Tuberculosis
Conditions
Keywords
diagnosis, polymerase chain reaction, sputum smear, stepped-wedge design, cost-effectiveness, Xpert MTB/Rif
Brief summary
Diagnosis of tuberculosis (TB) is a challenge because sputum smear, the most rapid and inexpensive test, often fails to detect the disease, in around 20 to 30% of cases. Culture of sputum yields a correct diagnosis in up to 90% of cases, but results are only available in 4 to 8 weeks, depending on the method. A new test (Xpert MTB/Rif) based on a rapid technique, named polymerase chain reaction (PCR), detects TB in less than 2 hours over 95% of cases, in addition to identification of cases resistant to certain drugs used to treat TB. The test is expensive, but several studies have demonstrated its accuracy, and since most steps are automatized, savings can be expected from human resources work. The aims of our study are (1) to evaluate this tool as a substitute test for sputum smears in routine conditions; (2) evaluate if it is cost-effective, meaning that effectiveness of the test may outweigh the extra cost, and (3) evaluate the acceptability of the test among patients and health care workers.
Detailed description
The main study consisted of a group-randomized pragmatic trial following a stepped-wedge design. The GeneXpert machines will be installed in laboratories of the basic health units in Rio de Janeiro and Manaus, two cities with a high burden of the disease in Brazil. Doctors will prescribe routine tests in the clinics. When sputum specimens arrive in the laboratory, instead of performing smears, the Xpert MTB/Rif will be performed during the intervention period. If positive, a sputum smear will also be performed. The intervention period will be preceded by an observation period during which routine will be kept unchanged, i.e., only smears will be performed. The observation period will serve as a comparator (control). The investigators will then see how many more cases were detected during the intervention period, and in particular, how many smear-negative cases were detected, compared to the observation period. A total of 35,000 specimens are expected to be tested with the new technology in 14 laboratories. Laboratories, not individuals, will be randomized.
Interventions
OTHERXpert MTB/Rif
Automatized RT-PCR for the detection of Mycobacterium tuberculosis, the agent of TB, in sputum samples
OTHERSmear microscopy
Sputum smears arriving in the laboratory during the observation period will be submitted to the classic routine smear staining. This would be the non-intervention (control) arm.
Sponsors
Bill and Melinda Gates Foundation
Ataulpho de Paiva Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
laboratories -and not subjects - will be randomized. All laboratories will start doing smears, when indicated by randomization, they will switch to Xpert MTB/Rif. There are no inclusion or
Exclusion criteria
for the labs. Sputum specimens from non-diagnostic (follow up) patients, second samples for diagnostic tests, insufficient volume/visible blood specimens will be excluded from the Xpert testing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Notification Rate Ratio | October 2012 (up to 2 years) | Proportion of additional bacteriologically confirmed notified TB cases during intervention period compared to the observation period Patients notified who had a positive test result. The notification rate (NR, i.e., number of notifications/100,000 population/year) ratio (NRR) is defined as the NR in the intervention period/NR in the observation period, and is presented in the statistical analysis section. |
| Costs Per Detected Case | October 2012 (up to 2 years) | Costs per detected case were analyzed using a decision tree model from the national health system perspective. Incremental cost-effectiveness ratio (ICER) was calculated as (costs with Xpert - costs with smears)/(cases detected with Xpert - cases detected with smears). Negative ICERs mean cost saving. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NRR of Non-laboratory Tested TB (Cluster-averaged). | October 2012 (up to 2 years) | The notification rate (NR, i.e., number of notifications/100,000 population/year) ratio (NRR) is defined as the NR in the intervention period/NR in the observation period, and is presented in the statistical analysis section. Numbers are participants in the notification database who were not in the lab (all tests done) database; denominators are population taking into account growth of the population during the study period, adjusted for variations in monthly number of opening days (by weighing the number of person-months for the proportion of suspects with samples examined each month out of the total number examined by the laboratory during the whole study period), stratified by sex and age group. Routine practices were not changed; patients with a high suspicion of TB were, as prior to the study, notified regardless of a confirmatory test. |
| NRR of Negative-laboratory TB (Cluster-averaged). | October 2012 (up to 2 years) | The notification rate (NR, i.e., number of notifications/100,000 population/year) ratio (NRR) is defined as the NR in the intervention period/NR in the observation period, and is presented in the statistical analysis section. Numbers are driven from linkage between lab (all tests done) and notification databases; denominators are population taking into account growth of the population during the study period, adjusted for variations in monthly number of opening days (by weighing the number of person-months for the proportion of suspects with samples examined each month out of the total number examined by the laboratory during the whole study period), stratified by sex and age group. Routine practices were not changed; patients with a high suspicion of TB were, as prior to the study, notified regardless of a confirmatory test. |
Countries
Brazil
Participant flow
Recruitment details
From Feb 4 to Oct 4 2012, all 11 primary care laboratories in Rio de Janeiro and 3 labs covering 70% of PTB diagnosis in Manaus participated. Over the same period, 4,660 patients were notified with PTB to SINAN (disease information database). Of these, 2,745 (59%) could be linked to test results in GAL (lab information system).
Pre-assignment details
Samples (and not patients) were included if it was a first diagnostic sample in the intervention arm. Follow up (non diagnostic) samples were excluded for both arms, as were inadequate samples (insufficient material, blood stained-specimens) in the intervention group.
