Cost-effectiveness of Telaprevir Combination Therapy for Chronic Hepatitis C

<div><p>Objective</p><p>To explore the expected long-term health and economic outcomes of telaprevir (TVR) plus peginterferon alfa-2a and ribavirin (PR), a regimen that demonstrated substantially increased sustained virologic response (SVR) compared with PR alone in adults with chronic genotype 1 hepatitis C virus (HCV) and compensated liver disease in the Phase III studies ADVANCE (treatment-naïve patients) and REALIZE (relapsers, partial responders, and null responders to previous PR treatment).</p><p>Study Design</p><p>A decision-analytic model was developed to assess the cost-effectiveness of TVR+PR vs. PR in the United States (US).</p><p>Methods</p><p>Patients first moved through the 72-week decision-tree treatment phase of the model and then entered the cyclic Markov post-treatment phase. Clinical data (patient characteristics, SVR rates, and adverse event rates and durations) were obtained from ADVANCE and REALIZE. Health-state transition probabilities, drug and other costs (in 2012/2013 US dollars), and utility values were obtained from the trials, published studies, and publicly available sources. Outcomes were discounted at 3% per year.</p><p>Results</p><p>Regardless of treatment history, patients receiving TVR+PR were projected to experience fewer liver-disease complications, more life-years, and more quality-adjusted life-years (QALYs) than patients receiving PR. In prior relapsers, TVR+PR was dominant, with lower total medical costs and more QALYs. For the other patient subgroups, incremental costs per QALY gained were between $16,778 (treatment-naïve patients) and$34,279 (prior null responders). Extensive sensitivity analyses confirmed robust model results.</p><p>Conclusions</p><p>At standard willingness-to-pay thresholds, TVR+PR represents a cost-effective treatment option compared with PR alone for patients with chronic genotype 1 HCV and compensated liver disease in the US. Future analyses are needed to compare TVR+PR with all existing HCV treatment options.</p></div

Input Parameter Values, by Health State, Age, and Sex.

<p>DCC indicates decompensated cirrhosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PR, peginterferon alfa-2a plus ribavirin; SVR, sustained virologic response; TVR, telaprevir; US, United States.</p>a<p>Annual probabilities of progression in METAVIR fibrosis score for patients with SVR and with no or mild fibrosis (F0–F2) were assumed to be zero, which was consistent with data reported in various published studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Poynard1" target="_blank">[18]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Poynard2" target="_blank">[34]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Camm2" target="_blank">[35]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Sherman1" target="_blank">[36]</a>.</p>b<p>Patients in the TVR+PR arm of the model received TVR for a total of 12 weeks and peginterferon alfa-2a plus ribavirin for a total of 24 or 48 weeks (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone-0090295-g001" target="_blank">Figure 1</a>).</p>c<p>Post-treatment costs for patients who did not achieve SVR represent incremental costs over those incurred by patients who achieved SVR. Therefore, the model assumed post-treatment costs for patients who achieved SVR were $0. These post-treatment costs do not include additional costs incurred by patients who progressed to DCC, HCC, or liver transplant, which are shown separately.</p>d<p>Consistent with the clinical trial protocols, anemia was managed with ribavirin dose reductions; therefore, costs of epoetin alfa were excluded from the analysis.</p

Input Parameter Values, by Patient Subgroup and Treatment Regimen.^a

<p>HCV indicates hepatitis C virus; N/A, not applicable; PR, peginterferon alfa-2a plus ribavirin; SVR, sustained virologic response; TVR, telaprevir.</p>a<p>All parameter estimates are derived from ADVANCE and REALIZE <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Jacobson1" target="_blank">[13]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Zeuzem1" target="_blank">[14]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295-Vertex1" target="_blank">[15]</a> (Vertex Pharmaceuticals, unpublished data, 2011).</p>b<p>Fibrosis score distributions reflect the combined patient populations of 12-week TVR+PR and PR-alone treatment arms of the clinical trials. Values in each column do not sum to 100% due to rounding; actual values sum to 100%.</p>c<p>Data from ADVANCE and REALIZE were available for patients with baseline fibrosis scores F0 and F1 combined. The model assumed half had baseline fibrosis score F0 and half had baseline fibrosis score F1.</p>d<p>The model included severe treatment-related adverse events that occurred in 2% or more of patients in at least one treatment arm of ADVANCE and REALIZE. Incidence of anemia included moderately severe cases. From REALIZE, data were available for all previously treated patients combined.</p>e<p>See Table S2 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090295#pone.0090295.s001" target="_blank">Appendix S1</a> for utility scores from ADVANCE and REALIZE, from which average utility values were calculated.</p

Base-Case Model Results: Average Per-Patient Lifetime Health and Cost Outcomes by Patient Subgroup.

<p>DCC indicates decompensated cirrhosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICER, incremental cost-effectiveness ratio; PR, peginterferon alfa-2a plus ribavirin; QALY, quality-adjusted life-year; TVR, telaprevir.</p>a<p>Modeled cases of cirrhosis that developed following treatment.</p>b<p>Due to rounding, ICERs differ slightly from calculations using costs, life-years, and QALYs shown in this table.</p>c<p>One treatment dominates another if it exhibits more QALYs at a lower total cost.</p

Differential Mobility Spectrometry Coupled with Multiple Ion Monitoring in Regulated LC-MS/MS Bioanalysis of a Therapeutic Cyclic Peptide in Human Plasma

A differential mobility spectrometry (DMS) in combination with a multiple ion monitoring (MIM) method was developed and validated for quantitative LC-MS/MS bioanalysis of pasireotide (SOM230) in human plasma. Pasireotide, a therapeutic cyclic peptide, exhibits poor collision-induced dissociation (CID) efficiency for multiple reaction monitoring (MRM) detection. Therefore, in an effort to increase the overall sensitivity of the assay, a DMS-MIM approach was explored. By selecting the most abundant doubly charged precursor ion in both the Q1 and Q3 of the mass analyzer in MIM and combining the DMS capability to significantly reduce the high matrix/chemical background noise, this new LC-DMS-MIM method overcomes the sensitivity challenge in the typical MRM method due to poor CID fragmentation of the analyte. Human plasma was spiked with pasireotide with concentrations in the range 0.01–50 ng/mL. Weak cation-exchange solid-phase extraction was employed for sample preparation. The sample extracts were analyzed with a SCIEX QTRAP 6500 system equipped with an ESI source and DMS device. The separation voltage and compensation voltage of the DMS and other parameters of the MS system were optimized to maximize signal responses. The performance of the LC-DMS-MIM assay for quantitative analysis of pasireotide in human plasma was evaluated and compared to those obtained via LC-MRM and LC-MIM without DMS. Overall, the assay sensitivity with DMS-MIM was approximately 5-fold better than that observed in MRM or MIM without DMS. The assay was validated with accuracy (% bias) and precision (% CV) of the QC results at eight concentration levels (0.01, 0.02, 0.05, 0.15, 0.3, 1.5, 15, and 37.5 ng/mL) evaluated ranging from −4.8 to 5.0% bias and 0.7 to 8.6% CV for the intraday and interday runs. The current LC-DMS-MIM workflow can be expanded to quantitative analysis of other molecules that have poor fragmentation efficiency in CID