Abrocitinib monotherapy in Investigator's Global Assessment nonresponders: improvement in signs and symptoms of atopic dermatitis and quality of life.

BACKGROUND: Abrocitinib, a once-daily, oral Janus kinase 1 selective inhibitor, was shown to be an effective treatment for moderate-to-severe atopic dermatitis in phase 2 b/3 monotherapy trials. METHODS: These analyses included data for Investigator's Global Assessment responder (clear [0] or almost clear [1] with ≥2-grade improvement) and nonresponder patients with moderate-to-severe atopic dermatitis who received abrocitinib (200 mg or 100 mg) or placebo in three abrocitinib monotherapy trials (phase 2 b, NCT02780167; two phase 3, NCT03349060/JADE MONO-1 and NCT03575871/JADE MONO-2). Outcomes measuring skin clearance, itch, and quality of life were evaluated. RESULTS: Both nonresponders (n = 548) and responders (n = 260) treated with abrocitinib had rapid and clinically meaningful improvement in skin clearance, itch, and quality of life compared with placebo. CONCLUSION: Patients with moderate-to-severe atopic dermatitis treated with abrocitinib who did not achieve an Investigator's Global Assessment 0/1 response at week 12 still experienced rapid, clinically meaningful improvements across several other validated measures of efficacy and quality of life. CLINICALTRIALS.GOV: NCT02780167, NCT03349060, NCT03575871.

Drug repurposing for Chagas disease: In vitro assessment of nimesulide against Trypanosoma cruzi and insights on its mechanisms of action.

Chagas disease is a neglected illness caused by Trypanosoma cruzi and its treatment is done only with two drugs, nifurtimox and benznidazole. However, both drugs are ineffective in the chronic phase, in addition to causing serious side effects. This context of therapeutic limitation justifies the continuous research for alternative drugs. Here, we study the in vitro trypanocidal effects of the non-steroidal anti-inflammatory drug nimesulide, a molecule that has in its chemical structure a toxicophoric nitroaromatic group (NO2). The set of results obtained in this work highlights the potential for repurposing nimesulide in the treatment of this disease that affects millions of people around the world.

Cost-effectiveness of a 12-month fixed-duration venetoclax treatment in combination with obinutuzumab in first-line, unfit chronic lymphocytic leukemia in the United States.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a significant health and economic burden in the United States. Treatments include chemoimmunotherapy, such as obinutuzumab (G) plus chlorambucil (Clb) or bendamustine plus rituximab (BR), and chemotherapy-free regimens incorporating oral targeted therapies such as ibrutinib (Ibr), acalabrutinib (Acala), or venetoclax (Ven). Most chemotherapy-free regimens require continuous treatment to progression, while Ven plus G (VenG) is given for a fixed duration of 12 months, based on the CLL14 trial that led to its approval. Fixed-duration VenG has the potential for cost savings compared with treat-to-progression chemotherapy-free regimens. OBJECTIVE: To evaluate the cost-effectiveness of 12 months fixed-duration VenG in first-line treatment of unfit patients with CLL from a US health care payer perspective compared with GClb, BR, Ibr, Ibr + G, Ibr + R, Acala, and Acala + G. METHODS: A partitioned survival model was developed with 3 health states: progression-free survival (PFS), postprogression survival, and dead. The patient population, as based on the CLL14 trial, comprised previously untreated unfit patients with CLL (mean age 71.1 years, 33.1% female). The distribution of patients in each health state over time was estimated using extrapolated PFS and overall survival (OS) curves for VenG and GClb, based on CLL14 data 2 or more years after treatment cessation. PFS and OS for the other comparators were estimated using hazard ratios vs VenG, based on a network metaanalysis. Adverse events, utility values, and costs were obtained from published literature. The model estimated life-years gained, quality-adjusted life-years (QALYs) gained, and costs. The time horizon was 20 years, with a cycle time of 28 days. Outcomes and costs were discounted at 3.0% per year, and costs were estimated from a US health care payer perspective. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In this cross-trial analysis of unfit CLL patients, in the base case, VenG had lower projected total costs than all comparators investigated. VenG also had larger projected health benefits (more QALYs gained) than GClb, BR, Ibr, and Ibr + R. VenG was therefore more effective and less costly than these comparators (dominant). Ibr + G, Acala, and Acala + G showed higher QALYs gained vs VenG (0.022, 0.672, and 0.961, respectively), and substantially higher projected costs vs VenG ($1,488,400, $1,579,737, and $1,656,154, respectively). Thus, Ibr + G, Acala, and Acala + G would cost more than $1,000,000 per QALY gained vs VenG. At the commonly used willingness-to-pay threshold of $150,000 per QALY gained, Ibr + G, Acala, and Acala + G were not cost-effective compared with VenG. CONCLUSIONS: Fixed-duration VenG for 12 months is a cost-effective first-line treatment option for unfit CLL patients compared with other available options and provides value for money to US health care payers at a threshold of $150,000 per QALY gained. Future studies with longer trial follow-up and more mature survival data may help to confirm longer-term cost benefits of VenG. DISCLOSURES: Genentech Inc. and AbbVie provided financial support for this study. Genentech Inc., AbbVie, and Pharmerit - An OPEN Health Company participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Venetoclax is being developed in a collaboration between Genentech Inc. and AbbVie. Ravelo and Shapouri are employed by Genentech Inc. and have ownership interests. Manzoor and Sail are employed by AbbVie and have ownership interests. Chatterjee, van de Wetering, and Qendri, employees of Pharmerit - An OPEN Health Company, received consultancy fees from AbbVie. Davids has received consultancy fees from AbbVie, AstraZeneca, Eli Lilly, Genentech Inc., Janssen, MEI Pharma, Novartis, Pharmacyclics, and Verastem; research funding from Ascentage Pharma, Genentech Inc., MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem; and has served on board of directors or advisory committees for AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Eli Lilly, Genentech Inc., Janssen, Pharmacyclics, TG Therapeutics, and Verastem. This study was presented as a poster at ASH 61st Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in the community, European Union/European Economic Area, 1997-2017.

