Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV: policy update (2019): evidence to decision tables

1 WHO/CDS/TB/2019.21 Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV Policy update (2019) Evidence to Decision Tables 2 WHO/CDS/TB/2019.21 WHO/CDS/TB/2019.21 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC- SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014). 4 WHO/CDS/TB/2019.21 Table of Contents Evidence to Decision table 1. ......................................................................................................................................................................................................... 4 Evidence to Decision table 2. ...................................................................................................................................................................................................... 14 Evidence to Decision table 3. ...................................................................................................................................................................................................... 22 Evidence to Decision table 4. ...................................................................................................................................................................................................... 35 Evidence to Decision table 5. ...................................................................................................................................................................................................... 46 Evidence to decision table 6. ...................................................................................................................................................................................................... 59 Evidence to decision table 7. ...................................................................................................................................................................................................... 70 Evidence to Decision table 1. Should AlereLAM vs. no AlereLAM be used for HIV-positive adults to reduce mortality associated with advanced HIV disease, inpatient setting? Population: HIV-positive adults to reduce mortality associated with advanced HIV disease, inpatient setting Intervention: AlereLAM Comparison: no AlereLAM Main outcomes: Mortality; Setting: inpatient 5 WHO/CDS/TB/2019.21 Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital deaths among people living with HIV despite the increased access to antiretroviral treatment (ART) (Ford 2016). A systematic review of the prevalence of TB identified at autopsy suggests that, in resource-limited settings, TB is responsible for around 40% of all HIV-related deaths and that TB often was disseminated and undiagnosed at the time of death (Gupta 2015). Globally in 2017, only 51% of the estimated 10.0 million TB cases were notified among people living with HIV (WHO Global Report 2018). However, most death from TB is preventable if TB is detected early and effectively treated. Non-sputum-based point-of-care TB diagnostic tests are highly desired to narrow the diagnostic gap and ensure timely treatment. Detection of mycobacterial antigen in urine is promising, as this would allow for a TB diagnosis that is non-site specific. Urine is easy to collect and store, and lacks the infection control risks associated with sputum collection. The lateral flow assay, Alere Determine™ TB LAM Ag assay ‘AlereLAM’, was developed as a simple point-of-care test for diagnosis of active TB in people living with HIV. AlereLAM is commercially available, does not require access to special laboratory equipment, and produces a result after 25 minutes, meeting many desired target product profile requirements. Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ○ Trivial ○ Small ○ Moderate ● Large ○ Varies ○ Don't know Voting: Moderate - 7 (including a chair); Large - 6. Outcomes With no AlereLAM With AlereLAM Difference Relative effect (95% CI) Mortality 230 per 1,000 196 per 1,000 (175 to 216) 35 fewer per 1,000 (55 fewer to 14 fewer) RR 0.85 (0.76 to 0.94) 35 saved lives per 100 admitted patients is a large effect. It will be further augmented by a reduction of transmission. From TB/HIV community perspective, every saved life is a large effect. 6 WHO/CDS/TB/2019.21 Undesirable Effects How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations ○ Large ○ Moderate ● Small ○ Trivial ○ Varies ○ Don't know Outcomes With no AlereLAM With AlereLAM Difference Relative effect (95% CI) Mortality 230 per 1,000 196 per 1,000 (175 to 216) 35 fewer per 1,000 (55 fewer to 14 fewer) RR 0.85 (0.76 to 0.94) Patient important outcomes: missed cases overtreatment empirical treatment was approximately balanced - 6% difference in treatment which will translate into some side effects (which will be balanced against the benefits of a mortality reduction). Doing TB treatment in presumably false-positive cases also assumes doing TB preventive therapy, which partially withraws negative effect of avertreatment. Certainty of evidence What is the overall certainty of the evidence of effects? Judgement Research evidence Additional considerations 7 WHO/CDS/TB/2019.21 ○ Very low ○ Low ● Moderate ○ High ○ No included studies Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Comments Risk with no AlereLAM Risk with AlereLAM Mortality Study population RR 0.85 (0.76 to 0.94) 5102 (2 RCTs) ⨁⨁⨁◯ MODERATEa,b 230 per 1,000 196 per 1,000 (175 to 216) In Gupta-Wright 2018, investigators, all study staff (other than the laboratory technician and statistician), hospital attending clinical teams, and patients were masked to the study group allocation. In Peter 2016, neither patients nor research nurses were masked to either allocation or test results. However, we doubt that the test results were biased in light of this. We did not downgrade. The two trials were conducted in African countries and we do not have direct evidence of the applicability of the findings to other settings outside of Africa. In Gupta-Wright et al, the test was conducted in the laboratory, not at the point of care. In addition, in Gupta-Wright, the intervention was a combination of urine LAM and urine Xpert. In Peter et al, the intervention was urine LAM plus a 'nurse- informed' treatment decision. These additional considerations may not reflect how the test will be performed in routine practice. We downgraded one level for indirectness. Values Is there important uncertainty about or variability in how much people value the main outcomes? Judgement Research evidence Additional considerations 8 WHO/CDS/TB/2019.21 ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability It is likely that no important variability exists in how much people value following important outcomes: Mortality. Cure from (TB). Treatment side effects (in false positives). Drug resistance. Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ● Favors the intervention ○ Varies ○ Don't know Summary of the above: Large benefits, Small harms. Probably very little variation to how people value the outcomes Resources required How large are the resource requirements (costs)? Judgement Research evidence Additional considerations 9 WHO/CDS/TB/2019.21 ○ Large costs ● Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ○ Don't know Systematic review by A. Zwerling: No detailed micro-costing of AlereLAM implementation was performed in inpatient settings. Using published costing data for South Africa limited to unit test cost, Boyles 2018 calculated the cost per patient for each AlereLAM containing algorithm among inpatients. Cost per patient screened by each algorithm generally increased with increasing diagnostic yield and ranged from $10.5 for Xpert/Culture and AlereLAM/Xpert, $12.5 for the AlereLAM/Xpert/culture, $37.2 for the AlereLAM/Xpert SI, $49.6 for Xpert SI/culture, and $42 for AlereLAM/Xpert SI/culture approach. Boyles 2018 did not perform a cost-effectiveness analysis or calculate incremental cost-effectiveness ratios. While implemented in hospitals presents relatively low incremental cost. Implementation in a weak health system would cost more. Cost of avoided transmission need to be equated. Cost will vary depending if the LAM alone or Dx cascade are implemented? Cost will differ by context. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ○ Very low ○ Low ○ Moderate ○ High ● No included studies Systematic review by A. Zwerling: Models found cost-effectiveness of AlereLAM to be robust across a variety of sensitivity analyses, variations in key parameters and across different country settings and scenarios. Key parameters that are likely influential on cost-effectiveness include: TB prevalence, target population, and AlereLAM specificity, cost of treating TB and HIV and life expectancy post TB survival, and time horizon. However, one detailed micro-costing study published in 2018 estimates unit test costs for AlereLAM implementation several fold higher ($23) than most current models ($2- 4). Modeling studies may contribute to the certainty of the evidence in this domain Modeling studies may contribute to the certainty of the evidence in this domain High variability Only one trial Variety of models No empirical studies Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Judgement Research evidence Additional considerations 10 WHO/CDS/TB/2019.21 ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ● Varies ○ No included studies Systematic review by A. Zwerling: Reddy et al assessed cost-effectiveness of AlereLAM algorithms in unselected hospitalized PLHIV. Using the modified CEPAC-I model calibrated to STAMP trial results, Reddy 2019 found Xpert + AlereLAM + urine Xpert to be cost-effective among unselected hospitalized HIV patients with ICERs of $450/YLS (Years of life saved, YLS) in Malawi and $840/YLS in South Africa compared with standard of care (Xpert alone). The modified intervention of Xpert + AlereLAM was even more cost-effective with ICERs of $420/YLS in Malawi and $810/YLS in South Africa compared with standard of care. Increased ICERs are due to inclusion of downstream costs associated with lifelong ART and HIV care. Only data for Africa are available SA results more definitive and Malawi results are less definitive Equity What would be the impact on health equity? Judgement Research evidence Additional considerations ○ Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ● Increased ○ Varies ○ Don't know As test can be performed at all levels of the health care system, it will likely increase health care equity. Universal test Potential to reduce inequity Because extrapulmonary TB are already disadvantaged it is potential to improve care for them Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know Report on user perspectives on TB LAM testing: results from qualitative research : Test is generally described as acceptable by key stakeholders. Patients: Providers: Policy-makers/programs: Payers: Others: In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the 11 WHO/CDS/TB/2019.21 caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Feasibility Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know Voting: Probably yes – 5, Yes – 6, Varies – 1, Abstained - 1. MSF study (H. Huerga) Advantages of using LAM: • LAM implementation required little increase in clinician workload and no additional workspace • Test successfully performed at the point of care, no need to transport samples, no need of laboratory, no additional equipment • Test was perceived as easy to use with good inter-reader agreement • Most patients were able to submit a urine sample in contrast to sputum samples • LAM results available in very short time and allowed TB treatment initiation on the same day Challenges of using LAM: • There maybe challenges with reading grade 1 and interpreting faint bands. • It is important to train on the interpretation of results and ensure the use of the reading card. • CD4 to select patients is problematic because not always immediately available. • Alternative clinical criteria such as seriously ill alone would miss a lot of patients who could benefit from LAM. Qualitative study (N. Engel) Advantages of using LAM: • Urine sample is easily available, less stigmatized & safe • Minimal user skills • Low maintenance/equipment requirements • Short TAT of 25’ Challenges of using LAM: • Not everybody can produce, or collect urine samples • Visibility of faint results • Stockouts of urine containers, micropipettes unavailable, no running water/toilets for patients • Delays in Rx initiation In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). What seems simple in the actual scale up may be difficult. Everything is feasible, giving proper resources, but millions are spent already for this test without much progress. Summary of judgements Judgement Problem No Probably no Probably yes Yes Varies Don't know 12 WHO/CDS/TB/2019.21 Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of evidence Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Certainty of evidence of required resources Very low Low Moderate High No included studies Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ○ ○ ○ ○ ● 13 WHO/CDS/TB/2019.21 Conclusions Recommendation