Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation

Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme

Policy climates and climate policies: Analysing the politics of building urban climate change resilience

This paper examines the process of building resilience to climate change in urban areas by scrutinising the manner in which initiatives to build resilience interact with the urban policy environments in which they unfold. The urban policy environment is broken into three analytical areas of actors, spaces and discourses. This illustrates the influence of actor networks, epistemic communities and policy entrepreneurs in helping climate change resilience gain traction in urban settings, how discourses attached to Resilience urban resilience are dissonant with those prevailing in ossified Discourses urban policy environments, and the dynamic interaction of interest, agendas and power in decision making that accompanies resilience building processes. The paper applies this framework to case studies of two Indian cities within a major international urban climate change resilience initiative. Using data gathered through a variety of rigorous qualitative research methods, the paper provides insights into the politics of policy processes around urban climate change initiatives. Findings from this study can inform urban development policies and allow resilience project planners to calibrate their efforts to better suit urban policy environments. The paper highlights how issues of politics and power are more significant determinants of such policy processes than conventional, science-led analyses would suggest

Care and communication between health professionals and patients affected by severe or chronic illness in community care settings: a qualitative study of care at the end of life

Background: Advance care planning (ACP) enables patients to consider, discuss and, if they wish, document their wishes and preferences for future care, including decisions to refuse treatment, in the event that they lose capacity to make decisions for themselves. ACP is a key component of UK health policy to improve the experience of death and dying for patients and their families. There is limited evidence about how patients and health professionals understand ACP, or when and how this is initiated. It is evident that many people find discussion of and planning for end of life care difficult, and tend to avoid the topic. Aim: To investigate how patients, their relatives and health professionals initiate and experience discussion of ACP and the outcomes of advance discussions in shaping care at the end of life. Design and data collection: Qualitative study with two workstreams: (1) interviews with 37 health professionals (general practitioners, specialist nurses and community nurses) about their experiences of ACP; and (2) longitudinal case studies of 21 patients with 6-month follow-up. Cases included a patient and, where possible, a nominated key relative and/or health professional as well as a review of medical records. Complete case triads were obtained for 11 patients. Four cases comprised the patient alone, where respondents were unable or unwilling to nominate either a family member or a professional carer they wished to include in the study. Patients were identified as likely to be within the last 6 months of life. Ninety-seven interviews were completed in total. Setting: General practices and community care settings in the East Midlands of England. Findings: The study found ACP to be uncommon and focused primarily on specific documented tasks involving decisions about preferred place of death and cardiopulmonary resuscitation, supporting earlier research. There was no evidence of ACP in nearly half (9 of 21) of patient cases. Professionals reported ACP discussions to be challenging. It was difficult to recognise when patients had entered the last year of life, or to identify their readiness to consider future planning. Patients often did not wish to do so before they had become gravely ill. Consequently, ACP discussions tended to be reactive, rather than pre-emptive, occurring in response to critical events or evidence of marked deterioration. ACP discussions intersected two parallel strands of planning: professional organisation and co-ordination of care; and the practical and emotional preparatory work that patients and families undertook to prepare themselves for death. Reference to ACP as a means of guiding decisions for patients who had lost capacity was rare. Conclusions: Advance care planning remains uncommon, is often limited to documentation of a few key decisions, is reported to be challenging by many health professionals, is not welcomed by a substantial number of patients and tends to be postponed until death is clearly imminent. Current implementation largely ignores the purpose of ACP as a means of extending personal autonomy in the event of lost capacity. Future work: Attention should be paid to public attitudes to death and dying (including those of culturally diverse and ethnic minority groups), place of death, resuscitation and the value of anticipatory planning. In addition the experiences and needs of two under-researched groups should be explored: the frail elderly, including those who manage complex comorbid conditions, unrecognised as vulnerable cases; and those patients affected by stigmatised conditions, such as substance abuse or serious mental illness who fail to engage constructively with services and are not recognised as suitable referrals for palliative and end of life care. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial

