PI Perspective #24

April 1998     View PDF

Progressive Multifocal Leukoencephalopathy (PML)

PML is a rare AIDS-related condition, caused by the JC Virus. Between 80–85% of all adults, world wide, are exposed to this virus at some time in their lives, but it only appears to cause disease in people with a weakened immune system. Prior to AIDS, PML was rarely seen except in people with cancer or who received bone marrow transplants. Today, the majority of all PML cases occur in HIV-infected people, primarily those in advanced stages of disease with very low CD4+ cell counts. It can occasionally appear in people with CD4+ counts as high as 400, however, and is the first AIDS-defining condition diagnosed in about 1% of people with HIV. Because it is so rare and because it affects the brain, an organ that is difficult to study, its diagnosis and treating are poorly understood.

Treatment
Heretofore, a diagnosis of PML was quite grim. The one therapy used for treating it, a toxic antiviral called ARA-C (cytosine arabinoside, Cytosar-U), delivered through a shunt directly into the brain, has shown marginal, if any, evidence of benefit. The average time from diagnosis of PML to death, prior to the availability of highly active anti-HIV therapies (HAART) including a potent protease inhibitor, was 1–3 months. It is unclear why, if the majority of people with HIV are infected with the JC virus, the incidence of JC virus-related disease remains so low. When it does strike, however, the disease course can be quite rapid. The infection rapidly forms lesions on the brain and begins affecting various functions controlled by the brain and nervous system. The most frightening aspect of PML is that there is no “usual” course of disease. Whatever functions are controlled in the area of the brain being ravished by the JC virus will determine the manifestations of PML. For example, if the virus strikes the part of the brain that controls sight, vision could be lost. If it strikes the part of the brain that controls speech or motor skills, one could lose the ability to talk or walk. There is no predicting where or how the virus will attack, and thus what functions will be impaired.

Prior to the availability of HAART, there has been little encouraging news with regard to PML. But several groups at the recent Retrovirus Conference reported symptom-free survival after a PML diagnosis of over two years and counting for some patients using HAART. An Atlanta group reported on factors associated with survival among 375 people with HIV and PML. The median survival after a PML diagnosis was 1 month, overall (including people with PML in the pre-protease inhibitor era). Additionally, about 85% of those diagnosed with PML had died within 6 months of diagnosis. Prolonged survival (greater than 6 months) was associated with use of protease inhibitors and other anti-HIV therapies.

In a study reported by a French group, 71 people diagnosed with PML between January 1990 and September 1997 were observed for factors influencing survival. Many were diagnosed in the pre-protease inhibitor era. PML was the first AIDS defining event for about half of the study participants. It was the event that led to an HIV diagnosis in eight of the volunteers, suggesting it was the first serious symptomatic illness they experienced. A little less than half of the individuals had been on anti-HIV therapy prior to PML diagnosis. This study showed that of those participants who had previously been on anti-HIV therapy, those who modified their regimen after the PML diagnosis, had a longer survival (ten months) than those who did not change therapies (three months). Moreover, those individuals employing an anti-HIV regimen that included a potent protease inhibitor had prolonged survival (twelve months compared to 3.5 months among those not using protease inhibitors). Among those using a protease inhibitor containing regimen since their broadened availability in 1996, over half (54.2%) are still alive. Seven people have survived more than two years after their PML diagnosis.

A second French group looked at the use of cidofovir (Vistide) for PML. People received cidofovir through an expanded access program and all were receiving HAART. While this observational group is quite small, a preliminary look at survival rates suggests that cidofovir may be useful PML therapy for some people. A prospective study to evaluate this effect is underway. Cidofovir is an approved treatment for CMV retinitis.

In Spain, another group studied use of HAART in 13 people with PML (12 of 13 also received Ara-C). The median survival time post PML diagnosis was 273 days. Historical results suggest that in this particular population, survival is typically about 72 days. Thus, triple-drug therapy nearly quadrupled survival time post PML diagnosis.

Diagnosis
Diagnosing PML is tricky. Many HIV-related conditions produce similar initial symptoms. PML, toxoplasmosis, and even herpes virus infections in the brain can have similar appearances on an MRI scan, which is equivalent to an X-ray of the brain. Because the lesions can look similar, it’s important to pursue definitive diagnosis by means of a brain biopsy so that the cause can be determined appropriately. A small hole is drilled in the skull and a piece of tissue is collected and analyzed. If the JC virus is found in the tissue, a diagnosis of PML is made. A brain biopsy is quite invasive, however, and therefore less invasive diagnostic techniques need to be developed. A lumbar puncture (i.e. spinal tap) is hardly non-invasive, but compared to a brain biopsy it’s far more palatable for many people. The use of polymerase chain reaction (PCR) technology, the same technology used in the new tests to measure HIV levels, to look for the presence of the JC virus in cerebral spinal fluid is currently under investigation.

Among people with HIV, about 30% without and 70% with PML have detectable JC virus in the blood circulation. Given the large percentage of people with measurable levels of JC virus without PML, using blood as a source for diagnosing PML is not practical. Far too many people without PML could be misdiagnosed as having PML. Exploring the use of cerebral spinal fluid (CSF) to diagnose PML may provide a median ground. Dr. Major, of the National Institutes of Health, has presented data showing that 80% of people with PML confirmed by brain biopsy have JC virus in the CSF. While this provides a step toward a simpler diagnostic tool, it’s still not without problems. Dr. Major presented information showing a very small number of people with other (not PML) neurological conditions who also had the JC virus measurable in the CSF. When it comes to neurological manifestations, appropriate diagnosis is critical. For example, herpes infections in the brain can produce symptoms similar to those of PML, yet these infections may be readily and easily treated with a 21-day course of intravenous acyclovir (Zovirax). Until the technology is further refined, using CSF as a primary mode of diagnosis may lead to misdiagnosis. The beginning of research into this field is long overdue, however, and these first steps toward less invasive diagnostic techniques are extremely important.

While there are no standard of care guidelines regarding anti-HIV therapy and PML, the numerous reports outlined above suggest it would be fair to make a few assumptions. After presumptive diagnosis with PML, regardless of whether an individual elects a brain biopsy for definitive diagnosis, initiating or changing a HAART regimen seems advisable. The studies outlined above, in conjunction with anecdotal reports of complete resolution of PML lesions after initiating HAART are extremely encouraging. Survival after PML diagnosis among those initiating HAART, in a number of reported cases, is two years and counting.