Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P=0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P<0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P=0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Vitamin D Assessment Over 48 Weeks in Treatment-Naive HIV Individuals Starting Lopinavir/Ritonavir Monotherapy.

BACKGROUND: Vitamin D deficiency is common in HIV population and has been associated with increased comorbidity risk and poor immunologic status. OBJECTIVE: To evaluate the effect of protease inhibitor lopinavir/ritonavir monotherapy on changes in serum 25-hydroxyvitamin D [25(OH)D] over 48 weeks. METHODS: Thirty-four treatment-naïve HIV individuals initiating lopinavir/ritonavir monotherapy and receiving clinical care from private practice in Houston, Texas, were included. Serum 25-hydroxyvitamin D levels from stored plasma samples collected from IMANI-2 pilot study at both baseline and 48 weeks were analyzed using LC-MS assays. Mean 25(OH)D at baseline and 48 weeks were compared using paired t-tests. Linear regression analysis was used to evaluate factors associated with changes in 25(OH)D. Logistic regression analyses were used to determine the effect of vitamin D status and covariates on CD4 cell count recovery. RESULTS: Mean 25(OH)D was significantly higher at 48 weeks (26.3 ng/mL (SD + 14.9); p=0.0003) compared to baseline (19.8 ng/mL (SD +12.1), with fewer individuals having vitamin D deficiency (41.2%) and severe deficiency (11.8%). Both body mass index and baseline CD4 cell count were significant independent covariates associated with 25(OH)D changes over 48 weeks. Baseline vitamin D status did not affect CD4 cell count recovery. However, in a 24-week multivariate analysis, current tobacco use was significantly associated with a decreased odds of CD4 cell count recovery (AOR 0.106, 95% CI 0.018-0.606; p=0.012). CONCLUSION: Individuals treated with lopinavir/ritonavir monotherapy had significantly higher 25(OH)D after 48 weeks. Current tobacco users had significantly diminished CD4 cell count recovery after starting treatment, warranting further clinical investigation.

Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.

Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.

Conflicting Perspectives on the Value of Neprilysin Inhibition in Heart Failure Revealed During Development of a Decision Aid Focusing on Patient Costs for Sacubitril/Valsartan.

BACKGROUND: Despite concerns about rising costs in health care, cost is rarely an issue discussed by patients and clinicians when making treatment decisions in a clinical setting. This study aimed to understand stakeholder perspectives on a patient decision aid (PtDA) meant to help patients with heart failure choose between a generic and relatively low-cost heart failure medication (ACE [angiotensin-converting enzyme] inhibitor or angiotensin II receptor blocker) and a newer, but more expensive, heart failure medication (angiotensin II receptor blocker neprilysin inhibitor). METHODS AND RESULTS: Feedback on the PtDA was solicited from 26 stakeholders including patients, clinicians, and the manufacturer. Feedback was recorded and discussed among development team members until consensus regarding both the interpretation of the data and the appropriate changes to the PtDA was reached. Stakeholders found the PtDA sufficient in clarifying the different treatment options for heart failure. However, patients, physicians, and the manufacturer had different opinions on the importance of highlighting cost in a PtDA. Patients indicated issues of cost were crucial to the decision while physicians and manufacturers expressed that the cost issue was secondary and should be de-emphasized. CONCLUSIONS: The stratified perspectives on the role of cost in medical decision-making expressed by our participants underscore the importance and challenge of having clear, frank discussions during clinic visits about treatment cost and perceived value.

Angiotensin Receptor Neprilysin Inhibitors-2019 Update.

An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.

A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC).

BACKGROUND: Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA. METHODS: The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0-10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded. DISCUSSION: NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02693093 . Registered through the National Institutes of Health on 26 February 2016.

[Current drug treatment of hepatitis C : Useful therapy algorithms taking into consideration economical aspects]. / Aktuelle Arzneimitteltherapie der Hepatitis C : Sinnvolle Therapiealgorithmen unter Berücksichtigung ökonomischer Aspekte.