Participants by arm
| Arm | Count |
|---|---|
| Xpert MTB/Rif One sample of sputum specimens arriving during intervention period were submitted to this technology instead, a real-time automated polymerase chain reaction test | 2,610 |
| Sputum Smear Sputum smears arriving in the laboratory during the observation period will be submitted to the classic routine smear staining | 2,050 |
| Total | 4,660 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | age not recorded (used for cross-linkage | 117 | 354 |
| Overall Study | duplicate records | 736 | 3,177 |
| Overall Study | non-diagnostic | 2,621 | 1,124 |
| Overall Study | non-resident | 156 | 76 |
| Overall Study | smear during intervention | 2,170 | 0 |
Baseline characteristics
| Characteristic | Total | Sputum Smear | Xpert MTB/Rif |
|---|---|---|---|
| Age, Customized <=14 years | 112 participants | 56 participants | 56 participants |
| Age, Customized >=60 years | 568 participants | 244 participants | 324 participants |
| Age, Customized Between 15 and 39 years | 2463 participants | 1068 participants | 1395 participants |
| Age, Customized Between 40 and 59 years | 1517 participants | 682 participants | 835 participants |
| Region of Enrollment Brazil | 4660 participants | 2050 participants | 2610 participants |
| Sex: Female, Male Female | 1664 Participants | 736 Participants | 928 Participants |
| Sex: Female, Male Male | 2996 Participants | 1314 Participants | 1682 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Costs Per Detected Case
Costs per detected case were analyzed using a decision tree model from the national health system perspective. Incremental cost-effectiveness ratio (ICER) was calculated as (costs with Xpert - costs with smears)/(cases detected with Xpert - cases detected with smears). Negative ICERs mean cost saving.
Time frame: October 2012 (up to 2 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xpert MTB/Rif | Costs Per Detected Case | 714.95 American dollars |
| Sputum Smear | Costs Per Detected Case | 799.02 American dollars |
Primary
Notification Rate Ratio
Proportion of additional bacteriologically confirmed notified TB cases during intervention period compared to the observation period Patients notified who had a positive test result. The notification rate (NR, i.e., number of notifications/100,000 population/year) ratio (NRR) is defined as the NR in the intervention period/NR in the observation period, and is presented in the statistical analysis section.
Time frame: October 2012 (up to 2 years)
Population: Only patients found both in laboratory and in the notification databases were included since this is an outcome based on notification rates. Population growth during time was estimated. NR per 100,000 population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xpert MTB/Rif | Notification Rate Ratio | 48.7 notifications/100,000 persons/year |
| Sputum Smear | Notification Rate Ratio | 30.5 notifications/100,000 persons/year |
Comparison: cluster-averaged NNR=1.59 (CI95% 1.31-1.88) Absolute numbers informed in table do not allow calculation of notification rates; they are based on population size, not in total numbers and percentagesp-value: <0.0195% CI: [1.32, 1.87]Clustered Avareged
Comparison: Secondary analysis: Mixed multi-level modelp-value: <0.00195% CI: [1.51, 1.92]Mixed Models Analysis
Secondary
NRR of Negative-laboratory TB (Cluster-averaged).
The notification rate (NR, i.e., number of notifications/100,000 population/year) ratio (NRR) is defined as the NR in the intervention period/NR in the observation period, and is presented in the statistical analysis section. Numbers are driven from linkage between lab (all tests done) and notification databases; denominators are population taking into account growth of the population during the study period, adjusted for variations in monthly number of opening days (by weighing the number of person-months for the proportion of suspects with samples examined each month out of the total number examined by the laboratory during the whole study period), stratified by sex and age group. Routine practices were not changed; patients with a high suspicion of TB were, as prior to the study, notified regardless of a confirmatory test.
Time frame: October 2012 (up to 2 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xpert MTB/Rif | NRR of Negative-laboratory TB (Cluster-averaged). | 7.3 notifications/100,000 persons/year |
| Sputum Smear | NRR of Negative-laboratory TB (Cluster-averaged). | 12.1 notifications/100,000 persons/year |
p-value: 0.00495% CI: [0.21, 0.84]Agregated cluster-averaged
Secondary
NRR of Non-laboratory Tested TB (Cluster-averaged).
The notification rate (NR, i.e., number of notifications/100,000 population/year) ratio (NRR) is defined as the NR in the intervention period/NR in the observation period, and is presented in the statistical analysis section. Numbers are participants in the notification database who were not in the lab (all tests done) database; denominators are population taking into account growth of the population during the study period, adjusted for variations in monthly number of opening days (by weighing the number of person-months for the proportion of suspects with samples examined each month out of the total number examined by the laboratory during the whole study period), stratified by sex and age group. Routine practices were not changed; patients with a high suspicion of TB were, as prior to the study, notified regardless of a confirmatory test.
Time frame: October 2012 (up to 2 years)
Population: The result is the notification rate ratio
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xpert MTB/Rif | NRR of Non-laboratory Tested TB (Cluster-averaged). | 35.8 notifications/100,000 persons/year |
| Sputum Smear | NRR of Non-laboratory Tested TB (Cluster-averaged). | 36.9 notifications/100,000 persons/year |
p-value: 0.92395% CI: [0.64, 1.32]Agregated cluster-averaged