Petra Harris

The Effectiveness of Interventions to Treat Severe Acute Malnutrition in Young Children: A Systematic Review

BACKGROUND Severe acute malnutrition (SAM) arises as a consequence of a sudden period of food shortage and is associated with loss of a persons body fat and wasting of their skeletal muscle. Many of those affected are already undernourished and are often susceptible to disease. Infants and young children are the most vulnerable as they require extra nutrition for growth and development, have comparatively limited energy reserves and depend on others. Undernutrition can have drastic and wide-ranging consequences for the childs development and survival in the short and long term. Despite efforts made to treat SAM through different interventions and programmes, it continues to cause unacceptably high levels of mortality and morbidity. Uncertainty remains as to the most effective methods to treat severe acute malnutrition in young children. OBJECTIVES To evaluate the effectiveness of interventions to treat infants and children aged < 5 years who have SAM. DATA SOURCES Eight databases (MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, CAB Abstracts Ovid, Bioline, Centre for Reviews and Dissemination, EconLit EBSCO and The Cochrane Library) were searched to 2010. Bibliographies of included articles and grey literature sources were also searched. The project expert advisory group was asked to identify additional published and unpublished references. REVIEW METHODS Prior to the systematic review, a Delphi process involving international experts prioritised the research questions. Searches were conducted and two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full texts of retrieved papers by one reviewer and checked independently by a second. Included studies were mapped to the research questions. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. Studies were synthesised through a narrative review with tabulation of the results. RESULTS A total of 8954 records were screened, 224 full-text articles were retrieved, and 74 articles (describing 68 studies) met the inclusion criteria and were mapped. No evidence focused on treatment of children with SAM who were human immunodeficiency virus sero-positive, and no good-quality or adequately reported studies assessed treatments for SAM among infants < 6 months old. One randomised controlled trial investigated fluid resuscitation solutions for shock, with none adequately treating shock. Children with acute diarrhoea benefited from the use of hypo-osmolar oral rehydration solution (H-ORS) compared with the standard World Health Organization-oral rehydration solution (WHO-ORS). WHO-ORS was not significantly different from rehydration solution for malnutrition (ReSoMal), but the safety of ReSoMal was uncertain. A rice-based ORS was more beneficial than glucose-based ORSs, and provision of zinc plus a WHO-ORS had a favourable impact on diarrhoea and need for ORS. Comparisons of different diets in children with persistent diarrhoea produced conflicting findings. For treating infection, comparison of amoxicillin with ceftriaxone during inpatient therapy, and routine provision of antibiotics for 7 days versus no antibiotics during outpatient therapy of uncomplicated SAM, found that neither had a significant effect on recovery at the end of follow-up. No evidence mapped to the next three questions on factors that affect sustainability of programmes, long-term survival and readmission rates, the clinical effectiveness of management strategies for treating children with comorbidities such as tuberculosis and Helicobacter pylori infection and the factors that limit the full implementation of treatment programmes. Comparison of treatment for SAM in different settings showed that children receiving inpatient care appear to do as well as those in ambulatory or home settings on anthropometric measures and response time to treatment. Longer-term follow-up showed limited differences between the different settings. The majority of evidence on methods for correcting micronutrient deficiencies considered zinc supplements; however, trials were heterogeneous and a firm conclusion about zinc was not reached. There was limited evidence on either supplementary potassium or nicotinic acid (each produced some benefits), and nucleotides (not associated with benefits). Evidence was identified for four of the five remaining questions, but not assessed because of resource limitation. LIMITATIONS The systematic review focused on key questions prioritised through a Delphi study and, as a consequence, did not encompass all elements in the management of SAM. In focusing on evidence from controlled studies with the most rigorous designs that were published in the English language, the systematic review may have excluded other forms of evidence. The systematic review identified several limitations in the evidence base for assessing the effectiveness of interventions for treating young children with severe acute malnutrition, including a lack of studies assessing the different interventions; limited details of study methods used; short follow-up post intervention or discharge; and heterogeneity in participants, interventions, settings, and outcome measures affecting generalisability. CONCLUSIONS For many of the most highly ranked questions evidence was lacking or inconclusive. More research is needed on a range of topic areas concerning the treatment of infants and children with SAM. Further research is required on most aspects of the management of SAM in children < 5 years, including intravenous resuscitation regimens for shock, management of subgroups (e.g. infants < 6 months old, infants and children with SAM who are human immunodeficiency virus sero-positive) and on the use of antibiotics.