Treatment of chronic hepatitis C (HCV) has changed dramatically since the approval of the direct-acting antivirals (DAA). Depending on the HCV genotype and the stage of liver disease, sustained HCV clearance can be achieved in more than 95% of patients with a treatment duration of 8-12 weeks in most of the cases. The selection and combination of the drugs depends on previous antivirals therapies, the stage of liver fibrosis, HCV genotype and subtype, viral load at baseline, and renal function. Nowadays, potent antiviral therapy with minimal side effects can be offered to almost every patient. In the real-world setting, a high quality of HCV therapy considering economic aspects has been documented in the German Hepatitis C Registry. A reduction of clinical complications of chronic liver disease by clearance of HCV has already been documented.

Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy

ABSTRACT Introduction. Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. Material and methods. Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. Results. One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. Conclusion. The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.

Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy.

INTRODUCTION: Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. MATERIAL AND METHODS: Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. RESULTS: One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. CONCLUSION: The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.

Outcomes and Costs of Treating Hepatitis C Patients in the Era of First Generation Protease Inhibitors - Results from the PAN Study.

1 OBJECTIVE: Chronic hepatitis C virus infections (HCV) cause a significant public health burden. Introduction of telaprevir (TVR) and boceprevir (BOC) has increased sustained virologic response rates (SVR) in genotype 1 patients but were accompanied by higher treatment costs and more side effects. Aim of the study was to assess outcomes and costs of treating HCV with TVR or BOC in routine care. 2 MATERIAL AND METHODS: Data was obtained from a non-interventional study. This analysis relates on a subset of 1,786 patients for whom resource utilisation was documented. Sociodemografic and clinical parameters as well as resource utilisation were collected using a web-based data recording system. Costs were calculated using official remuneration schemes. 3 RESULTS: Mean age of patients was 49.2 years, 58.6% were male. In treatment-naive patients SVR-rates of 62.2% and 55.7% for TVR and BOC were observed (prior relapser: 68.5% for TVR and 63.5% for BOC; prior non-responder: 45.6% for TVR and 39.1% for BOC). Treatment costs are dominated by costs for pharmaceuticals and range between €39,081 and €53,491. We calculated average costs per SVR of €81,347 (TVR) and €70,163 (BOC) in treatment-naive patients (prior relapser: 78,089 €/SVR for TVR and 82,077 €/SVR for BOC; prior non-responder: 116,509 €/SVR for TVR and 110,156 €/SVR for BOC). Quality of life data showed a considerable decrease during treatment. 4 CONCLUSION: Our study is one of few investigating both, outcomes and costs, of treating HCV in a real-life setting. Data can serve as a reference in the discussion of increasing costs in recently introduced agents.

The cost-effectiveness of daclatasvir-based regimens for the treatment of hepatitis C virus genotypes 1 and 4 in the UK.

OBJECTIVE: This study aimed to determine the cost-effectiveness of daclatasvir in combination with other medicinal products for the treatment of patients with hepatitis C virus genotypes 1 and 4 and advanced liver disease in the UK. METHODS: A published and validated Markov model designed to simulate the natural history of chronic hepatitis C was used to compare daclatasvir with relevant treatment options for patients with hepatitis C virus genotypes 1 and 4 and a METAVIR score of F3-F4. Patients were defined according to their treatment status; that is, naive, experienced or interferon ineligible/intolerant. Data inputs for the analysis were derived from published sources, UK-specific where possible. A lifetime horizon was used, with costs and benefits discounted at 3.5%. RESULTS: Daclatasvir-based regimens are estimated to be cost-effective versus no treatment and established standard-of-care regimens, including telaprevir in combination with pegylated interferon-α+ribavirin (PR), boceprevir in combination with PR and PR alone (incremental cost-effectiveness ratio range: £3715-£15,408). The cost-effectiveness of daclatasvir-based regimens versus emerging regimens (sofosbuvir or simeprevir based) is less consistent, but was dominant or cost-effective (incremental cost-effectiveness ratio range: £1394-£28,393) in all except two scenarios. CONCLUSION: Daclatasvir-based regimens are expected to be highly cost-effective for the majority patients with advanced disease versus relevant comparator regimens, including newer direct-acting antiviral regimens.

[Cost-effectiveness and safety of telaprevir and boceprevir for chronic hepatitis C in real-world clinical practice]. / Coste-efectividad y seguridad de telaprevir y boceprevir para el tratamiento de la hepatitis C crónica en la práctica clínica.