PubMed ID: 15639293Background Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. Methods 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 µg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 µg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32-52 the pegylated interferon dose was 50 µg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment. Findings 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0·91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0·01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0·01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%). Interpretation Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.Schering-Plough Foundation for Liver Research Schering-Plough Commonwealth Scientific and Industrial Research Organisation Erasmus Medisch Centrum, Erasmus MC GlaxoSmithKline, GSK Research and DevelopmentThe study was organised and sponsored by the Foundation for Liver Research, Rotterdam, the Netherlands. Financial support, study medication, and drugs were provided by Schering-Plough International and GlaxoSmithKline Research and Development. Companies providing financial support to the Foundation for Liver Research approved the study design. No funding source had any role in the collection, management, analysis, or interpretation of the data; writing of the report; or the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. -- The current standard initial therapy for patients with chronic HBV infection is interferon alfa, lamivudine, or adefovir dipivoxil. 23,24 The introduction of pegylated interferons, with their better pharmacokinetic profiles, has led to higher response rates in chronic hepatitis C, 25,26 and a preliminary study suggested improvements in the response rates in HBeAg-positive patients with chronic hepatitis B. 17 In this large, randomised study, the rate of sustained response (HBeAg loss) in HBeAg-positive patients with chronic hepatitis B assigned pegylated interferon alfa-2b monotherapy was 36% (49 of 136 patients ) . Treatment with pegylated interferon alfa-2b and lamivudine combination therapy was superior to monotherapy at the end of treatment, but not at the end of follow-up. Two previous randomised controlled trials comparing combination therapy and standard interferon monotherapy in chronically HBV-infected patients positive for HBeAg had a shorter duration of lamivudine therapy in the group assigned combination therapy than in the group assigned monotherapy. 5,19 This feature and the timing of the primary efficacy endpoint (after treatment for combination therapy or interferon alone versus on-treatment for lamivudine alone) precluded a definitive conclusion on the efficacy of combination therapy. The investigators concluded that the potential benefit of combining lamivudine with interferon therapy should be investigated further with different regimens of combination therapy. Our study advanced these investigations and helped progress towards a definitive conclusion on the efficacy of combination therapy versus monotherapy in two ways. First, it compared equivalent durations of treatment in the two groups. Second, the long follow-up period extended further beyond the end of treatment with lamivudine than in previous studies, which enabled the extent of relapse to be monitored after 26 weeks of follow-up. Our study highlights differences in response to interferon and to nucleoside analogues. Although patients initially responded to lamivudine, the responses (HBeAg loss and HBV DNA reduction) were not sustained. This finding accords with those of previous studies, with HBeAg relapse rates of 49% to 54%. 12,27 Lack of durability could be due to the mechanism of action of lamivudine, which suppresses viral replication without inducing the HBV-specific immune response necessary for sustained viral eradication. Long-term therapy with lamivudine is not an option because it leads to drug resistance in most cases. 23,28 The lack of this option is particularly difficult for patients with chronic hepatitis B, because many patients develop the disorder when quite young and have to be treated for several decades with resistance-prone medication for which long-term toxicity is unknown. A study with the nucleotide analogue adefovir dipivoxil suggested that response was achieved with development of phenotypic resistance in less than 1·6% of the patients. 