Is it time for China to prioritize pan-genotypic regimens for treating patients with hepatitis C?

INTRODUCTION: The treatment of hepatitis C has entered the pan-genotypic era, but the effectiveness is not good for the genotype 3b patients who have a large proportion in China. The guidelines for hepatitis C recommend the use of gene-specific regimens when the regional 3b prevalence rate greater than 5%. This study is to explore rationality of this proportion and the cost-effectiveness to implement pan-genotypic regimens in China. METHODS: A decision Markov model was developed from the health system perspective to evaluate the effectiveness and cost-effectiveness between pan-genotypic and gene-specific treatment regimens for hepatitis C patients. Additionally, we set a regional genotype 3b patient proportion of 0-100% to explore at which proportion it is necessary to perform genotype identification and typing therapy on patients. Model parameters were derived from published literature and public databases. Effectiveness was measured by cured patient numbers, newly diagnosed cases of decompensated cirrhosis, hepatocellular carcinoma, need for liver transplantation, and quality-adjusted life years (QALYs). Cost-effectiveness outcomes included costs and the incremental cost-effectiveness ratio (ICER). The 1-3 times 2022 Chinese per capita gross domestic product was used as the willingness-to-pay threshold. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty of the model parameters. RESULTS: Compared with gene-specific regimens, pan-genotypic regimens resulted in an additional 0.13 QALYs and an incremental cost of $165, the ICER was $1,268/QALY. From the view of efficacy, the pan-genotypic regimens cured 5,868 more people per 100,000 patients than gene-specific regimens, avoiding 86.5% of DC cases, 64.6% of HCC cases, and 78.2% of liver transplant needs. Identifying 3b patients before treatment was definitely cost-effectiveness when their prevalence was 12% or higher. The results remained robust in sensitivity analyses. CONCLUSIONS: In China, the prioritized recommendation of pan-genotypic therapeutics proves to be both cost-effective and efficacious. But, in regions where the prevalence of genotype 3b exceeds 12%, it is necessary to identify them to provision of more suitable therapies.

Cost-effectiveness and potential budget impact of non-pharmacological interventions for early management in prehypertensive people: an economic evaluation for China.

BACKGROUND: Non-pharmacological interventions (NPIs) could be considered in the early management of prehypertensive population. This study aimed to evaluate the potential cost-effectiveness of NPIs and the budget impact of implementing NPIs on prehypertensive population in China and provide evidence of chronic disease management innovation for decision-makers. METHODS: Five NPIs including usual care, lifestyle, strengthen exercise, relaxation, and diet therapy were selected based on the practice of hypertension management in China. A nine-state Markov model was constructed to evaluate the lifetime costs and health outcomes of five NPIs and a non-intervention group from the perspective of Chinese healthcare system. The effectiveness of NPIs was obtained from a published study. Parameters including transition probabilities, costs and utilities were extracted or calculated from published literature and open-access databases. Sensitivity analyses were conducted to test the uncertainty of all parameters. The impact of duration of intervention was considered in scenario analyses. A budget impact analysis (BIA) was conducted to evaluate the total cost and the medical cost saving of a hypothetical nationwide implementation of potential cost-effective NPI in prehypertensive people. Management strategies including focusing on patients with specific ages or different CVE risk levels, and different duration of implementation were taken into consideration. RESULTS: Strengthen exercise was the most cost-effective intervention with a probability of 78.1% under the given WTP threshold. Our results were sensitive to the cost of interventions, and the utility of prehypertension and hypertension. The duration of implementation had limited impact on the results. BIA results showed that the program cost was hefty and far more than the medical cost saving with the course of simulation time. Applying management strategies which focused on individual characteristics could largely reduce the program cost despite it remained higher than medical cost saving. CONCLUSIONS: Strengthen exercise was a potential NPI that can be considered in priority for early management in prehypertensive population. Although early management can acquire medical cost saving, the related program cost can be quite hefty. Precise strategies which may help reduce the cost of early management should be taken into consideration in program design.

Impact of Extrapolation Model Choices on the Structural Uncertainty in Economic Evaluations for Cancer Immunotherapy: A Case Study of Checkmate 067.

