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 metaanalysis 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. Keywords: Systematic review, Meta-analysis, Anti-retroviral agents, Hepatitis C, HI

EarlyCDT Lung blood test for risk classification of solid pulmonary nodules : systematic review and economic evaluation

BACKGROUND: EarlyCDT Lung (Oncimmune Holdings plc, Nottingham, UK) is a blood test to assess malignancy risk in people with solid pulmonary nodules. It measures the presence of seven lung cancer-associated autoantibodies. Elevated levels of these autoantibodies may indicate malignant disease. The results of the test might be used to modify the risk of malignancy estimated by existing risk calculators, including the Brock and Herder models. OBJECTIVES: The objectives were to determine the diagnostic accuracy, clinical effectiveness and cost-effectiveness of EarlyCDT Lung; and to develop a conceptual model and identify evidence requirements for a robust cost-effectiveness analysis. DATA SOURCES: MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE), EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, EconLit, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database ( NHS EED ) and the international Health Technology Assessment database were searched on 8 March 2021. REVIEW METHODS: A systematic review was performed of evidence on EarlyCDT Lung, including diagnostic accuracy, clinical effectiveness and cost-effectiveness. Study quality was assessed with the quality assessment of diagnostic accuracy studies-2 tool. Evidence on other components of the pulmonary nodule diagnostic pathway (computerised tomography surveillance, Brock risk, Herder risk, positron emission tomography-computerised tomography and biopsy) was also reviewed. When feasible, bivariate meta-analyses of diagnostic accuracy were performed. Clinical outcomes were synthesised narratively. A simulation study investigated the clinical impact of using EarlyCDT Lung. Additional reviews of cost-effectiveness studies evaluated (1) other diagnostic strategies for lung cancer and (2) screening approaches for lung cancer. A conceptual model was developed. RESULTS: A total of 47 clinical publications on EarlyCDT Lung were identified, but only five cohorts (695 patients) reported diagnostic accuracy data on patients with pulmonary nodules. All cohorts were small or at high risk of bias. EarlyCDT Lung on its own was found to have poor diagnostic accuracy, with a summary sensitivity of 20.2% (95% confidence interval 10.5% to 35.5%) and specificity of 92.2% (95% confidence interval 86.2% to 95.8%). This sensitivity was substantially lower than that estimated by the manufacturer (41.3%). No evidence on the clinical impact of EarlyCDT Lung was identified. The simulation study suggested that EarlyCDT Lung might potentially have some benefit when considering intermediate risk nodules (10-70% risk) after Herder risk analysis. Two cost-effectiveness studies on EarlyCDT Lung for pulmonary nodules were identified; none was considered suitable to inform the current decision problem. The conceptualisation process identified three core components for a future cost-effectiveness assessment of EarlyCDT Lung: (1) the features of the subpopulations and relevant heterogeneity, (2) the way EarlyCDT Lung test results affect subsequent clinical management decisions and (3) how changes in these decisions can affect outcomes. All reviewed studies linked earlier diagnosis to stage progression and stage shift to final outcomes, but evidence on these components was sparse. LIMITATIONS: The evidence on EarlyCDT Lung among patients with pulmonary nodules was very limited, preventing meta-analyses and economic analyses. CONCLUSIONS: The evidence on EarlyCDT Lung among patients with pulmonary nodules is insufficient to draw any firm conclusions as to its diagnostic accuracy or clinical or economic value. FUTURE WORK: Prospective cohort studies, in which EarlyCDT Lung is used among patients with identified pulmonary nodules, are required to support a future assessment of the clinical and economic value of this test. Studies should investigate the diagnostic accuracy and clinical impact of EarlyCDT Lung in combination with Brock and Herder risk assessments. A well-designed cost-effectiveness study is also required, integrating emerging relevant evidence with the recommendations in this report. STUDY REGISTRATION: This study is registered as PROSPERO CRD42021242248. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 49. See the NIHR Journals Library website for further project information

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

The effectiveness of ablative and non-surgical therapies for early hepatocellular carcinoma: systematic review and network meta-analysis of randomised controlled trials

Background & Aims Non-surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta-analysis (NMA) was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. Methods Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non-surgical therapy versus any comparator in patients with HCC ≤ 3cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence. Results Thirty-seven eligible RCTs were included (including over 3700 patients). Most were from China (n=17) or Japan (n=7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16-1.82), progression-free survival (HR: 1.36, 95% CrI: 1.11-1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02-1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19-2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons. Conclusions It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake. Funding: National Institute for Health and Care Research (UK). Registration: PROSPERO CRD42020221357