In inpatient settings, WHO recommends using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children with signs or symptoms of TB (pulmonary and extrapulmonary) or advanced HIV disease or who are seriously ill (strong recommendation; moderate certainty in the evidence about the intervention effects). Remark: AlereLAM should not be used as a replacement or triage test. It should be used as add on to clincial judgment in combination with other tests. * as per prior definition The recommendation for seriously ill PLHIV also applies to outpatient settings. Implementation considerations in many settings sequential testing during multiple visits may be challenging to implement Needs to be done in the context of an algorithm that considers other testing Quality control of the assay will have to be undertaken. Use of the reading card when applying the test For children in particular hygenic sample conditions Monitoring and evaluation Data collection and linkage to other assays Research priorities 14 WHO/CDS/TB/2019.21 Extrapulmonary disease data Algorithms Data in Children LAM positive has higher mortality risk - is this a different group? Global data Implementation studies pragmatic and operational studies Evidence to Decision table 2. Should AlereLAM vs. no AlereLAM be used for HIV-positive adults to reduce mortality associated with advanced HIV disease, inpatient setting, CD4 ≤ 200? Population: HIV-positive adults to reduce mortality associated with advanced HIV disease, inpatient setting, CD4 ≤ 200 Intervention: AlereLAM Comparison: no AlereLAM Main outcomes: Mortality; Setting: inpatient Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital deaths among people living with HIV despite the increased access to antiretroviral treatment (ART) (Ford 2016). A systematic review of the prevalence of TB identified at autopsy suggests that, in resource-limited Non-sputum-based point-of-care TB diagnostic tests are highly desired to narrow the diagnostic gap and ensure timely treatment. Detection of mycobacterial antigen in urine is 15 WHO/CDS/TB/2019.21 ● Yes ○ Varies ○ Don't know settings, TB is responsible for around 40% of all HIV-related deaths and that TB often was disseminated and undiagnosed at the time of death (Gupta 2015). Globally in 2017, only 51% of the estimated 10.0 million TB cases were notified among people living with HIV (WHO Global Report 2018). However, most death from TB is preventable if TB is detected early and effectively treated. promising, as this would allow for a TB diagnosis that is non-site specific. Urine is easy to collect and store, and lacks the infection control risks associated with sputum collection. The lateral flow assay, Alere Determine™ TB LAM Ag assay ‘AlereLAM’, was developed as a simple point-of-care test for diagnosis of active TB in people living with HIV. AlereLAM is commercially available, does not require access to special laboratory equipment, and produces a result after 25 minutes, meeting many desired target product profile requirements. Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ○ Trivial ○ Small ○ Moderate ● Large ○ Varies ○ Don't know Outcomes With no AlereLAM With AlereLAM Difference Relative effect (95% CI) Mortality follow up: 56 weeks 285 per 1,000 248 per 1,000 (219 to 282) 37 fewer per 1,000 (65 fewer to 3 fewer) RR 0.87 (0.77 to 0.99) 37 saved lives per 100 admitted patients is a large effect. It will be further augmented by a reduction of transmission. From TB/HIV community perspective, every saved life is a large effect. Undesirable Effects How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations 16 WHO/CDS/TB/2019.21 ○ Large ○ Moderate ● Small ○ Trivial ○ Varies ○ Don't know Outcomes With no AlereLAM With AlereLAM Difference Relative effect (95% CI) Mortality follow up: 56 weeks 285 per 1,000 248 per 1,000 (219 to 282) 37 fewer per 1,000 (65 fewer to 3 fewer) RR 0.87 (0.77 to 0.99) Patient important outcomes: missed cases overtreatment empirical treatment was approximately balanced - 6% difference in treatment which will translate into some side effects (which will be balanced against the benefits of a mortality reduction). TB treatment in presumably false-positive cases would have positive external effect of TB preventive therapy, which partially compensate for the negative effect of overtreatment. Certainty of evidence What is the overall certainty of the evidence of effects? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Comments Risk with no AlereLAM Risk with AlereLAM Mortality follow up: 56 weeks Study population RR 0.87 (0.77 to 0.99) 2886 (2 RCTs) ⨁⨁⨁◯ MODERATEa,b 285 per 1,000 248 per 1,000 (219 to 282) In Gupta-Wright 2018a, investigators, all study staff (other than the laboratory technician and statistician), hospital attending clinical teams, and patients were masked to the study group allocation. In Peter 2016, neither patients nor research nurses were masked to either 17 WHO/CDS/TB/2019.21 allocation or test results. However, we doubt that the test results were biased in light of this. We did not downgrade for risk of bias. The two trials were conducted in African countries and we do not have direct evidence of the applicability of the findings to other settings outside of Africa. In Gupta-Wright et al, the test was conducted in the laboratory, not at the point of care. In addition, in Gupta-Wright, the intervention was a combination of urine LAM and urine Xpert. In Peter et al, the intervention was urine LAM plus a 'nurse-informed' treatment decision. These additional considerations may not reflect how the test will be performed in routine practice. We downgraded one level for indirectness. Values Is there important uncertainty about or variability in how much people value the main outcomes? Judgement Research evidence Additional considerations ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability It is likely that no important variability exists in how much people value following important outcomes: Mortality. Cure from (TB). Treatment side effects (in false positives). Drug resistance. Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ● Favors the intervention ○ Varies ○ Don't know Summary of the above: Large benefits, Small harms. Probably very little variation to how people value the outcomes 18 WHO/CDS/TB/2019.21 Resources required How large are the resource requirements (costs)? Judgement Research evidence Additional considerations ○ Large costs ● Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ○ Don't know Systematic review by A. Zwerling: No detailed micro-costing of AlereLAM implementation was performed in inpatient settings. Using published costing data for South Africa limited to unit test cost, Boyles 2018 calculated the cost per patient for each AlereLAM containing algorithm among inpatients. Cost per patient screened by each algorithm generally increased with increasing diagnostic yield and ranged from $10.5 for Xpert/Culture and AlereLAM/Xpert, $12.5 for the AlereLAM/Xpert/culture, $37.2 for the AlereLAM/Xpert SI, $49.6 for Xpert SI/culture, and $42 for AlereLAM/Xpert SI/culture approach. Boyles 2018 did not perform a cost-effectiveness analysis or calculate incremental cost-effectiveness ratios. While implemented in hospitals presents relatively low incremental cost. Implementation in a weak health system would cost more. Cost of avoided transmission need to be equated. Cost will vary depending if the LAM alone or Dx cascade are implemented? Cost will differ by context. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ○ Very low ○ Low ○ Moderate ○ High ● No included studies Systematic review by A. Zwerling: Models found cost-effectiveness of AlereLAM to be robust across a variety of sensitivity analyses, variations in key parameters and across different country settings and scenarios. Key parameters that are likely influential on cost-effectiveness include: TB prevalence, target population, and AlereLAM specificity, cost of treating TB and HIV and life expectancy post TB survival, and time horizon. However, one detailed micro-costing study published in 2018 estimates unit test costs for AlereLAM implementation several fold higher ($23) than most current models ($2- 4). Modeling studies may contribute to the certainty of the evidence in this domain Modeling studies may contribute to the certainty of the evidence in this domain High variability Only one trial Variety of models No empirical studies Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Judgement Research evidence Additional considerations 19 WHO/CDS/TB/2019.21 ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ● Varies ○ No included studies Systematic review by A. Zwerling: Reddy et al assessed cost-effectiveness of AlereLAM algorithms in unselected hospitalized PLHIV. Using the modified CEPAC-I model calibrated to STAMP trial results, Reddy 2019 found Xpert + AlereLAM + urine Xpert to be cost-effective among unselected hospitalized HIV patients with ICERs of $450/YLS (Years of life saved, YLS) in Malawi and $840/YLS in South Africa compared with standard of care (Xpert alone). The modified intervention of Xpert + AlereLAM was even more cost-effective with ICERs of $420/YLS in Malawi and $810/YLS in South Africa compared with standard of care. Increased ICERs are due to inclusion of downstream costs associated with lifelong ART and HIV care. Only data for Africa are available SA results more definitive and Malawi results are less definitive Equity What would be the impact on health equity? Judgement Research evidence Additional considerations ○ Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ● Increased ○ Varies ○ Don't know As test can be performed at all levels of the health care system, it will likely increase health care equity. Universal test Potential to reduce inequity Because extrapulmonary TB are already disadvantaged it is potential to improve care for them Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know Report on user perspectives on TB LAM testing: results from qualitative research : Test is generally described as acceptable by key stakeholders. Patients: Providers: Policy-makers/programs: Payers: Others: 20 WHO/CDS/TB/2019.21 In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Feasibility Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know MSF study (H. Huerga) Advantages of using LAM: • LAM implementation required little increase in clinician workload and no additional workspace • Test successfully performed at the point of care, no need to transport samples, no need of laboratory, no additional equipment • Test was perceived as easy to use with good inter-reader agreement • Most patients were able to submit a urine sample in contrast to sputum samples • LAM results available in very short time and allowed TB treatment initiation on the same day Challenges of using LAM: • There maybe challenges with reading grade 1 and interpreting faint bands. • It is important to train on the interpretation of results and ensure the use of the reading card. • CD4 to select patients is problematic because not always immediately available. • Alternative clinical criteria such as seriously ill alone would miss a lot of patients who could benefit from LAM. Qualitative study (N. Engel) Advantages of using LAM: • Urine sample is easily available, less stigmatized & safe • Minimal user skills • Low maintenance/equipment requirements • Short TAT of 25’ Challenges of using LAM: • Not everybody can produce, or collect urine samples • Visibility of faint results • Stockouts of urine containers, micropipettes unavailable, no running water/toilets for patients • Delays in Rx initiation In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). What seems simple in the actual scale up may be difficult. Everything is feasible, giving proper resources, but millions are spent already for this test without much progress. Summary of judgements 21 WHO/CDS/TB/2019.21 Judgement Problem No Probably no Probably yes Yes Varies Don't know Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of evidence Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Certainty of evidence of required resources Very low Low Moderate High No included studies Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation 22 WHO/CDS/TB/2019.21 Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ○ ○ ○ ○ ● Conclusions Recommendation In inpatient settings, WHO suggests using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults irrespective of TB symptoms with a CD4 count < 200 (strong recommendation; moderate certainty in the evidence about the intervention effects). Evidence to Decision table 3. Should AlereLAM be used to diagnose active TB in HIV-positive adults with TB symptoms, outpatient settings? Population: HIV-positive adults with TB symptoms, outpatient settings Intervention: AlereLAM Setting: outpatient Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital deaths among people living with HIV despite the increased access to antiretroviral treatment (ART) (Ford 2016). A systematic review of the prevalence of TB identified at autopsy suggests that, in resource-limited settings, TB is responsible for around 40% of all HIV- Non-sputum-based point-of-care TB diagnostic tests are highly desired to narrow the diagnostic gap and