Cost-effectiveness of pan-genotypic direct-acting antiviral regimens for treatment of chronic Hepatitis C in the United States

Objectives: Given the goal of hepatitis C virus elimination by 2030, World Health Organization guidelines recommend treatment of chronic hepatitis C (CHC) with pan-genotypic direct-acting antivirals, such as sofosbuvir/velpatasvir (SOF/VEL), SOF/VEL/voxilaprevir (VOX) or glecaprevir/pibrentasvir (GLE/PIB). The study evaluated the cost-effectiveness of pan-genotypic regimens in initial (SOF/VEL or GLE/PIB) and re-treatment (SOF/VEL/VOX or GLE/PIB+SOF+ribavirin (RBV)) of CHC. Methods: A Markov state-transition model projected lifetime CHC health and economic outcomes from the US payer perspective. Model inputs were sourced from clinical trials or published literature and validated by hepatologists. Model outcomes included numbers of advanced liver disease events, life-years and quality-adjusted life-years (QALYs) gained, and total lifetime costs. One-way sensitivity analyses were performed on model results. Results: SOF/VEL followed by SOF/VEL/VOX resulted in comparable cure rates to the GLE/PIB treatment pathway (99.94% vs. 99.93%, respectively). SOF-based regimens provided similar QALYs at a lower lifetime cost versus a GLE/PIB treatment pathway ($30,749 vs.$36,255), resulting in cost savings of $5,506 per patient. Results were robust in sensitivity analyses. Conclusion: SOF/VEL followed by SOF/VEL/VOX leads to comparable cure rates in the overall CHC population relative to the GLE/PIB treatment pathway. Based on wholesale acquisition prices, the SOF/VEL treatment pathway led to lower lifetime costs.</p

Adverse events reported among chronic hepatitis C patients treated at a single centre in Germany.

Adverse events reported among chronic hepatitis C patients treated at a single centre in Germany.</p

Proportion achieving SVR12 among SOF/VEL patients overall, and by genotype treated at a single centre in Germany.

GT1: genotype 1; GT2: genotype 2; GT3: genotype 3; GT4: genotype 4; GT5: genotype 5; GT6: genotype 6; SVR12: sustained virologic response at 12 weeks. 1One patient did not achieve SVR with the following characteristics; male, 69 years old, white, GT1a, F4-CC and TN.</p

Real-world effectiveness and safety of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir hepatitis C treatment in a single centre in Germany

BackgroundNewer direct-acting antiviral therapies are increasingly becoming the therapy of choice in patients with hepatitis C virus (HCV) infection. Here, we report the safety and effectiveness of sofosbuvir/velpatasvir (SOF/VEL) and ledipasvir/sofosbuvir (LDV/SOF) in real-world cohorts in Germany.MethodsPatients initiated on SOF/VEL 12 weeks or LDV/SOF 8, 12 or 24 weeks regimens in a single German centre were included in this study. Data on treatment outcomes and adverse events (AE) were analysed in patients with available sustained virologic response 12 weeks after cessation of treatment (SVR12) information overall and by subgroups.ResultsThis study included 115 patients who received SOF/VEL from July-2016 to July-2017, and 249 patients who received LDV/SOF from November-2014 to September-2015. Overall, SVR12 was achieved in 99% of patients on SOF/VEL ± ribavirin 12 weeks independent of HCV genotype, treatment history, or cirrhosis status, and in 96% of patients treated with LDV/SOF 8 weeks or LDV/SOF ± ribavirin 12 or 24 weeks. In genotype 1 treatment-naïve, non-cirrhotic patients, ≥99% achieved SVR12 across SOF/VEL and LDV/SOF regimens. Likewise, 100% of genotype 3-cirrhotic patients on SOF/VEL ± ribavirin regimens achieved SVR12. Grade 3/4 AE were reported in 13 (5.2%) patients on LDV/SOF and in 1 (ConclusionOverall, SOF/VEL and LDV/SOF achieved high SVR rates in a broad patient population. We showed the effectiveness of SOF/VEL as a pan-genotypic regimen, and regardless of treatment history or cirrhosis status. Use of such therapies improves outcomes and contributes towards the global efforts to eradicate HCV.</div

Cost-effectiveness of increased screening and treatment of chronic hepatitis C in Korea

