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

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 (ICERs) 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% CrI 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 understand the consequences of histology-independent vs histology-specific decisions

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)