OBJECTIVES: Data on consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of main subgroups of tetracyclines, sulphonamides and trimethoprim and other antibacterials. METHODS: For the period 1997-2017, data on consumption of tetracyclines (ATC group J01A), sulphonamides and trimethoprim (ATC group J01E), and other antibacterials (ATC group J01X) in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials was analysed based on ATC-4 subgroups and presented as trends, seasonal variation, presence of change-points and compositional changes. RESULTS: In 2017, consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in the community expressed in DDD per 1000 inhabitants per day varied considerably between countries. Between 1997 and 2017, consumption of tetracyclines did not change significantly, while its seasonal variation significantly decreased over time. Consumption of sulphonamides and trimethoprim significantly decreased until 2006, and its seasonal variation significantly decreased over time. The consumption of other antibacterials showed no significant change over time or in seasonal variation. CONCLUSIONS: Consumption and composition of tetracyclines, sulphonamides and trimethoprim, and other antibacterials showed wide variations between EU/EEA countries and over time. This represents an opportunity to further reduce consumption of these groups in some countries and improve the quality of their prescription.

Frailty Status Predicts New Long-term Care Insurance Certification in Hepatitis C Patients Receiving Antiviral Therapy.

BACKGROUND/AIM: Direct-acting antiviral (DAA) therapies for patients with hepatitis C virus (HCV) infection deliver higher cure rates and lower frequencies of adverse events than existing therapies, though DAA treatment costs $45,000-64,000 in Japan. The prognosis of patients who require new long-term care insurance (LTCI) certification is inferior to that of patients who do not. Here, we clarify the factors associated with new LTCI certification in elderly patients with HCV infection who undergo DAA therapy. PATIENTS AND METHODS: We retrospectively surveyed 53 patients aged ≥70 years who were treated with DAAs, and evaluated the factors associated with new LTCI certification. RESULTS: Of 53 patients, 10 required new LTCI certification. Age ≥85 years and a modified Japanese Cardiovascular Health Study index ≥2 were independently associated with new LTCI certification. CONCLUSION: In elderly HCV patients, poor frailty status strongly predicted new LTCI certification after DAA therapy.

