Toward Defining the Incidence, Risk Factors and Long-term Outcome of a Unique, HAART-related Disease: Immune Reconstitution Inflammatory Syndrome (IRIS)

The widespread use of HAART among HIV positive individuals has resulted in a significant decrease in the rates of opportunistic infections, progression to AIDS and death. Paradoxically, clinicians noticed that some of their patients experienced a clinical decline soon after starting HAART, even though these individuals had low HIV RNA levels and rising CD4 T cell counts.

In these individuals, HAART caused a pathological inflammatory response to either previously treated infections or subclinical infections. The inflammation, which can result in adverse clinical outcomes, has been labeled “immune reconstitution disease (IRD)” or “immune reconstitution inflammatory syndrome (IRIS).”

The most common infections associated with IRIS are ophthalmic cytomegalovirus (CMV) disease, disseminated infection with Mycobacterium tuberculosis (TB) or Mycobacterium avium complex (MAC), and central nervous system (CNS) involvement with Cryptococcus neoformans (C neoformans). So far there is little information regarding the incidence of IRIS. In addition, there are few data regarding risk factors for developing IRIS. Information on the long-term clinical outcomes of patients with IRIS is even more scant.

The present study was undertaken to determine the incidence, risk factors, and long-term outcome of IRIS in HIV-infected patients receiving HAART who were coinfected with one of three common opportunistic pathogens.

The investigators hypothesized that patients who started HAART in closer proximity to the diagnosis of their underlying opportunistic infection and who had a more robust response to HAART in terms of declining HIV-1 RNA levels would be at an increased risk for developing IRIS.

A retrospective chart review was performed for 180 HIV-infected patients in a cohort identified through a city-wide prospective surveillance program. The study participants were patients who received HAART and were coinfected with M. tuberculosis, M. avium complex, or C. neoformans between 1997 and 2000. Medical records were reviewed for baseline demographics, receipt and type of HAART, response to antiretroviral therapy, development of IRIS, and long-term outcome.

Results

31.7% of patients who received HAART developed IRIS.

Patients with IRIS were more likely to have initiated HAART nearer to the time of diagnosis of their opportunistic infection, to have been antiretroviral naive at time of diagnosis of their opportunistic infection, and to have a more rapid initial fall in HIV-1 RNA level in response to HAART.

The majority of cases of IRIS occurred within the first 60 days of initiating HAART, which is in accord with prior individual reports and case series.

The onset of IRIS continues for up to 2 years following the initiation of HAART.

In the 12 months after starting HAART, patients with IRIS required increased numbers of invasive procedures, such as lumbar punctures to relieve increased intracranial pressure, and had a higher number of hospitalizations. This implies that, in the short term, these patients require intensification of their healthcare, thereby suggesting that preventive strategies might be cost effective, especially in developing countries where coinfection with C. neoformans or M. tuberculosis is relatively common.

Although there may be short-term morbidity associated with IRIS, these patients appear to have comparably good long-term outcomes. After 24 months of HAART, patients with IRIS were more likely to have successful viral suppression and immune reconstitution than patients without the syndrome. In addition, there was no significant mortality difference between the two groups of patients. In fact, the survival trend was in favor of the IRIS patients, which is likely a reflection of the durable viral suppression and immune reconstitution seen in these patients.

Conclusions

IRIS is common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans.

Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV-1 RNA level should be monitored for development of this disorder.

Further studies looking at how to decrease the rate of IRIS in high-risk patients appear warranted by its prevalent nature and the association of IRIS with increased hospitalizations and invasive procedures.

Harris County Hospital District and the Houston Veterans Affairs Medical Center in Houston, Texas.

03/11/05

Reference
S A Shelburne and others. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19(4): 399-406, March 4, 2005.

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