Cost effectiveness of antiviral treatment Angeline Oi-Shan Lo - - PowerPoint PPT Presentation

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

HKASLD 27th Annual Scientific Meeting and International Symposium on Hepatology

Treatment options for chronic hepatitis B (CHB)

Peginterferon (PEG-IFN)

• Immunomodulation

Nucleos(t)ide analogues (NUC)

• Suppress HBV DNA

Lamivudine; Adefovir; Entecavir; Telbivudine; Tenofovir

Long term treatment Drug resistance Oral administration  Minimal side effects  Finite period of treatment  No problem of resistance  Subcutaneous administration Adverse effects

Response guided therapy in PEG-IFN: 12 week stopping rule

Peginterferon in CHB Sustained response 30-40% Cost, SC administration and side effects Identify good responder for treatment Early stop treatment for non-responders

12-week stopping rule

Sonneveld et al. Hepatology 2013; Rijckborst et al. J Hepatol 2012; Moucari et al. Hepatology 2009 At week 12: HBeAg +ve: HBsAg level > 20,000 IU/ml (NPV 92-98%) HBeAg –ve: fail to achieve quantitative HBsAg decline and ≥ 2 logs HBV DNA reduction (NPV 95%)

Response guided therapy in NUC: Roadmap concept

Low genetic barrier to drug resistance High genetic barrier

Ayoub and Keeffe. Aliment Pharmacol Ther 2011

Response guided therapy in NUC: Roadmap concept

Keeffe et al. Clin Gastroenterol Hepatol 2007

Tenofovir monotherapy Entecavir monotherapy Telbivudine monotherapy Telbivudine roadmap Peginterferon (48 weeks) Peginterferon (12 week stopping rule) No Treatment

24 weeks 24 weeks

CHB treatment strategies

PEG-IFN

TDF ETV

If HBV DNA + switch to TDF

LdT LdT

If HBV DNA – continue LdT

PEG-IFN PEG-IFN

ETV

Continue

If develop resistance, switch to another potent antiviral without cross resistance ETV ETV

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

• utcome?

• ICER Plane
• ICER Equation

Area of rejection Area of acceptance Area of uncertainty Area of uncertainty New treatment less effective New treatment more effective New treatment more costly New treatment less costly

Costs (B) – Costs (A) Effects (B) – Effects (A)

Incremental Cost-effectiveness Ratio (ICER): Plane and Equation

New treatment dominates Old treatment dominates

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 investigations Productivity loss 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 (productivity/ quality of life) The concept of utility (range from 0-1) 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?

How?

• Individual drugs
• Peginterferons
• Nucleos(t)ide analogues
• Strategies, for example:
• Roadmap
• Stopping rule

When?

• 35? 40? 45?

Who?

• According to APASL, EASL,

AASLD guidelines

• NICE guideline

X% Virological response Y% Cirrhosis/HCC/liver related death

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

Tenofovir monotherapy Entecavir monotherapy Telbivudine monotherapy Telbivudine roadmap Peginterferon (48 weeks) Peginterferon (12 week stopping rule) No Treatment

24 weeks 24 weeks

CHB treatment strategies

PEG-IFN

TDF ETV

If HBV DNA + switch to TDF

LdT LdT

If HBV DNA – continue LdT

PEG-IFN PEG-IFN

ETV

Continue

If develop resistance, switch to another potent antiviral without cross resistance ETV ETV

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?

Transition and outcome probabilities follow international and local data A cohort of 35 year-old subjects Both HBeAg +ve and –ve Fulfill treatment criteria

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

4000 6000 8000 10000 12000 14000 Cost of Telbivudine Cost of Peginterferon Peginterferon cessation % under stopping rule Cost of HCC treatment (initial year) Cost of Tenofovir HBV DNA undetectability by Entecavir Utility of Peginterferon HBV DNA undetectability by Peginterferon HBeAg seroconversion rate of Peginterferon HBsAg seroclearance rate of Peginterferon Reactivation rate of Peginterferon Cost of Entecavir

Entecavir cost is most influential on cost-effectiveness

• f PEG-IFN (stopping rule) in HBeAg +ve model
• 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

2000 4000 6000 8000 10000 12000 14000 16000 1500 1500 2000 2000 2500 2500 3000 3000 3500 3500

Cost-effectivess Ratio (USD/QALY) Annual cost of entecavir treatment (USD/year)

PegIFN (stopping rule) PegIFN (48 weeks) Entecavir

Intersection point Entecavir = US$ 2.6/day

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.