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
People living with HIV/AIDS have increased risk of developing tuberculosis (TB)
Rise in TB rates since 1990 and this is driven by the HIV epidemic
Cite graph
High early mortality among people with HIV-TB rapid diagnosis required to avoid death
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
Can say that urine is easily accessible; Many HIV+ pts also have extrapulm TB

4. Lateral-Flow Urine LAM Assay
Immunochromatographic point-of care test
Requires minimal training
No additional equipment or biosafety
Cite the company
Principle of the test
Determine® TB LAM Ag is a lateral flow immunochromatographic rapid test for the qualitative detection of lipoarabinomannan (LAM) antigen in urine. The test is performed by applying 60 μL of urine and examining the reaction line 25 min thereafter. If LAM antigen is present in the sample, it binds to colloidal gold conjugated anti-LAM polyclonal antibodies and proceeds to bind to anti-LAM polyclonal antibodies on the capture line, forming a gray-purple line at the test window (marked patient). The results are stable up to 35 minutes. To assure assay validity, a procedural control line is incorporated in the assay device.
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
Date of evaluation for South African pts

7. Decision Analytic Model
HIV+ (CD4<100) with clinical symptoms of TB
Existing Diagnostics (CXR, SS, etc.) TB
No TB
Existing Diagnostics +
LAM
Assumed that at baseline all participants had an unspecified array of diagnostic tests etc.
Comparing to added urine LAM testing to the same existing array of diagnostic tests
Cost of these diagnostic tests the same in both arms

8. Decision Analytic Model: Base Case ScenarioTB
TB diagnosed by existing tests
Treat
Recover
Die
TB not diagnosed by existing tests
Don’t Treat
Assumptions:
SS+ or LAM+ would definitely get treated
A proportion of patients testing negative will also receive txt based on clinical judgment of treating physician
This proportion remains constant regardless of availability of lateral flow urine LAM
Undiagnosed, untreated TB has case fatality of 1.0 in this immunocompromised population

9. Existing Diagnostics negative for TB
Decision Analytic Model: Base Case Scenario TB
Existing Diagnostics
(CXR, SS, etc.)
indicate TB
Treat
Recover
Die
LAM indicate TB
Existing Diagnostics negative for TB
Don’t Treat
Edit so that LAM doesn’t appear to occur after existing dx

10. Decision Analytic Model: LAM addedTB
Existing Diagnostics
(CXR, SS, etc.)
indicate TB
Treat
Recover
Die
LAM indicate TB
Existing diagnostics negative for TB
Don’t Treat
Edit so that LAM doesn’t appear to occur after existing dx
Existing diagnostics and LAM negative for TB

11. Parameter Values Name Value Range Reference TB Dynamics
TB Prevalence among individuals with HIV and CD4+ <100 cells/uL
0.38
Study data
Probability of death in those with TB and given TB treatment
0.2
WHO
Characteristics of TB Diagnosis
Probability of empiric treatment among smear-negative TB cases
0.53
0-0.75
Field et. al.
Probability of empiric treatment among patients without TB
0.21
0-0.5
Martinson et. al.
LAM Sensitivity
0.66
0.3-1
LAM Specificity
0.95
0.7-1
Sputum Smear Sensitivity
0.345
Lawn et. al.
Sputum Smear Specificity
0.998
Life Expectancy (yrs)
HIV on ART (WHO Clinical Stage IV)
1.45
1-10
ASSA
Unit Cost (2010 USD)
TB Treatment
$850
LAM
$3.50
Sputum Smear
$1.58
Vassall et. al.

12. Existing Diagnostics +
Cost-Effectiveness of Adding Lateral-flow LAM to Standard TB Diagnostics
Cohort Size
TB Cases
TB Cases Treated
False-Positives Treated
DALYs
DALYs averted
Cost
Incr.
ICER
$/DALY
Existing Diagnostics
1000
380
262
130
495
$299,000
(ref)
Existing Diagnostics +
Urine LAM
342
155
437 58
$378,000
$79,000
$1370
Put in GDP per capita
DALYS are so low b/c used conservative estimates.  still LAM was cost-effective  ICER < per capita gdp
* Could also put the prob of ICER <GDP per capita
Addition of urine lateral-flow LAM averts 58 DALYs at a cost of $1370 per DALY averted (95% uncertainty range: $ ).
This is much less than the GDP per capita of South Africa ($7275).

13. Probability of cost-effectiveness
May be able to take out this slide!
Multivariable uncertainty analysis – varied all parameters to see whether urine LAM would fall under threshold
Describe x & y axis
* Per capita GDP is the WHO threshold for highly cost-effective interventions
Falls to 86.3% at a threshold of $2000 and 33.6% at a threshold of $1000.
The probability that urine LAM would cost less than the per-capita gross domestic product ($7275) was 98.3%.

14. Sensitivity Analysis $370 $1370 $2370 $3370
$ $ $ $3370
Comment that the per capita gdp is way off the graph

15. Three-way Sensitivity Analysis
Life Expectancy after TB Cure: 1.5 yrs Life Expectancy after TB Cure: 5 yrs
Three way sensitivity analysis on prevalence, spec, and LE
The black line is the set of parameters at which the ICER for urine LAM = per capita gdp for SA. Above line it’s more cost effective
Mention ARTs!
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%

16. 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
For high-burden settings- mention lower resources than SA

17. 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
Increasing life expectancy to 5 years, which is feasible with prompt antiretroviral agents, substantially improves cost-effectiveness
In hospitalized, HIV-coinfected South African adults, addition of urine lateral-flow LAM testing to standard TB diagnostics detected an additional 80 cases of TB at an incremental cost of $79,000 per 1,000 individuals tested, or $1370 per DALY averted.
Cost effectiveness- 50 years of life lived by one person = 1 year of life lived by 50; 1 yr of guaranteed life or 1/50 chance at 50 yrs

18. References
WHO | Global tuberculosis control (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. (accessed 2 Feb2012).
Actuarial Society of South Africa. ASSA2008 AIDS and Demographic Model. (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:e
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.

19. 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
CDRC logo