A systematic review of the cost-effectiveness of anti-VEGF drugs for the treatment of diabetic retinopathy

Background Non-proliferative and proliferative diabetic retinopathy (DR) are common complications of diabetes and a major cause of sight loss. Anti-vascular endothelial growth factor (anti-VEGF) drugs represent a treatment option for people with DR and are routinely used to treat various other eye conditions. Anti-VEGF drugs are, however, expensive relative to current care options and it is unclear whether this additional cost would be justified in DR, where immediate risks of sight loss are low compared to those for patients with more aggressive ophthalmological conditions. Objective To systematically review the existing evidence supporting the cost-effectiveness of alternative treatments for DR considering a UK decision-making perspective. Methods A systematic review of all comparative cost-effectiveness studies was conducted evaluating any treatment for DR. Included studies were synthesised narratively and evaluated with reference to UK decision-making. Studies were grouped by population, non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). Results The review identified five studies in the PDR population, all of which examined the cost-effectiveness of anti-VEGF treatments compared to pan-retinal photocoagulation (PRP). Results of these studies suggest that anti-VEGF treatments offer some additional benefits in terms of preserved visual acuity, but also incur substantial additional costs relative to PRP. Most authors expressed reservations about the additional costs outweighing the limited benefits, especially in certain patient subgroups without pre-existing oedema. The majority of the identified evidence considered a US perspective, it is unclear how these results would translate to a UK setting. Two studies were identified in the NDPR population. There was limited evidence to support the early use of anti-VEGF treatment. One UK study, however, suggested that early treatment of NPDR with PRP is cost-effective compared to delayed PRP. Conclusions Overall, there is a dearth of cost-effectiveness evidence considering the UK context. The identified studies raised doubts about the cost-effectiveness of anti-VEGF treatments for PDR. No conclusions can be made regarding the cost-effectiveness of anti-VEGF for NPDR. Future research should focus on developing rigorous model-based cost-effectiveness analyses integrating all available evidence

Anti-VEGF drugs compared with laser photocoagulation for the treatment of diabetic retinopathy : a systematic review and meta -analysis

Background Diabetic retinopathy is a major cause of sight loss in people with diabetes. The most severe form, proliferative diabetic retinopathy (PDR), carries a high risk of vision loss risk, vitreous haemorrhage, macular oedema and other harms. Panretinal photocoagulation (PRP) is the primary treatment for PDR. Anti-vascular endothelial growth factor (anti-VEGF) drugs are used to treat various eye conditions and may be beneficial for people with diabetic retinopathy. Objective To investigate the efficacy of anti-VEGF therapy for the treatment of diabetic retinopathy when compared to PRP. Methods A systematic review and network meta-analysis of all published randomised controlled trials comparing anti-VEGF (alone or in combination) to PRP in people with diabetic retinopathy. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Results A total of 14 trials were included: 3 of aflibercept, 5 of bevacizumab and 6 of ranibizumab. Two trials were of patients with non-proliferative diabetic retinopathy ); all others were in PDR. Overall anti-VEGF was better than PRP at preventing vison loss, measured as best corrected visual acuity (BCVA), at up to two years follow-up (BCVA mean difference in logMAR -0.064, 95% confidence interval (CI) -0.122 to -0.015). There was no clear evidence of any difference between the anti-VEGFs, but potential for bias and differences in trial complicated the comparison. Anti-VEGF was superior to PRP at preventing macular edema (Relative risk 0.29, 95% CI 0.18 to 0.49) and vitreous haemorrhage (Relative risk 0.77, 95% CI 0.61 to 0.99). There was no evidence that the effectiveness of anti-VEGF varied over time, but one trial found no benefit of anti-VEGF over laser therapy after 5 years. Conclusions Anti-VEGF injection appears to be superior to using laser photocoagulation, but the benefit in preservation of eyesight appears to be modest. Long-duration observational studies are needed to examine how anti-VEGF may be beneficial in the long term

Anti-VEGF drugs compared with laser photocoagulation for the treatment of proliferative diabetic retinopathy : a systematic review and IPD meta-analysis

