study quality was assessed using a modified Newcastle-Ottawa scale. Results were synthesised narratively and by meta-analysis. RESULTS: Fourteen observational studies were included. In analyses that adjusted for potential confounders, risk of liver-related mortality was significantly lower in patients receiving cART (hazard ratio/odds ratio 0.31, 95 % CI 0.14 to 0.70). Results were similar in unadjusted analyses (relative risk 0.40, 95 % CI 0.29 to 0.55). For outcomes where meta-analysis could not be performed, results were less consistent. Some studies found cART was associated with lower incidence of, or slower progression of liver disease, fibrosis and cirrhosis, while others showed no evidence of benefit. We found no evidence of liver-related harm from cART or ARV monotherapy compared with no HIV therapy. CONCLUSIONS: cART was associated with significantly lower liver-related mortality in patients co-infected with HIV and HCV. Evidence of a positive association between cART and/or ARV monotherapy and liver-disease progression was less clear, but there was no evidence to suggest that the absence of antiretroviral therapy was preferable.

Daclatasvir for the Treatment of Chronic Hepatitis C: A Critique of the Clinical and Economic Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of daclatasvir (Bristol-Myers Squibb) to submit clinical and cost-effectiveness evidence for daclatasvir in combination with other medicinal products within its licensed indication for the treatment of chronic hepatitis C, as part of the Institute's single technology appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article presents the ERG's critical review of the evidence presented in the company submission in the context of a description of the company submission, and the resulting NICE guidance. The main clinical effectiveness data for daclatasvir in combination with sofosbuvir (daclatasvir + sofosbuvir) were derived from two uncontrolled open-label trials. Among patients with genotype 1 infection, 98-100 % of patients had a sustained virologic response at week 12 (SVR12), overall. Among genotype 3 patients, between 85 and 100 % had SVR12 across patient populations and regimens. The main evidence for daclatasvir + pegylated interferon-α and ribavirin (PR) came from one randomised controlled trial comparing daclatasvir + PR with PR in patients with genotype 4. This found an SVR12 rate of 82 % in previously untreated patients. Serious adverse event rates associated with daclatasvir were low. The lack of comparative trial evidence for daclatasvir + sofosbuvir and many of the comparators defined in the NICE scope meant that established methods for comparing interventions either directly via head-to-head trial comparisons or via adjusted indirect comparisons were not feasible. Comparisons of SVR rates were therefore largely based on unadjusted estimates drawn from individual trial arms and subgroups of individual trial arms. The ERG concluded that, despite limited evidence, daclatasvir in combination with other treatments appeared to be associated with a high SVR rate. Daclatasvir + sofosbuvir was unlikely to be inferior to comparator treatments in genotype 1 patients; but, due to limited evidence, the relative efficacy of daclatasvir and other treatments in genotype 3 and 4 patients or patients with compensated cirrhosis was uncertain. The economic evaluation compared daclatasvir + sofosbuvir and daclatasvir + PR with a wide range of NICE-approved treatments for hepatitis C. The company submission focused on a series of subgroups defined by disease severity (METAVIR fibrosis stage F3, compensated cirrhosis), genotype and treatment history. In the cost-effectiveness analysis, daclatasvir-containing regimens were cost effective at a £20,000-£30,000 per QALY threshold in the following F3 populations: genotype 1 treatment naïve (Incremental cost-effectiveness ratio [ICER] = £19,739/QALY) and treatment experienced (£15,687/QALY) and genotypes 1, 3 and 4 interferon ineligible or intolerant (£5906-£9607/QALY depending on subgroup). In patients with cirrhosis, daclatasvir-containing regimens were not cost effective. The ERG found the company's economic analyses to be highly uncertain and in places biased. However, the ERG found that daclatasvir-containing regimens were cost effective in certain populations with significant fibrosis, and following new analyses by the company after a price reduction, in certain populations with cirrhosis, including patients who were not eligible for or who were intolerant to interferon therapy. The NICE Appraisal Committee's preliminary recommendation was that daclatasvir + sofosbuvir should be available as an option in genotype 1 and 4 patients with significant fibrosis but without cirrhosis, who had either been treated previously or were ineligible or intolerant to interferon. In response to the preliminary recommendation, the manufacturer submitted additional information including comparator SVR rates and a revised confidential price. Following this, the Committee expanded its original recommendation in its Final Appraisal Determination. The recommendation was expanded to include daclatasvir + sofosbuvir as an option for patients with significant fibrosis but without cirrhosis (in previously untreated patients with genotype 1, and genotype 3 patients ineligible or intolerant to interferon) and genotype 1, 3 and 4 cirrhotic patients who were ineligible or intolerant to interferon. Daclatasvir + PR was also recommended as an option for genotype 4 patients who had significant fibrosis or compensated cirrhosis.