HKASLD 27 th Annual Scientific Meeting and International Symposium on Hepatology Cost effectiveness of antiviral treatment Angeline Oi-Shan Lo MBChB, MRCP, FHKCP, FHKAM(Medicine) Specialist, Clinical Assistant Professor (Honorary) Division of Gastroenterology and Hepatology The Chinese University of Hong Kong
Treatment options for chronic hepatitis B (CHB) Nucleos(t)ide analogues (NUC) Peginterferon (PEG-IFN) - Suppress HBV DNA - Immunomodulation Lamivudine; Adefovir; Entecavir; Telbivudine; Tenofovir Long term treatment Finite period of treatment Drug resistance No problem of resistance Oral administration Subcutaneous administration Minimal side effects Adverse effects
Response guided therapy in PEG-IFN: 12 week stopping rule Peginterferon in CHB Cost, SC Sustained response administration and 30-40% side effects Identify good Early stop treatment responder for for non-responders treatment At week 12: HBeAg +ve: HBsAg level > 20,000 IU/ml (NPV 92-98%) 12-week stopping rule HBeAg – ve: fail to achieve quantitative HBsAg decline and ≥ 2 logs HBV DNA reduction (NPV 95%) Sonneveld et al. Hepatology 2013; Rijckborst et al. J Hepatol 2012; Moucari et al. Hepatology 2009
Response guided therapy in NUC: Roadmap concept High genetic barrier Low genetic barrier to drug resistance Ayoub and Keeffe. Aliment Pharmacol Ther 2011
Response guided therapy in NUC: Roadmap concept Keeffe et al. Clin Gastroenterol Hepatol 2007
CHB treatment strategies TDF Tenofovir monotherapy ETV Entecavir monotherapy Telbivudine monotherapy LdT If HBV DNA + switch to TDF Telbivudine roadmap LdT If HBV DNA – continue LdT ETV PEG-IFN Peginterferon (48 weeks) ETV Peginterferon PEG-IFN (12 week stopping rule) ETV PEG-IFN No Treatment Continue 24 weeks 24 weeks If develop resistance, switch to another potent antiviral without cross resistance
Start Treatment - Agreed by All Consensus • HBeAg positive patients with ALT persistently >2x ULN • HBeAg negative patients with ALT >2x ULN and HBV DNA >2000 - 20000 IU/ml • Compensated liver cirrhosis with HBV DNA > 2000 IU/ml • Decompensated liver cirrhosis Lok ASF and McMahon BJ. Hepatology 2009 Liaw YF et al. Hepatol Int 2012 EASL. J Hepatol 2012
The NICE guideline • The NICE guideline has presented the data on cost-effectiveness of peginterferon and oral antivirals (mainly lamivudine/adefovir), and take into account when making recommendations. • “… Peginterferon alfa-2a should be recommended as an option in first-line therapy for both HBeAg-positive and HBeAg-negative chronic hepatitis B …”
The recurrent expenditure on medical and health services for 2013-14 will reach $49 billion, an increase of $2.7 billion over 2012-13. The bulk of the additional funding is for new recurrent allocation to the Hospital Authority (HA) to enhance and expand appropriate public medical services … Drug cheaper = better? Pay more to get more?
Incremental Cost-effectiveness Ratio (ICER) How much extra it worth paying for a better clinical outcome?
