Risk Factors for Immune Reconstitution Inflammatory Syndrome after Starting Antiretroviral Therapy

By Liz Highleyman

Immune reconstitution inflammatory syndrome (IRIS) is a complication caused by reactivation of the immune system that can occur after starting antiretroviral therapy. Typically, IRIS presents as a flare-up of symptoms when the recovering immune system begins to respond to an existing infection, for example, tuberculosis (TB) or cytomegalovirus (CMV).

IRIS occurs in an estimated 10% to 40% of HIV patients (based mainly on retrospective studies), and is more common in those who had a very low CD4 cell count before starting therapy.

IRIS may contribute to the increased risk of death that remains after starting ART in patients with advanced HIV disease, and due to concern about IRIS, some clinicians have favored deferring ART until after opportunistic infection (OI) treatment. However, few prospective studies have evaluated risk factors for IRIS and mortality in this setting.

As reported at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, Philip Grant from Stanford University and colleagues with the ACTG A5164 study team looked at risk factors for IRIS and mortality in patients with acute OIs who received either early or deferred antiretroviral therapy.

As reported at last year's CROI, in ACTG A5164, a total of 282 HIV patients with opportunistic infections (excluding TB) were randomly assigned to either start early ART at study entry or to delay ART for at least 28 days while OIs were treated.

At study entry, participants had advanced HIV disease, with a median baseline CD4 cell count of 29 cells/mm3, HIV viral load of 5.07 log copies/mL, and most had not previously taken any antiretroviral drugs. Pneumocystis pneumonia (PCP) was the most common OI (64%), followed by bacterial infections and cryptococcal infection (15% each).

Results

During the study period, 23 participants (8.2%) died.

20 participants (7.6%) developed IRIS, after a median of 33 days on ART:

8 of 135 patients (5.9%) in the early ART arm;

12 of 127 patients (44.4%) in the delayed ART arm.

Patients with fungal infections (other than PCP) were more than twice as likely to develop IRIS, and this was the only significant risk factor (hazard ratio [HR] 2.6; P = 0.03).

There was no difference in IRIS incidence between patients who received corticosteroids during their OIs and those who did not.

However, no participants developed IRIS while receiving corticosteroids.

Viral load decline and increased CD4 cell percentage at 4 weeks were associated with IRIS, but change in absolute CD4 cell count was not.

In univariate analyses, baseline factors significantly associated with increased mortality were:

Mycobacterial infection (HR 5.9; P <0.01);
Number of OIs (HR 2.2 per additional OI; P <0.01);
Hospitalization (HR 3.7; P = 0.002);
Low serum albumin (HR 3.6; P = 0.02);
Low hemoglobin (HR 2.8; P = 0.02);
Low CD4 count (HR 1.3 for each 10 cells/mm3 decrement; P = 0.02).

Conversely, having PCP at baseline was associated with a lower risk of death (HR 0.4; P = 0.04).

" In a multivariate analysis controlling for confounding factors, mycobacterial infection (HR 4.6; P < 0.002), hospitalization (HR 3.2; P = 0.007), and low CD4 count (HR 1.2 for each 10 cells/ mm3 decrement; P = 0.04) remain independent predictors of mortality.

"In patients with an acute OI, it is difficult to predict who will develop IRIS from baseline characteristics," the investigators surmised, although those with fungal disease other than PCP may be at increased risk.

"Change in viral load and change in CD4 percentage at 4 weeks are both clearer predictors of IRIS than change in CD4 count," they stated, but "CD4 counts obtained at baseline during an acute OI should not be discounted, as they predict survival, with lower values associated with an increased risk of death."

"Corticosteroids, as used in this study, do not appear to prevent IRIS but may delay its presentation," the researchers noted.

Risk factors for increased mortality in the pre-ART era -- including low albumin, low hemoglobin, and low CD4 count -- "remain important in patients with an opportunistic infection initiating ART," they concluded. "Mycobacterial infections are associated with high rates of mortality despite ART."

But early ART does not lead to an increase in IRIS in patients with non-TB OIs, they continued, and "concern for IRIS should not be a reason to defer ART."

3/10/09

References
P Grant, L Komarow, I Sereti, and others. Risk Factor Analyses for Immune Reconstitution Inflammatory Syndrome and Mortality during a Randomized Trial of Early versus Deferred ART in the Setting of Acute Opportunistic Infections: ACTG A5164. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 775.