Background: Given a hepatitis C virus (HCV) elimination goal by 2030, World Health Organization (WHO) guidelines recommend scaling up HCV screening and treatment with highly-effective direct-acting antivirals (DAAs). This study investigated the cost-effectiveness of various screening and treatment strategies for chronic HCV patients in South Korea in patients aged over 40 as compared to currently screening only high-risk patients. Methods: A published Markov disease progression model was used with a screening/treatment decision-tree to model different screening and treatment strategies for Korean HCV patients (aged over 40) from a national payer perspective over a lifetime time horizon. The screening strategies included ‘screen-all’ (upfront only: ‘once’; or upfront and age 65: ‘twice’) or a ‘high-risk only’ screening strategy followed by treatment. Treatment strategies included either ledipasvir/sofosbuvir (LDV/SOF), SOF + ribavirin (SOF + RBV; in GT2 only), or glecaprevir/pibrentasvir (GLE/PIB). Model inputs were sourced from published literature and costing databases and validated by Korean hepatologists. Results: Regardless of treatment strategy, a ‘screen all twice’ scenario led to the lowest rates of advanced liver disease events compared to ‘screen all once’ and ‘high-risk only’ screening scenarios. In this screening scenario, treatment with LDV/SOF for GT1/2 dominates (i.e., is more effective and less4costly) LDV/SOF in GT1 and SOF + RBV in GT2, while GLE/PIB is not cost-effective relative to LDV/SOF (₩105,124,920/QALY) at a willingness-to-pay threshold of 1xGDP per capita. Conclusion: Screening all South Korean patients twice followed by LDV/SOF treatment is cost-effective as compared current high-risk screening. Adopting this strategy can help achieve WHO HCV elimination goals.</p

Baseline characteristics of chronic hepatitis C patients treated at a single centre in Germany.

Baseline characteristics of chronic hepatitis C patients treated at a single centre in Germany.</p

Proportion achieving SVR12 among GT1, treatment-naïve, non-cirrhotic patients on LDV/SOF or SOF/VEL treated at a single centre in Germany.

LDV: ledipasvir; SOF: sofosbuvir; SVR12: sustained virological response at 12 weeks; VEL: velpatasvir.</p

Supplementary Tables – Real-world treatment patterns and overall survival in BRAF-mutant melanoma patients treated with immunotherapy or targeted therapy

   Sensitivity analysis 1: Statistical adjustment without inverse probability of treatment weighting (IPTW)    Sensitivity analysis 2: Censoring patients in the practice subanalysis who initiate a therapy off-sequence    Sensitivity analysis 3: Restricting to CPI patients receiving ipilimumab + nivolumab    Supplemental Table 1. Comparison of statistical adjustments with and without inverse probability of treatment weighting (IPTW).    Supplemental Table 2. Baseline Characteristics of Patients With Advanced BRAF-Mt Melanoma by 1L Treatment</p

Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3

<p>Cyclin-dependent kinase (Cdk) in complex with a corresponding cyclin plays a pivotal role in neurogenic differentiation. In particular, Cdk4 activity acts as a signaling switch to direct human mesenchymal stem cells (MSCs) to neural transdifferentiation. However, the molecular evidence of how Cdk4 activity converts MSCs to neurogenic lineage remains unknown. Here, we found that Cdk4 inhibition in human MSCs enriches the populations of neural stem and progenitor pools rather than differentiated glial and neuronal cell pools. Interestingly, Cdk4 inhibition directly inactivates Smads and subsequently STAT3 signaling by hypophosphorylation, and both Cdk4 and Smads levels are linked during the processes of neural transdifferentiation and differentiation. In summary, our results provide novel molecular evidence in which Cdk4 inhibition leads to directing human MSCs to a multipotent neurogenic fate by inactivating Smads-STAT3 signaling.</p

Supplementary Figures – Real-world treatment patterns and overallsurvival in BRAF-mutant melanoma patientstreated with immunotherapy or targetedtherapy

   Supplemental Figure 1. Kaplan-Meier Estimates of Overall Survival (OS) in Patients With Advanced BRAF-Mt Melanoma Receiving 1L Treatment With CPI (ipilimumab/nivolumab) or TT.    Supplemental Figure 2. Kaplan-Meier estimates of Overall Survival (OS) in Patients With Advanced BRAF-Mt Melanoma Receiving 1L Treatment With CPI (ipilimumab/nivolumab) or TT weighted by IPTW.</p