Real-world treatment sequencing and healthcare costs among CLL/SLL patients treated with venetoclax.

OBJECTIVE: This study aimed to describe treatment sequencing and healthcare costs among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients treated with venetoclax in a US managed care population. METHODS: CLL/SLL patients initiating venetoclax between 04/11/2016 and 06/30/2019 were selected from Optum's de-identified Clinformatics Data Mart Database. Costs per-patient-per-month were described during the first 60 days of venetoclax-based treatment (initiation phase) and subsequent post-initiation phase. Based on venetoclax prescribing information, clinical event-related costs were identified through claims for tumor lysis syndrome (TLS) diagnosis, monitoring, prophylaxis, immunoglobulin treatment, neutropenia, thrombocytopenia, infection, renal impairment, hypertension, or cardiac arrhythmia. Statistical testing was not conducted due to small sample size. RESULTS: Twenty-five, 30, and 66 patients initiated venetoclax as their first observed regimen (1L), second observed regimen (2L), and third or later observed regimen (3L+), respectively. Most 2L (56.7%) and 3L+ (74.2%) venetoclax recipients previously received ibrutinib. Mean monthly all-cause costs during the initiation phase were $26,429 (1L cohort), $19,580 (2L cohort), and $23,918 (3L + cohort). Among the 2L cohort, mean monthly all-cause [clinical event-related] (including TLS) costs during initiation and post-initiation phases of venetoclax treatment were $15,506 [$6368] (initiation phase) and $14,318 [$5273] (post-initiation phase; median duration: 3.7 months) for patients receiving 1L ibrutinib, and $24,908 [$12,198] (initiation phase) and $16,905 [$7066] (post-initiation phase; median duration: 3.0 months) for patients not receiving 1L ibrutinib. CONCLUSIONS: In this descriptive study, highest mean costs were observed during venetoclax initiation phase. Venetoclax patients previously receiving ibrutinib had lower mean total all-cause and clinical event-related (including TLS) costs during their venetoclax line of therapy than those previously receiving non-ibrutinib therapy.

Cost-effectiveness of a "treat-all" strategy using Direct-Acting Antivirals (DAAs) for Japanese patients with chronic hepatitis C genotype 1 at different fibrosis stages.

AIM: To evaluate the cost-effectiveness of therapeutic strategies initiated at different stages of liver fibrosis using three direct-acting antivirals (DAAs), sofosbuvir-ledipasvir (SL), glecaprevir-pibrentasvir (GP), and elbasvir plus grazoprevir (E/G), for Japanese patients with chronic hepatitis C (CHC) genotype 1. METHODS: We created an analytical decision model reflecting the progression of liver fibrosis stages to evaluate the cost-effectiveness of alternative therapeutic strategies applied at different fibrosis stages. We compared six treatment strategies: treating all patients regardless of fibrosis stage (TA), treating individual patients with one of four treatments starting at four respective stages of liver fibrosis progression (F1S: withholding treatment at stage F0 and starting treatment from stage F1 or higher, and three successive options, F2S, F3S, and F4S), and administering no antiviral treatment (NoRx). We adopted a lifetime horizon and Japanese health insurance payers' perspective. RESULTS: The base case analysis showed that the incremental quality-adjusted life years (QALY) gain of TA by SL, GP, and E/G compared with the strategies of starting treatments for patients with the advanced fibrosis stage, F2S, varied from 0.32 to 0.33, and the incremental cost-effectiveness ratios (ICERs) were US$24,320, US$18,160 and US$17,410 per QALY, respectively. On the cost-effectiveness acceptability curve, TA was most likely to be cost-effective, with the three DAAs at the willingness to pay thresholds of US$50,000. CONCLUSIONS: Our results suggested that administration of DAA treatment for all Japanese patients with genotype 1 CHC regardless of their liver fibrosis stage would be cost-effective under ordinary conditions.

Conversion of Functional Assessment of Chronic Illness Therapy-Fatigue to Patient-Reported Outcomes Measurement Information System Fatigue Scores in Two Phase III Baricitinib Rheumatoid Arthritis Trials.

