Patients with cryptococcus who start HAART may develop an IRIS up to three years later

An immune reconstitution inflammatory syndrome (IRIS) response to crytococcus occurred in 19% of HIV-positive patients who had previously had cryptococcal meningitis and who subsequently started potent anti-HIV therapy, Thai researchers report in the August 15^th edition of the Journal of Acquired Immune Deficiency Sydromes.

The cryptococcal IRIS developed between three and 27 months after antiretroviral therapy was initiated, and the investigators could not identify any factors to identify which patients were at particular risk, nor predict when the IRIS might occur.

Cryptococcus is the most common fatal fungal infection in HIV-positive patients. It typically occurs in patients with very weak immune systems, and as with almost all other AIDS-defining illnesses, the incidence of the infection has fallen markedly since the introduction of potent anti-HIV therapy.

But after starting antiretroviral therapy, some patients, particularly if they had a very low CD4 cell count when anti-HIV therapy was initiated, experience an IRIS. The syndrome has been well described for a number of infections including MAI, tuberculosis, CMV and hepatitis.

Earlier studies suggest that 8 -50% of HIV-infected patients with cryptococcal infections who started HIV therapy developed an IRIS, despite continuing therapy with the anti-fungal drug, fluconazole.

One study suggested that a low CD4 cell count when antiretrovirals were started, ongoing fungal replication, and the initiation of HIV treatment within two months of cryptococcal disease, were independent risk factors for the development of an IRIS.

There are, however, few data about when a cryptococcal IRIS might develop amongst patients starting anti-HIV therapy. Previous small studies have suggested that it can develop within two and 22 weeks.

Thai investigators therefore performed a retrospective analysis including 52 patients with previous cryptococcal disease to try and determine when a cryptococcal IRIS would occur, and what the risk factors for the condition might be.

The patients had a mean age of 34 years, and 60% were men. Median CD4 cell count was 26 cells/mm³ when the first proven episode of cryptococcus occurred. All 52 patients were receiving secondary prophylaxis against cryptococcus.

A good response to anti-HIV therapy was observed with median CD4 cell count increasing to 121 cells/mm³ after six months of treatment and 237 cells/mm³ after a year of antiretrovirals. At six months, 88% of patients had an undetectable viral load, as did 78% after a year.

Patients were followed up for a median of 15 months (range, 8 – 54 months). In total, ten patients (19%) developed a cryptococcal IRIS a median of ten months after starting anti-HIV therapy (range, three three - 27 months). All the patients continued antiretroviral drugs and none died because of the illness.

The investigators were unable to identify any particular characteristics to suggest which patients had the highest risk of developing an IRIS.

“The results from the present study have demonstrated that the timing of cryptococcal IRIS seems to be quite variable”, comment the investigators, adding, “unfortunately, there was no predictive factor for the occurrence or timing of cryptococcal IRIS in the present study.”

They speculate that the delayed nature of the IRIS in many patients may be because the immune system was responding to non-viable cryptococcus. “This may explain why secondary prophylaxis of cryptococcis cannot prevent cryptococcal IRIS.”

The investigators conclude that doctors should be aware of the risk of a cryptococcal IRIS during the first three years of antiretroviral therapy for patients with a previous history of the disease, adding, “in patients with culture-negative cryptococcus…occurrence of this syndrome should not indicate ART failure.”