INTRODUCTION: Triple therapy with telaprevir or boceprevir has proven to be effective in the treatment of chronic hepatitis C with response rates of up to 88%. However, the treatment may be associated with important adverse effects and a high economic impact. OBJECTIVE: To assess the cost-effectiveness and safety of triple therapy with telaprevir or boceprevir for the treatment of chronic hepatitis C. METHODS: Retrospective observational study. We included all patients who had started treatment with protease inhibitors before July 31(st), 2013. We evaluated sustained virological response, the cost per patient achieving sustained virological response, and the cost of the supportive treatment for adverse events associated with triple therapy. RESULTS: Fifty-nine patients were included; 35 had been treated with telaprevir (59.3%) and 24 with boceprevir (40.7%). Sustained virological response was achieved by 38 (64.4%) patients: 24 (68.6%) patients in the telaprevir treatment arm and 14 (58.3%) patients in the boceprevir treatment arm. The cost per patient with sustained virological response was 43,555 € (95% CI 35,389-51,722 €). There were no statistically significant differences between the overall costs of therapy with telaprevir, 43,494 € (95% CI 34,795 €-55,092 €) versus boceprevir, 42,005 € (95% CI 32,122-64,243€). The mean cost of supportive care per patient was 1,500 €, while the maximum cost was 11,374 €. Due to adverse events, 8 (13.6%) patients required hospital admission, 22 (37.3%) patients attended the accident and emergency department, and 26 (44.1%) patients needed additional medical consultations. CONCLUSIONS: The treatment of triple therapy with telaprevir or boceprevir resulted in high cost per patient with sustained virological response. Due to adverse events, a high number of patients required supportive care, whose costs should be added to those of triple therapy.

A cost utility analysis of simeprevir used with peginterferon + ribavirin in the management of genotype 1 hepatitis C virus infection, from the perspective of the UK National Health Service.

INTRODUCTION: Triple therapy using a protease inhibitor (PI) with peginterferon and ribavirin (PR) is increasingly used in patients with chronic hepatitis C virus (HCV) infection. The most recently introduced PI, simeprevir (SMV), offers high levels of viral eradication combined with a reduced overall duration of therapy. The objective of this study was to compare the cost-effectiveness of SMV + PR vs PR alone or in combination with telaprevir (TVR) or boceprevir (BOC) in patients infected with genotype 1 HCV Method: A cost-utility model was constructed, incorporating two phases, capturing the efficacy of therapy in an initial treatment phase, followed by a long-term post-treatment Markov phase, capturing lifetime outcomes according to whether a sustained viral response (SVR) had been achieved on treatment. Dosage regimens were based on the EMA approved label for each treatment. SVR estimates and adverse event rates were derived from a mixed treatment comparison. Baseline characteristics were drawn from an analysis of a UK HCV data-set and clinician opinion. Health state transition probabilities, utilities, and health state costs were drawn from previously published economic analyses. The model considered direct health costs only, and the perspective was that of the UK National Health Service. RESULTS: The model yielded an ICER for SMV + PR vs PR alone of £9725/QALY for treatment-naïve and £7819/QALY for treatment-experienced. Benefit was driven by increased likelihood of achieving SVR, with consequent long-term utility gains. SMV + PR dominated TVR + PR and BOC + PR in both patient groups. This principally reflected the QALY benefit of an increased likelihood of SVR with SMV, combined with lower overall drug costs, due to reduced mean treatment duration. CONCLUSION: Compared to other currently licensed treatment options, SMV + PR represents a cost effective treatment option for patients with chronic genotype 1 HCV infection.

Triple therapy with first generation HCV protease inhibitors: lead-in or no lead-in phase?