OBJECTIVE: The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is validated for measuring fatigue in rheumatoid arthritis (RA). However, 10 of 13 FACIT-F items are identified as relevant to patients with RA. The Patient-Reported Outcomes Measurement Information System (PROMIS) uses an item response theory-calibrated T score metric. The PROMIS Fatigue item bank includes the FACIT-F items, enabling score conversion. The performance of converted PROMIS Fatigue scores has not been evaluated in RA populations or clinical trials. Our objective was to assess the performance of converted PROMIS Fatigue scores in 2 RA clinical trials of baricitinib. METHODS: Crosswalk tables and pattern-scoring methods converted FACIT-F scores to PROMIS Fatigue for both the 13-item FACIT-F and the 10-item RA-optimized FACIT-F instrument, in 2 RA clinical trials evaluating baricitinib, RA-BEAM, and RA-BEACON. RA-BEAM patients had an inadequate response to methotrexate. RA-BEACON patients had an inadequate response or intolerance to ≥1 tumor necrosis factor inhibitor. Baricitinib was compared to all treatment arms via analysis of covariance on PROMIS Fatigue score conversions. RESULTS: Baseline FACIT-F-derived PROMIS Fatigue scores reflected severe fatigue across treatment groups and were similar using different scoring methods. At week 24 in both studies, baricitinib was associated with clinically meaningful improvements in PROMIS Fatigue scores. PROMIS Fatigue scores were consistent for conversion methods and for the 13-item or 10-item FACIT-F. CONCLUSION: All 4 conversion methods showed differentiation of active treatment compared with placebo from week 12, supporting the use of the PROMIS Fatigue and converting the 10-item FACIT-F to assess fatigue and demonstrate treatment benefit in RA clinical trials on a standardized metric.

Financial Implications of Avapritinib for Treatment of Unresectable Gastrointestinal Stromal Tumors in Patients With a PDGFRA Exon 18 Variant or After 3 Previous Therapies in a Hypothetical US Health Plan.

Importance: With the approval of avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 variant, including PDGFRA D842V variants, and National Comprehensive Cancer Network guideline recommendations as an option for patients with GIST after third-line treatment, it is important to estimate the potential financial implications of avapritinib on a payer's budget. Objective: To estimate the budget impact associated with the introduction of avapritinib to a formulary for metastatic or unresectable GISTs in patients with a PDGFRA exon 18 variant or after 3 or more previous treatments from the perspective of a US health plan. Design, Setting, and Participants: For this economic evaluation, a 3-year budget impact model was developed in March 2020, incorporating costs for drug acquisition, testing, monitoring, adverse events, and postprogression treatment. The model assumed that avapritinib introduction would be associated with increased PDGFRA testing rates from the current 49% to 69%. The health plan population was assumed to be mixed 69% commercial, 22% Medicare, and 9% Medicaid. Base case assumptions included a GIST incidence rate of 9.6 diagnoses per million people, a metastatic PDGFRA exon 18 mutation rate of 1.9%, and progression rate from first-line to fourth-line treatment of 17%. Exposures: The model compared scenarios with and without avapritinib in a formulary. Main Outcomes and Measures: Annual, total, and per member per month (PMPM) budget impact. Results: In a hypothetical 1-million member plan, fewer than 0.1 new patients with a PDGFRA exon 18 variant per year and 1.2 patients receiving fourth-line therapy per year were eligible for treatment. With avapritinib available, the total increase in costs in year 3 for all eligible adult patients with a PDGFRA exon 18 variant was $46 875, or $0.004 PMPM. For patients undergoing fourth-line treatment, the total increase in costs in year 3 was $69 182, or $0.006 PMPM. The combined total budget impact in year 3 was $115 604, or $0.010 PMPM, including an offset of $3607 in postprogression costs avoided or delayed. The higher rates of molecular testing resulted in a minimal incremental testing cost of $453 in year 3. Conclusions and Relevance: These results suggest that adoption of avapritinib as a treatment option would have a minimal budget impact to a hypothetical US health plan. This would be primarily attributable to the small eligible patient population and cost offsets from reduced or delayed postprogression costs.

