Cidofovir (Vistide) in Addition to Antiretroviral Therapy Is Not Effective for AIDS-related Progressive Multifocal Leukoencephalopathy (PML)

By Ronald Baker, PhD

Progressive multifocal leukoencephalopathy (PML) results from infection with polyomavirus JC, often called JC virus. In immunosuppressed individuals, such as people with AIDS, the infection causes the loss of white matter (comprised of myelin, a substance that surrounds and protects nerve fibers) in multiple areas of the brain.

The most prominent symptoms of PML are clumsiness, progressive weakness, and visual, speech, and sometimes, personality changes.

A positive diagnosis of PML can be made by means of brain biopsy, or by combining observation of a progressive course of the disease, white matter lesions visible on a magnetic resonance image (MRI) scan, and the detection of JC virus in spinal fluid.

Previous study results suggest that prior to the availability of HAART, as many as 5% of people with AIDS eventually developed PML, and the disease was most often rapidly fatal.

Immediate initiation of effective antiretroviral therapy will usually benefit most patients with AIDS-related PML. However, as recently reported, the disease is still a risk -- and remains life-threatening -- in the HAART era.

The purpose of the present analysis, published in the September 12, 2008 issue of AIDS, was to establish the effectiveness of cidofovir (Vistide) -- a drug often used to treat cytomegalovirus (CMV) retinitis -- for AIDS-related PML in individuals concomitantly receiving combination antiretroviral therapy.

The study analyzed raw data pooled from 1 prospective and 5 cohort studies that together included 370 HIV positive patients with PML diagnosed since 1996 and treated with combination antiretroviral therapy, with or without cidofovir. All studies had already published their results, but for 4 of them, additional patients and follow-up data were included in this analysis.

The main study outcomes were time to PML-related death and odds of 12-month moderately severe to severe disability (Rankin score >4).

Results

• 64% of the PML cases were confirmed by histopathology or JC virus DNA detection in cerebrospinal fluid.

• 185 patients (50%) received cidofovir (median 5 cycles).

• During 463 person-years of follow-up, 167 PML-related deaths occurred (36.6 per 100 person-years).

• The estimated 1 year survival was 56%.

• In multivariate models stratified by cohort and adjusted for type of diagnosis and relevant prognostic confounders, cidofovir treatment was not associated with improved survival.

• Results were similar using an outcome of time to death from any cause.

• In addition, the odds of 12-month moderately severe to severe disability were not improved with the use of cidofovir.

According to the study authors, "In combination antiretroviral therapy-treated PML patients, cidofovir use did not influence PML-related mortality or residual disability."

"New treatments for AIDS-related PML are urgently needed," they concluded.

9/12/08

Reference
A De Luca, A Ammassari, P Pezzotti, and others (for Gesida 9/99, IRINA, and ACTG 363 study groups). Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS. 22(14): 1759-1767. September 12, 2008.
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