Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis.

INTRODUCTION: The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) is12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC. METHODS: Literature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan-Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy. RESULTS: Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval [CrI] 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for erlotinib. There was no evidence for differences between EGFR-TKI monotherapies, as all 95% CrIs included the null value. CONCLUSION: Although data for erlotinib plus bevacizumab came from a single Phase 2 study, the results of the NMA suggest that adding bevacizumab to erlotinib may be a promising approach to improving the outcomes achieved with EGFR-TKI monotherapy in patients with advanced EGFR+ NSCLC.

An evaluation of variation in published estimates of schizophrenia prevalence from 1990─2013: a systematic literature review.

BACKGROUND: There is a lack of consistency in findings across studies on the prevalence of schizophrenia, and no recent systematic review of the literature exists. The purpose of this study is to provide an updated systematic review of population-based prevalence estimates and to understand the factors that could account for this variation in prevalence estimates. METHODS: MEDLINE, Embase, and PsycInfo databases were searched for observational studies describing schizophrenia prevalence in general populations from 2003-2013 and supplemented by studies from a prior review covering 1990-2002. Studies reporting prevalence estimates from specialized populations such as institutionalized, homeless, or incarcerated persons were excluded. Prevalence estimates were compared both across and within studies by factors that might contribute to variability using descriptive statistics. RESULTS: Sixty-five primary studies were included; thirty-one (48 %) were from Europe and 35 (54 %) were conducted in samples of ≥50,000 persons. Among 21 studies reporting 12-month prevalence, the median estimate was 0.33 % with an interquartile range (IQR) of 0.26 %-0.51 %. The median estimate of lifetime prevalence among 29 studies was 0.48 % (IQR: 0.34 %-0.85 %). Prevalence across studies appeared to vary by study design, geographic region, time of assessment, and study quality scores; associations between study sample size and prevalence were not observed. Within studies, age-adjusted estimates were higher than crude estimates by 17 %-138 %, the use of a broader definition of schizophrenia spectrum disorders compared to schizophrenia increased case identification by 18 %-90 %, identification of cases from inpatient-only settings versus any setting decreased prevalence by 60 %, and no consistent trends were noted by differing diagnostic criteria. CONCLUSIONS: This review provides updated information on the epidemiology of schizophrenia in general populations, which is vital information for many stakeholders. Study characteristics appear to play an important role in the variation between estimates. Overall, the evidence is still sparse; for many countries no new studies were identified.

HIV treatment and reproductive health in the health system in Burkina Faso: resource allocation and the need for integration.

Organizational changes, increased funding and the demands of HIV antiretroviral (ARV) treatment create particular challenges for governance in the health sector. We assess resource allocation, policy making and integration of the national responses to ARV provision and reproductive health in Burkina Faso, using national and district budgets related to disease burden, policy documents, organizational structures, and coordination and implementation processes. ARV provision represents the concept of a "crisis scenario", in which reforms are pushed due to a perception of urgent need, whereas the national reproductive health programme, which is older and more integrated, represents a "politics-as-usual scenario". Findings show that the early years of the national response to HIV and AIDS were characterized by new institutions with overlapping functions, and failure to integrate with and strengthen existing structures. National and district budget allocations for HIV compared to other interventions were disproportionately high when assessed against burden of disease. Strategic documents for ARV provision were relatively less developed and referred to, compared to those of the Ministry of Health Directorates for HIV and for Family Health and district health planning teams for reproductive health services. Imbalances and new structures potentially trigger important adverse effects which are difficult to remedy and likely to increase due to the dynamics they create. It therefore becomes crucial, from the outset, to integrate HIV/AIDS funding and responses into health systems.

Scaling up antiretroviral therapy in Uganda: using supply chain management to appraise health systems strengthening.

BACKGROUND: Strengthened national health systems are necessary for effective and sustained expansion of antiretroviral therapy (ART). ART and its supply chain management in Uganda are largely based on parallel and externally supported efforts. The question arises whether systems are being strengthened to sustain access to ART. This study applies systems thinking to assess supply chain management, the role of external support and whether investments create the needed synergies to strengthen health systems. METHODS: This study uses the WHO health systems framework and examines the issues of governance, financing, information, human resources and service delivery in relation to supply chain management of medicines and the technologies. It looks at links and causal chains between supply chain management for ART and the national supply system for essential drugs. It combines data from the literature and key informant interviews with observations at health service delivery level in a study district. RESULTS: Current drug supply chain management in Uganda is characterized by parallel processes and information systems that result in poor quality and inefficiencies. Less than expected health system performance, stock outs and other shortages affect ART and primary care in general. Poor performance of supply chain management is amplified by weak conditions at all levels of the health system, including the areas of financing, governance, human resources and information. Governance issues include the lack to follow up initial policy intentions and a focus on narrow, short-term approaches. CONCLUSION: The opportunity and need to use ART investments for an essential supply chain management and strengthened health system has not been exploited. By applying a systems perspective this work indicates the seriousness of missing system prerequisites. The findings suggest that root causes and capacities across the system have to be addressed synergistically to enable systems that can match and accommodate investments in disease-specific interventions. The multiplicity and complexity of existing challenges require a long-term and systems perspective essentially in contrast to the current short term and program-specific nature of external assistance.

A cross-country review of strategies of the German development cooperation to strengthen human resources.

BACKGROUND: Recent years have seen growing awareness of the importance of human resources for health in health systems and with it an intensifying of the international and national policies in place to steer a response. This paper looks at how governments and donors in five countries--Cameroon, Indonesia, Malawi, Rwanda and Tanzania--have translated such policies into action. More detailed information with regard to initiatives of German development cooperation brings additional depth to the range and entry doors of human resources for health initiatives from the perspective of donor cooperation. METHODS: This qualitative study systematically presents different approaches and stages to human resources for health development in a cross-country comparison. An important reference to capture implementation at country level was grey literature such as policy documents and programme reports. In-depth interviews along a predefined grid with national and international stakeholders in the five countries provided information on issues related to human resources for health policy processes and implementation. RESULTS: All five countries have institutional entities in place and have drawn up national policies to address human resources for health. Only some of the countries have translated policies into strategies with defined targets and national programmes with budgets and operational plans. Traditional approaches of supporting training for individual health professionals continue to dominate. In some cases partners have played an advocacy and technical role to promote human resources for health development at the highest political levels, but usually they still focus on the provision of ad hoc training within their programmes, which may not be in line with national human resources for health development efforts or may even be counterproductive to them. Countries that face an emergency, such as Malawi, have intensified their efforts within a relatively short time and by using donor funding support also through new initiatives such as the Global Fund to Fight AIDS, Tuberculosis and Malaria. CONCLUSION: The country case studies illustrate the range of initiatives that have surged in recent years and some main trends in terms of donor initiatives. Though attention and priority attributed to human resources for health is increasing, there is still a focus on single initiatives and programmes. This can be explained in part by the complexity of the issue, and in part by its need to be addressed through a long-term approach including public sector and salary reforms that go beyond the health sector.