Assessment of Predictive Biomarkers of the Response to Pazopanib Based on an Integrative Analysis of High-grade Soft-tissue Sarcomas: Analysis of a Tumor Sample from a Responder and Patients with Other Soft-tissue Sarcomas.

BACKGROUND: Soft-tissue sarcomas are a rare group of malignant tumors that usually are treated with surgical excision and radiation therapy, but recently, pazopanib, an oral tyrosine kinase inhibitor, has been used in patients with metastases who do not respond to standard chemotherapy regimens. Based on patients with advanced soft-tissue sarcomas who had received prior chemotherapy, several clinical studies have reported the survival and sensitivity (approximately 5% to 10% sensitive) of patients with soft-tissue sarcomas treated with pazopanib. Recently, next-generation sequencing (NGS) technologies have been used to provide a wide genetic information and to develop personalized medicine in cancer treatment. However, there are few reports and no genetic analyses of patients with soft-tissue sarcomas who had a complete response (CR) to pazopanib. QUESTIONS/PURPOSES: We described the clinicopathologic features of a patient with a rare, advanced soft-tissue sarcoma who achieved a CR to pazopanib treatment. Furthermore, integrative analyses using NGS and arrays were performed to elucidate characteristic alterations, including gene mutations, copy number changes, and protein expression that were associated with response to pazopanib. Additionally, functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified alterations were associated with oncogenic abilities and drug responses. METHODS: In a sample from a 70-year-old woman with an advanced soft-tissue sarcoma treated for 1 month with 800 mg of oral pazopanib daily, CT scans demonstrated a CR to treatment. To our knowledge, there have been no patients with soft-tissue sarcomas among several clinical trials of pazopanib that have achieved a CR and therefore, our patient is considered to be extremely rare. We performed an integrative analysis including whole-exome sequencing, transcriptome sequencing, and phosphorylation profiling of receptor tyrosine kinases (RTK) using tumor samples from a patient with a CR matched to normal samples. From here on we will refer to this patient as having a CR, although a short term high-grade partial response may be more accurate. These analyses were performed using NGS and the phosphoreceptor tyrosine kinase (phospho-RTK) array. As a validation study, we also performed target sequencing using three samples from patients with long-term stable disease and two samples from patients with progressive disease who responded to pazopanib treatment. In addition, characteristic gene alterations that were identified according to the response to pazopanib in one patient with a CR, in three patients with long-term stable disease, and in 27 patients with high-grade soft-tissue sarcomas with different histologic subtypes and different responses to pazopanib were verified by quantitative real-time polymerase chain reaction. We conducted a focus formation assay to evaluate the transforming activities of these genomic alterations. RESULTS: In the patient with a CR to pazopanib, we identified several somatic mutations including Fms related receptor tyrosine kinase 1 (FLT1) p.G38S, platelet-derived growth factor receptor alpha (PDGFRA) p.T83S, and platelet-derived growth factor receptor beta (PDGFRB) exon 13 skipping. Amplification at chromosome 12q13-14 encompassing GLI family zinc finger 1 (GLI1) and cyclin-dependent kinase-4 (CDK4) was also detected. Furthermore, an elevated PDGFRB phosphorylation level was observed in the tumor. In target sequencing analyses in five patients, one of three patients with long-term stable disease had 12q13-14 amplification. The mRNA expression of GLI1, CDK4, and pazopanib targets including PDGFRA, PDGFRB, vascular endothelial growth factor receptor (VEGFR)1-3, and stem cell factor receptor (KIT) in samples from the patient with a CR, and 27 patients with high-grade soft-tissue sarcomas was verified. The expression of GLI1 was characteristically increased in the patient with a CR and in those with long-term stable disease relative to other patients with soft-tissue sarcomas. Overexpression of GLI1 showed strong transforming potential in 3T3 cells. Moreover, the overexpression of GLI1 upregulated the expression of the PDGFRB protein and promoted phosphorylation, which was dose-dependently inhibited by pazopanib. However, inhibition of GLI1-induced transformation by pazopanib was limited in the focus formation assay; therefore, mechanisms other than PDGFRB activation may contribute to transformation. CONCLUSIONS: We identified several gene alterations that might be associated with a CR and long-term stable disease in patients who received pazopanib for advanced soft-tissue sarcomas. We therefore believe that this distinct molecular profile warrants further investigation to identify predictive biomarkers of the response to pazopanib. CLINICAL RELEVANCE: Our findings identify molecular mechanisms that possibly explain the high sensitivity of soft-tissue sarcomas to pazopanib and may lead to the development of predictive biomarkers and novel therapies in patients with this and other types of soft-tissue sarcomas.