ensure timely treatment. Detection of mycobacterial antigen in 23 WHO/CDS/TB/2019.21 ● Yes ○ Varies ○ Don't know related deaths and that TB often was disseminated and undiagnosed at the time of death (Gupta 2015). Globally in 2017, only 51% of the estimated 10.0 million TB cases were notified among people living with HIV (WHO Global Report 2018). However, most death from TB is preventable if TB is detected early and effectively treated. urine has attracted great attention over time. Urine- based antigen testing would allow for a TB diagnosis that is non-site specific. Urine is further easy to collect and store, and lacks the infection control risks associated with sputum collection. Multiple platforms have been developed to detect lipoarabinomannan (LAM), initially as enzyme-linked immunosorbent (ELISA) assays that were evaluated in several clinical settings. Later, the lateral flow assay, Alere Determine™ TB LAM Ag assay ‘AlereLAM’, was developed as a simple point-of-care test for diagnosis of active TB in people living with HIV. AlereLAM is commercially available, does not require access to special laboratory equipment, and produces a result after 25 minutes, meeting many desired target product profile requirements. Test accuracy How accurate is the test? Judgement Research evidence Additional considerations ○ Very inaccurate ○ Inaccurate ● Accurate ○ Very accurate ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.29 (95% CI: 0.17 to 0.47) Specificity: 0.96 (95% CI: 0.91 to 0.99) Prevalence (Pre-testing probability) 10% Typically seen in symptomatic persons in outpatient settings Test result Number of results per 1000 patients tested (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Prevalence 1% Prevalence 10% Prevalence 30% True positives patients with active TB 3 (2 to 5) 29 (17 to 47) 87 (51 to 141) 409 (4) The review only included studies with a microbiological reference standard (culture or Xpert). The review, does not assess performance against a composite reference standard that uses microbiological or clinical information to classify TB. This was done in the original WHO and Cochrane Review (WHO Lipoarabinomannan Policy Guidance 2015; Shah 2016), but found little difference against a microbiological reference standard. A substantial number of TB cases may not be verified by microbiological testing if only sputum is tested and when patients with advanced HIV are assessed, which may lead to underestimation of sensitivity and increase of number of FN. Furthermore, while CD4 counts decrease, the sickest patients may not be able to produce a sputum specimen or they have extrapulmonary TB. Exclusion of latter patient groups (individuals without sputa) may also lead to underestimation of sensitivity. 24 WHO/CDS/TB/2019.21 False negatives patients incorrectly classified as not having active TB 7 (5 to 8) 71 (53 to 83) 213 (159 to 249) ⨁⨁◯◯ LOWa,b,c True negatives patients without active TB 950 (901 to 980) 864 (819 to 891) 672 (637 to 693) 787 (4) ⨁⨁◯◯ LOWa,d,e False positives patients incorrectly classified as having active TB 40 (10 to 89) 36 (9 to 81) 28 (7 to 63) The median TB prevalence in the studies was 43% and thus the results tend to be more applicable to settings with a higher TB prevalence. We did not downgrade for indirectness. The 95% CrI around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. We did not downgrade for imprecision. As assessed by QUADAS-2, in the patient selection domain, we judged all studies at high risk of bias because they did not avoid inappropriate exclusions. We downgraded two levels for risk of bias. The 95% CrI around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. As assessed by QUADAS-2, in the reference standard domain, we judged three studies (75%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded one level for risk of bias. Impact of nontuberculous mycobacteria and other environmental factors on test specificity remains unclear, but may possibly lead to FP results. Only a single study outside of Africa Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ○ Trivial ○ Small ● Moderate ○ Large ○ Varies ○ Don't know In outpatients settings, (10% prevalence) out of 1000 patients with signs and symptoms of TB, for 29 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, only 45 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation Furthermore, in outpatients settings, out of 1000 patients with signs and symptoms of TB, for 864 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 92 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. However, out of 1000 patients with signs and symptoms of TB, for 36 patients the TB diagnosis will be falsely established. Out of 100 patients with positive test result, 55 would not have active TB, and thus would have risk of As urine LAM does not provide information about drug resistance, thus a positive result (both TP and FP) will necessitate additional testing (Xpert, culture) in order to identify evidence for phenotypic or molecular drug resistance. As urine LAM sensitivity does not allow identification of all cases of MTB, additional testing may be required following a negative result (TN and FN). 25 WHO/CDS/TB/2019.21 unnecessary treatment and stigma. Furthermore, out of 1000 patients with signs and symptoms of TB, for 71 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 8 would actually not have active TB, and thus will be exposed to increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. Change of the PTT would mostly affect number of FN: 10% - 71; 30% - 213. As the test can be performed on an easy to collect urine sample outside a laboratory, the time to diagnosis can be reduced The desirable effect of the test may be further augmented by the fact that in low-resource settings, certain proportion of TB patients may be diagnosed by LF-LAM and not by WHO recommended rapid TB diagnostic test (Xpert) due to the following reasons: 1) sputum Xpert has lower sensitivity in HIV-positive than HIV-negative people; 2) patients may not be able to produce sputum; 3) patients may not have access to Xpert. Undesirable Effects How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations ○ Large ● Moderate ○ Small ○ Trivial ○ Varies ○ Don't know In outpatients settings, (10% prevalence) out of 1000 patients with signs and symptoms of TB, for 29 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, only 45 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation Furthermore, in outpatients settings, out of 1000 patients with signs and symptoms of TB, for 864 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 92 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. However, out of 1000 patients with signs and symptoms of TB, for 36 patients the TB diagnosis will be falsely established. Out of 100 patients with positive test result, 55 would not have active TB, and thus would have risk of unnecessary treatment and stigma. Furthermore, out of 1000 patients with signs and symptoms of TB, for 71 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 8 would actually not have active TB, and thus will be exposed to increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. Change of the PTT would mostly affect number of FN: 10% - 71; 30% - 213. As CD4 counts decrease, the sickest patients may be not able to produce a sputum specimen or would have EPTB. Thus their TP results would not be confirmed by microbiological reference standard and will be misclassified as FP. NTM and other environmental factors may possibly lead to FP results. Undesirable effects maybe partially compensated by the use of other tests in an algorithm. Certainty of the evidence of test accuracy 26 WHO/CDS/TB/2019.21 What is the overall certainty of the evidence of test accuracy? Judgement Research evidence Additional considerations ○ Very low ● Low ○ Moderate ○ High ○ No included studies The median TB prevalence in the studies was 43% and thus the results tend to be more applicable to settings with a higher TB prevalence. We did not downgrade for indirectness. The 95% CrI around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. We did not downgrade for imprecision. As assessed by QUADAS-2, in the patient selection domain, we judged all studies at high risk of bias because they did not avoid inappropriate exclusions. We downgraded two levels for risk of bias. The 95% CrI around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. As assessed by QUADAS-2, in the reference standard domain, we judged three studies (75%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded one level for risk of bias. Certainty of the evidence of test's effects What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? 27 WHO/CDS/TB/2019.21 Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies No adverse events were associated with LAM testing (Peter 2016). High quality evidence. Even though, Dx trial may not capture side effects as effectively as treatment trials, in case of major side-effects would occur likely they would be reported. Similarly as for inpatients (see 1.1) POC benefits for the test. We assume that there are no adverse effects associated with the test. The AlereLAM assay can be performed at the patient bedside, in a clinic or a laboratory with minimal training. There was no difficulty in urine collection, no discussion on patient harms, it was deemed as easy to perform. Direct benefit – being quickly diagnosed. Risk - Not following the result, if test is not part of an algorithm. Burden is considered unimportant. Certainty of the evidence of management's effects What is the overall certainty of the evidence of effects of the management that is guided by the test results? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies 2 RCTs in hospitalized HIV-positive adults showed a decrease in mortality associated with use of the AlereLAM comparing to the non-use of AlereLAM. Pooled risk ratio was 0.85 (95% CI 0.76 to 0.94) i.e. study participants undergoing AlereLAM testing had 0.85 times the risk or 15% lower risk of mortality than participants undergoing routine TB diagnostic testing without AlereLAM. The absolute effect was 35 fewer deaths per 1,000 (from 14 fewer to 55 fewer) (high-certainty evidence). In additional analyses, the review authors demonstrated that within diagnostic accuracy studies that included follow-up for clinical outcomes, without using AlereLAM results for clinical decision making, there appeared to be an association between AlereLAM positivity among both participants with and without confirmed TB (by microbiological and/or clinical study reference standards) and mortality. These data must be interpreted cautiously as they represent secondary analyses within observational cohorts, are limited in size, and may not 28 WHO/CDS/TB/2019.21 control for important biases or other factors. It is likely that these findings may represent the effect of missed diagnoses (that could be averted through earlier diagnosis using rapid AlereLAM testing) and/or that there is a biological association between disease severity resulting in AlereLAM excretion in urine. Certainty of the evidence of test result/management How certain is the link between test results and management decisions? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies Report on user perspectives on TB LAM testing: results from qualitative research: testing makes a critical difference for many patients from a hard to diagnose group. In one RCT, > 95% of clinicians acted on a positive test result (Peter 2016). The tests can be performed at the patient bedside, in a clinic or a laboratory with minimal training. Patients in trials do promptly receive anti-TB therapy after testing and there is little concern that this would not happen outside of trials. For a negative LAM test result, clinicians may use empirical treatment for TB. Certainty of effects What is the overall certainty of the evidence of effects of the test? Judgement Research evidence Additional considerations ○ Very low ● Low ○ Moderate ○ High ○ No included studies Summary of the above conclusions Values Is there important uncertainty about or variability in how much people value the main outcomes? 29 WHO/CDS/TB/2019.21 Judgement Research evidence Additional considerations ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability It is likely that no important variability exists in how much people value following important outcomes: Mortality. Cure from (TB). Treatment side effects (in false positives). Drug resistance. Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ● Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know Summary of the above Given the high mortality in persons living with HIV, acting on all positive LAM results likely balances any possible adverse effects associated with unnecessary treatment with reducing mortality. Resources required How large are the resource requirements (costs)? Judgement Research evidence Additional considerations 30 WHO/CDS/TB/2019.21 ○ Large costs ● Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ○ Don't know Systematic review by A. Zwerling: Mukora 2018 employed a detailed micro-costing approach among outpatient clinics testing PLHIV with CD4 ⩽150 cells/μL including costs from both the clinic level and above clinic level, across non-governmental organizations (NGO) and department of health (DoH) implementers/clinics and included costs from both start-up and implementation periods. Mukora 2018 estimated a total unit cost of AlereLAM testing at $23.55 (NGO clinics) and $22.72 (department of health (DOH) operated clinics). Unit costs were higher than have been reported in other studies from South Africa (~$3-4.00) largely driven by the inclusion of both clinic level ($11.49 NGO & $10.85 DOH) and above clinic level costs ($12.06 NGO & $11.87 DOH). Impacts modelling data on reduction and transmission Cost is more significant for outpatient, exceeding 3.5 USD, assuming investment in outpatient activities. Use of LF-LAM should be seen as part of algorithm. Better diagnostics always include additional cost Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Systematic review by A. Zwerling: Models found cost-effectiveness of AlereLAM to be robust across a variety of sensitivity analyses, variations in key parameters and across different country settings and scenarios. Key parameters that are likely influential on cost-effectiveness include: TB prevalence, target population, and AlereLAM specificity, cost of treating TB and HIV and life expectancy post TB survival, and time horizon. However, one detailed micro-costing study published in 2018 estimates unit test costs for AlereLAM implementation several fold higher ($23) than most current models ($2-4). Modeling studies may contribute to the certainty of the evidence in this domain Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Judgement Research evidence Additional considerations 31 WHO/CDS/TB/2019.21 ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ● Varies ○ No included studies Systematic review by A. Zwerling: Models consistently demonstrated AlereLAM containing approaches could be cost-effective among African HIV positive adults across a range of settings and parameters evaluated despite heterogeneous diagnostic approaches evaluated. Equity What would be the impact on health equity? Judgement Research evidence Additional considerations ○ Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ● Increased ○ Varies ○ Don't know As test can be performed at all levels of the health care system, it will likely increase health care equity. Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know Report on user perspectives on TB LAM testing: Test is generally described as acceptable by key stakeholders. Patients: Providers: Policy-makers/programs: Payers: Others: In children: Urine collection was more cumbersome especially in younger and sicker children as it requires 32 WHO/CDS/TB/2019.21 both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Feasibility Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know MSF study (H. Huerga) Advantages of using LAM: • LAM implementation required little increase in clinician workload and no additional workspace • Test successfully performed at the point of care, no need to transport samples, no need of laboratory, no additional equipment • Test was perceived as easy to use with good inter-reader agreement • Most patients were able to submit a urine sample in contrast to sputum samples • LAM results available in very short time and allowed TB treatment initiation on the same day Challenges of using LAM: • There maybe challenges with reading grade 1 and interpreting faint bands. • It is important to train on the interpretation of results and ensure the use of the reading card. • CD4 to select patients is problematic because not always immediately available. • Alternative clinical criteria such as seriously ill alone would miss a lot of patients who could benefit from LAM. Qualitative study (N. Engel) Advantages of using LAM: • Urine sample is easily available, less stigmatized & safe • Minimal user skills • Low maintenance/equipment requirements • Short TAT of 25’ Challenges of using LAM: • Not everybody can produce, or collect urine samples • Visibility of faint results • Stockouts of urine containers, micropipettes unavailable, no running water/toilets for patients • Delays in Rx initiation At scale implementation may be tricky. Concerns were raised by the panel about quality control that needs to be implemented. Outpatient setting will add additional challenges. In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Summary of judgements Judgement Problem No Probably no Probably yes Yes Varies Don't know 33 WHO/CDS/TB/2019.21 Judgement Test accuracy Very inaccurate Inaccurate Accurate Very accurate Varies Don't know Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of the evidence of test accuracy Very low Low Moderate High No included studies Certainty of the evidence of test's effects Very low Low Moderate High No included studies Certainty of the evidence of management's effects Very low Low Moderate High No included studies Certainty of the evidence of test result/management Very low Low Moderate High No included studies Certainty of effects Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Certainty of evidence of required resources Very low Low Moderate High No included studies 34 WHO/CDS/TB/2019.21 Judgement Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ○ ○ ○ ● ○ Conclusions Recommendation 1.2. In outpatient settings, WHO suggests using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children with TB with signs or symptoms of TB (pulmonary and extrapulmonary) (conditional recommendation; low certainty in the evidence about test accuracy). Research priorities 35 WHO/CDS/TB/2019.21 Cost and cost-effectiveness studies, in particular for outpatients and LMIC - applies to all recommendations Test accuracy in pregnant women better test to be developed or ... applies to all recommendations More trials and studies focusing on patient important outcomes Evidence to Decision table 4. Should AlereLAM be used to diagnose active TB in HIV-positive adults irrespective of symptoms, outpatient settings, CD4 ≤ 100? Population: HIV-positive adults irrespective of symptoms, outpatient settings, CD4 ≤ 100 Intervention: AlereLAM Setting: outpatient Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know problem Test accuracy 36 WHO/CDS/TB/2019.21 How accurate is the test? Judgement Research evidence Additional considerations ○ Very inaccurate ○ Inaccurate ● Accurate ○ Very accurate ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.40 (95% CI: 0.20 to 0.64) Specificity: 0.87 (95% CI: 0.68 to 0.94) Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ○ Trivial ○ Small ● Moderate ○ Large ○ Varies ○ Don't know Test result Number of results per 1000 patients tested (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Prevalence 1% Prevalence 10% Prevalence 30% True positives patients with active TB 4 (2 to 6) 40 (20 to 64) 120 (60 to 192) 46 (2) ⨁◯◯◯ VERY LOWa,b False negatives patients incorrectly classified as not having active TB 6 (4 to 8) 60 (36 to 80) 180 (108 to 240) True negatives patients without active TB 861 (673 to 931) 783 (612 to 846) 609 (476 to 658) 171 (2) ⨁◯◯◯ VERY LOWc,d 37 WHO/CDS/TB/2019.21 False positives patients incorrectly classified as having active TB 129 (59 to 317) 117 (54 to 288) 91 (42 to 224) As assessed by QUADAS-2, in the patient selection domain, we considered both studies at high risk of bias because they did not avoid inappropriate exclusions. We downgraded two levels for risk of bias. There were few participants in this analysis. We downgraded two levels for imprecision. The very wide 95% CrIs around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded two levels for imprecision. As assessed by QUADAS-2, in the reference standard domain, we considered both studies at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded two levels for risk of bias. Undesirable Effects How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations 38 WHO/CDS/TB/2019.21 ○ Large ● Moderate ○ Small ○ Trivial ○ Varies ○ Don't know Test result Number of results per 1000 patients tested (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Prevalence 1% Prevalence 10% Prevalence 30% True positives patients with active TB 4 (2 to 6) 40 (20 to 64) 120 (60 to 192) 46 (2) ⨁◯◯◯ VERY LOWa,b False negatives patients incorrectly classified as not having active TB 6 (4 to 8) 60 (36 to 80) 180 (108 to 240) True negatives patients without active TB 861 (673 to 931) 783 (612 to 846) 609 (476 to 658) 171 (2) ⨁◯◯◯ VERY LOWc,d False positives patients incorrectly classified as having active TB 129 (59 to 317) 117 (54 to 288) 91 (42 to 224) As assessed by QUADAS-2, in the patient selection domain, we considered both studies at high risk of bias because they did not avoid inappropriate exclusions. We downgraded two levels for risk of bias. There were few participants in this analysis. We downgraded two levels for imprecision. The very wide 95% CrIs around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded two levels for imprecision. As assessed by QUADAS-2, in the reference standard domain, we considered both studies at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded two levels for risk of bias. Certainty of the evidence of test accuracy 39 WHO/CDS/TB/2019.21 What is the overall certainty of the evidence of test accuracy? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Outcome Study design Test accuracy CoE Effect per 1000 patients/year for pre-test probability of 1% Effect per 1000 patients/year for pre-test probability of 10% Effect per 1000 patients/year for pre-test probability of 30% Importance True positives cross- sectional (cohort type accuracy study) ⨁◯ ◯◯ VERY LOWa,b 4 (2 to 6) 40 (20 to 64) 120 (60 to 192) False negatives 6 (4 to 8) 60 (36 to 80) 180 (108 to 240) True negatives cross- sectional (cohort type accuracy study) ⨁◯ ◯◯ VERY LOWc,d 861 (673 to 931) 783 (612 to 846) 609 (476 to 658) False positives 129 (59 to 317) 117 (54 to 288) 91 (42 to 224) As assessed by QUADAS-2, in the patient selection domain, we considered both studies at high risk of bias because they did not avoid inappropriate exclusions. We downgraded two levels for risk of bias. There were few participants in this analysis. We downgraded two levels for imprecision. The very wide 95% CrIs around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded two levels for imprecision. As assessed by QUADAS-2, in the reference standard domain, we considered both studies at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded two levels for risk of bias. Certainty of the evidence of test's effects 40 WHO/CDS/TB/2019.21 What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies Certainty of the evidence of management's effects What is the overall certainty of the evidence of effects of the management that is guided by the test results? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies Certainty of the evidence of test result/management How certain is the link between test results and management decisions? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies 41 WHO/CDS/TB/2019.21 Certainty of effects What is the overall certainty of the evidence of effects of the test? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Judgement Research evidence Additional considerations ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations 42 WHO/CDS/TB/2019.21 ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ● Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know Resources required How large are the resource requirements (costs)? Judgement Research evidence Additional considerations ○ Large costs ○ Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ● Don't know Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ○ Very low ○ Low ○ Moderate ○ High ● No included studies Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? 