Incremental Cost-effectiveness Ratio (ICER): Plane and Equation • ICER Plane • ICER Equation Old treatment dominates New treatment more costly Costs (B) – Costs (A) Area of Area of Effects (B) – Effects (A) uncertainty rejection New treatment New treatment less effective more effective Area of Area of acceptance uncertainty New treatment dominates New treatment less costly
Cost-effective threshold • Definition: US$ 50000/LY or QALY gained • 3 x Gross domestic product per capita (usually applied to less developed areas with a low GDP) GDP per capita in 2013: US$ 37,401 If US$ 37,401 x 3 >> 50,000…
Direct Cost Indirect Cost Drug cost Transportation Follow up: clinic visit, lab, radiological Productivity loss investigations Cost of disease complication e.g. transplantation, endoscopy, surgery etc - Decompensated cirrhosis - HCC Life year Quality adjusted life year (QALY) Healthy is better than diseased How the quality of the year perceived by individual subject Young seems to worth more than elderly The concept of utility (range from 0-1) (productivity/ quality of life) e.g. Stable carrier (>0.9), Cirrhosis (0.6-0.7)
Purpose of cost-effectiveness analysis (CEA) in CHB treatment Which antiviral drug or strategy is better? When? - 35? 40? 45? X% Virological response Y% Cirrhosis/HCC/liver related death How? Who? - Individual drugs - According to APASL, EASL, - Peginterferons AASLD guidelines - Nucleos(t)ide analogues - NICE guideline - Strategies, for example: - Roadmap - Stopping rule
Markov modeling Andrey Andreyevich Markov (1856-1922) Russian Mathematician Markov chain, Markov property, Markov decision process… A stochastic (random) model that models the state of a system with a random variable that changes through time
Why do we use Markov modeling for CHB treatment? • Recurrent events are important in CHB patients. • The study time frame is usually long. • The chance of falling into each health state is random year after year. Lo AO et al. Clin Gastroenterol Hepatol. 2014
CHB treatment strategies TDF Tenofovir monotherapy ETV Entecavir monotherapy Telbivudine monotherapy LdT If HBV DNA + switch to TDF Telbivudine roadmap LdT If HBV DNA – continue LdT ETV PEG-IFN Peginterferon (48 weeks) ETV Peginterferon PEG-IFN (12 week stopping rule) ETV PEG-IFN No Treatment Continue 24 weeks 24 weeks If develop resistance, switch to another potent antiviral without cross resistance
Is PEG-IFN (12-week stopping rule) more cost-effective than NUCs in CHB treatment? Lo AO et al. Clin Gastroenterol Hepatol. 2014 [Epub ahead of print]
Is PEG-IFN (12-week stopping rule) more cost-effective? A cohort of 35 year-old subjects Both HBeAg +ve and – ve Fulfill treatment criteria Transition and outcome probabilities follow international and local data Lo AO et al. Clin Gastroenterol Hepatol. 2014
Lifetime costs (USD) and QALYs gained by different strategies in HBeAg +ve patients Peginterferon (stopping rule) ICER = US$ 9501/QALY
Lifetime costs (USD) and QALYs gained by different strategies in HBeAg -ve patients Entecavir ICER = US$ 34,310/QALY Tenofovir ICER = US$ 715,200/QALY
Entecavir cost is most influential on cost-effectiveness of PEG-IFN (stopping rule) in HBeAg +ve model Cost of Entecavir Reactivation rate of Peginterferon HBsAg seroclearance rate of Peginterferon HBeAg seroconversion rate of Peginterferon HBV DNA undetectability by Peginterferon Utility of Peginterferon HBV DNA undetectability by Entecavir Cost of Tenofovir Cost of HCC treatment (initial year) Peginterferon cessation % under stopping rule Cost of Peginterferon Cost of Telbivudine 4000 6000 8000 10000 12000 14000 • Tornado diaphragm of one-way sensitivity analyses on all parameters. • In contrast, the cost of Peginterferon plays a little role in affecting the overall cost- effectiveness. Lo AO et al. Clin Gastroenterol Hepatol. 2014
Effect of entecavir cost reduction 16000 14000 Cost-effectivess Ratio (USD/QALY) Intersection point 12000 Entecavir = US$ 2.6/day 10000 8000 PegIFN (stopping rule) PegIFN (48 weeks) Entecavir 6000 4000 2000 0 1500 1500 2000 2000 2500 2500 3000 3000 3500 3500 Annual cost of entecavir treatment (USD/year) Lo AO et al. Clin Gastroenterol Hepatol. 2014
Take home message • For HBeAg +ve patients, we may consider using peginterferon with 12-week stopping rule as first-line strategy, which is the most cost- effective with a better QALY due to its finite treatment duration. • If the cost of entecavir is less than US$ 2.6/day, entecavir would become the most cost-effective option in HBeAg +ve model. • For HBeAg – ve patients, NUCs have a better QALY and entecavir is currently the most cost-effective treatment option. However, if there is a price reduction in other NUCs (tenofovir / telbivudine), the cost- effectiveness story may have a different ending.
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