Progressive multifocal leukoencephalopathy (PML) is a rare disease of the central nervous system which results in the destruction of the sheath that covers the nerves. It affects about 4% of people with AIDS.

PML is caused either by primary infection or reactivation of a virus called the JC virus which is a type of papovavirus. The JC virus is named after the initials of the first person with PML in whom the virus was identified. The majority of the population is believed to have been exposed to this virus and to carry it without symptoms in their kidneys, lymphoid tissue, bone marrow and lymphocytes. In an adult or child with a weakened immune system, the virus can be reactivated and spread to the brain by lymphocytes.

Once in the brain, the JC virus infects oligodendrocytes, the brain cells responsible for producing the protective sheath (myelin) around the nerves. Without this protection on the nerves, the nerve cells die and cause lesions in the brain. Neurologic dysfunction may follow quickly, and the condition can rapidly cause serious, life-threatening disease.

Prior to the introduction of highly active antiretroviral therapy (HAART) people with PML survived an average of two to four months after diagnosis. Survival for longer than one year appears to be more likely among people for whom PML is the first AIDS-defining event, or who have relatively high CD4 cell counts.

HAART has extended the average survival time of people with PML. A recent study found that approximately one-third of patients died within two years of their PML diagnosis, despite treatment with HAART. On average, deaths occurred within twelve weeks of PML diagnosis. Experts have calculated that people with PML will survive an average of three to four years, depending on their baseline CD4 cell count (Berenguer 2003).

Symptoms and diagnosis

PML can cause a variety of symptoms related to mental functioning, including confusion, disorientation, lack of energy, loss of balance, weakness in the arms or legs (usually on only one side of the body), blurred or double vision, speech difficulties and loss of vision in one eye.

Brain scans such as computerised tomography or magnetic resonance imaging can reveal the presence of lesions in the brain. To determine whether these lesions are caused by PML or by other opportunistic infections or cancers (e.g. toxoplasmosis, lymphoma), a polymerase chain reaction (PCR) test can be performed. A PCR test looks for the presence or absence of the DNA of the JC virus in a sample of spinal fluid. However, the PCR test does not produce a definitive diagnosis because some people are JC-negative when diagnosed with PML.

A brain biopsy remains the definitive way to confirm a diagnosis of PML.

Plasma and urine PCR tests for the JC virus have been developed, although their uses in the clinical setting are yet to be determined. In one study, only 41% of people with detectable JC virus in a brain biopsy also had detectable JC virus DNA in their blood (Hou 2000; Whiley 2001).

PCR tests which quantify how much JC virus is in the cerebrospinal fluid (CSF) have also been developed. There is some evidence that high JC viral load is associated with a poor clinical outcome (Garcia de Viedma 2002; Giri 2001). However, as with the plasma and urine tests, they are not currently used outside the research setting.

Progressive multifocal leukoencephalopathy in the age of highly active antiretroviral therapy

PML in the age of HAART remains a life-threatening condition with a relatively poor prognosis. Nevertheless, several studies have shown improved survival of individuals with PML since the introduction of HAART:

• A CDC review of 415 cases of PML in the United States found that protease inhibitor use was the most likely factor to improve survival after diagnosis (Dworkin 1999).

• Spanish researchers have reported that 30% of people die within two years of their PML diagnosis and that a CD4 cell count above 100 cells/mm³ at diagnosis is associated with increased survival (Berenguer 2003).

• A review of the Italian Register Investigative Neuro AIDS (IRINA) Study found that people with PML survived an average of 245 days when prescribed HAART and 66 days when HAART was not available (Antinori 2001).

• Retrospective analysis of PML cases at the Johns Hopkins University HIV clinic found survival associated with HAART, but not with use of up to two anti-HIV drugs (Geschwind 2001).

• A review of 29 cases found that the average survival of a group of people with PML who received a HAART regimen was greater than 500 days, compared with 127 days for people treated with nucleoside analogues alone, and 123 days for people receiving no anti-HIV therapy (Albrecht 1998).

