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  EASL 46th Annual Meeting
March 30th - April 3rd 2011
Berlin, Germany
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Cost Benefit Analysis of Response Guided Therapy: Dynamic Disease Markov Modeling for Patients with Chronic Hepatitis CVirus (HCV) by Fibrosis Stages
  EASL 2011 Berlin Germany Marc 30-Apr 2
Phil McEwan I Yang Yuan Gilbert Litalien3 Ray Kim4
1. Center for Health Economics, Swansea Univ, Wales
2. Cardiff Research Limited, Cardif UK
3. Global Health Economics & Outcomes Research, BMS, Princeton NJ
4. Mayo Clinic Col of Med Rochester, MN, USA
RGT is a cost-effective alternative to SDT (standard duration therapy) in patients with CHC. This result is primarily driven by the substantial cost savings in the RGT arm which were a result of shorter treatment times in those patients achieving RVR.
The greatest potential cost savings were obtained in patients treated in the earlier stages of disease progression (FO-F2). This contrasts with current clinical guidelines where a watchful waiting approach is typically advocated. However, there is a risk involved with initiating therapy sooner as patients destined to have a benign or slow progression might be needlessly treated. Thus, further research is required to investigate earlier treatment in CHC.
Cost savings in patients with more advanced disease are more limited due to reduced treatment response and increased disease progression rates. However, despite this, RGT remains a dominant strategy when compared to SDT suggesting that this important sub-group would benefit from timely and appropriate treatments.
Background and aims
Chronic hepatitis C (CHC) is associated with a significant and increasing burden in terms of morbidity, mortality and cost. The choice of treatment is continuously evolving to find the most effective way to manage CHC. Treatment decisions are necessarily required to be individualized based on the severity of liver disease, the potential for serious side effects, the likelihood of treatment response, the presence of co-morbid conditions and the patient's readiness for treatment.
In general, Hepatitis C virus (HCV) genotyping has been used to adjust drug dosage and length of therapy. However, more recently, response guide therapy has emerged (RGT) as an alternative way of tailoring treatment. This Innovative concept involves measuring viral kinetics during treatment and adjusting the treatment strategy in accordance with the findings. Thus, patients with a prompt response benefit from a shorter duration of treatment compared to the recommended duration.
Despite the potential benefits of such a treatment approach, there has not been a comprehensive economic evaluation of RGT. This study aims to develop and validate a new modelling design and methodology and thus quantify the costs and benefits of RGT compared to standard duration of therapy (SOT) in patients with HCV genotype 1 using existent study data.
The study utilises the modelling the natural history and Cost-effectiveness of Hepatitis (MONARCH) model, which is a cohort-based Markov model developed in Microsoft Excel. The model simulates the natural history of HCV over a 40-year (lifetime) time horizon. It runs in four-weekly cycles for the first three years to enable anti-viral therapy treatment patterns to be modelled flexibly; following this period, the model progresses in annual cycles. The flow diagram of the MONARCH model is shown in Figure 1.


Patients enter the model at various disease stages defined by the Metavir states; FO - no fibrosis; F1 -portal fibrosis with no septa, F2 - portal fibrosis with few septa; F3 - portal fibrosis with. numerous septa and F4 - compensated cirrhosis; and can be partitioned into Rapid Vlroliglcal Response (RVR); complete Early Virological Response (cEVR); partial Early Virological Response (pEVR), and non-response (NR). Progression though fibrosis stages is controlled via dynamic age-dependent transition probabilities'. At the start of the simulation, the average age of patients in stages FO-F2 and F3-F4 was assumed to be 35 and 45 years old, respectively.
Sustained virological response (SVR) by fibrosis stage with RGT was contrasted with SOT in treatment naive HCV genotype 1 patients. We utilised published data from a large contemporary international trial of peginterferon alfa-2a in combination with ribavirin In treatment naive HCV genotype 1 patientsii. The overall SVR rate, across all fibrosis stages, was 50.5% with a progressively declining response rate from 70% (FO); 60% (F1); 51 % (F2); 31% (F3) and 10% (F4).
The impact of early treatment response was reported by fibrosis groups FO-F2 and F3-F4 with an overall SVR of 57% (FO - F2) and 26% (F3 - F4). Overall 34% of patients in fibrosis stages FO - F2 and 21% of patients in fibrosis stages F3 and F4 had undetectable HCV levels at week Week 4 and this information was used to derive the numbers of patients eligible for shortened treatment duration.
UK costs and utilities were used with costs indexed to 2010; both costs and benefits were discounted at 3.5%.
Table 1 details the results for predicted lifetime per patient costs and benefits for RGT versus SDT, stratified by fibrosis stages at treatment for a cohort of 1000 patients.


It can be seen that RGT was dominant (cost savings and QALY gains) compared to SDT in both fibrosis score groups. Note that the key benefit of RGT compared to SOT is primarily a reduction in cost with only modest improvements observed in QALYs. It can also be seen that better outcomes were obtained in patients with a lower fibrosis score (i.e. higher QALYs and lower costs in FO-F2 compared to F3-F4).
To further evaluate the dominant position of RGT against SOT, cost savings and improved outcomes were assessed by baseline age and fibrosis stage, as shown in Figure 2.


The greatest costs savings were achieved when treating patients in the fibrosis stage FO; with more advanced disease being consistently associated with lower cost savings. The difference in cost is largely independent of treatment age due to savings being predominantly driven by reduced therapy cost.
Better outcomes (in terms of QALYs) were consistently associated with treatment in younger individuals. In terms of fibrosis stage, F2 was associated with the greatest overall QALY gain across all groups.
i Thein HH et al Hepatology 2008;48:418-431
ii CHARIOT study group. J Hepatol 2010 Oct 53(4): 616-23. Epub 2010 Jun 16
iii Hartwell D et al Health Technology Assessment 2009