Selective effects of upper respiratory tract infection on cognition, mood and emotion processing: A prospective study

Observational and experimentally induced infection studies show that upper respiratory tract infections (URTI) affect mood and cognition. This study tested the effects of naturally occurring URTI on cognition, mood and emotional processing, using a prospective design, with a broader array of tests than previous research, and with well matched control participants. Eighty participants (42 younger, M age 20.3 years; 38 older, M age 64.3 years) underwent neuropsychological assessment at baseline. Once a participant had URTI symptoms, s/he and a healthy, matched participant were retested. The Cognitive Drug Research computerised assessment battery was used to assess Power and Continuity of Attention, Quality of Episodic and Working Memory, Speed of Memory, and mood. Additionally, emotional processing was measured on matching of emotionally-negative faces with faces and faces with labels. Forty-two of 80 participants were matched (21 well, 21 ill). Well participants improved in Speed of Memory and face-label reaction time. Despite a lack of fever, ill participants demonstrated significantly smaller improvements. Older participants reported feeling less alert if ill, and less stressed if well, than at baseline. All ill participants reported less contentment than at baseline than well participants. Severity of URTI symptoms correlated with changes in Speed of Memory and mood. Even without fever, infectious disease produces large disturbances in speed of cognitive processing, particularly that reflecting retrieval from memory, and these effects are more marked in older participants. URTIs also affect mood. Future studies need to examine the role of inflammatory molecules and the brain regions implicated in mediating these findings.

Telbivudine for the treatment of chronic hepatitis B infection.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of telbivudine for the treatment of chronic hepatitis B (CHB) in adults based upon a review of the manufacturers submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submissions evidence came from one randomised controlled trial (RCT) (GLOBE) of reasonable methodological quality comparing telbivudine with lamivudine. One other RCT that appeared to meet the inclusion criteria was excluded from the submission. For the primary outcome of therapeutic response telbivudine was statistically superior to lamivudine at weeks 52 and 104 for hepatitis B e antigen (HBeAg)-positive patients, and at week 104 for HBeAg-negative patients. There were statistically significant differences in favour of telbivudine for some secondary outcomes at 2 years including hepatitis B virus (HBV) DNA reduction, HBV DNA non-detectability and alanine aminotransferase normalisation though not for HBeAg-positive patients. In HBeAg-positive patients there was no significant difference between treatment groups for HBeAg loss or seroconversion at any time point. The incidence of adverse events was similar between treatments. Two RCTs comparing entecavir with lamivudine were included in the indirect comparison; however, this was poorly conducted and the results should be treated with caution. The manufacturer developed two economic models to determine the cost-effectiveness of telbivudine. Evidence on the efficacy of telbivudine and lamivudine was taken from the GLOBE trial; efficacy of adefovir was based on assumption. There was a lack of critical assessment and assurance of the quality of the data used to populate the models. The manufacturer concluded that telbivudine is a cost-effective option compared with lamivudine using evidence from the viral load model [HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 19,087 pounds/49,003 pounds, mean quality-adjusted life-year (QALY) gain 1.30/4.67, incremental cost-effectiveness ratio (ICER) 14,665 pounds/10,497 pounds per QALY]. Resubmitted results after a request for clarification by the ERG gave less favourable ICERs (HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 23,983 pounds/41,910 pounds, mean QALY gain 1.56/2.07, ICER 15,377 pounds/20,256 pounds per QALY). The manufacturer concluded that telbivudine is a cost-effective option (on its own or followed by adefovir) for patients who have developed resistance to first-line telbivudine treatment; however, the presentation of the results was not ideal. In conclusion, although telbivudine was statistically superior to lamivudine for most antiviral outcomes, the difference was not clinically significant; in addition, the cost-effectiveness evidence for telbivudine presented in the manufacturers submission was limited. The NICE guidance issued as a result of the STA states that telbivudine is not recommended for the treatment of chronic hepatitis B and that people currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

The clinical effectiveness and cost-effectiveness of second-eye cataract surgery: a systematic review and economic evaluation