43 WHO/CDS/TB/2019.21 Judgement Research evidence Additional considerations ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● No included studies Equity What would be the impact on health equity? Judgement Research evidence Additional considerations ○ Reduced ○ Probably reduced ○ Probably no impact ● Probably increased ○ Increased ○ Varies ○ Don't know Potential to improve equity Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know Generally acceptable 44 WHO/CDS/TB/2019.21 Feasibility Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know Generally feasible Summary of judgements Judgement Problem No Probably no Probably yes Yes Varies Don't know Test accuracy Very inaccurate Inaccurate Accurate Very accurate Varies Don't know Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of the evidence of test accuracy Very low Low Moderate High No included studies Certainty of the evidence of test's effects Very low Low Moderate High No included studies Certainty of the evidence of management's effects Very low Low Moderate High No included studies 45 WHO/CDS/TB/2019.21 Certainty of the evidence of test result/management Very low Low Moderate High No included studies Certainty of effects Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Certainty of evidence of required resources Very low Low Moderate High No included studies Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ○ ○ ○ ● ○ 46 WHO/CDS/TB/2019.21 Conclusions Recommendation 3.6. In outpatients settings, WHO suggests using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children without TB signs and symptoms (pulmonary and extrapulmonary) and a CD4 count of less than 100 (conditional recommendation; very low certainty in the evidence about test accuracy) Evidence to Decision table 5. Should AlereLAM be used to diagnose active TB in HIV-positive adults irrespective of symptoms, outpatient settings? Population: HIV-positive adults irrespective of symptoms, outpatient settings Intervention: AlereLAM Setting: outpatient Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital deaths among people living with HIV despite the increased access to antiretroviral treatment (ART) (Ford 2016). A systematic review of the prevalence of TB identified at autopsy suggests that, in resource-limited settings, TB is responsible for around 40% of all HIV- related deaths and that TB often was disseminated and undiagnosed at the time of death (Gupta 2015). Globally in 2017, only 51% of the estimated 10.0 million TB cases were notified among people living with HIV (WHO Global Report 2018). However, most death from TB is preventable if TB is detected early and effectively treated. Non-sputum-based point-of-care TB diagnostic tests are highly desired to narrow the diagnostic gap and ensure timely treatment. Urine-based antigen testing would allow for a TB diagnosis that is non-site specific. Urine is further easy to collect and store, and lacks the infection control risks associated with sputum collection. Multiple platforms have been developed to detect 47 WHO/CDS/TB/2019.21 ○ Don't know lipoarabinomannan (LAM), initially as enzyme-linked immunosorbent (ELISA) assays that were evaluated in several clinical settings. Later, the lateral flow assay, Alere Determine™ TB LAM Ag assay ‘AlereLAM’, was developed as a simple point-of-care test for diagnosis of active TB in people living with HIV. AlereLAM is commercially available, does not require access to special laboratory equipment, and produces a result after 25 minutes, meeting many desired target product profile requirements. Test accuracy How accurate is the test? Judgement Research evidence Additional considerations ○ Very inaccurate ● Inaccurate ○ Accurate ○ Very accurate ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.31 (95% CI: 0.18 to 0.47) Specificity: 0.95 (95% CI: 0.87 to 0.99) Prevalence (Pre-testing probability) 5% Typically seen in a mix of persons with and without szmptoms in outpatient settings Test result Number of results per 1000 patients tested (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Prevalence 1% Prevalence 5% Prevalence 10% True positives patients with active TB 3 (2 to 5) 16 (9 to 24) 31 (18 to 47) 273 (6) ⨁⨁⨁◯ MODERATEa,b,c False negatives patients incorrectly classified as not having active TB 7 (5 to 8) 34 (26 to 41) 69 (53 to 82) 5 % PTT is reasonable for all-comers. In pre-ART era, PTT was presumably higher (10%), now it goes down. For this patient population test accuracy is of concern. 48 WHO/CDS/TB/2019.21 True negatives patients without active TB 941 (861 to 980) 903 (827 to 941) 855 (783 to 891) 2555 (6) ⨁◯◯◯ VERY LOWd,e,f False positives patients incorrectly classified as having active TB 49 (10 to 129) 47 (9 to 123) 45 (9 to 117) For individual studies, sensitivity ranged from 0% to 63%. We thought that the percentage of patients with TB symptoms or CD4 count could explain in part the heterogeneity. One study (LaCourse 2016) with sensitivity 0% differed from the other studies by including a) a population of exclusively pregnant women attending an antenatal care setting, b) a low proportion of symptomatic participants (19%), c) a low TB prevalence (1%), and d) a high median CD4 cell count (437 cells per µL). One study (Thit 2017) with sensitivity 63% differed from the other studies by being conducted in Myanmar, and is the only study included in this review that evaluated AlereLAM in a setting outside sub-Saharan Africa. We did not downgrade for inconsistency. We thought the wide 95% Crls around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. We did not downgrade for imprecision. As assessed by QUADAS-2, in the patient selection domain, we judged four studies (67%) at high risk of bias because they did not avoid inappropriate exclusions. We downgraded one level for risk of bias. For individual studies, specificity ranged from 67% to 99%. Five of the studies had specificity of 94% or higher. One study (Thit 2017) with specificity 67% differed from the other studies by being conducted in Myanmar, and is the only study included in this review that evaluated AlereLAM in a setting outside sub- Saharan Africa. We did not downgrade further for inconsistency. As assessed by QUADAS-2, in the reference standard domain, we judged five studies (83%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded two levels for risk of bias. The wide 95% CrIs around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ○ Trivial ● Small ○ Moderate ○ Large In outpatients settings (5% prevalence) out of 1000 patients with signs and symptoms of TB, for 16 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, only 25 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation. Furthermore, in outpatients settings, out of 1000 patients with signs and symptoms of TB, for 903 patients the TB diagnosis will be correctly As urine LAM does not provide information about drug resistance, thus a positive result (both TP and FP) will necessitate additional testing (Xpert, culture) in order to 49 WHO/CDS/TB/2019.21 ○ Varies ○ Don't know excluded. Out of 100 patients with negative test result, 96 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. In the same time, in outpatient settings, out of 1000 patients with signs and symptoms of TB, there will be 47 with TB diagnosis falsely established. Out of 100 patients with negativetest result, 96 would not have active TB. Furthermore, out of 1000 patients with signs and symptoms of TB, for 34 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 4 would actually have active TB, and thus will be exposed to Increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. identify evidence for phenotypic or molecular drug resistance. As urine LAM sensitivity does not allow identification of all cases of MTB, additional testing may be required following a negative result (TN and FN). As the test can be performed on an easy to collect urine sample outside a laboratory, the time to diagnosis can be reduced The desirable effect of the test may be further augmented by the fact that in low-resource settings, certain proportion of TB patients may be diagnosed by LF-LAM and not by WHO recommended rapid TB diagnostic test (Xpert) due to the following reasons: 1) sputum Xpert has lower sensitivity in HIV-positive than HIV-negative people; 2) patients may not be able to produce sputum; 3) patients may not have access to Xpert. Undesirable Effects How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations ○ Large ● Moderate ○ Small ○ Trivial ○ Varies ○ Don't know In outpatients settings (5% prevalence) out of 1000 patients with signs and symptoms of TB, for 16 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, only 25 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation. Furthermore, in outpatients settings, out of 1000 patients with signs and symptoms of TB, for 903 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 96 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. In the same time, in outpatient settings, out of 1000 patients with signs and symptoms of TB, there will be 47 with TB diagnosis falsely established. Out of 100 patients with negativetest result, 96 would not have active TB. Furthermore, out of 1000 patients with signs and symptoms of TB, for 34 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 4 would actually have active TB, and thus will be exposed to Increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. As CD4 counts decrease, the sickest patients may be not able to produce a sputum specimen or would have EPTB. Thus their TP results would not be confirmed by microbiological reference standard and will be misclassified as FP. NTM and other environmental factors may possibly lead to FP results. Undesirable effects maybe partially compensated by the use of other tests in an algorithm. Certainty of the evidence of test accuracy What is the overall certainty of the evidence of test accuracy? 50 WHO/CDS/TB/2019.21 Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies For individual studies, sensitivity ranged from 0% to 63%. We thought that the percentage of patients with TB symptoms or CD4 count could explain in part the heterogeneity. One study (LaCourse 2016) with sensitivity 0% differed from the other studies by including a) a population of exclusively pregnant women attending an antenatal care setting, b) a low proportion of symptomatic participants (19%), c) a low TB prevalence (1%), and d) a high median CD4 cell count (437 cells per µL). One study (Thit 2017) with sensitivity 63% differed from the other studies by being conducted in Myanmar, and is the only study included in this review that evaluated AlereLAM in a setting outside sub-Saharan Africa. We did not downgrade for inconsistency. We thought the wide 95% Crls around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. We did not downgrade for imprecision. As assessed by QUADAS-2, in the patient selection domain, we judged four studies (67%) at high risk of bias because they did not avoid inappropriate exclusions. We downgraded one level for risk of bias. For individual studies, specificity ranged from 67% to 99%. Five of the studies had specificity of 94% or higher. One study (Thit 2017) with specificity 67% differed from the other studies by being conducted in Myanmar, and is the only study included in this review that evaluated AlereLAM in a setting outside sub-Saharan Africa. We did not downgrade further for inconsistency. 51 WHO/CDS/TB/2019.21 As assessed by QUADAS-2, in the reference standard domain, we judged five studies (83%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded two levels for risk of bias. The wide 95% CrIs around true negatives and false positives may lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. Certainty of the evidence of test's effects What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies No adverse events were associated with LAM testing (Peter 2016). High quality evidence. Even though, Dx trial may not capture side effects as effectively as treatment trials, in case of major side-effects would occur likely they would be reported. Similarly as for inpatients (see 1.1) POC benefits for the test. We assume that there are no adverse effects associated with the test. The AlereLAM assay can be performed at the patient bedside, in a clinic or a laboratory with minimal training. There was no difficulty in urine collection, no discussion on patient harms, it was deemed as easy to perform. Direct benefit – being quickly diagnosed. Risk - Not following the result, if test is not part of an algorithm. Burden is considered unimportant. Certainty of the evidence of management's effects What is the overall certainty of the evidence of effects of the management that is guided by the test results? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High How confident we are in effects of the intervention? How certain we are in expected benefits from treatment? LAM+ patients have higher risk for mortality, than LAM- ones. TB Treatment is rather effective in drug-sensitive TB patients. 52 WHO/CDS/TB/2019.21 ○ No included studies 2 RCTs in hospitalized HIV-positive adults showed a decrease in mortality associated with use of the AlereLAM comparing to the non-use of AlereLAM. Pooled risk ratio was 0.85 (95% CI 0.76 to 0.94) i.e. study participants undergoing AlereLAM testing had 0.85 times the risk or 15% lower risk of mortality than participants undergoing routine TB diagnostic testing without AlereLAM. The absolute effect was 35 fewer deaths per 1,000 (from 14 fewer to 55 fewer) (high-certainty evidence). Treatment may be less effective in more sick (immunocompromized) or drug-resistant patient groups. Certainty of the evidence of test result/management How certain is the link between test results and management decisions? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies Report on user perspectives on TB LAM testing: results from qualitative research: testing makes a critical difference for many patients from a hard to diagnose group. In one RCT, > 95% of clinicians acted on a positive test result (Peter 2016). Clinicians know it is an inaccurate test. Are they going to ignore results of it? Or do something? Patients in trials do promptly receive anti-TB therapy after testing and there is little concern that this would not happen outside of trials. For a negative LAM test result, clinicians may use empirical treatment for TB. Certainty of effects What is the overall certainty of the evidence of effects of the test? Judgement Research evidence Additional considerations 53 WHO/CDS/TB/2019.21 ● Very low ○ Low ○ Moderate ○ High ○ No included studies Summary of the above conclusions Values Is there important uncertainty about or variability in how much people value the main outcomes? Judgement Research evidence Additional considerations ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability It is likely that no important variability exists in how much people value following important outcomes: Mortality. Cure from (TB). Treatment side effects (in false positives). Drug resistance. Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations ○ Favors the comparison ● Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know Summary of the above Given the high mortality in persons living with HIV, acting on all positive LAM results likely balances any possible adverse effects associated with unnecessary treatment with reducing mortality. Resources required 54 WHO/CDS/TB/2019.21 How large are the resource requirements (costs)? Judgement Research evidence Additional considerations ○ Large costs ○ Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ● Don't know Systematic review by A. Zwerling: Mukora 2018 employed a detailed micro-costing approach among outpatient clinics testing PLHIV with CD4 ⩽150 cells/μL including costs from both the clinic level and above clinic level, across non-governmental organizations (NGO) and department of health (DoH) implementers/clinics and included costs from both start-up and implementation periods. Mukora 2018 estimated a total unit cost of AlereLAM testing at $23.55 (NGO clinics) and $22.72 (department of health (DOH) operated clinics). Unit costs were higher than have been reported in other studies from South Africa (~$3-4.00) largely driven by the inclusion of both clinic level ($11.49 NGO & $10.85 DOH) and above clinic level costs ($12.06 NGO & $11.87 DOH). The cost are likely large but the panel opted to choose don't know because of the uncertainty. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Systematic review by A. Zwerling: Models found cost-effectiveness of AlereLAM to be robust across a variety of sensitivity analyses, variations in key parameters and across different country settings and scenarios. Key parameters that are likely influential on cost-effectiveness include: TB prevalence, target population, and AlereLAM specificity, cost of treating TB and HIV and life expectancy post TB survival, and time horizon. However, one detailed micro-costing study published in 2018 estimates unit test costs for AlereLAM implementation several fold higher ($23) than most current models ($2-4). Modeling studies may contribute to the certainty of the evidence in this domain Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Judgement Research evidence Additional considerations 55 WHO/CDS/TB/2019.21 ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● No included studies Systematic review by A. Zwerling: Two cost-effectiveness analyses conducted in outpatient settings: Shah 2013 and Orlando 2018, both modelling studies, not based on trial data. Compared with the standard of care (smear microscopy for those positive on symptom screen), Orlando 2018 found the Xpert and Xpert/Alere approaches were highly cost-effective with ICERs of $56.54/DALY averted for the Xpert approach and $72.34/DALY averted for AlereLAM/Xpert. The smaller ICERs compared with earlier studies are driven largely by increased benefits associated with averted transmission and new infections. Available studies were for only 10% prevalence Equity What would be the impact on health equity? Judgement Research evidence Additional considerations ○ Reduced ● Probably reduced ○ Probably no impact ○ Probably increased ○ Increased ○ Varies ○ Don't know As test can be performed at all levels of the health care system, it is possibly can improve health care equity Patients getting false positive results, would suffer from harms (not needed TB treatment) that would work for them differently, comparing to other patient groups. Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ○ No ● Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know “End-user survey”: Test is generally described as acceptable by key stakeholders. Patients: Providers: Policy-makers/programs: Payers: Others: 56 WHO/CDS/TB/2019.21 In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Feasibility Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ● Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know MSF study (H. Huerga) Advantages of using LAM: • LAM implementation required little increase in clinician workload and no additional workspace • Test successfully performed at the point of care, no need to transport samples, no need of laboratory, no additional equipment • Test was perceived as easy to use with good inter-reader agreement • Most patients were able to submit a urine sample in contrast to sputum samples • LAM results available in very short time and allowed TB treatment initiation on the same day Challenges of using LAM: • There maybe challenges with reading grade 1 and interpreting faint bands. • It is important to train on the interpretation of results and ensure the use of the reading card. • CD4 to select patients is problematic because not always immediately available. • Alternative clinical criteria such as seriously ill alone would miss a lot of patients who could benefit from LAM. Qualitative study (N. Engel) Advantages of using LAM: • Urine sample is easily available, less stigmatized & safe • Minimal user skills • Low maintenance/equipment requirements • Short TAT of 25’ Challenges of using LAM: • Not everybody can produce, or collect urine samples • Visibility of faint results • Stockouts of urine containers, micropipettes unavailable, no running water/toilets for patients • Delays in Rx initiation Volumes change, but feasibility does not change, remains feasible but less acceptable (comparing with symptomatic patients) At scale implementation may be tricky. Concerns were raised by the panel about quality control that needs to be implemented. Outpatient setting will add additional challenges. In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Summary of judgements 57 WHO/CDS/TB/2019.21 Judgement Problem No Probably no Probably yes Yes Varies Don't know Test accuracy Very inaccurate Inaccurate Accurate Very accurate Varies Don't know Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of the evidence of test accuracy Very low Low Moderate High No included studies Certainty of the evidence of test's effects Very low Low Moderate High No included studies Certainty of the evidence of management's effects Very low Low Moderate High No included studies Certainty of the evidence of test result/management Very low Low Moderate High No included studies Certainty of effects Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know 58 WHO/CDS/TB/2019.21 Certainty of evidence of required resources Very low Low Moderate High No included studies Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ● ○ ○ ○ ○ Conclusions Recommendation 2.2 In outpatient settings, WHO recommends against using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children without assessing TB signs and symptoms (pulmonary and extrapulmonary) (strong; very low certainty in the evidence about test accuracy). 2.2.b In outpatient settings, WHO recommends against using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children without TB signs and symptoms (pulmonary and extrapulmonary) and unknown CD4 count or without TB signs and symptoms (pulmonary and extrapulmonary) and CD4 count over 200 (strong; very low certainty in the evidence about test accuracy) (in table 3.3). Implementation considerations 59 WHO/CDS/TB/2019.21 in children other signs and symptoms will be used - for all recommendations (to be defined) Research priorities Data Children Studies on test accuracy and on patient important outcomes in PLHIV without symptoms Frequency of testing needs to be addressed (across all recommendations). Evidence to decision table 6. Should AlereLAM be used to diagnose active TB in HIV-positive adults no symptoms and no CD4 count available? Population: HIV-positive adults no symptoms and no CD4 count available Intervention: AlereLAM Setting: outpatient Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital deaths among people living with HIV despite the increased access to antiretroviral treatment (ART) (Ford 2016). A systematic review of the prevalence of TB identified at autopsy suggests that, in resource- 60 WHO/CDS/TB/2019.21 ● Yes ○ Varies ○ Don't know limited settings, TB is responsible for around 40% of all HIV-related deaths and that TB often was disseminated and undiagnosed at the time of death (Gupta 2015). Globally in 2017, only 51% of the estimated 10.0 million TB cases were notified among people living with HIV (WHO Global Report 2018). However, most death from TB is preventable if TB is detected early and effectively treated. Test accuracy How accurate is the test? Judgement Research evidence Additional considerations ○ Very inaccurate ● Inaccurate ○ Accurate ○ Very accurate ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.21 (95% CI: 0.08 to 0.48) Specificity: 0.96 (95% CI: 0.89 to 0.99) Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ● Trivial ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.21 (95% CI: 0.08 to 0.48) Specificity: 0.96 (95% CI: 0.89 to 0.99) In out-patients settings, (10% prevalence) out of 1000 patients with signs and symptoms of TB, for 21 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, 37 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation Furthermore, in inpatients settings, out of 1000 patients with signs and symptoms of TB, for 864 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 92 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. 61 WHO/CDS/TB/2019.21 In the same time, in out-patient settings, out of 1000 patients with signs and symptoms of TB, for 36 patients the TB diagnosis will be falsely established. Out of 100 patients with positive test result, 63 would not have active TB, and thus would have risk of unnecessary treatment and stigma. Furthermore, in all settings, out of 1000 patients with signs and symptoms of TB, for 79 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 8 would actually have active TB, and thus will be exposed to Increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. Undesirable Effects How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations ● Large ○ Moderate ○ Small ○ Trivial ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.21 (95% CI: 0.08 to 0.48) Specificity: 0.96 (95% CI: 0.89 to 0.99) In out-patients settings, (10% prevalence) out of 1000 patients with signs and symptoms of TB, for 21 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, 37 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation Furthermore, in inpatients settings, out of 1000 patients with signs and symptoms of TB, for 864 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 92 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. In the same time, in out-patient settings, out of 1000 patients with signs and symptoms of TB, for 36 patients the TB diagnosis will be falsely established. Out of 100 patients with positive test result, 63 would not have active TB, and thus would have risk of unnecessary treatment and stigma. Furthermore, in all settings, out of 1000 patients with signs and symptoms of TB, for 79 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 8 would actually have active TB, and thus will be exposed to Increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. Undesirable effects would be mitigated, if other tests are performed according to diagnostic algorithm LAM does not provide information on drug-resistance For FP, some misclassification is possible, as some of them may be true positive Certainty of the evidence of test accuracy What is the overall certainty of the evidence of test accuracy? 62 WHO/CDS/TB/2019.21 Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Outcome Study design Test accuracy CoE Effect per 1000 patients/year for pre-test probability of 1% Effect per 1000 patients/year for pre-test probability of 10% Effect per 1000 patients/year for pre-test probability of 30% Importance True positives cross- sectional (cohort type accuracy study) ⨁◯ ◯◯ VERY LOWa,b,c 2 (1 to 5) 21 (8 to 48) 63 (24 to 144) False negatives 8 (5 to 9) 79 (52 to 92) 237 (156 to 276) True negatives cross- sectional (cohort type accuracy study) ⨁⨁ ◯◯ LOWd,e 950 (881 to 980) 864 (801 to 891) 672 (623 to 693) False positives 40 (10 to 109) 36 (9 to 99) 28 (7 to 77) As assessed by QUADAS-2, in the patient selection domain, we judged one study (50%) at high risk of bias because this study did not avoid inappropriate exclusions. We downgraded one level for risk of bias. The wide 95% CrI around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. However, there were few participants in this analysis. We downgraded two levels for imprecision. We thought that differences in the percentage of patients with TB symptoms in the two studies could explain some of the heterogeneity. We did not downgrade for inconsistency. As assessed by QUADAS-2, in the reference standard domain, we judged one study (50%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded one level for risk of bias. The wide 95% CrIs around true negatives and false positives would likely lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. 