New strategies for inpatients with HIV and tuberculosis
Authors: Ruvandhi R Nathavitharana, Madhukar Pai
Journal: The Lancet (2018)

Decreasing tuberculosis-related mortality—particularly in people living with HIV infection, who account for 22% of all tuberculosis deaths—is a pressing global health concern.1Chihota VN Ginindza S McCarthy K Grant AD Churchyard G Fielding K Missed opportunities for TB investigation in primary care clinics in South Africa: experience from the XTEND trial.PLoS One. 2015; 10: e0138149Crossref PubMed Scopus (30) Google Scholar Tuberculosis cascade-of-care analyses show that diagnosis is the weakest link.2Subbaraman R Nathavitharana RR Satyanarayana S et al.The tuberculosis cascade of care in India's public sector: a systematic review and meta-analysis.PLoS Med. 2016; 13: e1002149Crossref PubMed Scopus (156) Google Scholar, 3Naidoo P Theron G Rangaka MX et al.The South African tuberculosis care cascade: estimated losses and methodological challenges.J Infect Dis. 2017; 216: S702-S713Crossref PubMed Scopus (128) Google Scholar There is an urgent need for a non-sputum based, point-of-care diagnostic test for tuberculosis, particularly for groups such as those living with HIV infection who are often unable to produce sputum.4Kik SV Denkinger CM Casenghi M Vadnais C Pai M Tuberculosis diagnostics: which target product profiles should be prioritised?.Eur Respir J. 2014; 44: 537-540Crossref PubMed Scopus (59) Google Scholar The urine lipoarabinomannan assay (Determine TB-LAM; Alere, MA, USA) was conditionally endorsed by WHO in 2015 for use in adults with HIV who are admitted to hospital with signs and symptoms of tuberculosis, and have a CD4 count less than 100 cells per μL or are seriously ill.5WHOThe use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV: policy guidance. World Health Organization, Geneva2015http://www.who.int/tb/publications/use-of-lf-lam-tb-hiv/en/Date accessed: June 14, 2018Google Scholar In 2016, a randomised controlled trial6Peter JG Zijenah LS Chanda D et al.Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial.Lancet. 2016; 387: 1187-1197Summary Full Text Full Text PDF PubMed Scopus (171) Google Scholar showed that the use of urine LAM could reduce mortality in symptomatic patients with HIV and low CD4 cell counts admitted to hospital. However, despite the WHO policy and the trial results, uptake of urine LAM has been poor,7Médecins Sans FrontièresOut of Step 2017: TB policies in 29 countries: a survey of prevention, testing and treatment policies and practices.https://reliefweb.int/report/world/out-step-2017-tb-policies-29-countries-survey-prevention-testing-and-treatment-policiesDate: July, 2017Date accessed: June 14, 2018Google Scholar perhaps due to challenges in interpreting the current conditional policy and the fact that national tuberculosis programmes are usually not engaged in managing severely ill patients who are admitted to hospital. The STAMP trial, reported in The Lancet, by Ankur Gupta-Wright and colleagues8Gupta-Wright A Corbett EL van Oosterhout JJ et al.Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.Lancet. 2018; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(18)31267-4Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar randomly assigned 2600 HIV-positive patients to the standard-of-care screening group (sputum Xpert MTB/RIF [Xpert], Cepheid, CA, USA) and intervention screening group (sputum and urine Xpert plus urine LAM) in Malawi and South Africa. The primary endpoint was all-cause 56-day mortality, and was not significantly different between the two groups (absolute adjusted risk reduction −2·8%, 95% CI −5·8 to 0·3; p=0·074. However, Gupta-Wright and colleagues' trial showed that in three of 12 prespecified patient subgroups, which were underpowered, a significant mortality reduction was observed between the intervention group and standard-of-care group: adjusted risk reduction was −7·1% (95% CI −13·7 to −0·4) in patients with CD4 counts less than 100 cells per μL, −9·0% (−16·6 to −1·3) in those with haemoglobin less than 8 g/dL, and −5·7% (−10·9 to −0·5) in those with clinically suspected tuberculosis at admission. Their study8Gupta-Wright A Corbett EL van Oosterhout JJ et al.Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.Lancet. 