Di Sun 1 ; Susan Dorman 2,3,4 ; Maunank Shah 2,3,4 ; Yukari C. Manabe 3,5 ; David W. Dowdy 1,3,4

1. Cost-Effectiveness of a Lateral-Flow Urine Lipoarabinomannan Test for TB diagnosis in HIV-infected South African Adults Di Sun1; Susan Dorman2,3,4; Maunank Shah2,3,4; Yukari C. Manabe3,5; David W. Dowdy1,3,4 1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA;2Johns Hopkins School of Medicine, Baltimore, MD, USA; 3Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA;4Tuberculosis Clinical Diagnostics Research Consortium (TB-CDRC); 5 Infectious Disease Institute, Kampala, Uganda

2. TB and HIV in South Africa WHO Global Tuberculosis Control 2011 • TB is the leading cause of non-injury death in South Africa • TB diagnosis is especially difficult in HIV+ patients • Sputum Smear Microscopy (SSM) sensitivity range as low as 20% • Atypical clinical characteristics • Novel modalities required to rapidly diagnose and treat these patients

3. Lipoarabinomannan (LAM) • LAM is an immunogenic glycolipid found in the cell wall of Mycobacterium tuberculosis • LAM antigen can be detected in urine • Highest sensitivity in patients with high bacillary burden who have more detectable antigen in urine • Immunosuppressed patients • Disseminated TB • Sensitivity is limited in individuals with CD4 >100 http://www.birmingham.ac.uk/staff/profiles/biosciences/alderwick-luke.aspx

4. Lateral-Flow Urine LAM Assay • Immunochromatographic point-of care test • Requires minimal training • No additional equipment or biosafety Determine TB-LAM Alere, Waltham, MA, USA

5. Purpose Evaluate the cost-effectiveness of lateral-flow urine LAM assay in HIV-infected South African adults and the economic conditions under which it is most likely to be preferred

6. Methods • Cohort study of hospitalized South African adults • Cost-effectiveness analysis • Decision analysis • Primary outcome: Incremental Cost-Effectiveness Ratio ($/DALY averted) • Sensitivity and uncertainty analyses performed on all parameters • To determine the settings in which urine LAM may be cost-effective

7. Decision Analytic Model

8. Decision Analytic Model: Base Case Scenario

9. Decision Analytic Model: LAM added • Existing diagnostics and LAM negative for TB

10. Parameter Values

11. Cost-Effectiveness of Adding Lateral-flow LAM to Standard TB Diagnostics • Addition of urine lateral-flow LAM averts 58 DALYs at a cost of $1370 per DALY averted (95% uncertainty range: $710-3396). • This is much less than the GDP per capita of South Africa ($7275).

12. Sensitivity Analysis • $370 $1370 $2370 $3370

13. Three-way Sensitivity Analysis Life Expectancy after TB Cure: 1.5 yrs Life Expectancy after TB Cure: 5 yrs • To be cost-effective at an assay specificity of 95% • When life expectancy is 1.5 yrs, TB prevalence must be at least 5% • When life expectancy is 5 yrs, TB prevalence must be at least 1%

14. Limitations • Study outcomes: Sensitivity and Specificity • No empirical evidence that addition of urine LAM improves survival • Did not model transmission • Transmission time unlikely to be reduced with addition of urine LAM due to advanced disease • May not be generalizable to other populations • Outpatient setting • Other high-burden settings

15. Conclusions • Lateral-flow urine LAM is a feasible point-of-care test in hospitalized South African adults • Urine LAM is a cost-effective diagnostic strategy • ICER: $1370/DALY averted, South Africa GDP: $7275 • Robust across wide range of sensitivity and uncertainty analysis • Cost-effectiveness depends most strongly on LAM specificity, life expectancy, and TB prevalence • Highly cost-effective with longer life expectancy

16. References • WHO | Global tuberculosis control 2011. http://www.who.int/tb/publications/global_report/en/ (accessed 22 Feb2012). • Salpeter SR. Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis. West J Med 1993; 159:560–564. • Field N, Murray J, Wong ML, Dowdeswell R, Dudumayo N, Rametsi L, et al. Missed opportunities in TB diagnosis: a TB process-based performance review tool to evaluate and improve clinical care. BMC Public Health 2011; 11:127. • Martinson NA, Karstaedt A, Venter WF, Omar T, King P, Mbengo T, et al. Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. AIDS 2007; 21:2043–2050. • Lawn SD, Ayles H, Egwaga S, Williams B, Mukadi YD, Santos Filho ED, et al. Potential utility of empirical tuberculosis treatment for HIV-infected patients with advanced immunodeficiency in high TB-HIV burden settings [Unresolved issues]. The International Journal of Tuberculosis and Lung Disease 2011; 15:287–295. • WHO | The global burden of disease: 2004 update. http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html (accessed 2 Feb2012). • Actuarial Society of South Africa. ASSA2008 AIDS and Demographic Model. http://aids.actuarialsociety.org.za/ASSA2008-Model-3480.htm (accessed 8 Feb2012). • Vassall A, van Kampen S, Sohn H, Michael JS, John KR, den Boon S, et al. Rapid Diagnosis of Tuberculosis with the Xpert MTB/RIF Assay in High Burden Countries: A Cost-Effectiveness Analysis. PLoS Med 2011; 8:e1001120. • Russell LB, Gold MR, Siegel JE, Daniels N, Weinstein MC. The role of cost-effectiveness analysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine. JAMA 1996; 276:1172–1177.

17. Acknowledgements • Susan Dorman, MD • David Dowdy, MD/PhD • Yukari Manabe, MD • Maunank Shah, MD • Johns Hopkins Center for TB Research • TB Clinical Diagnostics Research Consortium • Doris Duke Clinical Research Foundation