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

TB and HIV in South Africa

• TB is the leading cause of non-injury death in South Africa

• TB diagnosis is especially difficult in HIV+ patientso Sputum Smear Microscopy (SSM) sensitivity range as low as 20%

o Atypical clinical characteristics

• Novel modalities required to rapidly diagnose and treat these patients

WHO Global Tuberculosis Control 2011

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

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

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

Methods

• Cohort study of hospitalized South African adults

• Cost-effectiveness analysis o Decision analysiso Primary outcome: Incremental Cost-Effectiveness Ratio ($/DALY averted)

• Sensitivity and uncertainty analyses performed on all parameterso To determine the settings in which urine LAM may be cost-effective

Decision Analytic Model

HIV+ (CD4<100)

with clinical

symptoms of TB

Existing Diagnostics (CXR, SS, etc.)

TB

No TB

Existing Diagnostics

+

LAM

TB

No TB

TB

Existing Diagnostics

(CXR, SS, etc.)

indicate TB

Treat

Recover

Die

LAM indicate TB Treat

Recover

Die

Existing Diagnostics negative for TB

Treat

Recover

Die

Don’t Treat Die

Decision Analytic Model: Base Case Scenario

Decision Analytic Model: LAM added

TB

Existing Diagnostics

(CXR, SS, etc.)

indicate TB

Treat

Recover

Die

LAM indicate TB Treat

Recover

Die

Existing diagnostics negative for TB

Treat

Recover

Die

Don’t Treat Die

Existing diagnostics and LAM negative for TB

Name Value Range Reference

TB Dynamics      TB Prevalence among individuals with HIV and CD4+ <100 cells/uL

0.38 0.12-0.5 Study data

Probability of death in those with TB and given TB treatment

0.2 0.17-.23 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 Study dataLAM Specificity 0.95 0.7-1 Study dataSputum Smear Sensitivity 0.345 0.2-0.5 Lawn et. al.Sputum Smear Specificity 0.998 0.8483-1 Lawn et. al.

Life Expectancy (yrs)      HIV on ART (WHO Clinical Stage IV) 1.45 1-10 ASSA

Unit Cost (2010 USD)      TB Treatment $850 500-2000 WHOLAM $3.50 2.98-30 Lawn et. al.Sputum Smear $1.58 1.34-1.82 Vassall et. al.

Parameter Values

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.Cost

ICER$/DALY

Existing Diagnostics

1000 380 262 130 495 $299,000 (ref)

Existing Diagnostics

+ Urine LAM

1000 380 342 155 437 58 $378,000 $79,000 $1370

• 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).

Sensitivity Analysis

Sputum Smear Sensitivity

Probability of empiric treatment, no TB

Time to death, untreated TB and CD4<100

LAM cost

Probability of empiric treatment, TB cases

LAM sensitivity

Prevalence of TB among suspects, CD4<100

Life expectancy, TB suspect and CD4<100

Cost of TB treatment

LAM specificity

ICER ($/DALY averted)

Low ValuesHigh Values

$370 $1370 $2370 $3370

Three-way Sensitivity Analysis

Life Expectancy after TB Cure: 1.5 yrs Life Expectancy after TB Cure: 5 yrs

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TB Prevalence Among Suspects

LA

M S

pe

cif

icit

y

Existing diagnosticsPreferred

LAM Preferred

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TB Prevalence Among Suspects

LA

M S

pe

cif

icit

y

ExistingDiagnosticsPreferred

LAM Preferred

• 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%

Limitations

• Study outcomes: Sensitivity and Specificityo No empirical evidence that addition of urine LAM improves survival

• Did not model transmissiono 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

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

References

1. WHO | Global tuberculosis control 2011. http://www.who.int/tb/publications/global_report/en/ (accessed 22 Feb2012).

2. Salpeter SR. Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis. West J Med 1993; 159:560–564.

3. 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.

4. 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.

5. 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.

6. 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).

7. Actuarial Society of South Africa. ASSA2008 AIDS and Demographic Model. http://aids.actuarialsociety.org.za/ASSA2008-Model-3480.htm (accessed 8 Feb2012).

8. 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.

9. 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.

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