Early ART only increases TB IRIS risk for people with HIV who have a CD4 cell count below 50

Michael Carter
Published: 28 November 2013

A low CD4 cell count increases the risk of immune reconstitution inflammatory syndrome (IRIS) for people starting antiretroviral therapy (ART) within two weeks of treatment for tuberculosis (TB), investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes. The timing of antiretroviral therapy had no impact on the risk of IRIS for people with a CD4 count above 50 cells/mm3

“The increased risk of TB IRIS with earlier ART is concentrated in those with very low CD4 cell counts,” write the authors.

Findings also showed that approximately a third of patients required an invasive procedure to manage their IRIS, a finding that the authors believe has implications for the resourcing, planning and delivery of ART-TB programmes.

Globally, TB is the leading cause of serious illness and death in people with HIV. To reduce the risk of mortality, people with HIV and TB often need to start ART soon after they start TB therapy. But the risk of a paradoxical IRIS – the worsening of TB symptoms despite effective treatment – means that the initiation of ART is usually delayed until two weeks of TB therapy have been completed.

Investigators from the international A5221 STRIDE study wanted to establish a clearer understanding of the risk and severity of TB IRIS according to whether patients started early ART (within two weeks of initiating TB treatment) or delayed ART (after eight to twelve weeks of TB therapy) and also according to whether they had a CD4 cell count above or below 50 cells/mm3.

The study population included 806 people, all of whom were ART naive (had not taken HIV treatment before) and had a CD4 cell count below 250 cells/mm3. The study participants were recruited between 2006 to 2009 and were randomised to receive early or delayed ART.

TB IRIS occurred in 8% of participants, an overall incidence of 9.0 per 100 person-years.

The rate was twice as high among people who started early versus delayed ART (10 vs 5%) and also in people with a CD4 cell count below 50 cells/mm3 compared to a CD4 cell count above that level (12 vs 5%, p = 0.014).

In people with a CD4 cell count above 50 cells/mm3, there was no difference in the rate of IRIS according to ART initiation (early = 6% vs delayed = 5%).

Almost all (93%) IRIS cases involved major symptoms, such as new or worsening lymphadenopathy, radiological manifestations and serositis. Common minor IRIS symptoms included constitutional symptoms such as fevers, night sweats and weight loss or cough.

IRIS symptoms developed sooner in people who took early compared to delayed ART (29 vs 82 days, p < 0.001).

Corticosteroids were used for the treatment of 54% of people who experienced IRIS and the median duration of therapy was 15 days. Just over a third of patients (34%) had an invasive procedure to manage their IRIS.

There were no deaths and only six people – three in each arm of the study – interrupted their HIV therapy for seven days or longer.

Overall, 31% of cases were classified as severe and required hospitalisation; 41% were moderate, requiring therapy with steroids or an invasive procedure and the remaining 28% were mild.

IRIS severity did not differ according to the use of early or delayed HIV therapy.

“TB IRIS was more common in participants with earlier ART initiation and CD4 cell counts < 50 cell/mm3,” conclude the authors. “As ART is increasingly implemented within 2 weeks after TB treatment initiation to reduce AIDS-related complications and mortality, HIV-TB programmes will need diagnostic capabilities, clinical resources and provider training necessary to diagnose and manage tuberculosis-related immune reconstitution inflammatory syndrome.”


Luetkemeyer AF et al. Tuberculosis immune reconstitution inflammatory syndrome in A5221 STRIDE: timing, severity and implications for TB-programs. J Acquir Immune Defic Syndr, online edition. DOI: 10/1097/QAI.000000000000030, 2013.

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