Cost-Effectiveness Analysis of Raltegravir in Treatment-Experienced HIV Patients in Spain

1. 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

2. 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.

3. 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.

4. Model Overview • Continuous-time state-transition cohort model developed in Mathematica version 6 • Markov process with limited history • Two treatment strategies • Placebo + OBT • Raltegravir + OBT • Three sets of differential equations corresponding to opportunistic infection (OI) status: • No OI • History of OI • Current OI

5. Opportunistic Infections 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 • Patients progress through each health state depending on the transition rates, treatment group and other factors • Followed up until death.

6. HIV Diseases Progression Model

7. BENCHMRK population

8. 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 EuroSIDA • Model assumes treatment effect would remain stable in first 5 years and diminish at a rate of 8% per year thereafter (Phillips et al 2004)

9. 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)

10. 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

11. Quality of Life Inputs • Simpson KN et al (2004) [Base case] • Weights by CD4 and VL strata • EQ-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]

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

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

14. Sensitivity Analysis - II(Assuming 5-Year Raltegravir Treatment Duration) *Base case used pre cCRT OI rates adjusted by data from CASCADE collaboration

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

16. 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

17. 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

18. References • 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. • Chaisson RE, Gallant JE, Keruly JC, Moore RD. Impact of opportunistic disease on survival in patients with HIV infection. Aids 1998; 12:29-33. • Cooper DA et al., Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection, N Engl J Med 2008;359:355-65 • Freedberg KA, Scharfstein JA, Seage GR, III et al. The cost-effectiveness of preventing AIDS-related opportunistic infections. JAMA 1998; 279:130-136. • Jackson CH, Multi-state Modeling with R, the msm package, Version 0.7.6, The R Foundation for Statistical Computing, Version 2.7.0, 2008. • Kalbfleisch JD and Lawless JF . The analysis of panel data under a Markov assumption. Journal of the American Statistical Association, 80(392):863–871, 1985. • Ledergerber B, Lundgren JD, Walker AS et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes (PLATO Collaboration). Lancet 2004; 364:51-62. • Mocroft A, Ledergerber B, Viard JP et al. Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group. J Infect Dis 2004; 190:1947-1956. • Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban clinical cohort. Ann Intern Med 1996; 124:633-642.

19. References (Contd.) • 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. • 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. • 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. • 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. • 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. • Steigbigel RT et al., Raltegravir with optimized background therapy for resistant HIV-1 Infection, N Engl J Med 2008;359:339-54. • 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.