The standard therapeutic approach currently recommended for patients infected with genotype 1 hepatitis C virus (HCV) is the triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV)and NS3/NS4 protease inhibitors, boceprevir or telaprevir [1]. Protease inhibitors (PIs) are direct acting antiviral drugs (DAA) which, when added to PEG-IFN and RBV, are able to achieve a significant gain in terms of sustained virological response (SVR), both in naïve and treatment-experienced patients [2­5]. The use of these new molecules, despite its in contestable benefits, reveals on the other hand new challenges: the emergence of variants with reduced sensitivity to PIs, the development of new or higher rate of side effects, drug to drug interactions, and significant increase in the overall cost of antiviral therapy. Among the two DAAs commonly used in combination with PEG-IFN and RBV (PEG-IFN/RBV) for the treatment of genotype 1 HCV patients, boceprevir has been licensed with a lead-in phase, while telaprevir has been licensed without. EMA approved regimens of both drugs are reported in Figs. 1 and 2. The lead-in phase represents an initial period of 4 weeks of dual therapy with PEG-IFN/RBV, in standard doses, followed by triple therapy. The concept of lead-in phase was initiated by the Schering­Plough company in order to improve efficacy of boceprevir-based triple therapy. Indeed, by lowering HCV RNA level, a short course of PEG-IFN/RBV may theoretically reduce the risk of viral breakthrough or resistance. However, there is still much controversy regarding the utility of the lead-in phase, some authors advocating its role in improving, and/or predicting triple therapy effectiveness, while others view it as a useless complication of the therapeutic regimen, its chief disadvantage being the inconvenience to the patient.

Telaprevir: a hepatitis C NS3/4A protease inhibitor.

BACKGROUND: Telaprevir is a hepatitis C NS3/4A protease inhibitor approved by the US Food and Drug Administration as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection. OBJECTIVE: The article reviews published literature on telaprevir, including its chemistry, mechanism of action, resistance, pharmacodynamic and pharmacokinetic properties, drug interactions, therapeutic efficacy, HIV/HCV coinfection, pharmacogenomics, adverse events, pharmacoeconomics, and dosing and administration. METHODS: English-language literature was included. Searches of MEDLINE and BIOSIS databases from 1975 through January 2012 were performed. Emphasis was placed on reference citations involving clinical trials, randomized controlled trials, and research in humans. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from recent scientific meetings. Search terms included, but were not limited to, telaprevir, VX-950, hepatitis C virus genotype 1, resistance, pharmacology, pharmacokinetics, pharmacodynamics, drug interactions, pharmacogenomics, adverse events, and therapeutic use. RESULTS: Review of the databases revealed 471 publications/abstracts on this subject. Of these, 85 were chosen based on the review criteria. Two Phase III studies investigated the efficacy and tolerability of telaprevir administered for 12 weeks (T12) when used with peginterferon alfa and ribavirin (PR) in treatment-naive subjects. The ADVANCE study reported that patients who had an extended rapid virologic response (eRVR; an undetectable HCV RNA level at both 4 and 12 weeks of treatment) with triple therapy could be treated with PR for a total of 24 weeks (T12PR24 group) versus standard PR treatment for 48 weeks (PR48 group [control]). The proportions of patients who achieved sustained virologic response (SVR; undetectable HCV RNA concentration at 24 weeks after the completion of therapy) in the T12PR24 and PR48 groups were 89% and 44%, respectively. The ILLUMINATE study reported T12PR24 was noninferior to T12PR48 in patients with an eRVR to combination therapy. In the REALIZE study, patients with a history of relapse responded well to T12PR48 compared with PR48 (SVR, 83% vs 24%). Telaprevir is a substrate/inhibitor of cytochrome P450 (CYP3A4) and a substrate/inhibitor of P-glycoprotein and poses an important risk for drug interactions. Adverse drug events (ADEs) reported most commonly with triple therapy compared with the T or PR regimen alone were rash, pruritus, nausea, diarrhea, and anemia. The serious AEs most commonly reported during T + PR therapy were anemia, rash, and pruritus. Two reports concluded that T combined with PR was not cost-effective due to the high cost of telaprevir. One study reported that the combination of T + PR would be cost-effective if the treatment rate of HCV genotype 1 infected patients reached 50%. CONCLUSION: Including telaprevir as part of triple therapy for the management of chronic HCV genotype 1 infection significantly increases the likelihood of achieving an SVR over standard dual drug therapy (PR) in both treatment-naive and -experienced patients. However, due to the high cost, the use of triple therapy with telaprevir will likely be limited to patient groups known to respond poorly to dual therapy.

Impact of adverse events on costs and quality of life in protease inhibitor-based combination therapy for hepatitis C.