Background Proliferative diabetic retinopathy (PDR) is a major cause of sight loss in people with diabetes, with a high risk of vitreous haemorrhage, tractional retinal detachment and other complications. Panretinal photocoagulation (PRP) is the primary established treatment for PDR. Anti-vascular endothelial growth factor (anti-VEGF) drugs are used to treat various eye conditions and may be beneficial for people with PDR. Objective To investigate the efficacy and safety of anti-VEGF therapy for the treatment of proliferative diabetic retinopathy when compared to PRP. Methods A systematic review and network meta-analysis of randomised controlled trials comparing anti-VEGF (alone or in combination) to PRP in people with PDR. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Key outcomes were best corrected visual acuity (BCVA), diabetic macular oedema (DMO) and vitreous haemorrhage. Individual participant data (IPD) was obtained and analysed for three large, high-quality trials in combination with published data from other trials. Network meta-analyses of BCVA and meta-analyses of other outcomes combined IPD with published data from other trials; regression analyses against patient covariates used just the IPD. Results Twelve trials were included: 1 of aflibercept, 5 of bevacizumab and 6 of ranibizumab. When considered together, anti-VEGFs produced a modest, but not clinically meaningful, benefit over PRP in BCVA, after 1 year of follow-up (mean difference in logMAR -0.116, 95% credible interval (CrI) -0.183 to -0.038). There was no clear evidence of a difference in effectiveness between the anti-VEGFs. The benefit of anti-VEGF appears to decline over time. Analysis of the IPD trials suggested that anti-VEGF therapy may be more effective in people with poorer visual acuity, in those who have vitreous haemorrhage, and possibly in people with poorer vision generally. Anti-VEGF was superior to PRP at preventing macular oedema after 1 year (Relative risk (RR) 0.48, 95% CI 0.28 to 0.83) and possibly at preventing vitreous haemorrhage (RR 0.72, 95% CI 0.47 to 1.10). Anti-VEGF reduced the incidence of retinal detachment when compared to PRP (RR 0.41, 95% CI 0.22 to 0.77). Data on other adverse events was generally too limited to identify any differences between anti-VEGF and PRP. Conclusions Anti-VEGF has no clinically meaningful benefit over PRP for preserving visual acuity. However, anti-VEGF therapy appears to delay or prevent progression to macular oedema and vitreous haemorrhage. The possibility that anti-VEGF therapy may be more effective in patients with poorer health and poorer vision merits further clinical investigation. The long-term effectiveness and safety of anti-VEGF treatment is unclear, particularly as additional PRP and anti-VEGF treatment will be required over time. Registration This review is registered on PROSPERO (CRD42021272642) Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR132948)

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) : meta-analysis of individual participant data from randomised controlled trials

BACKGROUND: Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes. METHODS: We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299. FINDINGS: Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68-0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68-1·01), and oral progesterone (two trials, 181 women; 0·60, 0·40-0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84-1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92-1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1·59, 95% CI 1·15-2·22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC. INTERPRETATION: Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence. FUNDING: Patient-Centered Outcomes Research Institute

Projected Changes in the Arctic Frontal Zone and Summer Arctic Cyclone Activity in the CESM Large Ensemble

The Arctic frontal zone (AFZ) is a narrow band of strong horizontal temperature gradients that develops along the Arctic Ocean coastline each summer in response to differential heating of the atmosphere over adjacent land and ocean surfaces. Past research has linked baroclinicity within the AFZ to summer Arctic cyclone development, especially by intensifying storms that migrate northward from the Eurasian continent. This study uses the Community Earth System Model Large Ensemble in conjunction with an advanced cyclone detection and tracking algorithm to assess how the AFZ, summer Arctic cyclone activity, and the relationship between them respond to warming under the representative concentration pathway 8.5 (RCP8.5) scenario. Under this strong warming scenario, the AFZ remains a significant cyclone intensifier. Changes to the AFZ are largely restricted to June, when earlier snowmelt leads to strengthening of land–ocean temperature contrasts. This strengthening is accompanied by enhanced cyclogenesis along the east Siberian coast, but no change is observed for overall cyclone frequency over the Arctic Ocean. However, simultaneous changes to subpolar storm tracks impact Arctic cyclone activity in all summer months, sometimes in opposition to the impact of the AFZ. In June, the storms migrating poleward to the Arctic Ocean become weaker under RCP8.5, leading to lower Arctic cyclone intensity. In July and August, the poleward shift of the North Pacific storm track enhances cyclone activity in the Beaufort and Chukchi Seas