Cost-effectiveness of Using Kidneys From HCV-Viremic Donors for Transplantation Into HCV-Uninfected Recipients.

RATIONALE & OBJECTIVE: Less than 4% of patients with kidney failure receive kidney transplants. Although discard rates of hepatitis C virus (HCV)-viremic kidneys are declining, ~39% of HCV-viremic kidneys donated between 2018 and 2019 were discarded. Highly effective antiviral agents are now available to treat chronic HCV infection. Thus, our objective was to examine the cost-effectiveness of transplanting kidneys from HCV-viremic donors into HCV-uninfected recipients. STUDY DESIGN: Markov state transition decision model. Data sources include Medline search results, bibliographies from relevant English language articles, Scientific Registry of Transplant Recipients, and the US Renal Data System. SETTING & POPULATION: US patients receiving maintenance hemodialysis who are on kidney transplant waiting lists. INTERVENTION(S): Transplantation with an HCV-unexposed kidney versus transplantation with an HCV-viremic kidney and HCV treatment. OUTCOMES: Effectiveness measured in quality-adjusted life-years and costs measured in 2018 US dollars. MODEL, PERSPECTIVE, AND TIMEFRAME: We used a health care system perspective with a lifelong time horizon. RESULTS: In the base-case analysis, transplantation with an HCV-viremic kidney was more effective and less costly than transplantation with an HCV-unexposed kidney because of the longer waiting times for HCV-unexposed kidneys, the substantial excess mortality risk while receiving dialysis, and the high efficacy of direct-acting antiviral agents for HCV infection. Transplantation with an HCV-viremic kidney was also preferred in sensitivity analyses of multiple model parameters. The strategy remained cost-effective unless waiting list time for an HCV-viremic kidney exceeded 3.1 years compared with the base-case value of 1.56 year. LIMITATIONS: Estimates of waiting times for patients willing to accept an HCV-viremic kidney were based on data for patients who received HCV-viremic kidney transplants. CONCLUSIONS: Transplanting kidneys from HCV-viremic donors into HCV-uninfected recipients increased quality-adjusted life expectancy and reduced costs compared with a strategy of transplanting kidneys from HCV-unexposed donors.

Drug Resistance Assessment Following Administration of Respiratory Syncytial Virus (RSV) Fusion Inhibitor Presatovir to Participants Experimentally Infected With RSV.

BACKGROUND: Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner. METHODS: Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed. RESULTS: Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease. CONCLUSIONS: Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.

Cost-Effectiveness Analysis of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir With or Without Ribavirin Regimen for Patients Infected With Chronic Hepatitis C Virus Genotype 1 in Malaysia.

OBJECTIVES: The combination of pegylated-interferon and ribavirin (PegIFN+RBV) is currently the gold standard in treating chronic hepatitis C virus (HCV) patients in Malaysia and is reimbursed by the Malaysian authorities. This analysis evaluated the cost-effectiveness (CE) of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (OBT/PTV/r+DSB±RBV) regimen as compared with the PegIFN+RBV or no treatment in chronic HCV Genotype 1 (GT1) treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia. METHODS: A Markov model based on previously published CE models of HCV was adapted for the Malaysian public healthcare payer perspective, based on good modeling practices. Treatment attributes included efficacy, regimen duration, and EQ-5D treatment-related health utility. Transitional probabilities and health state health utilities were derived from previous studies. Costs were derived from Malaysian data sources. Costs and outcomes were discounted at 3.0% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties around key variables. RESULTS: Based on the analysis, patients treated with the OBT/PTV/r+DSB±RBV showed less frequent progression to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths when compared with standard care (ie, PegIFN+RBV or no treatment). At a price of MYR 1846/day, the OBT/PTV/r+DSB±RBV regimen is cost-effective over PegIFN+RBV and yields better outcomes in terms of life-years (LYs) gained and quality-adjusted life-years (QALYs) at a higher cost, which is still well below the implied willingness to pay threshold of MYR 384 503/QALY. CONCLUSION: The OBT/PTV/r+DSB±RBV regimen is cost-effective for treatment naïve, treatment experienced, cirrhotic, and noncirrhotic GT1 chronic HCV patients in Malaysia.

