Stephanie Bjerrum, Bianca Sossen, Kinuyo Chikamatsu, Satoshi Mitarai, Aurélien Macé, Mark P. Nicol, Stefano Ongarello, Charlotte Schutz, Rita Székely, Isik Somuncu Johansen, Tobias Broger, Japheth A Opintan, Andrew D. Kerkhoff, Graeme Meintjes, Claudia M. Denkinger, and Samuel G Schumacher
Background Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV), yet TB often goes undiagnosed since many patients are not able to produce a sputum specimen, and traditional diagnostics are costly or unavailable. A novel, rapid lateral flow assay, Fujifilm SILVAMP TB LAM (SILVAMP-LAM), detects the presence of TB lipoarabinomannan (LAM) in urine, and is substantially more sensitive for diagnosing TB in PLHIV than an earlier LAM assay (Alere Determine TB LAM lateral flow assay [LF-LAM]). Here, we present an individual participant data meta-analysis of the diagnostic accuracy of SILVAMP-LAM in adult PLHIV, including both published and unpublished data. Methods and findings Adult PLHIV (≥18 years) were assessed in 5 prospective cohort studies in South Africa (3 cohorts), Vietnam, and Ghana, carried out during 2012 to 2017. Of the 1,595 PLHIV who met eligibility criteria, the majority (61%) were inpatients, median age was 37 years (IQR 30–43), 43% had a CD4 count ≤ 100 cells/μl, and 35% were receiving antiretroviral therapy. Most participants (94%) had a positive WHO symptom screen for TB on enrollment, and 45% were diagnosed with microbiologically confirmed TB, using mycobacterial culture or Xpert MTB/RIF testing of sputum, urine, or blood. Previously published data from inpatients were combined with unpublished data from outpatients. Biobanked urine samples were tested, using blinded double reading, with SILVAMP-LAM and LF-LAM. Applying a microbiological reference standard for assessment of sensitivity, the overall sensitivity for TB detection was 70.7% (95% CI 59.0%–80.8%) for SILVAMP-LAM compared to 34.9% (95% CI 19.5%–50.9%) for LF-LAM. Using a composite reference standard (which included patients with both microbiologically confirmed as well as clinically diagnosed TB), SILVAMP-LAM sensitivity was 65.8% (95% CI 55.9%–74.6%), and that of LF-LAM 31.4% (95% CI 19.1%–43.7%). In patients with CD4 count ≤ 100 cells/μl, SILVAMP-LAM sensitivity was 87.1% (95% CI 79.3%–93.6%), compared to 56.0% (95% CI 43.9%–64.9%) for LF-LAM. In patients with CD4 count 101–200 cells/μl, SILVAMP-LAM sensitivity was 62.7% (95% CI 52.4%–71.9%), compared to 25.3% (95% CI 15.8%–34.9%) for LF-LAM. In those with CD4 count > 200 cells/μl, SILVAMP-LAM sensitivity was 43.9% (95% CI 34.3%–53.9%), compared to 10.9% (95% CI 5.2%–18.4%) for LF-LAM. Using a microbiological reference standard, the specificity of SILVAMP-LAM was 90.9% (95% CI 87.2%–93.7%), and that of LF-LAM 95.3% (95% CI 92.2%–97.7%). Limitations of this study include the use of biobanked, rather than fresh urine samples, and testing by skilled laboratory technicians in research laboratories, rather than at the point of care. Conclusions In this study, we found that SILVAMP-LAM identified a substantially higher proportion of TB patients in PLHIV than LF-LAM. The sensitivity of SILVAMP-LAM was highest in patients with CD4 count ≤ 100 cells/μl. Further work is needed to demonstrate accuracy when implemented as a point-of-care test., Claudia Denkinger and colleagues investigate whether a new assay for lipoarabinomannan (LAM) can diagnose tuberculosis in people living with HIV more accurately than an earlier LAM assay., Author summary Why was this study done? Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV); however, TB is difficult to diagnose in PLHIV because patients may have extrapulmonary disease, difficulty producing a sputum sample, or few TB bacilli in their sputum. Rapid point-of-care urine testing for TB with the Alere Determine TB LAM lateral flow assay (LF-LAM) reduces mortality in patients with advanced HIV disease, but LF-LAM has only moderate sensitivity, and its uptake in countries with high burdens of TB has been slow. Several recent studies have shown that the Fujifilm SILVAMP TB LAM (SILVAMP-LAM) test has improved sensitivity over LF-LAM and comparable specificity in PLHIV. What did the researchers do and find? We did an individual patient meta-analysis of the accuracy of SILVAMP-LAM across 5 cohort studies in South Africa, Ghana, and Vietnam, and compared SILVAMP-LAM results with those of LF-LAM. SILVAMP-LAM was twice as sensitive as LF-LAM in detecting TB in PLHIV, irrespective of whether a reference standard of microbiologically proven or clinically diagnosed TB was used. There were more apparent false-positive results associated with SILVAMP-LAM than with LF-LAM, although this difference between the 2 tests was small (4.4 percentage point difference in specificity). What do these findings mean? SILVAMP-LAM is a promising new rapid urine test for TB in PLHIV, particularly in those with advanced HIV disease, who are at highest risk of death. Further work is needed to determine whether SILVAMP-LAM, which is slightly more complex to perform than LF-LAM, can be reliably done at the point of care, and what impact the implementation of SILVAMP-LAM has on mortality in PLHIV with TB.