Protease inhibitor with pegylated interferon and ribavirin therapy (PI-PR) increases hepatitis C virus treatment efficacy versus standard of care pegylated interferon and ribavarin therapy [PR]. The adverse event (AE) impact of PI-PR remains under-reported. The authors estimated the AE impact on costs, treatment discontinuation and health-related quality of life (HRQoL) in PI-PR- and PR-treated patients through literature review and cost analysis. HRQoL and safety data were synthesized by instrument, AE and discontinuation rate. AE-related treatment costs were estimated with trial-based AE rates and literature-based protocols, resource utilization and standard costs. No PI-PR study reported HRQoL outcomes. Five PR studies reported that anemia, depression, fatigue and/or influenza-like symptoms negatively affected HRQoL. Decreased HRQoL predicted treatment discontinuation in two PR studies. PI-PR and PR had comparable AE-related treatment discontinuation rates (~12%). Weighted AE-related treatment costs were US$2042, $1835 and $1076 in boceprevir-based PI-PR, PR and telaprevir-based PI-PR, respectively. AE-related burden may increase with PI-PR. Future studies should incorporate AE-related economic and HRQoL outcomes to comprehensively assess costs/benefits.

New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis.

BACKGROUND: Chronic hepatitis C virus is difficult to treat and affects approximately 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy, but they are costly. A genetic assay may identify patients most likely to benefit from this treatment advance. OBJECTIVE: To assess the cost-effectiveness of new protease inhibitors and an interleukin (IL)-28B genotyping assay for treating chronic hepatitis C virus. DESIGN: Decision-analytic Markov model. DATA SOURCES: Published literature and expert opinion. TARGET POPULATION: Treatment-naive patients with chronic, genotype 1 hepatitis C virus monoinfection. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy [pegylated interferon with ribavirin]; triple therapy [standard therapy and a protease inhibitor]). Interleukin-28B-guided triple therapy stratifies patients with CC genotypes to standard therapy and those with non-CC types to triple therapy. OUTCOME MEASURES: Discounted costs (in 2010 U.S. dollars) and quality-adjusted life-years (QALYs); incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B-guided triple therapy were smaller. If the protease inhibitor costs $1100 per week, universal triple therapy costs $102,600 per QALY (mild fibrosis) or $51,500 per QALY (advanced fibrosis) compared with IL-28B-guided triple therapy and $70,100 per QALY (mild fibrosis) and $36,300 per QALY (advanced fibrosis) compared with standard therapy. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the cost of protease inhibitors and treatment adherence rates. LIMITATION: Data on the long-term comparative effectiveness of the new protease inhibitors are lacking. CONCLUSION: Both universal triple therapy and IL-28B-guided triple therapy are cost-effective when the least-expensive protease inhibitor are used for patients with advanced fibrosis. PRIMARY FUNDING SOURCE: Stanford University.

Formulary management of the protease inhibitors boceprevir and telaprevir for chronic hepatitis C virus.

BACKGROUND: Hepatitis C virus (HCV) is the most common chronic bloodborne illness in the United States. The incidence of acute hepatitis C in the United States peaked near 50,000 cases in the late 1980s but has stabilized since 2003 to less than 5,000 cases annually. The combination of pegylated interferon (peginterferon) and ribavirin has been the standard recommended treatment for HCV. Protease inhibitors telaprevir and boceprevir were approved by the FDA in May 2011 for the treatment of hepatitis C genotype 1 in combination with peginterferon and ribavirin. OBJECTIVE: To review the phase 3 trials for telaprevir and boceprevir and provide managed care considerations. METHODS: A MEDLINE review was performed for articles published and available through September 15, 2011, using keywords "boceprevir" or "telaprevir" with an emphasis on phase 3 trials. The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Additional information was obtained from the FDA website. RESULTS: Three phase 3 trials are available for telaprevir, which provided data that were the basis for FDA approval. Boceprevir demonstrated efficacy and safety in 2 pivotal phase 3 trials. Both agents demonstrated statistically significantly higher rates of virologic response compared with the standard of care involving peginterferons and ribavirin. Telaprevir and boceprevir also demonstrated efficacy in the treatment of patients who had previously failed dual therapy for hepatitis C. Safety concerns for both agents include anemia, drug interactions, skin rashes, and gastrointestinal adverse events. CONCLUSIONS: Decision makers have many factors to consider in developing a strategy around hepatitis C. Increased drug costs, patient management, adherence, comparative safety and efficacy, and appropriate utilization management controls are important issues. Payers may consider developing clinical programs to encourage adherence and appropriate use and leverage an appropriate channel to ensure cost-effective therapy.