Supplemental Digital Content 1: Additional Modeling Parameters
Additional Parameters
Median Age of HIV-infected TB suspect
Percentage of TB suspects with low CD4 (<100)
Base-Case
33
0.61
Range
24-45
0-1
1 (1)
0.5-0.83 years
12.9years
0.05
1.25
1.33
0.75
0.10
.221
0.547
0.053
$12
$1.50
0.75-1 (0.5-1)
0.0833-2years
2-33.5
0-0.3
1-2
1-2
0-1
0-0.75
.146-0.310
0.382-0.715
0.034-0.079
$3-$25
$0-$12
0.77
0.105
0.06
0.065
.62-0.95
0.04-0.30
0.01-0.15
--
[3,16,17,25,26]
[3,16,25]
[3,16]
Drug-Sensitive TB—History of Prior Treatment (second line TB treatment—
Category II)
Treatment success
Death in those given TB treatment
Treatment failure
Treatment default
0.75
0.115
0.065
0.07
0.62-0.95
0.050-0.3
0.04-0.15
--
[3,16,17,25]
[3,16]
[3]
Multi-Drug Resistant TB
Treatment success—MDR-TB regimen
Mortality—MDR-TB regimen
Failure—MDR-TB regimen
Treatment default—MDR-TB regimen
Treatment success with inappropriate treatment (1st or 2nd line TB regimen)
Failure— Treatment with 1st or 2nd line TB regimen
Mortality— Treatment with 1st or 2nd line TB regimen
0.61
0.20
0.08
.11
0.16
0.45
0.34
0.48-0.85
0.04-0.37
0.016-0.15
-0-0.33
0.1-0.55
0.23-0.47
[3, 26, 35, 36]
[3, 26, 35]
[3, 26, 35]
Mortality of untreated HIV-associated smear positive TB (smear-neg/disseminated TB)°°
Life-Expectancy of HIV-infected individual with untreated TB
Life-Expectancy HIV+ after TB recovery (with HAART)
Mortality of TB Suspect without TB
Relative Risk of Death among treated TB cases with CD4 <100 compared to CD4>100
Relative Risk of Death among treated TB cases with diagnostic/therapeutic delay
Percentage of missed diagnoses that will return for repeat evaluation**
Progression to smear-positivity during repeat evaluation
Disability weight symptomatic HIV
Disability weight AIDS no ART
Disability weight HIV on ART
Cost of initial clinical evaluation (inclusive of health officer examination, CD4 and CXR)
Cost of Specimen Transport
New Drug-Sensitive TB Cases (first line treatment)
Treatment success
Death in those given TB treatment
Treatment failure
Treatment default
Diagnostic Parameters by CD4 and Smear-Status
CD4 strata
Sensitivity of ZN smear microscopy
Sensitivity of ZN smear microscopy
Sensitivity of sputum Xpert, Smear-positive TB
CD4<100
CD4>100
CD4>100 and
BaseCase
0.30
0.35
0.98
[3, 12]
[12], Assumption/Study
Data
[3]
[3]
[3,14,27,28]
Assumption;[24]
[28, 30], Assumption
[31, 32], Assumption
Assumption
[3]
[3, 29]
[3, 29]
[3, 29]
[33], [34],Site Data
Site data
[3, 26, 35]
[3, 26, 35]
[3, 26, 35]
Range
Source
0.30-0.44
0.30-0.60
0.85-1
Study Data, [12]
Study Data, [12]
[8, 12, 22], Study Data
CD4<100
Sensitivity of sputum Xpert, Smear-negative TB*
CD4<100
0.66
Sensitivity of sputum Xpert, Smear-negative TB*
CD4>100
0.72
Sensitivity of LF-LAM plus Smear microscopy
CD4<100
0.68
Sensitivity of LF-LAM plus Smear microscopy
CD4>100
0.38
Sensitivity of Xpert plus LF-LAM, Smear-positive TB
CD4<100
0.98
Sensitivity of Xpert plus LF-LAM, Smear-negative TB
CD4<100
0.84
Sensitivity of Xpert plus LF-LAM, Smear-positive TB
CD4>100
0.98
Sensitivity of Xpert plus LF-LAM, Smear-negative TB
CD4>100
0.75
Sensitivity of sputum MGIT culture, Smear-positive TB
-1
Sensitivity of sputum MGIT culture, Smear-negative TB
-0.90
*Smear-negative TB includes both pulmonary TB, as well as extrapulmonary or disseminated forms of HIV-associated TB
**We assumed repeat evaluations occur within 6 months of initial presentation
0.42-0.81
0.50-0.85
0.55-0.9
0.30-0.73
0.85-1
0.67-0.93
0.85-1
0.41-0.85
1
0.85-1
[8, 12, 22], Study Data
Study Data, [2, 12]
Study Data, [2, 12]
Study Data, [2, 12]
Study Data, [2, 12]
Study Data, [2, 12]
Study Data, [2, 12]
