Cost-Effectiveness Analysis of Raltegravir in Treatment-

Experienced HIV Patients in Spain

Mohammad A. Chaudhary, Santiago Moreno, Ritesh N. Kumar, Gonzalo Nocea & Elamin Elbasha

International AIDS Economics Network Symposium Cuernavava, Mexico, August 1-2, 2008

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Background

Raltegravir (ISENTRESS®), the first approved integrase inhibitor for managing treatment-experienced HIV patients

Superior efficacy observed at 16, 24, and 48 weeks in combination with optimized background therapy (OBT) versus OBT alone*

Safety profile comparable to placebo*

* N Engl J Med 2008;359:339-54.

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Objective

In light of proven efficacy and safety, the current study evaluates the economic benefits of raltegravir through a cost-effectiveness model

Cost-effectiveness is determined by dividing the incremental costs with the drug by the quality-adjusted life years (QALYs) gained by using the drug.

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Model Overview

Continuous-time state-transition cohort model developed in Mathematica version 6– Markov process with limited history

Two treatment strategies A. Placebo + OBT

B. Raltegravir + OBT

Three sets of differential equations corresponding to opportunistic infection (OI) status:

– No OI

– History of OI

– Current OI

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Model Overview

Each of the three broad health states further stratified by– 8 OI types, 7 HIV RNA levels & 6 CD4 levels

Number of health states

(1 Without + 8 Past + 8 Current) * 7 RNA * 6 CD4 = 714

Opportunistic Infections

Patients progress through each health state depending on the transition rates, treatment group and other factors

Followed up until death.

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HIV Diseases Progression Model

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BENCHMRK population

Characteristics Raltegravir + OBT

Placebo + OBT

Number of patients 462 237

Mean Age, years (SD) 45.7 (8.6) 45.1 (8.1)

Male, % 87.7 88.6

Caucasian, % 65.2 73.0

Mean CD4 Count, cells/mL (SD) 151.4 (141.2) 158.0 (150.4)

GM, HIV RNA, copies/mL 44,252 39,034

Mean HIV RNA, log10 copies/mL (SD) 4.6 (0.8) 4.6 (0.8)

History of AIDS, % 92.5 91.1

Median years of prior ART use 10.1 10.2

Median number of prior ARTs used 12.0 12.0

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Clinical Inputs: HIV RNA

Transition intensity matrices for HIV RNA states estimated from BENCHMRK data

(Kalbfleisch & Lawless, 1985)Two temporal phases– 0 to 4 weeks– 4 weeks to 48 weeks

Annual changes in CD4 are determined as a function of HIV RNA and CD4 levels following EuroSIDAModel assumes treatment effect would remain stable in first 5 years and diminish at a rate of 8% per year thereafter (Phillips et al 2004)

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Clinical Inputs: Mortality data

OIs could have a significant impact on mortality.

Three broad categories of mortality rates depending on OI status

–Without OI: Spanish male life table data

–History of OI: Excess deaths according to CD4 using EuroSIDA data, Olsen et al (2005), The PLATO Collaboration (2004)

–Current OI: Moore & Chaisson (1996) and Chaisson et al (1998)

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Cost Inputs

Drug Costs– OBT Cost: Average drug cost in Spain weighted by

the OBT drug frequencies in BENCHMRK (€ 54.90 per day)

– Raltegravir cost € 27 per day

Resource Use Cost– Resource use by HIV patients stratified by CD4 and

VL levels was obtained from BC Center of Excellence in HIV (Canada)

– Unit prices from Spain

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Quality of Life Inputs

Simpson KN et al (2004) [Base case] Weights by CD4 and VL strataEQ-5D, 21000 patients, recent

Stavem K et al (2005) [Sensitivity analysis]Small sample, recent, weights by CD4 only

Schackman et al. (2002) and Freedberg (1998)). Large sample, weights CD4 strata and by OI, history of OI,

and no OI history

[Sensitivity analysis]

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Cost Effectiveness

*Assumes 5-year treatment duration, raltegravir daily cost of €27; QALY = quality-adjusted life year; ICER = incremental cost effectiveness ratio

Strategy Life Expectancy

(years)

Dis. QALYs(years)

Dis. Cost (€)

ICER(€/QALY)

Placebo+OBT 24.65 10.18 275,50931,431Raltegravir+OB

T29.17 11.90 329,490

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Sensitivity Analysis – I(Assuming 5-Year Raltegravir Treatment Duration)