A Budget Impact and Cost Per Additional Responder Analysis for Baricitinib for the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients with an Inadequate Response to Tumor Necrosis Factor Inhibitors in the USA.

BACKGROUND/OBJECTIVE: Baricitinib is a selective and reversible Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor inhibitors (TNFis) and has been shown to improve multiple clinical and patient-reported outcomes. However, it is unclear what the budgetary impact would be for US commercial payers to add baricitinib to their formulary and how the efficacy of baricitinib compares to other disease-modifying antirheumatic drugs (DMARDs) with a similar indication. METHODS: A budget impact model (BIM) was developed for a hypothetical population of 1 million plan members that compared a world without and with baricitinib. A retrospective observational study was carried out to estimate market utilization of advanced therapies. Number needed to treat (NNT) and cost per additional responder were calculated for American College of Rheumatology (ACR) 20%/50%/70% improvement criteria (ACR20/50/70) response outcomes combining cost estimates from the BIM and efficacy values from a network meta-analysis (NMA). The model included costs related to drug acquisition and monitoring costs. RESULTS: Adding baricitinib would save a commercial payer $US169,742 for second-line therapy and $US135,471 for third-line therapy over a 2-year time horizon (all costs correspond to 2019 US dollars). Cost savings were driven by baricitinib drawing market share away from more expensive comparators. The NMA, based on nine studies, found no statistically significant differences in the median treatment difference between baricitinib and comparators except for versus a conventional synthetic DMARD (csDMARD), and thus NNT versus a csDMARD was similar. The cost per additional responder for baricitinib in patients with inadequate response to a TNFi was substantially lower than all other treatments for all three ACR response criteria at 12 weeks (ACR20: $US129,672; ACR50: $US237,732; ACR70: $US475,464), and among the lowest at 24 weeks (ACR20: $US167,811; ACR50: $US259,344; ACR70: $US570,557). CONCLUSIONS: Baricitinib, compared to other DMARDs, was a less expensive option (- $US0.01 incremental cost per member per month in second- and third-line therapy over a 2-year time horizon) with comparable efficacy in patients with inadequate response to TNFi. Adding baricitinib to formulary would likely be cost saving for US payers and expands treatment options for these patients.

A Cost-Effectiveness Analysis of Glecaprevir/Pibrentasvir Versus Existing Direct-Acting Antivirals to Treat Chronic Hepatitis C in Japan.

INTRODUCTION: The objective of the study was to evaluate the cost-effectiveness of glecaprevir/pibrentasvir versus other direct-acting antivirals (DAAs) for treating chronic hepatitis C virus (HCV) infections in Japan. METHODS: We developed a health state transition model to capture the natural history of HCV. A cost-effectiveness analysis of DAAs from the perspective of a public healthcare payer in Japan with a lifetime horizon over annual cycles was performed. Treatment attributes, baseline demographics, transition probabilities, health-state utilities, and costs data were extracted from publications. Costs and outcomes were discounted at 2% per annum. In the base case we focused on genotype 1 (GT1) treatment-naïve patients without cirrhosis. The scenario analysis examined a pan-genotype treatment in GT1-3 (i.e., portfolio), treatment-naïve, and treatment-experienced patients. The portfolio cost-effectiveness of DAAs was derived by calculating a weighted average of patient segments defined by treatment history, cirrhosis status, and genotype. RESULTS: The base case results indicated that glecaprevir/pibrentasvir was dominant (i.e., generating higher quality-adjusted life years [QALYs] and lower lifetime costs) compared to all other DAAs. The predicted lifetime risk of hepatocellular carcinoma was 3.66% for glecaprevir/pibrentasvir and sofosbuvir/ledipasvir, 4.99% for elbasvir/grazoprevir, and 5.27% for daclatasvir/asunaprevir/beclabuvir. In scenario analysis the glecaprevir/pibrentasvir (GLE/PIB) portfolio dominated the sofosbuvir (SOF)-based portfolio (namely sofosbuvir/ledipasvir in GT1-2 and sofosbuvir + ribavirin in GT3). The base case probabilistic sensitivity analysis (PSA) showed that glecaprevir/pibrentasvir was cost-effective in 93.4% of the simulations for a willingness-to-pay/QALY range of Japanese yen (JPY) 1.6-20 million. The PSA for the portfolio scenario indicated that the GLE/PIB portfolio was cost-effective in 100% of simulations until the willingness-to-pay/QALY reached JPY 5.2 million; this proportion decreased to 69.4% at a willingness-to-pay/QALY of JPY 20 million. Results were also robust in deterministic sensitivity analyses. CONCLUSION: In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio.

