Published in PLOS One on 2026-09-08, this study is presented as an attributed evidence briefing. The excerpts below are the original researchers’ words, reproduced under their Creative Commons Attribution licence. Health Signal has selected the abstract and, where needed, opening background paragraphs; the complete methods, results, limitations and references remain in the linked paper.
Original authors: Lydia Nakiyingi, Bernard Kikaire, Sarah Nakayenga, Louis Kamulegeya, Elizabeth Nakabugo, Juliet Nkugwa Asio, Bernard Bagaya, Willy Ssengooba, Harriet Mayanja-Kizza, Yukari C Manabe
Source: PLOS One • DOI 10.1371/journal.pone.0347436
Read the complete primary study ↗ · Creative Commons Attribution licence
From the researchers
Abstract
In sub-Saharan Africa where both tuberculosis (TB) and HIV are prevalent, empiric TB treatment in people living with HIV (PLHIV) persists due to limited sensitivity of sputum-based TB tests. We evaluated mortality among molecular test-negative presumptive TB adult PLHIV in a population with widespread antiretroviral therapy (ART) coverage, comparing those empirically treated and not treated for TB.
From November 2017 to December 2020, Xpert-negative adult PLHIV were recruited at Mulago Referral Hospital and Kisenyi Health Centre-IV in Kampala, Uganda. Clinical data including TB symptoms, chest X-ray, and empiric TB treatment decision were collected. Laboratory investigations included CD4 cell count, serum cryptococcal antigen (CrAg), urine TB-lipoarabinomannan (TB-LAM), microbiological blood cultures, and sputum mycobacterial growth indicator tube (MGIT) cultures. Participants were followed monthly for 12 months to ascertain vital status.
Overall, 300 participants were enrolled; 61.3% inpatients, 55.7% female, median age 37 (IQR 29–45) years, 82.3% on ART, median CD4 206 cells/mm³ (IQR 36–507). Of the 300, 68 (22.7%) received empiric TB treatment, of which 53 (77.9%) were inpatients. 12-month mortality was 31.0% (93/300); 72% within three months post-enrolment. TB cultures were positive in 5.0% (15/300), 12.3% had positive CrAg, and 3.7% had positive blood culture. Empirically treated participants had higher mortality (42.7%) than non-treated (27.6%) although the difference was not statistically significant after adjusting for factors indicative of severe illness (adjusted Mortality Rate Ratio- aMRR 1.05, p = 0.850). Inpatient (aMRR 3.80, p = 0.008) and poor functional status (aMRR 3.5 95%, p = 0.001) were independently associated with 12-month mortality.
We found high 12-month mortality among Xpert-negative PLHIV, predominantly inpatients and within three months post-enrolment. Although empiric TB treatment was associated with higher mortality, this association was lost after adjustment for severe illness indicators. Cryptococcal antigenemia and bacteremia were not uncommon, underscoring need for comprehensive evaluations for non-TB conditions alongside empiric TB treatment.
Introduction
Tuberculosis (TB) remains the leading cause of death among people living with HIV (PLHIV) globally, accounting for approximately one in every three AIDS-related deaths [1,2]. According to the World Health Organization (WHO) Global Tuberculosis Report 2025 [3], approximately 150,000 HIV/TB co-infected people died in 2024. TB often goes undiagnosed because standard sputum-based diagnostic tools such as Xpert MTB/RIF (herein referred to as Xpert) and sputum smear microscopy, have limited sensitivity in PLHIV [4,5]. Postmortem studies in sub-Saharan Africa (SSA) report up to 46% of TB cases remain undetected antemortem [6,7].
Among PLHIV with advanced immunosuppression, clinicians in high-burden HIV/TB settings often resort to empiric TB treatment; initiating TB therapy without microbiological confirmation, including situations where the Xpert result is negative [8,9]. In Uganda, one study found that up to 30% of smear-negative presumptive TB PLHIV received empiric TB treatment [9]. The introduction of Xpert, a more sensitive PCR-based test for MTB detection in HIV/TB high-burden settings, raised expectations for more rapid and accurate TB diagnosis, with decrease in TB-associated morbidity and mortality [10–13]. However, a considerable number of PLHIV still test negative on these assays [14–16], leading to minimal improvements in outcomes. An important limitation of Xpert is its low performance in paucibacillary disease commonly seen in PLHIV [5,11,16]. Xpert Ultra has shown better sensitivity than Xpert MTB/RIF for smear-negative and paucibacillary [13,16] and may reduce reliance on empiric TB treatment in this population. However, at the time of this study, Xpert Ultra had not yet been introduced as a TB diagnostic at the study site.
Reading this evidence
Use the full paper to check the study design, participant selection, comparator and outcome definitions before drawing a practical conclusion. An association does not by itself show cause and effect. A reported performance measure needs its denominator and uncertainty. A finding from a particular facility, sample or time period should retain that scope when it is discussed elsewhere.
This briefing makes the source accessible within the wider hospital systems desk. It does not assess an individual patient or certify a product. When considering relevance to another health system, examine the original authors’ account of context and limitations, then seek local implementation evidence. The related reporting below provides other studies to read alongside this one; it is a topic connection, rather than a claim that their results are directly comparable.
© 2026 Lydia Nakiyingi, Bernard Kikaire, Sarah Nakayenga, Louis Kamulegeya, Elizabeth Nakabugo, Juliet Nkugwa Asio, Bernard Bagaya, Willy Ssengooba, Harriet Mayanja-Kizza, Yukari C Manabe. Excerpts reproduced under CC BY. Selection, formatting and contextual notes by Health Signal. The researchers are the authors of the source study, not members of Health Signal’s staff.
Explore connected evidence
- Evidence brief: Inpatient mortality and associated clinical factors among people living with HIV with cryptococcal meningitis in Uganda: A retrospective cohort study
- Evidence brief: Contribution of xpert MTB/RIF assay and Urine LF-LAM for the diagnosis of tuberculosis in children aged 5 – 14 years, at selected health facilities in Ethiopia, 2016 – 2019
- Evidence brief: Change in plasma cryptococcal antigen titers in Uganda among outpatients with advanced HIV disease from 2017 to 2022 with rollout of national cryptococcal screening