Study Data, [2, 12]
Study Data, [2, 12]
Additional Model Details:
Patients were classified as ‘New’ or ‘Previous treatment’ based on receipt of prior TB therapy. All TB suspects were assumed to receive a clinical evaluation
including chest radiograph and CD4 testing in addition to TB diagnostic testing. In all arms, individuals with a history of prior TB treatment that have positive
rapid diagnostic testing (i.e. smear-microscopy and/or urine LF-LAM and/or Xpert) receive additional testing with mycobacterial culture and conventional
phenotypic drug-sensitivity testing (DST) to diagnose drug-resistance; individuals identified as Rifampin-resistant by Xpert also receive confirmatory
mycobacterial culture and conventional DST. Individuals with positive test results or clinical diagnosis of TB without prior history of TB treatment were
assumed to receive a regimen of Rifampin(R), Isoniazid(H), Pyrazinamide(Z), and Ethambutol(E) for a two month intensive phase followed by a four month
continuation phase of RH[37]. Patients with prior TB treatment were assumed to receive a second line regimen that included HRZE plus Streptomycin (S) for the
first two months, followed by one month of HRZE alone and five months of HRE; individuals diagnosed with rifampin-resistance by Xpert or by culture/DST
were assumed to receive an MDR-TB regimen that included four months of kanamycin, ethionamide, pyrazinamide, a floroquinolone, cycloserine followed by
eighteen months of ethionamide, a floroquinolone, and cycloserine[3, 37].
Clinical diagnosis and empiric treatment may decline with the availability of additional diagnostic results[22]. In the reference algorithm of smear-microscopy
and clinical evaluation, we assumed sensitivity of clinical diagnosis for individuals with TB was 30% and specificity was 89%[3, 22, 23]. In the base-case, we
assumed reductions in empiric treatment of TB of 5-10% for algorithms utilizing LF-LAM and/or Xpert, with concomitant increases in specificity of clinical
diagnosis; this parameter was varied in sensitivity analysis.
Schematic for decision tree is shown in Figure 1 for algorithms 1 and 4. Additional model arms for algorithm 2 and 3 are shown below. Breakdown of cost
components for diagnostic tests is also shown below.
Supplemental Figure--Schematic of algorithm utilizing smear-microscopy with LF-LAM alone versus algorithm utilizing Xpert alone
*Individuals are eligible to return to clinic/hospital for repeat evaluation, with incremental increases in diagnosis. We assumed increased TB treatment mortality
for individuals with delayed diagnoses.
Breakdown of cost components for diagnostic tests is shown below.
Labor cost
Diagnostic Test
Consumables cost (% total)
Equipment cost (% total)
Smear microscopy
$0.92 (59%)
$0.39 (20%)
$0.32 (16%)
$0.09 (5%)
MGIT
$8.63 (54%)
$5.87 (36%)
$0.36 (2%)
$1.20 (7.5%)
DST
$16.41 (72%)
$3.47 (15%)
$0.79 (4%)
$2.07 (9%)
Xpert MTB/RIF
$12.20 (70%)
$3.98 (23%)
$0.41 (2%)
$0.83(5%)
LF-LAM
$3.87 (92%)
$0.01 (0.01%)
$0.32 (8%)
$0(0%)
(% total)
Overhead cost (% total)
Total cost per sample (low, high)*
$1.99
($1.33-$3.50)
$16.06
(12.59-$29.80)
$22.73
($16.78-$41.72)
$17.42
($11.36- $40.47)
$4.19
($2.01-10.94)
* Testing volume was estimated based on discussion with clinical and laboratory staff; in the base-case we assumed usage of one 4 cartridge Xpert instrument
with an average of 2 runs per day. Low and high estimates were based on the estimated range of vendor pricing for consumables and equipment, variations in
laboratory wages, and volume of testing. All costs utilize FIND-Negotiated discounted pricing. Xpert cartridge cost was $9.98 per cartridge.
