1. Jason R. Andrews, MD Stephen D. Lawn, MD, DTM&H Corina Rusu, BA, BS Robin Wood, FCP, MMed, DTM&H Farzad Noubary, PhD Melissa A. Bender, MD, MPH Robert C. Horsburgh, MD, MS Elena Losina, PhD Kenneth A. Freedberg, MD, MSc Rochelle P. Walensky, MD, MPH for the CEPAC-International Investigators Supported by NIAID, NIGMS, Wellcome Trust, & Doris Duke Charitable Foundation Cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy in South Africa

2. Background In South Africa, 15-30% of individuals initiating ART have undiagnosed pulmonary TB Symptom screening followed by smear microscopy fails to identify a substantial proportion of these patients Sputum culture may identify these patients, but results are not available for weeks, and use is limited by laboratory requirements Bassett et al, Clin Infect Dis, 2010 Lawn et al., AIDS 2010 Lawn et al., PLoS Medicine, In Press

3. Background Xpert MTB/RIF (Xpert), a new, 90-minute TB/rifampicin-resistance diagnostic has demonstrated good performance characteristics in validation studies Concern that the cost of Xpert may present a barrier to its use in resource-limited settings Boehme et al., N Eng J Med 2010 Boehme et al., Lancet 2011 Lawn et al., PLoS Medicine, in Press

4. Study Rationale Operational data demonstrate that Xpert can reduce time to TB diagnosis compared with smear or culture These studies could not address questions about: –Long-term clinical impact of early diagnosis –Cost-effectiveness Boehme et al., Lancet 2011 Lawn et al., PLoS Med, In Press

5. Objective To project the clinical and economic outcomes of using Xpert for individuals initiating ART in a high TB-prevalence setting.

6. CEPAC-International Cost-effectiveness of Preventing AIDS Complications (CEPAC)-International Model –Microsimulation model of HIV and TB natural history and treatment –Simulates cohorts of individuals initiating ART –Clinical and cost data are from South Africa

7. Strategies Examined We examined 5 diagnostic strategies: 1) No TB screening 2) Smear microscopy (2 samples) 3) Culture and drug susceptibility testing (2 concurrent samples, including smear microscopy) 4) 1 Xpert sample 5) 2 Xpert samples (concurrent) Evaluated strategies in two populations initiating ART without known TB: -Patients with TB symptoms -All patients, regardless of symptoms

8. Outcomes Examined Life expectancy Per person lifetime costs Incremental cost-effectiveness ratio (ICER): Additional cost Additional benefit Ratios in USD per year of life saved ($/YLS)

9. Cost-effectiveness Thresholds The WHO defines strategies as: –“Very cost-effective”: ICER <1x per capita GDP –“Cost-effective”: ICER <3x per capita GDP An additional year of life at additional cost of the per capita GDP South Africa 2010 per capita GDP: $7,100 GDP: Gross Domestic Product WHO Commission on Macroeconomics and Health 2001

10. Cohort Input Data: Individuals Starting ART Mean CD4 count: 174 cells/ml 3 Prevalence of Active TB: 22% Prevalence of MDR TB: New Patients: 3.3% Previously Treated: 7.7% Lawn et al., PLoS Medicine, In press Bassett et al., Clin Infect Dis 2010 Lawn et al., AIDS 2010

11. Test Performance and Cost Input Data Test Sensitivity (%) Specificity (%) Cost (USD) WHO symptom screen8433-- Smear (2 samples)2399$9 Culture (2 samples)10099$32 Drug susceptibility testing (1 sample)NA $39 Xpert (smear-positive)99 $22 Xpert (1 sample, smear-negative)4399$22 Xpert (2 samples, smear-negative)6299$44 Lawn et al., PLoS Medicine, In press Lawn et al., AIDS 2010 DST: drug susceptibility testing Costs are in 2010 US Dollars

12. TB Treatment Costs Micro-costing including drugs, x-rays, visits, and hospitalizations First-line TB therapy: $89/month Second-line (MDR) TB therapy: $474/month Sinanovic and Kumaranayake, Cost Effect Res Allocation 2006 Master I. The KZN Program: A King George V Perspective. 2010

13. Results: Life Expectancy (LE) Strategy LE (months) Active TBPopulation No Screening90.6117.1 Smear, symptomatic92.2117.5 Smear, all patients92.5117.6 Culture, symptomatic94.6118.0 Culture, all patients95.3118.2 1 Xpert, symptomatic95.1118.1 1 Xpert, all patients96.0118.3 2 Xpert, symptomatic96.2118.4 2 Xpert, all patients97.2118.6

14. Results: Cost-effectiveness Strategy Cost ($) LE (months) Population ICER ($/YLS) No Screening30,900117.1-- Smear, symptomatic31,020117.54,000 Smear, all patients31,050117.64,200 Cultures, symptomatic31,260118.0dominated Cultures, all patients31,330118.2dominated 1 Xpert, symptomatic31,350118.1dominated 1 Xpert, all patients31,420118.3dominated 2 Xpert, symptomatic31,430118.4dominated 2 Xpert, all patients31,520118.65,200 dominated: less effective or cost-effective than another strategy

15. Lifetime Cost of Xpert Strategy

16. One-way Sensitivity Analysis: TB Prevalence

17. Two-way Sensitivity Analysis: TB Prevalence and Cost of Xpert

18. Limitations Assumed sputum culture is the gold standard for pulmonary TB diagnosis Excluded screening or diagnosis of extrapulmonary TB Excluded benefits of early diagnosis on reducing transmission, which make Xpert even more cost- effective

19. Screening all HIV-infected patients, not just those with symptoms, initiating ART in South Africa with Xpert MTB/RIF is very cost-effective Two samples of Xpert confer more benefit than one sample at minimally higher cost, making it a very favorable strategy Conclusions

20. Cost of Xpert has little impact on cost-effectiveness; the increased costs associated with Xpert are TB and HIV treatment costs in patients who benefit from early diagnosis Symptom screening and smear microscopy should be replaced by Xpert in patients initiating ART in South Africa Conclusions

21. South Africa Linda-Gail Bekker, MD, PhD Neil Martinson, MBBCh, MPH Robin Wood, MD Lerato Mohapi, MD Catherine Orrell, MBBCh, MMed CEPAC-South Africa Investigators United States Ingrid Bassett, MD, MPH Andrea Ciaranello, MD, MPH Madelin Dilorenzo Kenneth Freedberg, MD, MSc Naishin Fu, MPH Sue Goldie, MD, MPH Ben Linas, MD, MPH Elena Losina, PhD Zhigang Lu, MD Alethea McCormick, PhD Bethany Morris Farzad Noubary, PhD A. David Paltiel, PhD Asinath Rusibamayila Paul Sax, MD Bruce Schackman, PhD George Seage, III, PhD Caroline Sloan, AB Alexis Sypek Rochelle Walensky, MD, MPH Milton Weinstein, PhD