63 WHO/CDS/TB/2019.21 Certainty of the evidence of test's effects What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies No adverse events were associated with LAM testing (Peter 2016). We assume that there are no adverse effects associated with the test. Test can be performed at POC level. Positive effects of the test: - Detects any mycobacterial infection Negative effects of the test: - Cateterization can be risky - Misclassification of NTM for TB Certainty of the evidence of management's effects What is the overall certainty of the evidence of effects of the management that is guided by the test results? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies Certainty of the evidence of test result/management How certain is the link between test results and management decisions? Judgement Research evidence Additional considerations 64 WHO/CDS/TB/2019.21 ○ Very low ○ Low ● Moderate ○ High ○ No included studies (Report on user perspectives on TB LAM testing: results from qualitative research: testing makes a critical difference for many patients from a hard to diagnose group.) In one RCT, > 95% of clinicians acted on a positive LAM test result (Peter 2016). The tests can be performed at the patient bedside, in a clinic or a laboratory with minimal training. Patients in trials do promptly receive anti-TB therapy after testing and there is little concern that this would not happen outside of trials. For a negative LAM test result, clinicians may use empirical treatment for TB. In a RCT nurse made a specific recommendations, maybe different from practice, which would limit this positive effect in real settings High initial lost to follow up patients, in weak health systems for which LF-LAM is primarily designed for Qualitative research: Delayed intervention Interview for some individuals. Health providers tend to act slowly for urine test. Certainty of effects What is the overall certainty of the evidence of effects of the test? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Summary of the above conclusions Mortality: is important outcome for everyone (Cure from) TB: Treatment side effects (in false positives): Drug resistance: Values Is there important uncertainty about or variability in how much people value the main outcomes? Judgement Research evidence Additional considerations 65 WHO/CDS/TB/2019.21 ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations ● Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know Resources required How large are the resource requirements (costs)? Judgement Research evidence Additional considerations ○ Large costs ○ Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ● Don't know Projection from HIV Dept. 5 million PLHIV would be tested annually and have a CD4 count less than 200. 17% to 19% of PLHIV have CD4 counts below 200 in South Africa Population size is large but actual data not available and that made panel very uncertain. Unit cost, scaling up cost is unkwown. 66 WHO/CDS/TB/2019.21 Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ○ Very low ○ Low ○ Moderate ○ High ● No included studies Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Judgement Research evidence Additional considerations ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● No included studies One study found that utilized assumptions that the panel questioned in terms of applicability. Equity What would be the impact on health equity? Judgement Research evidence Additional considerations 67 WHO/CDS/TB/2019.21 ● Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ○ Increased ○ Varies ○ Don't know Concerns were raised about providing different services to outpatients that belong to the same group. Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ● No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know Feasibility Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know 68 WHO/CDS/TB/2019.21 Summary of judgements Judgement Problem No Probably no Probably yes Yes Varies Don't know Test accuracy Very inaccurate Inaccurate Accurate Very accurate Varies Don't know Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of the evidence of test accuracy Very low Low Moderate High No included studies Certainty of the evidence of test's effects Very low Low Moderate High No included studies Certainty of the evidence of management's effects Very low Low Moderate High No included studies Certainty of the evidence of test result/management Very low Low Moderate High No included studies Certainty of effects Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know 69 WHO/CDS/TB/2019.21 Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Certainty of evidence of required resources Very low Low Moderate High No included studies Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ● ○ ○ ○ ○ Conclusions Recommendation In outpatient settings, WHO recommends against using LF-LAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children without TB symptoms and unknown CD4 count or without TB symptoms and CD4 count greater than or equal to 200 (strong; very low certainty in the evidence about test accuracy) (3.3). Uncertain cost, harms 70 WHO/CDS/TB/2019.21 Evidence to decision table 7. Should AlereLAM be used to diagnose active TB in HIV-positive adults irrespective of symptoms, outpatient settings, CD4 ≤ 200? Population: HIV-positive adults irrespective of symptoms, outpatient settings, CD4 ≤ 200 Intervention: AlereLAM Setting: outpatient Assessment Problem Is the problem a priority? Judgement Research evidence Additional considerations ○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital deaths among people living with HIV despite the increased access to antiretroviral treatment (ART) (Ford 2016). A systematic review of the prevalence of TB identified at autopsy suggests that, in resource- limited settings, TB is responsible for around 40% of all HIV-related deaths and that TB often was disseminated and undiagnosed at the time of death (Gupta 2015). Globally in 2017, only 51% of the estimated 10.0 million TB cases were notified among people living with HIV (WHO Global Report 2018). However, most death from TB is preventable if TB is detected early and effectively treated. Non-sputum-based point-of-care TB diagnostic tests are highly desired to narrow the diagnostic gap and ensure timely treatment. Urine-based antigen testing would allow for a TB diagnosis that is non-site specific. Urine is further easy to collect and store, and lacks the infection control risks associated with sputum collection. Multiple platforms have been developed to detect lipoarabinomannan (LAM), initially as enzyme-linked immunosorbent (ELISA) assays that were evaluated in several clinical settings. Later, the lateral flow assay, Alere Determine™ TB LAM Ag assay ‘AlereLAM’, was developed as a simple point- of-care test for diagnosis of active TB in people living with HIV. AlereLAM is commercially available, does not require access to special laboratory equipment, and produces a result after 25 minutes, meeting many desired target product profile requirements. Test accuracy 71 WHO/CDS/TB/2019.21 How accurate is the test? Judgement Research evidence Additional considerations ○ Very inaccurate ● Inaccurate ○ Accurate ○ Very accurate ○ Varies ○ Don't know Test accuracy AlereLAM Sensitivity: 0.21 (95% CI: 0.08 to 0.48) Specificity: 0.96 (95% CI: 0.89 to 0.99) Prevalence of 10% was assumed. Test result Number of results per 1000 patients tested (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Prevalence 1% Prevalence 10% Prevalence 30% True positives patients with active TB 2 (1 to 5) 21 (8 to 48) 63 (24 to 144) 65 (2) ⨁◯◯◯ VERY LOWa,b,c False negatives patients incorrectly classified as not having active TB 8 (5 to 9) 79 (52 to 92) 237 (156 to 276) True negatives patients without active TB 950 (881 to 980) 864 (801 to 891) 672 (623 to 693) 587 (2) ⨁⨁◯◯ LOWd,e False positives patients incorrectly classified as having active TB 40 (10 to 109) 36 (9 to 99) 28 (7 to 77) As assessed by QUADAS-2, in the patient selection domain, we judged one study (50%) at high risk of bias because this study did not avoid inappropriate exclusions. We downgraded one level for risk of bias. 10 % PTT is reasonable for all-comers, in case of CD4 ≤ 200. 72 WHO/CDS/TB/2019.21 The wide 95% CrI around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. However, there were few participants in this analysis. We downgraded two levels for imprecision. We thought that differences in the percentage of patients with TB symptoms in the two studies could explain some of the heterogeneity. We did not downgrade for inconsistency. As assessed by QUADAS-2, in the reference standard domain, we judged one study (50%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded one level for risk of bias. The wide 95% CrIs around true negatives and false positives would likely lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. Desirable Effects How substantial are the desirable anticipated effects? Judgement Research evidence Additional considerations ○ Trivial ● Small ○ Moderate ○ Large ○ Varies ○ Don't know AlereLAM Sensitivity: 0.21 (95% CI: 0.08 to 0.48) Specificity: 0.96 (95% CI: 0.89 to 0.99) In out-patients settings, (10% prevalence) out of 1000 patients with signs and symptoms of TB, for 21 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, 37 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation Furthermore, in inpatients settings, out of 1000 patients with signs and symptoms of TB, for 864 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 92 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. In the same time, in out-patient settings, out of 1000 patients with signs and symptoms of TB, for 36 patients the TB diagnosis will be falsely established. Out of 100 patients with positive test result, 63 would not have active TB, and thus would have risk of unnecessary treatment and stigma. Furthermore, in all settings, out of 1000 patients with signs and symptoms of TB, for 79 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 8 would actually have active TB, and thus will be exposed to Increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. As urine LAM does not provide information about drug resistance, thus a positive result (both TP and FP) will necessitate additional testing (Xpert, culture) in order to identify evidence for phenotypic or molecular drug resistance. As urine LAM sensitivity does not allow identification of all cases of MTB, additional testing may be required following a negative result (TN and FN). As the test can be performed on an easy to collect urine sample outside a laboratory, the time to diagnosis can be reduced The desirable effect of the test may be further augmented by the fact that in low-resource settings, certain proportion of TB patients may be diagnosed by LF-LAM and not by WHO recommended rapid TB diagnostic test (Xpert) due to the following reasons: 1) sputum Xpert has lower sensitivity in HIV- positive than HIV-negative people; 2) patients may not be able to produce sputum; 3) patients may not have access to Xpert. Undesirable Effects 73 WHO/CDS/TB/2019.21 How substantial are the undesirable anticipated effects? Judgement Research evidence Additional considerations ○ Large ● Moderate ○ Small ○ Trivial ○ Varies ○ Don't know AlereLAM Sensitivity: 0.21 (95% CI: 0.08 to 0.48) Specificity: 0.96 (95% CI: 0.89 to 0.99) In out-patients settings, (10% prevalence) out of 1000 patients with signs and symptoms of TB, for 21 patients the TB diagnosis will be correctly established. Out of 100 patients with positive test result, 37 would actually have active TB, and thus benefit from rapid diagnosis and early treatment initiation Furthermore, in inpatients settings, out of 1000 patients with signs and symptoms of TB, for 864 patients the TB diagnosis will be correctly excluded. Out of 100 patients with negative test result, 92 would actually not have active TB, and thus benefit from sparing the unnecessary treatment; and also benefit of reassurance and alternative diagnosis. In the same time, in out-patient settings, out of 1000 patients with signs and symptoms of TB, for 36 patients the TB diagnosis will be falsely established. Out of 100 patients with positive test result, 63 would not have active TB, and thus would have risk of unnecessary treatment and stigma. Furthermore, in all settings, out of 1000 patients with signs and symptoms of TB, for 79 patients the TB diagnosis will be missed. Out of 100 patients with negative test result, 8 would actually have active TB, and thus will be exposed to Increased risk of morbidity and mortality, delayed treatment initiation and pose the continued risk of transmission. As CD4 counts decrease, the sickest patients may be not able to produce a sputum specimen or would have EPTB. Thus their TP results would not be confirmed by microbiological reference standard and will be misclassified as FP. NTM and other environmental factors may possibly lead to FP results. LAM does not provide information on drug-resistance Undesirable effects would be mitigated, if other tests are performed according to diagnostic algorithm Certainty of the evidence of test accuracy What is the overall certainty of the evidence of test accuracy? