PML-associated immune restoration disease associated with mortality

Highly active antiretroviral therapy (HAART) has significantly improved outcomes in HIV-infected patients. In some patients, however, the initial few months of HAART may be complicated by immune restoration disease (IRD), also known as immune reconstitution disorder.

In most patients who encounter IRD it is related to cytomegalovirus or nontuberculous mycobacteria (most notably, mycobacterium avium complex), but there have been reports of other opportunistic pathogens also being associated with IRD. While most cases of IRD that have been reported resolved spontaneously with continuation of HAART and, in some cases, treatment of the pathogen, there is a potential risk for severe morbidity and mortality in these patients.

In a report published in Clinical Infectious Diseases, two cases of progressive multifocal leukoencephalopathy (PML)-associated IRD were presented. This report is notable in that while in most HAART-treated patients PML improves as the patient’s immune function does, these two patients had a significant and “paradoxical” worsening after the commencement of HAART. Both of these patients, despite a transient response to high-dose corticosteroid therapy, subsequently died of progressive neurological deterioration.

In evaluating these two cases, the authors state: “IRD in these patients with PML was unexpected and occurred soon after they had started receiving active antiretroviral therapy, during the period of improved antigen-specific T-helper cell function. Predictors of patients’ proclivity for these adverse events are uncertain. Evaluation of targeted immunomodulatory therapy directed towards disease-specific IRD is critical and may play an important role in improved survival for patients who are at risk.”

These cases emphasise the importance of carefully monitoring patients starting HAART, especially those with low CD4+ T cell counts or a history of an opportunistic infection at HAART initiation, and also indicate the need for further research into methods for blunting or avoiding the severe IRD that may occur in some patients. Finally, this is yet another reason why starting therapy earlier rather than later may be important in avoiding morbidity and mortality associated with HIV and its complications.

Safdar A, Rubocki RJ, Horvath JA et al. Fatal immune restoration disease in HIV-1 infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002 Nov 15;35(10):1250-7