Risk of IRIS means that HIV treatment should be delayed for patients taking fluconazole for cryptococcal meningitis

Michael Carter
Published: 10 May 2010

The early initiation of antiretroviral therapy by HIV-infected patients being treated with fluconazole for cryptococcal meningitis is associated with an increased risk of death, according to a study published in the June 1st edition of Clinical Infectious Diseases.

The investigators believe that early initiation of antiretroviral therapy caused a cryptococcal immune reconstitution inflammatory syndrome (IRIS) to develop.

“Our data provide strong evidence that…it is important to clear cryptococcal infection prior to initiation of antiretroviral therapy,” comment the investigators.

It is estimated that cryptococcal meningitis causes between 20 and 30% of AIDS deaths in Africa.

Treatment with fluconazole is the standard treatment for cryptococcal meningitis in sub-Saharan Africa.

Access to antiretroviral therapy in Africa is increasing. However, the optimum time to start such treatment in patients receiving fluconazole is unknown.

Therefore, investigators in Harare, Zimbabwe, conducted a prospective, open-label, randomised study involving 54 patients HIV-infected patients with cryptococcal meningitis who were starting fluconazole therapy.

A total of 28 patients were randomised to initiate antiretroviral therapy (fixed-dose d4T, 3TC, and nevirapine) within 72 hours of starting fluconazole treatment. The remaining patients were randomised to start HIV treatment ten weeks after initiating fluconazole.

Median CD4 cell count at the time of entry to the study was 37 cells/mm3 and was comparable in the two arms of the study. The mean age of the patients was 37 years and 48% were women.

The overall duration of follow-up was 27 days. The three-year mortality rate was 73%. However, it was significantly higher amongst patients who started immediate antiretroviral therapy compared to those who deferred HIV treatment (88% vs 54%).

Median survival was 28 days for patients who started immediate HIV treatment, compared to 637 days for individuals randomised to defer taking anti-HIV drugs (p = 0.031).

Most deaths in both study arms (44% vs 58%) occurred within seven days of enrolment.

Statistical analysis showed that the only factor significantly associated with an increased risk of death was the early initiation of HIV treatment (p = 0.023).

After controlling for potentially confounding factors, the investigators found that the risk of death was over twice as high for individuals starting HIV treatment immediately after starting fluconazole treatment (hazard ratio, 2.34; 95% CI, 1.12 to 4.89).

The mortality rate adjusted for age, sex and CD4 cell count was 40 deaths per 1000 person-weeks for patients starting early HIV treatment compared to 11 deaths per 1000 person-weeks for those deferring such treatment (p < 0.05).

On the basis of these results, the study was stopped early.

“Early initiation of antiretroviral therapy most likely resulted in increased rates of cryptococcal IRIS and the excess mortality observed in the early antiretroviral treatment arm,” comment the investigators.

The investigators therefore recommend “where fluconazole monotherapy is used for treating cryptococcal meningitis, initiation of antiretroviral therapy should be delayed until the cryptococcal meningitis is adequately treated and, if possible, culture results are negative or titers have decreased significantly. On the basis of our data, outcomes are improved if treatment is initiated at least 10 weeks after initiation of treatment for cryptococcal meningitis.”


Makadzange AT et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-Saharan Africa. Clin Infect Dis 50: 1532-38, 2010.

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