Effect of the relationship between anaemia and systemic inflammation on the risk of incident tuberculosis and death in people with advanced HIV: a sub-analysis of the REMEMBER trial

Abstract

Background: Tuberculosis (TB) is an infectious morbidity that commonly occurs in people living with HIV (PWH) and increases the progression of HIV disease, as well as the risk of death. Simple markers of progression are much needed to identify those at highest risk for poor outcome. This study aimed to assess how baseline severity of anaemia and associated inflammatory profiles impact death and the incidence of TB in a cohort of PWH who received TB preventive therapy (TPT).

Methods: This study is a secondary posthoc analysis of the AIDS Clinical Trials Group A5274 REMEMBER clinical trial (NCT0138008), an open-label randomised clinical trial of antiretroviral-naïve PWH with CD4 <50 cells/μL, performed from October 31, 2011 to June 9, 2014, from 18 outpatient research clinics in 10 low- and middle-income countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda) who initiated antiretroviral therapy and either isoniazid TPT or 4-drug empiric TB therapy. Plasma concentrations of several soluble inflammatory biomarkers were measured prior to the commencement of antiretroviral and anti-TB therapies, and participants were followed up for at least 48 weeks. Incident TB or death during this period were primary outcomes. We performed multidimensional analyses, logistic regression analyses, survival curves, and Bayesian network analyses to delineate associations between anaemia, laboratory parameters, and clinical outcomes.

Findings: Of all 269 participants, 76.2% (n = 205) were anaemic, and 31.2% (n = 84) had severe anaemia. PWH with moderate/severe anaemia exhibited a pronounced systemic pro-inflammatory profile compared to those with mild or without anaemia, hallmarked by a substantial increase in IL-6 plasma concentrations. Moderate/severe anaemia was also associated with incident TB incidence (aOR: 3.59, 95% CI: 1.32-9.76, p = 0.012) and death (aOR: 3.63, 95% CI: 1.07-12.33, p = 0.039).

Interpretation: Our findings suggest that PWH with moderate/severe anaemia display a distinct pro-inflammatory profile. The presence of moderate/severe anaemia pre-ART was independently associated with the development of TB and death. PWH with anaemia should be monitored closely to minimise the occurrence of unfavourable outcomes.

Funding: National Institutes of Health.

Keywords: Anaemia; Death; HIV; Haemoglobin; Incident TB; Inflammation; Systemic inflammation; Tuberculosis.

Fig. 1

Association between anaemia severity and the systemic inflammatory profile. Among all people with HIV (PWH) (n = 269), 76.2% had anaemia: 45% mild anaemia and 31.2% moderate/severe anaemia. (a) A heatmap was designed to depict the overall pattern of inflammatory markers. A one-way hierarchical cluster analysis (Ward's method) was performed. Dendrograms represent Euclidean distance. A log10 fold change was performed comparing groups. Significant differences (p < 0.05) are highlighted in green bars. (b) Scatter plots of the DIP value grouped according to anaemia severity. Lines in the scatter plots represent median values and data were compared using the Mann–Whitney U test. The Cochran–Armitage test for trend was used to assess the tendency of increased levels or frequencies among groups. Without anaemia was defined as Hb value >13 g/dL for man and >12 g/dL for women. Mild anaemia was defined as Hb value >10 g/dL and <13 g/dL for men; and >10 and <12 g/dL for women, whereas moderate/severe anaemia was defined as Hb ≤10 g/dL for both sexes.

Fig. 2

The association between anaemia and incident TB and death. (a) Distribution of TB occurrence according anaemia severity. (b) Scatter plots of the DIP value grouped according to incident TB. Lines in the scatter plots represent median values and data were compared using the Mann–Whitney U test. (c) Kaplan–Meier curves show percentage of TB occurrence over 48 weeks. (d) Distribution of deaths according anaemia severity. (e) Scatter plots of the DIP value grouped according to mortality. Lines in the scatter plots represent median values and data were compared using the Mann–Whitney U test. (f) Kaplan–Meier curves show percentage of death occurrence over 48 weeks. Definitions: Without anaemia was defined as Hb value >13 g/dL for man and >12 g/dL for women. Mild anaemia was defined as Hb value >10 g/dL and <13 g/dL for men; and >10 and <12 g/dL for women, whereas moderate/severe anaemia was defined as Hb ≤10 g/dL for both sexes.

Fig. 3

Inflammatory profile of individuals according to TB development and death in people with HIV. (A) Four groups were established: non-TB who survived (n = 189); non-TB who died (n = 34); TB who survived (n = 39) and TB who died (n = 13) (B) Right panel: A heatmap was designed to depict the overall pattern of inflammatory markers in participants according to TB and death occurrence. A one-way hierarchical cluster analysis (Ward's method) was performed. Dendrograms represent Euclidean distance. Left panel: A log10 fold change was performed comparing each group with control (non-TB who survived). Significant differences (p < 0.05) are highlighted in green bars (C) Panel shows the time of TB development (in blue) and death (in purple) during the study for the TB participants who died. Without anaemia was defined as Hb value >13 g/dL for man and >12 g/dL for women. Mild anaemia was defined as Hb value >10 g/dL and <13 g/dL for men; and >10 and <12 g/dL for women, whereas moderate/severe anaemia was defined as Hb ≤10 g/dL for both sexes.

Fig. 4

Binomial logistic regression (stepwise method) to assess the independent risk factor for incident TB and death in PWH. Binomial logistic regression with stepwise method was used to test independent associations between all clinical measurements (described in Table 1) and (a) incident TB or (b) death. Odds are per increase in 1 unit of the continuous variables. The alpha-to-enter and alpha-to-remove were equal to 0.15. Only variables remained in the last step were plotted. Abbreviations: CI: confidence interval; BMI: body mass index; TB: tuberculosis. Without anaemia was defined as Hb value >13 g/dL for man and >12 g/dL for women. Mild anaemia was defined as Hb value >10 g/dL and <13 g/dL for men; and >10 and <12 g/dL for women, whereas moderate/severe anaemia was defined as Hb ≤10 g/dL for both sexes.