Parameter Assumption ICER (€/QALY)

---------------- Base case --------------- 31,431

Treatment duration 3 years 22,908

Treatment duration Lifetime 74,468

Analytic time horizon 10 years 59,753

Analytic time horizon 20 years 36,456

Analytic time horizon 30 years 32,495

Cost of OBT per month 50% higher 39,316

Cost of OBT per month 50% lower 23,546

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Sensitivity Analysis - II(Assuming 5-Year Raltegravir Treatment Duration)

Parameter Assumption ICER (€/QALY)

Cost of raltegravir per month 20% higher 36,183

Cost of raltegravir per month 20% lower 26,678

Discount rate/ year: costs & benefits None 21,325

Discount rate/ year: costs & benefits 3% 23,414

Incidence of OI per month None 30,938

Incidence of OI per month Pre cART 32,522

*Base case used pre cCRT OI rates adjusted by data from CASCADE collaboration

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Parameter Assumption ICER (€/QALY)

Decrement in quality of life 25% higher 29,919

Decrement in quality of life 25% lower 33,103

Decrement in quality of life None 39,389

Estimates of quality of life Stavem 28,047

Estimates of quality of life Schackman 42,399

Failure rate after treatment 1% 31,462

Failure rate after treatment 16% 31,396

Sensitivity Analysis – III(Assuming 5-Year Raltegravir Treatment Duration)

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Summary

Long-term outcomes of raltegravir therapy projected using a cohort state-transition model

Model suggests raltegravir provides substantial clinical benefits (e.g., longer life expectancy)

Based on model, raltegravir is cost-effective when added to OBT

Results are however sensitive to– Treatment duration

– Quality of life weights

– Analytical time horizon

ICER also sensitive to cost of OBT and raltegravir still raltegravir cost effective

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Limitations

A model is an abstraction of reality

Did not model explicitly

–Regimen changes over time

–Patient compliance

–Productivity losses

Long-term efficacy not known

Data limitations - multiple sources

–Incidence, duration, and mortality by CD4

–HIV-related mortality by CD4 and VL

–Quality of life weights

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References

1. Babiker A, Darbyshire J, Pezzotti P et al. Changes over calendar time in the risk of specific first AIDS-defining events following HIV seroconversion, adjusting for competing risks. Int J Epidemiol 2002; 31:951-958.

2. Chaisson RE, Gallant JE, Keruly JC, Moore RD. Impact of opportunistic disease on survival in patients with HIV infection. Aids 1998; 12:29-33.

3. Cooper DA et al., Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection, N Engl J Med 2008;359:355-65

4. Freedberg KA, Scharfstein JA, Seage GR, III et al. The cost-effectiveness of preventing AIDS-related opportunistic infections. JAMA 1998; 279:130-136.

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9. Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban clinical cohort. Ann Intern Med 1996; 124:633-642.

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References (Contd.)

10. Olsen CH, Gatell J, Ledergerber B et al. Risk of AIDS and death at given HIV-RNA and CD4 cell counts, in relation to specific antiretroviral drugs in the regimen. Aids 2005; 19:319-330.

11. Phillips AN, Ledergerber B, Horban A et al. Rate of viral rebound according to specific drugs in the regimen in 2120 patients with HIV suppression. Aids 2004; 18:1795-1804.

12. Schackman BR, Goldie SJ, Freedberg KA, Losina E, Brazier J, Weinstein MC. Comparison of health state utilities using community and patient preference weights derived from a survey of patients with HIV/AIDS. Medical Decision Making 2002; 22:27-38.

13. Simpson KN, Luo MP, Chumney E, Sun E, Brun S, Ashraf T. Cost-effectiveness of lopinavir/ritonavir versus nelfinavir as the first-line highly active antiretroviral therapy regimen for HIV infection. HIV Clin Trials 2004; 5:294-304.

14. Stavem K, Froland SS, Hellum KB. Comparison of preference-based utilities of the 15D, EQ-5D and SF-6D in patients with HIV/AIDS. Quality of Life Research 2005; 14:971-980.

15. Steigbigel RT et al., Raltegravir with optimized background therapy for resistant HIV-1 Infection, N Engl J Med 2008;359:339-54.

16. Weinstein MC, Goldie SJ, Losina E et al. Use of genotypic resistance testing to guide HIV therapy: Clinical impact and cost-effectiveness. Annals of Internal Medicine 2001; 134:440-450.