GMHC Treatment Issues, Volume 10, Number 5 - May 1995
Theo Smart

The JC Virus

PML is caused by the JC virus, which infects and kills oligodendrocytes. These brain cells produce the myelin that surrounds and protects nerve cells. The virus, named after the first patient with PML in whom it was isolated, belongs to a family of viruses that also includes wart viruses. The JC virus is common. By middle age, 80 percent of adults, have been exposed to it. The primary illness that it causes is unknown, but a case of meningoencephalitis has been observed in an otherwise healthy teenage girl with rising JC antibody titers.2

After acute infection, the virus can remain latent in the kidney, lymphoid organs, bone marrow and circulating B lymphocytes, but most researchers believe that the virus is not latent in the brain or central nervous system (CNS). A number of factors such as immune suppressive chemotherapies (most commonly, cyclosporine and methotrexate), and other viruses, including HIV and CMV can stimulate the virus out of latency. After reactivation, the researchers think that virus is transported to the brain by circulating B-cells. If this indeed is the case, early treatment of people with reactivated JC virus -- which has not yet taken up residence in the CNS -- possibly could prevent PML, should an effective anti-JC drug be discovered.

Once the virus enters the brain, treating it may become more difficult since the parts of the JC virus genome that drive reproduction are prone to mutation. A number of studies report that JC virus associated with PML lesions has unique genetic sequences in the part of the virus' genome that drives replication. These genes frequently differ from the genes of the JC virus found in the kidneys of the same patients.3 The genes in the "neurotropic" JC virus bear a strong resemblance to genes involved in making myelin and other neural proteins.4 Exactly how the virus adopts these changes is unknown, but these mutations may allow natural processes in the brain to accelerate spread of the virus there. This suggests yet another reason to treat before the virus invades the CNS. It also suggests that drugs being considered as possible treatments for PML should show activity against the neurotropic strain of the virus.

Improvements in Diagnosis

Although a brain biopsy is still considered the standard for definitive diagnosis in some cases, PML can be diagnosed without undergoing this invasive procedure. Many clinicians rely on axial computed tomography (CT) or magnetic resonance imaging (MRI). The MRI is more sensitive, and also can reveal the number and extent of lesions. With either technique, the pattern and enhancement of the PML lesions usually can be easily distinguished from toxoplasmosis, lymphoma and HIV encephalopathy.

Viremia (detectable virus) in the cerebral spinal fluid (CSF) is increasingly being used in diagnosis. A recent study by Dawn McGuire, M.D., and colleagues in San Francisco looked for JC virus in the CSF of 26 patients with PML plus 114 HIV- positive controls and sixteen HIV-negative controls.5 Using a very sensitive PCR test that could detect one copy of JC virus in 50 microliters of cerebrospinal fluid, the researchers found the virus in 24 of the 26 patients with PML, ten of the HIV-positive patients (who will be closely monitored for development of the condition) and one HIV- negative participant with neurologic abnormalities. An ongoing ACTG study of the treatment of PML (see below) should confirm the utility of JC virus PCR for diagnosis.

Viremia also may prove to be a prognostic tool. A team of French investigators has tested over 165 people with HIV along with 65 HIV-negative immune compromised persons and found that the incidence of detectable JC virus in peripheral blood leukocytes was almost twice as high in people with HIV (28.9 percent versus 16.4 percent in the HIV-negative patients).6 The individuals with both HIV and JC virus are being followed to ascertain the predictive value of the tests. Clearly, 28.9 percent of people with HIV do not develop PML, however, the study may determine whether a higher JC viral load or certain strain of the virus distinguishes those people more likely to develop the condition.

Limitations of Present Therapies

As there is no accepted treatment, patients with PML frequently are subjected to experimentation with toxic agents. These experiments have yielded a number of case reports claiming improvements in response to treatments such as cytarabine, alpha interferon, vidarabine (adenine arabinoside) and idoxuridine. Treatment with AZT has been reported to lead to stabilization, but it is unclear whether improvement was due to an anti-JC viral effect or treatment of the underlying HIV infection.7 In another study, three months of intrathecal treatment with AZT failed to improve the status of two patients with PML.8

Perhaps the most influential PML study was by Carolyn Britton, M.D., which reported clinical improvement in eight of thirteen patients (mean CD4 cell count of 106) treated with intrathecal cytarabine (ARA-C).9 One must view such clinical improvement with skepticism -- spontaneous remission of PML can occur in the absence of treatment, particularly in patients with higher CD4 cell counts. A number of other case reports and open label studies recount the failure of cytarabine,10 as well as every other drug that has shown activity in other case reports. One review of the published case reports even noted that people treated with cytarabine died faster. There is at least one published case of cytarabine causing PML in a person with cancer (by suppressing the immune system).11 On top of that, the drug is extremely neurotoxic. Nevertheless, because of Britton's open label studies, and because they have no other treatments to offer, many doctors and clinics administer cytarabine to patients with PML.