2018; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(18)31267-4Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar also showed a significant increase in the number of patients diagnosed with and treated for tuberculosis between the intervention group and the standard-of-care group. Although mortality reduction is a welcome outcome for a study of diagnostic test effectiveness, it should not be the only person-centred outcome that is prioritised. Successful completion of the entire care cascade is what saves lives.9Pai M Schumacher SG Abimbola S Surrogate endpoints in global health research: still searching for killer apps and silver bullets?.BMJ Glob Health. 2018; 3: e000755Crossref PubMed Scopus (27) Google Scholar Transmission from unsuspected tuberculosis is a major driver of the ongoing epidemic and therefore earlier diagnosis, followed by linkage and retention in care, is an important component of tuberculosis elimination efforts. Although forthcoming cost-effectiveness data from the STAMP trial and additional studies will help to inform updated WHO recommendations on LAM, the re-emergence of tuberculosis as the leading cause of infectious disease-related adult deaths is a reminder that the cost of not adopting more ambitious strategies to manage tuberculosis is too high. LAM is inexpensive and can be easily done in the majority of patients with HIV (99% in the STAMP trial), in contrast to sputum Xpert (57% in the STAMP trial). Therefore, even if the mortality reduction is modest (less than 5%), using LAM as a screening test for HIV-infected patients in hospitals with high tuberculosis and HIV co-prevalence might increase the yield of tuberculosis diagnosis, as well as reduce tuberculosis-related mortality. Of note, patients who were unable to consent because of critical illness were excluded, which might have biased the study towards the null since this group might have been more likely to benefit from rapid tuberculosis diagnosis using the LAM assay. The STAMP trial further emphasises the need for a non-sputum based, rapid, point-of-care tuberculosis diagnostic test. To have a bigger impact, additional work is needed to improve the sensitivity of urine LAM testing in HIV-negative patients, and there is proof of concept that this improvement can be done.10MacLean E Pai M Urine lipoarabinomannan for tuberculosis diagnosis: evolution and prospects.Clin Chem. 2018; (published online April 9.)DOI:10.1373/clinchem.2018.286625Crossref Scopus (7) Google Scholar In a study by Paris and colleagues,11Paris L Magni R Zaidi F et al.Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity.Sci Transl Med. 2017; 9: eaal2807Crossref PubMed Scopus (69) Google Scholar nanocage technology and a copper-complex reactive dye were used to evaluate the concentration of lipoarabinomannan in the pretreatment urine of 48 HIV-negative patients with microbiologically confirmed active pulmonary tuberculosis from a Peruvian hospital. Compared with age-matched healthy volunteers and those with non-tuberculosis diseases, Paris and colleagues reported a sensitivity of 96% and specificity of 81%. This finding is a promising step towards wider use of urine LAM, but substantial product development will be required to move this technology toward a standardised point-of-care test, along with larger field studies. Other product developers are also engaged in improving urine LAM testing, but published data are scarce.10MacLean E Pai M Urine lipoarabinomannan for tuberculosis diagnosis: evolution and prospects.Clin Chem. 2018; (published online April 9.)DOI:10.1373/clinchem.2018.286625Crossref Scopus (7) Google Scholar With the upcoming UN High Level Meeting on Tuberculosis, the tuberculosis community has prioritised among their Key Asks (ie, priority actions), affordable point-of-care tuberculosis diagnostics that can identify new infections and tests for drug resistance by 2025.12UN HLMUnited to end tuberculosis: an urgent global response to a global epidemic. Key Asks from TB stakeholders and communities.http://www.stoptb.org/assets/documents/global/advocacy/KEYASKS.PDFDate accessed: June 13, 2018Google Scholar While the tuberculosis community waits for such new tools, they must scale up the best tools they already have. This action is the surest way to spur development and facilitate implementation of novel technologies in the pipeline. Failure to do so endangers patients and communities. MP serves on the Scientific Advisory Committee of FIND and on the SAGE IVD Committee and STAG-TB Committee of WHO. Neither FIND nor WHO were involved in the STAMP trial or in the writing of this Comment. RRN declares no competing interests. Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trialUrine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. Full-Text PDF Open Access