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Outcome Study design Test accuracy CoE Effect per 1000 patients/year for pre-test probability of 1% Effect per 1000 patients/year for pre-test probability of 10% Effect per 1000 patients/year for pre-test probability of 30% Importance True positives cross- sectional 2 (1 to 5) 21 (8 to 48) 63 (24 to 144) 74 WHO/CDS/TB/2019.21 False negatives (cohort type accuracy study) ⨁◯ ◯◯ VERY LOWa,b,c 8 (5 to 9) 79 (52 to 92) 237 (156 to 276) True negatives cross- sectional (cohort type accuracy study) ⨁⨁ ◯◯ LOWd,e 950 (881 to 980) 864 (801 to 891) 672 (623 to 693) False positives 40 (10 to 109) 36 (9 to 99) 28 (7 to 77) As assessed by QUADAS-2, in the patient selection domain, we judged one study (50%) at high risk of bias because this study did not avoid inappropriate exclusions. We downgraded one level for risk of bias. The wide 95% CrI around true positives and false negatives would likely not lead to different decisions depending on which credible limits are assumed. However, there were few participants in this analysis. We downgraded two levels for imprecision. We thought that differences in the percentage of patients with TB symptoms in the two studies could explain some of the heterogeneity. We did not downgrade for inconsistency. As assessed by QUADAS-2, in the reference standard domain, we judged one study (50%) at high risk of bias because we thought the reference standard used was unlikely to correctly classify the target condition. We downgraded one level for risk of bias. The wide 95% CrIs around true negatives and false positives would likely lead to different decisions depending on which credible limits are assumed. We downgraded one level for imprecision. Certainty of the evidence of test's effects What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High No adverse events were associated with LAM testing (Peter 2016). High quality evidence. Even though, Dx trial may not capture side effects as effectively as treatment trials, in case of major side-effects would occur likely they would be reported. We assume that there are no adverse effects associated with the test. Test can be performed at POC level. 75 WHO/CDS/TB/2019.21 ○ No included studies The AlereLAM assay can be performed at the patient bedside, in a clinic or a laboratory with minimal training. There was no difficulty in urine collection, no discussion on patient harms, it was deemed as easy to perform. Direct benefit – being quickly diagnosed. Risk - Not following the result, if test is not part of an algorithm. Burden is considered unimportant. Effects of the test: - Detects any mycobacterial infection Negative effects of the test: - Cateterization can be risky - Misclassification of NTM for TB Certainty of the evidence of management's effects What is the overall certainty of the evidence of effects of the management that is guided by the test results? Judgement Research evidence Additional considerations ○ Very low ○ Low ● Moderate ○ High ○ No included studies How confident we are in effects of the intervention? How certain we are in expected benefits from treatment? 2 RCTs in hospitalized HIV-positive adults showed a decrease in mortality associated with use of the AlereLAM comparing to the non-use of AlereLAM. Pooled risk ratio was 0.85 (95% CI 0.76 to 0.94) i.e. study participants undergoing AlereLAM testing had 0.85 times the risk or 15% lower risk of mortality than participants undergoing routine TB diagnostic testing without AlereLAM. The absolute effect was 35 fewer deaths per 1,000 (from 14 fewer to 55 fewer) (high-certainty evidence). LAM+ patients have higher risk for mortality, than LAM- ones. TB Treatment is rather effective in drug-sensitive TB patients. Treatment may be less effective in more sick (immunocompromized) or drug-resistant patient groups. Certainty of the evidence of test result/management How certain is the link between test results and management decisions? Judgement Research evidence Additional considerations 76 WHO/CDS/TB/2019.21 ○ Very low ○ Low ● Moderate ○ High ○ No included studies (Report on user perspectives on TB LAM testing: results from qualitative research: testing makes a critical difference for many patients from a hard to diagnose group.) In one RCT, > 95% of clinicians acted on a positive LAM test result (Peter 2016). Patients in trials do promptly receive anti-TB therapy after testing and there is little concern that this would not happen outside of trials. For a negative LAM test result, clinicians may use empirical treatment for TB. In a RCT nurse made a specific recommendations, maybe different from practice, which would limit this positive effect in real settings High initial lost to follow up patients, in weak health systems for which LF-LAM is primarily designed for Qualitative research: Delayed intervention Interview for some individuals. Health providers tend to act slowly for urine test. Certainty of effects What is the overall certainty of the evidence of effects of the test? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Summary of the above conclusions Values Is there important uncertainty about or variability in how much people value the main outcomes? Judgement Research evidence Additional considerations ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability It is likely that no important variability exists in how much people value following important outcomes: Mortality. 77 WHO/CDS/TB/2019.21 ○ No important uncertainty or variability Cure from (TB). Treatment side effects (in false positives). Drug resistance. Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Judgement Research evidence Additional considerations ○ Favors the comparison ● Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know Summary of the above Given the high mortality in persons living with HIV, acting on all positive LAM results likely balances any possible adverse effects associated with unnecessary treatment with reducing mortality. Resources required How large are the resource requirements (costs)? Judgement Research evidence Additional considerations 78 WHO/CDS/TB/2019.21 ○ Large costs ○ Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ● Don't know Systematic review by A. Zwerling: Mukora 2018 employed a detailed micro-costing approach among outpatient clinics testing PLHIV with CD4 ⩽150 cells/μL including costs from both the clinic level and above clinic level, across non-governmental organizations (NGO) and department of health (DoH) implementers/clinics and included costs from both start-up and implementation periods. Mukora 2018 estimated a total unit cost of AlereLAM testing at $23.55 (NGO clinics) and $22.72 (department of health (DOH) operated clinics). Unit costs were higher than have been reported in other studies from South Africa (~$3-4.00) largely driven by the inclusion of both clinic level ($11.49 NGO & $10.85 DOH) and above clinic level costs ($12.06 NGO & $11.87 DOH). Uncertainty about actual unit cost, which may substantially affect of implementation/scaling up cost. Latter costs maybe underestimated. Projection from HIV Dept. 5 million PLHIV would be tested annually and have a CD4 count less than 200. 17% to 19% of PLHIV have CD4 counts below 200 in South Africa Population size is large but actual data not available and that made panel very uncertain. Unit cost, scaling up cost is unkwown. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Judgement Research evidence Additional considerations ● Very low ○ Low ○ Moderate ○ High ○ No included studies Systematic review by A. Zwerling: Models found cost-effectiveness of AlereLAM to be robust across a variety of sensitivity analyses, variations in key parameters and across different country settings and scenarios. Key parameters that are likely influential on cost-effectiveness include: TB prevalence, target population, and AlereLAM specificity, cost of treating TB and HIV and life expectancy post TB survival, and time horizon. However, one detailed micro-costing study published in 2018 estimates unit test costs for AlereLAM implementation several fold higher ($23) than most current models ($2-4). Modeling studies may contribute to the certainty of the evidence in this domain Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Judgement Research evidence Additional considerations 79 WHO/CDS/TB/2019.21 ○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ● Varies ○ No included studies One study found that utilized assumptions that the panel questioned in terms of applicability. Equity What would be the impact on health equity? Judgement Research evidence Additional considerations ○ Reduced ○ Probably reduced ● Probably no impact ○ Probably increased ○ Increased ○ Varies ○ Don't know As patient population to be tested is rather broad: all patients irrespective of symptoms, outpatient settings, probably no impact on equity. Concerns were raised about providing different services to outpatients that belong to the same patient group. Maybe increased equity of access rather than equity to high quality care. Acceptability Is the intervention acceptable to key stakeholders? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know Feasibility 80 WHO/CDS/TB/2019.21 Is the intervention feasible to implement? Judgement Research evidence Additional considerations ○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know MSF study (H. Huerga) Advantages of using LAM: • LAM implementation required little increase in clinician workload and no additional workspace • Test successfully performed at the point of care, no need to transport samples, no need of laboratory, no additional equipment • Test was perceived as easy to use with good inter-reader agreement • Most patients were able to submit a urine sample in contrast to sputum samples • LAM results available in very short time and allowed TB treatment initiation on the same day Challenges of using LAM: • There maybe challenges with reading grade 1 and interpreting faint bands. • It is important to train on the interpretation of results and ensure the use of the reading card. • CD4 to select patients is problematic because not always immediately available. • Alternative clinical criteria such as seriously ill alone would miss a lot of patients who could benefit from LAM. Qualitative study (N. Engel) Advantages of using LAM: • Urine sample is easily available, less stigmatized & safe • Minimal user skills • Low maintenance/equipment requirements • Short TAT of 25’ Challenges of using LAM: • Not everybody can produce, or collect urine samples • Visibility of faint results • Stockouts of urine containers, micropipettes unavailable, no running water/toilets for patients • Delays in Rx initiation At scale implementation may be tricky. Concerns were raised by the panel about quality control that needs to be implemented. Outpatient setting will add additional challenges. In children: Urine collection was more cumbersome especially in younger and sicker children as it requires both the child’s and the caregiver’s cooperation and may be affected by medical causes such as dehydration (Kroidl 2015). Summary of judgements Judgement Problem No Probably no Probably yes Yes Varies Don't know Test accuracy Very inaccurate Inaccurate Accurate Very accurate Varies Don't know 81 WHO/CDS/TB/2019.21 Desirable Effects Trivial Small Moderate Large Varies Don't know Undesirable Effects Large Moderate Small Trivial Varies Don't know Certainty of the evidence of test accuracy Very low Low Moderate High No included studies Certainty of the evidence of test's effects Very low Low Moderate High No included studies Certainty of the evidence of management's effects Very low Low Moderate High No included studies Certainty of the evidence of test result/management Very low Low Moderate High No included studies Certainty of effects Very low Low Moderate High No included studies Values Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Certainty of evidence of required resources Very low Low Moderate High No included studies Cost effectiveness Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies Equity Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know 82 WHO/CDS/TB/2019.21 Acceptability No Probably no Probably yes Yes Varies Don't know Feasibility No Probably no Probably yes Yes Varies Don't know Type of recommendation Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention ○ ● ○ ○ ○ Conclusions Recommendation 3.2 In outpatient settings, WHO suggest not using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children over 5 years of age without TB sign and symptoms (pulmonary and extrapulmonary) with CD4 counts between 100 and 200 (conditional; very low certainty in the evidence about test accuracy). Prevalence of 10% was assumed. 3.2.b In outpatient settings, WHO recommends against using AlereLAM to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children over 5 years of age without TB sign and symptoms (pulmonary and extrapulmonary) without TB sign and symptoms (pulmonary and extrapulmonary) and unknown CD4 count or without TB sign and symptoms (pulmonary and extrapulmonary) and CD4 count over 200 (strong; very low certainty in the evidence about test accuracy) (in table 3.3). CD4 count not used in children (% correlate) Implementation considerations Using LAM should not ignore other tests 83 WHO/CDS/TB/2019.21