OBJECTIVES: The aim of this study was to compare the performance of different extrapolation modeling techniques and analyze their impact on structural uncertainties in the economic evaluations of cancer immunotherapy. METHODS: The individual patient data was reconstructed through published Checkmate 067 Kaplan Meier curves. Standard parametric models and six flexible techniques were tested, including fractional polynomial, restricted cubic splines, Royston-Parmar models, generalized additive models, parametric mixture models, and mixture cure models. Mean square errors (MSE) and bias from raw survival plots were used to test the model fitness and extrapolation performance. Variability of estimated incremental cost-effectiveness ratios (ICERs) from different models was used to inform the structural uncertainty in economic evaluations. All indicators were analyzed and compared under cut-offs of 3 years and 6.5 years, respectively, to further discuss model impact under different data maturity. R Codes for reproducing this study can be found on GitHub. RESULTS: The flexible techniques in general performed better than standard parametric models with smaller MSE irrespective of the data maturity. Survival outcomes projected by long-term extrapolation using immature data differed from those with mature data. Although a best-performing model was not found because several models had very similar MSE in this case, the variability of modeled ICERs significantly increased when prolonging simulation cycles. CONCLUSIONS: Flexible techniques show better performance in the case of Checkmate 067, regardless of data maturity. Model choices affect ICERs of cancer immunotherapy, especially when dealing with immature survival data. When researchers lack evidence to identify the 'right' model, we recommend identifying and revealing the model impacts on structural uncertainty.

Serplulimab Plus Chemotherapy vs Chemotherapy for Treatment of US and Chinese Patients with Extensive-Stage Small-Cell Lung Cancer: A Cost-Effectiveness Analysis to Inform Drug Pricing.

BACKGROUND: Serplulimab is a potential valuable therapy, while patients, physicians, and decision-makers are uncertain about the cost-effectiveness of this novel drug and its corresponding reasonable price. This study aimed to simulate the price at which serplulimab was cost-effective as first-line therapy for United States (US) and Chinese extensive-stage small-cell lung cancer (ES-SCLC) patients. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of US and Chinese payers. Baseline characteristics of patients and critical clinical data were obtained from ASTRUM-005. Costs and utilities were collected from open-access databases and published literature. Cumulative costs (in US dollars), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured and compared. Price simulation was conducted to inform the pricing strategy at the given willingness-to-pay (WTP) threshold. The robustness of the model was assessed via sensitivity analyses and scenario analyses; subgroup analyses were also included. RESULTS: Base-case analysis indicated that serplulimab ($818.16/100 mg) would be cost-effective in the US at the WTP threshold of $150,000, with improved effectiveness of 0.61 QALYs and an additional cost of $64,918 (ICER $106,757). Serplulimab ($818.16/100 mg, patient assistance program considered) was cost-effective in China, with improved effectiveness of 0.58 QALYs and an increased overall cost of $19,369 (ICER $33,392). The price simulation results indicated that serplulimab was favored in the US when the price was less than $762.11/100 mg and $1261.57/100 mg at the WTP threshold of $100,000 and $150,000, respectively; it was cost-effective at the WTP threshold of $38,184 when the price was less than $373.37/100 mg in China. Sensitivity analyses revealed that the above results were stable. Subgroup analysis results indicated an overall trend for subgroups with better survival advantages to have a higher probability of cost-effectiveness, despite serplulimab not being cost-effective in some subgroups. CONCLUSIONS: Serplulimab might be a valuable and cost-effective therapy in both the US and China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about the budget impact and affordability for patients is needed.

A systematic review and network meta-analysis of first-line immune checkpoint inhibitor combination therapies in patients with advanced non-squamous non-small cell lung cancer.

