title: Detection of lipoarabinomannan (LAM) in urine is an independent predictor of mortality risk in patients receiving treatment for HIV-associated tuberculosis in sub-Saharan Africa: a systematic review and meta-analysis.
abstract: BACKGROUND
  Simple immune capture assays that detect mycobacterial lipoarabinomannan (LAM) antigen in urine are promising new tools for the diagnosis of HIV-associated tuberculosis (HIV-TB). In addition, however, recent prospective cohort studies of patients with HIV-TB have demonstrated associations between LAM in the urine and increased mortality risk during TB treatment, indicating an additional utility of urinary LAM as a prognostic marker. We conducted a systematic review and meta-analysis to summarise the evidence concerning the strength of this relationship in adults with HIV-TB in sub-Saharan Africa, thereby quantifying the assay's prognostic value.
  
  
  METHODS
  We searched MEDLINE and Embase databases using comprehensive search terms for 'HIV', 'TB', 'LAM' and 'sub-Saharan Africa'. Identified studies were reviewed and selected according to predefined criteria.
  
  
  RESULTS
  We identified 10 studies eligible for inclusion in this systematic review, reporting on a total of 1172 HIV-TB cases. Of these, 512 patients (44 %) tested positive for urinary LAM. After a variable duration of follow-up of between 2 and 6 months, overall case fatality rates among HIV-TB cases varied between 7 % and 53 %. Pooled summary estimates generated by random-effects meta-analysis showed a two-fold increased risk of mortality for urinary LAM-positive HIV-TB cases compared to urinary LAM-negative HIV-TB cases (relative risk 2.3, 95 % confidence interval 1.6-3.1). Some heterogeneity was explained by study setting and patient population in sub-group analyses. Five studies also reported multivariable analyses of risk factors for mortality, and pooled summary estimates demonstrated over two-fold increased mortality risk (odds ratio 2.5, 95 % confidence interval 1.4-4.5) among urinary LAM-positive HIV-TB cases, even after adjustment for other risk factors for mortality, including CD4 cell count.
  
  
  CONCLUSIONS
  We have demonstrated that detectable LAM in urine is associated with increased risk of mortality during TB treatment, and that this relationship remains after adjusting for other risk factors for mortality. This may simply be due to a positive test for urinary LAM serving as a marker of higher mycobacterial load and greater disease dissemination and severity. Alternatively, LAM antigen may directly compromise host immune responses through its known immunomodulatory effects. Detectable LAM in the urine is an independent risk factor for mortality among patients receiving treatment for HIV-TB. Further research is warranted to elucidate the underlying mechanisms and to determine whether this vulnerable patient population may benefit from adjunctive interventions.
authors.affiliation: Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. ankurgw@outlook.com.|Malawi-Liverpool-Wellcome Trust Clinical Research Program, College of Medicine, University of Malawi, Blantyre, Malawi. ankurgw@outlook.com.
authors.forename: Ankur
authors.identifier: http://orcid.org/0000-0002-5150-2970
authors.initials: A
authors.lastname: Gupta-Wright
authors.affiliation: Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Jurgens A
authors.initials: JA
authors.lastname: Peters
authors.affiliation: Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Flach
authors.affiliation: Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.|The Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lawn
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara; D015415:Biomarkers / Q000652:urine*; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008070:Lipopolysaccharides / Q000652:urine*; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D014376:Tuberculosis / Q000150:complications / Q000401:mortality* / Q000652:urine*
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; C050016:lipoarabinomannan
keywords: HIV; LAM; Lipoarabinomannan; Mortality; Systematic review; Tuberculosis