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The Fresh Hell Syndrome: Paradoxical Inflammatory Response After Initiating HIV Therapy: Presented at IDSA

By Kristina R. Anderson

SAN DIEGO, CA -- October 10, 2007 -- Patients with HIV initiating antiretroviral therapy (ART) may find themselves saddled with the immune reconstitution inflammatory syndrome (IRIS), a clinical worsening of active, latent, or previous infections.

This IRIS phenomenon occurs in patients with advanced HIV/AIDS, who have previously been unable to mount an effective immune response. In Africa, IRIS is considerably more common than in western countries, occurring in about one third of HIV-infected patients starting ART.

Research presented here on October 6 at the Infectious Diseases Society of America (IDSA) 45th Annual Meeting shows that while ART leads to an improvement in immune function, it can result in the activation of microbial antigens that were previously unrecognized by the immune system.

However, IRIS can potentially be predicted. The predictive findings were presented by lead author David Boulware, MD, Assistant Professor, Division of Infectious Diseases, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

"It can be dramatic and atypical," said Dr. Boulware, whose posted abstract featured two photos of advanced fungal infection on two different patients. "No one really knows for sure why this occurs, but it is usually self-limited as the immune system improves." He said the two patients were treated successfully.

Dr. Boulware said his study was conducted primarily to describe the phenomenon and to let treating clinicians know that some populations are at high risk for this cascade of immunological events, but that they can be pegged with the use of microarray technology to assess immune activation.

There are myriad IRIS scenarios, he said, including the unmasking of an occult opportunistic infection or paradoxical symptomatic relapse of a prior infection, even if initially successfully treated. A variety of microorganisms, including bacteria, mycobacterium, fungi, and viruses can trigger an IRIS response. Tuberculosis (TB) is the most common presenting IRIS disease; however, fungal infections and cryptococcal meningitis have also been documented.

Dr. Boulware and his colleagues looked for predictive biomarkers in a group of 48 ART-naive HIV-infected patients recruited from the Infectious Disease Institute in Kampala, Uganda. Microarray analysis was successful in assessing immune activation in these patients after they commenced ART.

They found a number of genes specifically related to the immune activation of T-lymphocytes as well as inflammation due to the tumor necrosis factor alpha and also interferon response pathways that are normally decreased over time with ART. This normal pattern of decreasing inflammation, however, was different among patients who later developed IRIS with persistent immune activation and inflammation, which could be predictive of future IRIS events.

"The majority of gene pathways involved are related to T-cell activation and involve cell signaling pathways and cell cycle/death pathways; this suggests increased T-cell turnover prior to ART and may be related to IRIS," Dr. Boulware and his team said in their poster.

The researchers concluded that they could potentially identify those patients who are at high risk of IRIS based on differences in cellular signaling and cycle pathways.


[Presentation title: Use of Microarrays to Assess Immune Activation in the HIV Immune Reconstitution Inflammatory Syndrome. Poster 921]

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