Introduction: Clinical evidence suggests that first-line immune checkpoint inhibitor (ICI) combination therapies can improve survival in patients with advanced non-squamous non-small cell lung cancer (nsq-NSCLC). However, the optimal strategy remains unknown without a systematic comparison of their long-term effects. Methods: We performed a systematic review and network meta-analysis by retrieving up-to-date literature from PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, Netherlands), MEDLINE® (National Library of Medicine), ClinicalTrials.gov (National Library of Medicine), and major international conference publications. Published studies and abstracts comparing first-line ICI combination therapies with other treatments for patients with advanced nsq-NSCLC were included. Restricted mean survival time (RMST) was measured over 12 months for progression-free survival (PFS) and 18 months for overall survival (OS), and the Royston-Parmar model was used to extrapolate and compare data for the long-term outcomes. Results: We included a total of 11 trials involving 12 therapies and 6,130 patients. Pembrolizumab plus chemotherapy exhibited the best overall survival (OS) benefit at both 18 and 60 months [RMST = 2.95, 95% confidence interval (CI) 1.96 to 3.97; life-years gained over a 5-year period = 2.18 years]. Nivolumab plus bevacizumab plus chemotherapy was found to present the best progression-free survival (PFS) benefit at 12 months (RMST 3.02, 95% CI 2.11 to 3.91), whereas atezolizumab plus bevacizumab plus chemotherapy showed the best PFS benefit at 36 months (life-years gained over 3 years = 1.22 years). Subgroup analyses showed that among patients with programmed death-ligand 1 (PD-L1) expression ≥ 50%, atezolizumab plus chemotherapy and nivolumab plus ipilimumab resulted in superior OS benefits at 18 and 60 months, respectively. Among patients with PD-L1 expression< 1%, pembrolizumab plus chemotherapy was associated with OS benefits at both 18 and 60 months. Sintilimab plus chemotherapy was associated with relatively fewer grade ≥ 3 adverse events than other ICI combination therapies. Conclusion: Our results show that ICI combination therapies showed better survival benefits than chemotherapy. Pembrolizumab plus chemotherapy could provide the best OS benefits to patients with advanced nsq-NSCLC, whereas atezolizumab plus bevacizumab plus chemotherapy could bring the best PFS benefits. The optimal ICI combination therapy varies depending on PD-L1 expression level. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=325005, identifier CRD42022325005.

Short-term efficacy of non-pharmacological interventions for global population with elevated blood pressure: A network meta-analysis.

Background: This study aims to compare the potential short-term effects of non-pharmacological interventions (NPIs) on prehypertensive people, and provide evidence for intervention models with potential in future community-based management. Methods: In this Bayesian network meta-analysis, Pubmed, Embase, and Web of science were screened up to 16 October 2021. Prehypertensive patients (systolic blood pressure, SBP 120-139 mmHg/diastolic blood pressure, DBP 80-89 mmHg) with a follow-up period longer than 4 weeks were targeted. Sixteen NPIs were identified during the scope review and categorized into five groups. Reduction in SBP and DBP was selected as outcome variables and the effect sizes were compared using consistency models among interventions and intervention groups. Grade approach was used to assess the certainty of evidence. Results: Thirty-nine studies with 8,279 participants were included. For SBP, strengthen exercises were the most advantageous intervention group when compared with usual care (mean difference = -6.02 mmHg, 95% CI -8.16 to -3.87), and combination exercise, isometric exercise, and aerobic exercise were the three most effective specific interventions. For DBP, relaxation was the most advantageous intervention group when compared with usual care (mean difference = -4.99 mmHg, 95% CI -7.03 to -2.96), and acupuncture, meditation, and combination exercise were the three most effective specific interventions. No inconsistency was found between indirect and direct evidence. However, heterogeneity was detected in some studies. Conclusion: NPIs can bring short-term BP reduction benefits for prehypertensive patients, especially exercise and relaxation. NPIs could potentially be included in community-based disease management for prehypertensive population once long-term real-world effectiveness and cost-effectiveness are proven. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=151518, identifier: CRD42020151518.

Hepatocellular Carcinoma Targeting and Pharmacodynamics of Paclitaxel Nanoliposomes Modified by Glycyrrhetinic Acid and Ferric Tetroxide.