10 Future studies are needed to find out whether this response is sustained beyond the end of therapy and whether, with continued therapy, clinically relevant drug resistance remains absent. Our study reveals prospectively the importance of HBV genotype as an independent predictor of response to pegylated interferon treatment for chronic hepatitis B. It accords with earlier retrospective studies, which indicated that HBV genotypes C and D are more difficult to treat than genotypes A and B. 29,30 Future intervention studies for chronic hepatitis B might need stratification according to genotype. The side-effects and frequency of adverse events observed with pegylated interferon alfa-2b monotherapy were similar to those encountered with standard interferon therapy. The rates of dose reductions and discontinuations were similar to those reported with pegylated interferons in patients with chronic hepatitis C, 16,25,26 and with pegylated interferon alfa-2a in chronic hepatitis B. 17 Pegylated interferon alfa-2b is effective and well tolerated for chronic hepatitis B. Rates of sustained clearance of serum HBeAg and reduction of viral load are as high as or higher than those that have previously been reported for any other therapy in this indication. Combination therapy with pegylated interferon alfa-2b and lamivudine is not superior to monotherapy with pegylated interferon alfa-2b. Contributors H L A Janssen and S W Schalm designed the study, prepared the protocol, coordinated the study, collected and analysed the data, and wrote the report. M van Zonneveld participated in data collection and study coordination. H G M Niesters was responsible for virological testing. P Zondervan did histological scoring. B Hansen contributed to and supervised the statistical analysis. H Senturk, S Zeuzem, U S Akarca, Y Cakaloglu, C Simon, T M K So, G Gerken, and R A de Man were involved with data acquisition and critically revised the report. Other members of the HBV 99-01 Study Group Netherlands —B C M Vroom (University Medical Center, Utrecht); C M J van Nieuwkerk (VU University Medical Center, Amsterdam); R A de Vries (Rijnstate Hospital, Arnhem); J Jansen, J Drenth, S J van den Hazel (University Medical Centre Radboud, Nijmegen); J W den Ouden-Muller (St Franciscus Hospital, Rotterdam); A C Tan (Canisius Wilhelmina Hospital, Nijmegen). Belgium —D M Adler (Hopital Erasme, Brussels); P Michielsen (University Hospital, Antwerp); H van Vlierberghe (University Hospital, Gent); F Nevens (University Hospital, Leuven); J Delwaide (Centre Hospitalier Universitaire, Liège); J Henrion (Hopital de Jolimont, Haine St Paul). Germany —S Bein, U Treichel (University Hospital, Essen); J Trojan (J W Goethe Universität, Frankfurt); M P Manns, J Hadem (Medizinische Hochschule, Hannover); C Niederau (St Jozef Hospital, Oberhausen). Denmark —M R Buhl, I M Hansen (Skejby Hospital, Arhus); K Krogsgaard (Copenhagen University Hospital, Hvidovre). Poland —J Cianciara, J Jablonska, J Kozlowska (Medical Academy of Warsaw, Warsaw); D Prokopowicz, R Flisiak (Medical Academy of Bialystok, Bialystok); T Mach (Collegium Medicum UJ, Kraków). Spain —M Buti, A Valdes, R Esteban (Hospital Valle Hebron, Barcelona); M Rodriguez, M Garcia Espiga (Hospital Central de Asturias, Oviedo). Italy —A Andriulli, G Stornaiulo, G B Gaeta (Ospedale Gesùe Maria, Napoli); G Montalto, F D'Antona (Università di Palermo, Palermo). Greece —G E Kitis, P Xiarchos Panagiotis (George Papanikolaou General Regional Hospital, Thessaloniki); N C Tassopoulos (West Attica Hospital, Athens). Turkey —G Ersöz (Ege University Faculty of Medicine, Izmir); S Karayalcin, C Yurdayin, H Bozkaya (Medical School Cebeci Kampusu, Ankara); H Simsek, Y Balaban (Hacettepe University Faculty of Medicine, Ankara), F Tabak (Istanbul University Cerrahpasa Medical School, Istanbul). Israel —Y Lurie (Sauraski Medical Center, Tel-Aviv). Canada —J Heathcote (Toronto Western Hospital, Toronto); S V Feinman (Mount Sinai Hospital, Toronto); S Greenbloom (General Hospital, Etobicoke). Indonesia —D A Sulaiman (Ciptomangunkusomo Hospital, Jakarta). Singapore —R Guan (Mount Elizabeth Medical Center Singapore). Malaysia —I Merican (Institute for Medical Research, Kuala Lumpur). Conflict of interest statement HLAJ is a Clinical Research Fellow from the Netherlands Organisation of Scientific Research. HLAJ, SZ, and SWS have served as consultants or received grants from Schering-Plough, GlaxoSmithKline, and other major pharmaceutical companies. The other authors declare that they have no conflict of interest. Acknowledgments The sponsor of this study was the Rotterdam Foundation for Liver Research. Financial support was given by: Schering-Plough International, Kenilworth, NJ, USA, and GlaxoSmithKline, Research and Development, Greenford, UK. Monitoring was coordinated by Mieke Denys, Denys Research Consultants bvba, De Haan, Belgium. Advice on statistical analysis was given by Wim Hop. Data collection and data management at the trial coordinating centre was supported by Elke Verheij, Hajo Flink, Annick van Nunen, Eva Leeuwenburg, and Maarten Meiburg, Clinical Research Bureau, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Netherlands. -- -- -- -- -