Cytarabine is being put to more rigorous challenge in ACTG 243, the first well controlled clinical trial for PML. The trial compares high-dose antiretroviral drugs alone to high doses of both intravenous and intrathecal cytarabine. The endpoints will be survival and changes in neurological condition. The mixed reports for these therapeutic approaches give few researchers faith that this study will advance treatment, though it will yield data on using JC viremia as a diagnostic tool.

New Leads

Camptothecin derivatives -- in particular, camptothecin, topotecan and irinotecan -- can suppress the neurotropic JC virus in glial cultures.12 These compounds are chemotherapeutic agents that work by inhibiting topoisomerase I, an enzyme that uncoils strands of DNA, a necessary step in transcription, and ultimately cell replication. These drugs are known to cause bone marrow suppression, diarrhea, nausea and other side effects.

A number of patients now have been treated with topotecan.13 Two end-stage patients failed to respond. Another patient experienced lesion remission and symptomatic improvement. Despite the bone marrow suppression that topotecan caused (in response to which the patient was given the growth-factors G- CSF and EPO), the patient's CD4 cell count increased. This patient had initiated therapy with a protease inhibitor six weeks earlier, though, which suggests that this response could have been due to the antiretroviral.

Nevertheless, the case has led SmithKline Beecham to design a study that should start next month in Los Angeles, San Francisco, Miami, and possibly New York City or Baltimore and a site in France. The study will enroll at least fifty volunteers with biopsy-proven PML who have been on stable antiviral therapy for six weeks. Trial participants will be randomized to treatment with topotecan or observation (no treatment). All in the latter study arm will be crossed over to the treatment arm after eight weeks -- or after only four weeks if there is progression in disease, defined as growth in PML lesions of at least 25% detected on MRI. For information on study enrollment call Sharyn Arnold at 215/751-7074.

A paper by a team of Belgian researchers, led by Erik de Clercq, M.D., at the Thirty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapies reported that cidofovir, a drug soon to be approved for the treatment of CMV retinitis, has activity against a murine (mouse) polyomavirus, which is very closely related to the JC virus.14 At a Japanese conference in May, the same group reported even greater activity against SV40, a more closely related simian polyomavirus that causes a condition similar to PML in immunosuppressed monkeys with SIV.15

They then treated one PML patient with 3 mg per kg of cidofovir once every ten days.16 Although after the second infusion there was a reduction in the size of the lesion, there was continued neurologic deterioration. Treatment was discontinued after the fourth infusion, and the patient died two months later. As there was change in the size of the lesion, the Belgian team concluded that the treatment had potential but that further studies should use more frequent dosing.

Researchers in London are planning a controlled clinical study that should begin by August. The dosing regimen in this study will be the same as used for the treatment of CMV retinitis -- 5 mg per kg per week for the first two weeks, and then every other week.

Treating PML by Treating HIV

Topotecan and cidofovir may prove to be more effective treatments than cytarabine, which again, has been shown to cause PML. Still, the most significant advance against PML may turn out to be the new treatments for AIDS. There are numerous anecdotes of people with PML experiencing lesion remission after starting treatment with protease inhibitors. These drugs may do a much better job of salvaging the immune system than treatments of the past, and improvement of PML is fairly common in people with higher CD4 cell counts. Although anti-HIV therapy may only work temporarily, people with PML should certainly be offered the best available antiretroviral agents before turning to unproven toxic chemotherapies that may actually aggravate their condition.

1 Major E and Ault G. Current Opinion in Neurology. June, 1995; 8(3):184-190.

2 Blake K et al. Archives of Disease in Childhood. Jul, 1992; 67(7):956-7.

3 Loeber G and Dorries K. Journal of Virology. May, 1988; 62(5):1730-1735.

4 Amemiya K et al. Journal of Biological Chemistry. Jul 15, 1992; 267(20):14204-14211.

5 Major E and Ault G. Current Opinion in Neurology. June, 1995; 8(3):184-190.

6 Dubois V et al. AIDS. April, 1996; 10(4):353-358.

7 Conway B et al. Reviews of Infectious Diseases. May- June, 1990; 12(3):479-82.

8 Allegre T el al. 9th International Conference on AIDS. June 6-11, 1993; 9(1):423 (abstract PO-B16-1727).

9 Britton CB et al. Eighth International Conference on AIDS. Jul 19-24, 1992; 8(1):Th67 (abstract ThB1512).

10 Antinori T et al. AIDS. July, 1994; 8(7):1022-4.

11 Hwang TL et al. Journal of Neuro-Oncology. 1986; 3(4):335-9.

12 Kerr DA et al. Virology. Oct, 1993; 196(2):612-618.

13 Broom, C. Personal Communication, April 22, 1996.

14 Snoeck R et al. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 1995, abstract H49, pg 188.

15 Andrei G et al. Ninth International Conference on Antiviral Research, May 19-24, 1996.

16 Snoeck et al. Ninth International Conference on Antiviral Research, May 19-24, 1996.

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