AIMS: Research on developing targeted delivery of anticancer drugs for the treatment of hepatocellular carcinoma (HCC) is ongoing. This study aimed to synthesize nanoliposomes modified by glycyrrhetinic acid (GA) and ferric tetroxide (Fe3O4) for targeted delivery of paclitaxel for selective and specific therapy of HCC. OBJECTIVE: During this project, GA and Fe3O4 were used to jointly modify the active targeting and magnetic orientation of paclitaxel nanoliposomes for enhanced targeting of HCC to improve the efficacy, while reducing the systemic toxicity and side effects of the drug. METHODS: In this study, liposomes were prepared utilizing a thin film dispersion method, in which the average particle size of GA/Fe3O4-PTX-LP was 148.9 ± 2.3 nm, and the average Zeta potential was -23.2 ± 3 mV. Based on TEM characterization, GA/Fe3O4-PTX-LP is a closed particle with bilayer membranes. In vitro release assessments of the drug indicated that the release of GA/Fe3O4- PTX-LP was sustained. RESULTS: In vitro cell tests have demonstrated that GA/Fe3O 4-PTX-LP can inhibit the proliferation, affect the morphology, migration and invasion, and interfere with the cycle of HCC cells. Uptake tests have confirmed that GA/Fe3O4-PTX-LP can promote the uptake of the drug in HCC cells. CONCLUSION: In vivo targeting experiments have shown that GA/Fe3O4-PTX-LP has a strong ability to target tumors. In vivo antitumor assessments have proven that GA/Fe3O4-PTX-LP can inhibit tumor growth without obvious toxicity. This project provides a promising nano-targeted drug delivery system for the treatment of HCC.

A Natural Membrane Vesicle Exosome-based Sinomenine Delivery Platform for Hepatic Carcinoma Therapy.

BACKGROUND: Recent evidence has been demonstrated that Sinomenine (SIN) exerts antitumor activity in vitro. However, the clinical utility of SIN remains limited mainly because of its poor bioavailability. Exosomes are nanoscale vesicles that play crucial roles in intracellular communications through functionally active substances such as DNA and RNA. Exosomes have been utilized as nanocarriers for targeted drug delivery of different anticancer drugs. METHODS: The present study aimed to evaluate the effectiveness of combined Exosomes-SIN for the treatment of hepatocellular carcinoma (HCC) in a rat model. To do so, we prepared a mixture of SIN and exosomes (Exo-SIN) to improve the bioavailability of SIN to treat liver cancer. The in vitro releasing profile of the Exo-SIN was examined. RESULTS: We observed a continuous, slow release of SIN from Exo-SIN in simulated body fluid as well as tumor microenvironment. In the cytotoxicity test, Exo-SIN exhibited a significantly stronger inhibition in HepG2 cells compared to free SIN. The flow cytometry assessments showed that Exo-SIN could suppress HepG2 cell migration in a Transwell assay and induce cell cycle arrest and cellular apoptosis. Western blotting showed that survivin, a crucial protein for the survival of living cells, was significantly downregulated after treatment with Exo-SIN. CONCLUSION: In conclusion, our data suggested that Exo-SIN could serve as a potential, effective delivery platform for hepatic carcinoma therapy.

Treatment for Hepatocellular Carcinoma Is Enhanced When Norcantharidin Is Encapsulated in Exosomes Derived from Bone Marrow Mesenchymal Stem Cells.

Mesenchymal stem cell-derived exosomes (MSC-Exos) have potential as drug-delivery vehicles and exhibit great promise for hepatocellular carcinoma (HCC) therapy. Here, we consider bone mesenchymal stem cell-derived exosomes (BMSC-Exos) as drug carriers to encase anticancer drug norcantharidin (NCTD) and explore their potential therapeutic effects against HCC. NCTD was loaded into purified exosomes from BMSCs via electroporation, and an in vitro drug release study showed that BMSC-Exos-NCTD provided a continuous and slow release of the drug. A series of in vitro and in vivo pharmacodynamic evaluations based on the HCC cell line HepG2 were conducted. The results showed that the BMSC-Exos-NCTD delivery system effectively promoted cellular uptake, induced cell cycle arrest, reduced tumor cell proliferation, increased apoptosis, and exerted obvious in vivo antitumor effects compared with the NCTD treatment alone, with BMSC-Exos-NCTD showing more significant antitumor effects. Furthermore, the in vivo detection results of the homing effect using the probe Cy5.5 showed that the BMSC-Exos carrier has an in situ homing effect on the tumor sites of HCC in mice. Moreover, BMSC-Exos-NCTD did not show body toxicity. Excitedly, BMSC-Exos-NCTD repaired damaged liver tissues in liver sections; specifically, the experimental effectiveness of the exosomes on the normal liver cell line L02 indicated that the damaged liver cells were repaired by the exosomes, as reflected by the increase in cellular proliferation and the inhibition of liver cell oxidation. Our results suggest that BMSC-Exos, as drug carriers with specific functions, have great potential in the HCC treatment in combination with anticancer drugs.