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. 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. 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. 4 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

5. 5 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.

6. 6 HIV Diseases Progression Model

7. 7 BENCHMRK population CharacteristicsRaltegravir + OBTPlacebo + OBT Number of patients462237 Mean Age, years (SD)45.7 (8.6)45.1 (8.1) Male, %87.788.6 Caucasian, %65.273.0 Mean CD4 Count, cells/mL (SD)151.4 (141.2)158.0 (150.4) GM, HIV RNA, copies/mL44,25239,034 Mean HIV RNA, log10 copies/mL (SD)4.6 (0.8) History of AIDS, %92.591.1 Median years of prior ART use10.110.2 Median number of prior ARTs used12.0

8. 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. 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. 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. 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. 12 Cost Effectiveness *Assumes 5-year treatment duration, raltegravir daily cost of € 27; QALY = quality- adjusted life year; ICER = incremental cost effectiveness ratio StrategyLife Expectancy (years) Dis. QALYs (years) Dis. Cost (€) ICER (€/QALY) Placebo+OBT24.6510.18275,509 31,431 Raltegravir+OBT29.1711.90329,490

13. 13 Sensitivity Analysis – I (Assuming 5-Year Raltegravir Treatment Duration) ParameterAssumptionICER (€/QALY) ---------------- Base case ---------------31,431 Treatment duration3 years22,908 Treatment durationLifetime74,468 Analytic time horizon10 years59,753 Analytic time horizon20 years36,456 Analytic time horizon30 years32,495 Cost of OBT per month50% higher39,316 Cost of OBT per month50% lower23,546

14. 14 Sensitivity Analysis - II (Assuming 5-Year Raltegravir Treatment Duration) ParameterAssumptionICER (€/QALY) Cost of raltegravir per month20% higher36,183 Cost of raltegravir per month20% lower26,678 Discount rate/ year: costs & benefitsNone21,325 Discount rate/ year: costs & benefits3%23,414 Incidence of OI per monthNone30,938 Incidence of OI per monthPre cART32,522 *Base case used pre cCRT OI rates adjusted by data from CASCADE collaboration

15. 15 ParameterAssumptionICER (€/QALY) Decrement in quality of life25% higher29,919 Decrement in quality of life25% lower33,103 Decrement in quality of lifeNone39,389 Estimates of quality of lifeStavem28,047 Estimates of quality of lifeSchackman42,399 Failure rate after treatment1%31,462 Failure rate after treatment16%31,396 Sensitivity Analysis – III (Assuming 5-Year Raltegravir Treatment Duration)

16. 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. 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

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