BACKGROUND Elective cataract surgery is the most commonly performed surgical procedure in the NHS. In bilateral cataracts, the eye with greatest vision impairment from cataract is operated on first. First-eye surgery can improve vision and quality of life. However, it is unclear whether or not cataract surgery on the second eye provides enough incremental benefit to be considered clinically effective and cost-effective. OBJECTIVE To conduct a systematic review of clinical effectiveness and analysis of cost-effectiveness of second-eye cataract surgery in England and Wales, based on an economic model informed by systematic reviews of cost-effectiveness and quality of life. DATA SOURCES Twelve electronic bibliographic databases, including MEDLINE, EMBASE, Web of Science, The Cochrane Library and the Centre for Reviews and Dissemination databases were searched from database inception to April 2013, with searches updated in July 2013. Reference lists of relevant publications were also checked and experts consulted. REVIEW METHODS Two reviewers independently screened references, extracted and checked data from the included studies and appraised their risk of bias. Based on the review of cost-effectiveness, a de novo economic model was developed to estimate the cost-effectiveness of second-eye surgery in bilateral cataract patients. The model is based on changes in quality of life following second-eye surgery and includes post-surgical complications. RESULTS Three randomised controlled trials (RCTs) of clinical effectiveness, three studies of cost-effectiveness and 10 studies of health-related quality of life (HRQoL) met the inclusion criteria for the systematic reviews and, where possible, were used to inform the economic analysis. Heterogeneity of studies precluded meta-analyses, and instead data were synthesised narratively. The RCTs assessed visual acuity, contrast sensitivity, stereopsis and several measures of HRQoL. Improvements in binocular visual acuity and contrast sensitivity were small and unlikely to be of clinical significance, but stereopsis was improved to a clinically meaningful extent following second-eye surgery. Studies did not provide evidence that second-eye surgery significantly affected HRQoL, apart from an improvement in the mental health component of HRQoL in one RCT. In the model, second-eye surgery generated 0.68 incremental quality-adjusted life-years with an incremental cost-effectiveness ratio of £1964. Model results were most sensitive to changes in the utility gain associated with second-eye surgery, but otherwise robust to changes in parameter values. The probability that second-eye surgery is cost-effective at willingness-to-pay thresholds of £10,000 and £20,000 is 100%. LIMITATIONS Clinical effectiveness studies were all conducted more than 9 years ago. Patients had good vision pre surgery which may not represent all patients eligible for second-eye surgery. For some vision-related patient-reported outcomes and HRQoL measures, thresholds for determining important clinical effects are either unclear or have not been determined. CONCLUSIONS Second-eye cataract surgery is generally cost-effective based on the best available data and under most assumptions. However, more up-to-date data are needed. A well-conducted RCT that reflects current populations and enables the estimation of health state utility values would be appropriate. Guidance is required on which vision-related, patient-reported outcomes are suitable for assessing effects of cataract surgery in the NHS and how these measures should be interpreted clinically. STUDY REGISTRATION This project is registered as PROSPERO CRD42013004211. FUNDING This project was funded by the National Institute for Health Research Health Technology Assessment programme.

Topotecan for relapsed small cell lung cancer: a systematic review and economic evaluation

BACKGROUND Topotecan is a relatively new drug for use as a second-line treatment in patients with relapsed small cell lung cancer (SCLC). We performed a systematic review and economic evaluation of topotecan, and consider it here in relation to the NICE end of life criteria. METHODS Seventeen bibliographic databases (including Cochrane library, Medline and Embase) were searched from 1990 to February 2009, and experts and manufacturers were consulted, to identify relevant randomised controlled trials (RCTs) which were selected according to prospectively defined criteria. An economic evaluation was undertaken to assess cost effectiveness compared with best supportive care (BSC) in the UK. RESULTS Five RCTs were included. The clinical evidence indicates a statistically significant benefit of oral topotecan plus BSC compared to BSC alone for overall survival. Intravenous topotecan was similar in efficacy to both oral topotecan and CAV (cyclophosphamide, doxorubicin and vincristine). In the survival model, oral topotecan plus BSC was associated with an average gain in life expectancy of approximately 4 months, resulting in a gain of 0.183 quality-adjusted life years (QALYs). At an incremental cost of approximately £6200 the incremental cost effectiveness ratio (ICER) is £33,851 per QALY gained. CONCLUSIONS Compared with BSC alone, oral topotecan for patients with relapsed SCLC was associated with improved health outcomes but at increased cost. The ICER is at the upper extreme of the range conventionally regarded as cost effective from an NHS decision making perspective. However, this treatment may fall under supplementary guidance for life extending, end of life treatments.

