HIV-associated PML: Changing epidemiology and clinical approach

MANAGEMENT OF HIV-ASSOCIATED PML

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A suppressed plasma HIV viral load is the strongest prognostic factor for an improved course in PML.⁴ In the pre-HAART era, the mean survival of HIV-associated PML was 3 to 6 months, with long-term survival estimated at 10%.⁵ The use of HAART has achieved a dramatic improvement in long-term survival, to upwards of 50%.⁶ Neurologic deficits are often irreversible even with HAART, but most HAART recipients show stability in neurologic status for years.

Other key characteristics associated with improved survival in HIV-associated PML appear to be younger age, PML as the heralding manifestation of AIDS, initiation of HAART upon diagnosis of PML, higher CD4 count, and absence of severe neurologic impairment.^5–7

Investigational therapies

Specific antiviral drug regimens targeting JCV have been tested empirically in case studies and in clinical trials in patients with AIDS- and non–AIDS-related PML.

Cytosine arabinoside (Ara-C). Ara-C is a nucleoside analog used as an antineoplastic agent; it terminates chain elongation and inhibits DNA polymerase to confer antiviral activity. Ara-C decreased JCV replication in vitro.⁸ Based on anecdotal reports of efficacy in cancer-related cases of PML,⁹ Ara-C was tested in a multicenter trial of 57 patients with HIV and biopsy-confirmed PML.¹⁰ Neither intravenous nor intrathecal Ara-C combined with established antiviral therapy for AIDS improved the prognosis of these patients, and Ara-C has since been abandoned as a strategy to treat HIV-related PML.

Cidofovir. The noncyclic nucleoside phosphonate cidofovir garnered attention as a potential treatment for PML based on case reports of efficacy in HIV as well as non-HIV patients. Subsequently, a large multicenter study failed to detect any significant added benefit with cidofovir beyond that of HAART.¹¹ Retrospective European studies confirmed the lack of clinical benefit with cidofovir.^6,7,12

Interferon alfa. Case reports with interferon alfa-2a and -2b for the treatment of PML show conflicting results with respect to clinical response, symptomatic improvement, and survival, but toxicity has been substantial. In a series of 97 patients with AIDS-related PML, Geschwind et al determined that interferon alfa had no effect on survival beyond that of HAART.¹³

Mirtazapine. Serotonin receptor antagonists such as mirtazapine can block JCV entry into glial cells via serotonin 5-hydroxytryptamine receptors, providing a rationale for their use as a potential treatment for PML. Verma et al describe a case of clinical improvement (stable neurologic deficit) and PML lesion regression in a 63-year-old bedbound woman with polycythemia vera with biopsy-proven non–HIV-related PML that had progressed to quadriparesis.¹⁴

Mefloquine. The antimalarial drug mefloquine inhibits viral replication in cultured human glial cells and astrocytes, inhibits JC viral DNA replication, and showed efficacy against two JCV strains in cell culture.¹⁵ A randomized study to assess the effectiveness of mefloquine for treatment of PML has been completed and its results await publication.

SUMMARY

The incidence of PML has remained unchanged from the pre-HAART to the HAART era, but the prognosis is greatly improved. The clinical presentation of PML in AIDS patients may deviate from the classic triad of progressive, multifocal, white matter disease. It may be static and unifocal, and it may involve gray matter and neurons as well as white matter. The number of neurologic manifestations is vast and can include the cerebellar syndrome. Lumbar puncture with a PCR negative for JCV does not confirm the absence of PML.

The standard of care for HIV-associated PML is HAART, with the goal of achieving immunologic recovery and optimal virologic control. Whether therapeutic results obtained in patients with HIV-associated PML can be translated to the setting of non–HIV-associated PML is unclear.

DISCUSSION

Dr. Simpson: As a followup to the Ara-C trial that was published,¹⁰ PML confirmed by brain biopsy was one of the enrolling criteria, and the planned study population was 65 patients. Longitudinal examination of viral load in cerebrospinal fluid (CSF) was a part of the study, and we found that the lower the viral load, the better the prognosis. Fifty-two patients were enrolled before the trial was stopped because it was clear that Ara-C was not producing a benefit. The patients had multifocal disease but, because Ara-C does not effectively cross the blood-brain barrier, penetration in the brain was minimal even with the use of an intrathecal shunt in this study.

Dr. Major: Do you think viral load in CSF is a predictor of disease severity and outcome in PML?

Dr. Rudick: Generally speaking, that’s probably true. We have found, as have many of our colleagues who run a lot of CSF samples, that high viral loads are not a good thing.

Dr. Bennett: How is it that the incidence of PML has not changed from the pre-HAART to the post-HAART era? How do you account for this in terms of the change in patients’ T-cell function from pre- to post-HAART?

Dr. Simpson: I don’t know. Intuitively, why do patients treated with HAART, who are relatively immune reconstituted, develop PML? The problem is that not everyone is immune reconstituted. HAART fails in some patients. Further, PML remains a disease that is more common in late-stage HIV among patients with low CD4 counts and high viral loads, meaning that a large population of patients is available to develop this disease. With that said, it is perplexing that the incidence has not gone down more than it has.

Dr. Major: There’s a phenomenon called “unmasking PML with HAART,” in which individuals have no signs of PML upon initiation of HAART, but then very shortly after, PML is diagnosed.

Dr. Berger: You’re talking about PML immune reconstitution inflammatory syndrome (IRIS).

Dr. Major: IRIS can occur before PML, or PML and IRIS can be concurrent. In some patients, once the infection starts, it persists; this suggests that the virus is carried to the brain through the infected lymphocyte populations and may explain why the incidence of PML has not changed from the pre-HAART to the HAART era.

Dr. Calabrese: In patients with HIV who develop PML within the first 6 months of HAART, are we seeing the IRIS phenomenon or is it a presenting sign of advanced HIV?

Dr. Simpson: It’s well known that a number of opportunistic infections can develop in the setting of HAART. In fact, whether one should delay HAART when initiating therapy for opportunistic infections has been debated for just this reason. Most people presume IRIS to be a massive immunologic hit to all organ systems, as CD4 counts rise dramatically to produce hyperimmune-mediated phenomena such as Guillain-Barré syndrome. To what extent immunologic recovery is or is not linked to PML and why it happens are fascinating questions.

Dr. Berger: Opportunistic infections, PML among them, that occur following the initiation of HAART and recovery of the immune system are almost always an IRIS-mediated phenomenon in which the disease has been smoldering and then surfaces because of the release of an inflammatory response.

Dr. Calabrese: In patients with cerebellar degeneration, do you typically detect JCV in PCR in the spinal fluid?

Dr. Simpson: Not in the early stages, but in some patients with later-stage disease,³ the answer is yes. Certainly, PCR of CSF samples to look for JCV is the diagnostic test of choice. But in the early days, when we had no idea what caused this cerebellar syndrome, we were doing cerebellar biopsies.