Supplemental Content 2: One-way sensitivity analysis comparing rapid TB diagnostic algorithms
Figure Legend: One-way sensitivity analysis of “Xpert/LF-LAM” algorithm vs “Xpert”, excluding HIV/ART costs. Only parameters impacting ICER
significantly are shown. HIV/ART costs impact on ICER not shown for scale. ICER ranges from $57/DALY-averted to $1709/DALY-averted for annual HIV
costs of $0.0 to $2000. Vertical line is at base-case ICER of $57/DALY-averted. No parameters increased the ICER to above the WTP threshold of per-capita
GDP per DALY-averted.
Figure Legend: One-way sensitivity analysis of “Xpert/LF-LAM” algorithm vs “Xpert”, excluding HIV/ART costs. Only parameters impacting ICER
significantly are shown. HIV/ART costs impact on ICER not shown for scale. ICER ranges from $52/DALY-averted to $1704/DALY-averted for annual HIV
costs of $0.0 to $2000. Vertical line is at base-case ICER of $52/DALY-averted. No parameters increased the ICER to above the WTP threshold of per-capita
GDP per DALY-averted.
Figure Legend: One-way sensitivity analysis of “Xpert/LF-LAM” algorithm vs “Xpert”, excluding HIV/ART costs. Only parameters impacting ICER
significantly are shown. HIV/ART costs impact on ICER not shown for scale. ICER ranges from $33/DALY-averted to $1652/DALY-averted for annual HIV
costs of $0.0 to $2000. Vertical line is at base-case ICER of $33/DALY-averted. No other parameters increased the ICER to above the WTP threshold of percapita GDP per DALY-averted.
Figure Legend: One-way sensitivity analysis of “Xpert/LF-LAM” algorithm vs “Xpert”, excluding HIV/ART costs. Only parameters impacting ICER
significantly are shown. ICER ranges from $108/DALY-averted to $1762/DALY-averted for annual HIV costs of $0.0 to $2000. Vertical line is at base-case
ICER of $108/DALY-averted.
*ICER becomes negative (i.e. cost-saving) when sensitivity of Xpert for smear-negative TB is below 46%, or when sensitivity of Smear/LF-LAM is above 84%
Figure Legend: One-way sensitivity analysis of “Xpert/LF-LAM” algorithm vs “Xpert”, excluding HIV/ART costs. Only parameters impacting ICER
significantly are shown. HIV/ART costs impact on ICER not shown for scale. ICER ranges from $58/DALY-averted to $1710/DALY-averted for annual HIV
costs of $0.0 to $2000. Vertical line is at base-case ICER of $58DALY-averted. No parameters increased the ICER to above the WTP threshold of per-capita
GDP per DALY-averted.
Supplemental Content 3: Costs and effects of rapid TB diagnostic algorithms for HIV infected patients by CD4 count
Supplemental Table 3a: Costs and effects of Diagnostic algorithms for a cohort of 10,000 HIV patients with CD4>100
Algorithm
% TB
Death
Total
DALY’s DALY's ICER
ICER
cases
among Costs
averted
Cost
including
Detected‡ those
(excluding
cohort
per
ART:
with
ART)
DALY
Cost per
TB
Averted DALY
averted
SmearAlone
68%
43%
$54.27 13.5149 REF
REF
REF
Smear plus
LAM
70%
42%
$57.73
13.4998
151
$229
$608
Xpert alone
90%
24%
$73.18
13.2919
2230
$85
$473
Xpert plus
LAM
91%
23%
$77.24
13.2800
2349
(119)*
$98
($343*)
$486
($727)
‡Includes clinical diagnoses with empiric TB treatment
*Comparison of the “Xpert plus LAM” algorithm with “Xpert” alone
Supplemental content 3b: Costs and effects of Diagnostic algorithms for a cohort of 10,000 HIV patients with CD4<100
Algorithm
% TB
Death Total
DALY’s DALY's ICER
ICER
cases
among Costs
averted
Cost per including
Detected‡ those
(excluding
for
DALY
ART:
with
ART)
cohort
Averted Cost per
TB
DALY
averted
SmearAlone
66%
48%
$81.29 14.6992 REF
REF
REF
Smear plus
LAM
83%
33%
$96.42
14.1846
5146
$29
$417
Xpert alone
87%
30%
$114.39
14.0611
6381
$52
$439
Xpert plus
LAM
94%
24%
$122.22
13.8675
8317
(1936*)
$49
($41*)
$437
($428)
‡Includes clinical diagnoses and empiric TB treatment
*Comparison of the “Xpert plus LAM” algorithm with “Xpert” alone