Are educational interventions to prevent catheter-related bloodstream infections in intensive care unit cost-effective?

BACKGROUND There is increasing interest in evidence-based educational interventions in central venous catheter care. It is unclear how effective these are at reducing the risk of bloodstream infections from the use of intravascular catheters (catheter-BSIs) and the associated costs and health benefits. AIM To estimate the additional costs and health benefits from introducing such interventions and the costs associated with catheter-BSIs. METHODS A comprehensive epidemiological and economic review was performed to develop the parameters for an economic model to assess the cost-effectiveness of introducing an educational intervention compared with clinical practice without the intervention. The model follows the clinical pathway of cohorts of patients from their admission to an intensive care unit (ICU), where some may acquire catheter-BSI, and estimates the associated costs, mortality and life expectancy. FINDINGS The additional cost per catheter-BSI episode was £3940. The results of this model demonstrate that introducing an additional educational intervention to prevent catheter-BSI improved patient life expectancy and reduced overall costs. CONCLUSION Introducing evidence-based education is likely to reduce the incidence of catheter-BSI and the model results suggest that the cost of introducing the interventions will be outweighed by savings related to reduced ICU bed occupancy costs.

Systematic review of cognitive behavioural therapy for the management of headaches and migraines in adults

Aim: This systematic review aimed to establish if cognitive behavioural therapy (CBT) can reduce the physical symptoms of chronic headache and migraines in adults. Methods: Evidence from searches of eight databases was systematically sought, appraised and synthesised. Screening of title and abstracts was conducted independently by two reviewers. Full papers were screened, data extracted and quality assessed by one reviewer and checked by a second. Data were synthesised narratively by intervention due to the heterogeneity of the studies. The inclusion criteria specified randomised controlled trials with CBT as an intervention in adults suffering from chronic headaches/migraines not associated with an underlying pathology/medication overuse. CBT was judged on the basis of authors describing the intervention as CBT. The diagnosis of the condition had to be clinician verified. Studies had to include a comparator and employ headache/migraine-specific outcomes such as patient-reported headache days. Results: Out of 1126 screened titles and abstracts and 20 assessed full papers, 10 studies met the inclusion criteria of the review. Some studies combined CBT with another intervention, as well as employing varying numbers of comparators. CBT was statistically significantly more effective in improving some headaches-related outcomes in CBT comparisons with waiting lists (three studies), in combination with relaxation compared with relaxation only (three studies) or antidepressant medication (one study), with no statistically significant differences in three studies. Conclusions: The findings of this review were mixed, with some studies providing evidence in support of the suggestion that people experiencing headaches or migraines can benefit from CBT, and that CBT can reduce the physical symptoms of headache and migraines. However, methodology inadequacies in the evidence base make it difficult to draw any meaningful conclusions or to make any recommendations.

Bone-anchored hearing aids for people with bilateral hearing impairment: a systematic review

Clin. Otolaryngol. 2011, 36, 419–441

The clinical effectiveness and cost-effectiveness of topotecan for small cell lung cancer: a systematic review and economic evaluation

OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of topotecan as second-line treatment for small cell lung cancer (SCLC). DATA SOURCES Bibliographic databases were searched from 1990 to February 2009, including the Cochrane library, MEDLINE (Ovid), EMBASE (Ovid), PREMEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were assessed and experts were contacted to identify additional references and the manufacturers submission to NICE was also searched. REVIEW METHODS Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers using a standard form. For the clinical effectiveness review, the studies were randomised controlled trials (RCTs), which included adult participants with relapsed SCLC who responded to first-line treatment and for whom re-treatment with first-line therapy was inappropriate. The treatment was topotecan (oral or intravenous, i.v.) compared with one another, best supportive care (BSC) or other chemotherapy regimens. Outcomes included measures of response or disease progression and measures of survival. For the cost-effectiveness review studies were eligible for inclusion if they reported cost-effectiveness, cost-utility, cost-benefit or cost-consequence analyses. Data extraction and quality assessment of included studies was undertaken by one reviewer and checked by a second. Studies were synthesised through a narrative review with full tabulation of results. An independent economic model estimated the cost-effectiveness of topotecan (oral or i.v.) compared with BSC. The model used survival analysis methods to derive estimates of mean survival for patients treated with topotecan or receiving BSC alone. These were combined with quality of life (QoL) weights to derive estimates of mean quality-adjusted life expectancy for patients receiving BSC alone or topotecan plus BSC. Categories of costs included in the model included drug use, chemotherapy administration and on-treatment monitoring, management of adverse events, monitoring for disease progression and palliative care. RESULTS A total of 434 references were identified of which five were included in the clinical effectiveness review. In these trials topotecan was compared with BSC, CAV [cyclophosphamide, Adriamycin (doxorubicin) and vincristine] or amrubicin, or oral topotecan was compared with i.v. topotecan. No economic evaluations were identified. There were no statistically significant differences between groups when i.v. topotecan was compared with either CAV or oral topotecan for overall response rate (ORR). Response rate was significantly better in participants receiving i.v. amrubicin than in those receiving a low dose of i.v. topotecan (38% versus 13%, respectively, p = 0.039). There was a statistically significant benefit in favour of oral topotecan compared with BSC (HR 0.61, 95% CI 0.43 to 0.87, p = 0.01). Drug acquisition costs for four cycles of treatment were estimated at 2550 pounds for oral topotecan and 5979 pounds for i.v. topotecan. Non-drug treatment costs accounted for an additional 1097 pounds for oral topotecan and 4289 pounds for i.v. topotecan. Total costs for the modelled time horizon of 5 years were 4854 pounds for BSC, 11,048 pounds for oral topotecan and between 16,914 pounds and 17,369 pounds for i.v. topotecan (depending on assumptions regarding time progression). Life expectancy was 0.4735, 0.7984 and 0.7784 years for BSC, oral topotecan and i.v. topotecan respectively. Total quality-adjusted life-years (QALYs) were 0.2247 and 0.4077, for BSC and oral topotecan respectively, resulting in an incremental cost-effectiveness ratio (ICER) of 33,851 pounds per QALY gained. Total QALYs for i.v. topotecan were between 0.3875 and 0.4157 (depending on assumptions regarding time progression) resulting in an ICER between 74,074 pounds and 65,507 pounds per QALY gained. CONCLUSIONS Topotecan appeared to be better than BSC alone in terms of improved survival, and was as effective as CAV and less favourable than i.v. amrubicin in terms of response. Oral topotecan and i.v. topotecan were similar in efficacy. Topotecan offers additional benefit over BSC, but at increased cost. ICERs for i.v. topotecan, compared with BSC, were high and suggest that it is unlikely to be a cost-effective option. The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective. Further research into the QoL of patients with relapsed SCLC could identify the impacts of disease progression and treatment response.

The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation

BACKGROUND Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and a limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated. OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of four biologic DMARDs [etanercept (Enbrel(®), Pfizer), abatacept (Orencia(®), Bristol-Myers Squibb), adalimumab (Humira(®), AbbVie) and tocilizumab (RoActemra(®), Roche) - with or without methotrexate where indicated] for the treatment of JIA (systemic or oligoarticular JIA are excluded). DATA SOURCES Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and the Database of Abstracts of Reviews of Effects were searched for published studies from inception to May 2015 for English-language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence. REVIEW METHODS Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision-analytic model was developed to compare the estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base-case time horizon was 30 years and the model took a NHS perspective, with costs and benefits discounted at 3.5%. RESULTS Four placebo-controlled randomised controlled trials (RCTs) met the inclusion criteria for the clinical effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi)-30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar, with fewer disease flares and greater proportions of ACR Pedi-50 and -70 responses among participants randomised to continued biologic DMARDs. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that, generally, ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between the treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality-of-life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratios (ICERs) for adalimumab, etanercept and tocilizumab versus methotrexate were £38,127, £32,526 and £38,656 per quality-adjusted life year (QALY), respectively. The ICER for abatacept versus methotrexate as a second-line biologic was £39,536 per QALY. LIMITATIONS The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs, and clinical evidence for specific JIA subtypes is limited. CONCLUSIONS Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA who have had an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow-up are needed to establish comparative effectiveness. RCTs for JIA subtypes for which evidence is lacking are also required. STUDY REGISTRATION This study is registered as PROSPERO CRD42015016459. FUNDING The National Institute for Health Research Health Technology Assessment programme.