Immune Biomarkers Predict Early Death in HIV Patients with TB

Doctors treating patients battling both human immunodeficiency virus (HIV) and tuberculosis (TB), many of whom live in Africa, are faced with the decision when to start those patients on antiretroviral therapy (ART) while they are being treated with antibiotics for active TB disease.

Some patients fare well on both interventions, with the immune system in check and the TB controlled while others undergo complications from TB, such as paradoxical immune reconstitution inflammatory syndrome (IRIS), a worsening of TB symptoms despite response to therapy, while still others experience immune failure and early death.

Scientists at the Perelman School of Medicine (Philadelphia, PA, USA) undertook a prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults, aged ≥21 years, with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. Patients were classified as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the six months after ART initiation.

Blood was collected at baseline and week four of ART for HIV viral load (NucliSENS Easy Q HIV-1; BioMérieux; Marcy l'Etoile, France), plasma, and peripheral blood mononuclear cells. The team used a 29-cytokine, chemokine, and growth-factor magnetic-bead Luminex panel (EMD Millipore; Billerica, MA, USA) to measure immune biomarkers.

The investigators found that lower levels of eight biomarkers, including interleukin 6 (IL-6), IL-15 and granulocyte-macrophage colony-stimulating factor (GM-CSF), pre-ART were independently associated with an increased risk of IRIS, while higher levels of monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor-alpha (TNFα) were independently associated with an increased risk of death. However, IRIS and early mortality patients both experienced rapid increases in immune activation and inflammation after initiating ART. Four biomarkers, including IL-6, TNF-alpha, and granulocyte-colony stimulating factor (G-CSF), were independently associated with an increased risk of TB-IRIS, and five biomarkers were associated with an increased risk of death, including interleukin-1 receptor antagonist (IL-1RA) and G-CSF.

The magnitude of early immune recovery, the CD4 cell count, differed drastically between the two after being in ART, as well as underscoring the need for a personalized approach in these two groups. Those who initiated ART and died early had an increase in inflammation without the immune system rebounding enough to control the TB, while IRIS patients recovered more quickly. Gregory P. Bisson, MD, MSCE, a senior author of the study said, “The differences between the two groups, which haven’t been shown before, should influence future studies in this vulnerable population, as interventions that seek to prevent IRIS could inadvertently be increasing the risk of death. In this population, it’s important to study treatments that can decrease inflammation while promoting functional immune recovery.”

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Perelman School of Medicine  
BioMérieux  
EMD Millipore