Paritaprevir, ritonavir, ombitasvir, and dasabuvir treatment in renal transplant patients with hepatitis C virus infection.

BACKGROUND/AIMS: The Social Security System of our country reimburses only paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD) regime in treatment-naive patients with hepatitis C regardless of kidney disease. Most of our renal transplant (RT) recipients were treated with PrOD. The aim of the present study was to investigate the efficacy and safety of PrOD in RT patients with hepatitis C virus (HCV) infection in a single center real-life experience. MATERIALS AND METHODS: RT recipients with a post-transplant follow-up of at least 1 year were included in the study. The patients were treated and monitored according to the guidelines. Blood levels of immunosuppressive patients were closely followed up and adjusted. RESULTS: A total of 21 (12 male and nine female) patients were assessed. The age of the patients was 50.8±8.5 years. Ten patients were infected with G1a, 10 patients with G1b, and one patient with G4 HCV. Two patients had compensated cirrhosis. Eighteen patients were treatment-naive, and three were peginterferon+ribavirin-experienced. Sustained virologic response (SVR12) was achieved in all patients. None of the patients discontinued the treatment. Cyclosporine (Csa) and tacrolimus (Tac) doses were reduced to once a day to once a week to maintain the blood level within normal range. The most common adverse effect was anemia in patients receiving ribavirin. Renal functions did not change during the treatment period. CONCLUSION: In this real-life experience, all of the 21 PrOD-treated RT recipients reached SVR12. Tac or Csa serum levels were maintained within the normal range with close monitoring. PrOD regime can be successfully and safely used in RT recipients with HCV infection with close follow-up.

Vonoprazan versus Lansoprazole for the Initial Treatment of Reflux Esophagitis: A Cost-effectiveness Analysis in Japan.

Objective Gastroesophageal reflux disease (GERD) is a highly prevalent disorder that negatively affects patients' quality of life and reduces their work productivity. The medical expenses associated with the treatment of GERD are the highest among all digestive diseases. Current guidelines recommend the administration of a standard dose of proton pump inhibitor (PPI) for eight weeks as an initial GERD treatment. However, there is growing concern regarding the safety of PPI treatment. Recently, a novel potassium-competitive acid blocker (P-CAB), vonoprazan (VPZ), was approved for the treatment of reflux esophagitis in Japan and may provide clinical benefits in GERD treatment. This study was conducted to evaluate the cost-effectiveness of a P-CAB, VPZ vs. a PPI, lansoprazole (LPZ), for the acute medical treatment of reflux esophagitis. Methods A clinical decision analysis was performed using a Markov chain approach to compare VPZ to LPZ in the acute treatment of reflux esophagitis in Japan. Results The P-CAB strategy was superior to the PPI strategy in terms of cost-effectiveness (direct cost per patient to achieve clinical success) and the number of days for which medication was required. Sensitivity analyses revealed that this superiority was robust within the plausible range of probabilities. This remained true even when the healing rates in cases of mild esophagitis were applied. Conclusion The P-CAB strategy was consistently superior to the conventional PPI strategy using the original LPZ in terms of cost-effectiveness and the number of days for which medication was required. Thus, VPZ appears to be the drug of choice for the acute medical treatment of reflux esophagitis.