• An American study found that HAART improves the survival of people with PML, although 15 of the 25 people in this study developed PML while taking antiretroviral therapy, including eight people with viral loads below 500 copies/ml (Clifford 1999).

• A Spanish review of 27 PML patients found HAART extended survival significantly. People on no antiretroviral treatment or one or two drugs survived for an average of two months, compared with a median survival time of 21.9 months among those on HAART (Asensi 1999).

• Researchers from the French Hospital Database compared 109 people who were diagnosed with PML before the introduction of protease inhibitors, with 137 people diagnosed after that time. The risk of death six months after diagnosis was reduced by 63% among people on HAART (Tassie 1999).

However, despite the documented benefits, PML has occurred in individuals being successfully treated with HAART, and there is evidence that PML may worsen in some individuals who experience immune recovery associated with HAART (Chocarro 2000).

This exacerbation of PML is thought to be associated with immune reconstitution, particularly in people with very low CD4 counts who have recently started HAART. For instance, Spanish researchers have argued that inflammatory changes in the brains of four of nine people on HAART and one of 19 on single or dual therapy, suggests a possible link between the potency of the antiviral drugs and the inflammatory reaction (Miralles 2001). A review of hospital admissions conducted at the Chelsea and Westminster Hospital, London, between January 1997 and October 1998 found HAART had uneven effects on PML. Three new cases of PML were reported, although immune recovery illness was unlikely to be the cause in one person who had been on HAART for over two years (Shaw 1999). American doctors have also reported cases of PML in people on HAART with low or undetectable viral loads (Clifford 1999;Tantisiriwat 1999).

Experts believe that antiretroviral therapy improves clinical outcomes by reducing the amount of JC virus in the fluid around the brain (Giudici 2000). In the age of HAART, both high JC viral load and low CD4 cell count at PML diagnosis have been identified as predictors of poor outcome and survival (de Luca 2001; Miralles 2001).

Treatment

HAART is currently used to treat people with AIDS who develop PML. There are no proven treatments specifically for PML although several drugs have been tested.

Cidofovir (Vistide) is one agent which has been investigated as a potential PML therapy although evidence to date is inconclusive. An Italian team has reported longer survival among 27 people treated with HAART plus cidofovir compared with 16 treated with HAART alone (De Luca 2001). In this study, cidofovir was independently associated with reduced risk of death. A Spanish team initially reported that cidofovir therapy was associated with survival in 118 people with PML who were treated with HAART but full analysis of these data showed that cidofovir had no impact on prognosis (Berenguer 2003).

Other studies have also found that cidofovir is ineffective against PML. An American study, ACTG 363, found that cidofovir had no impact on PML lesions or survival in 24 people (Marra 2002). Furthermore, a French study found that cidofovir provided no benefit additional to antiretroviral therapy as a treatment for PML (Gasnault 2001). Several case studies in wihch cidofovir was used to treat PML have also produced inconclusive results. Finally, one study has found that the addition of cidofovir to HAART in patients with PML reduced survival time (Wyen 2004).

There have been some anecdotal reports of reduction in symptoms among people treated with cytarabine (also known as ara-C) injected either into a vein (intravenously) or into the spinal column (intrathecally), but a controlled trial found no difference in the death rate between people treated with antiretroviral drugs alone and those who also received cytarabine (Hall 1998).

Similarly, case reports suggested that interferon alpha may have benefit, but a retrospective review found that interferon alfa had no benefit in addition to HAART (Geschwind 2001).

The anti-cancer drug topotecan (Hycamtin) is being tested as a possible treatment for PML in the United States. However, early data on this drug suggests it has little or no impact on PML (Dupont 2001).

Research into the JC virus

McGuire (1995) investigated the predictive value of a PCR test to detect JC virus DNA in the cerebrospinal fluid. The test was performed on samples from 26 people with PML (eight of whom had been confirmed by brain biopsy), 114 HIV-positive controls without PML and 16 HIV-negative controls. The test correctly identified 24 of the 26 people with PML, including all 8 with biopsy-confirmed PML. Ten of the 114 HIV-positive controls tested positive; they are being monitored to see whether the positive test result is a predictive marker for future risk of PML. One HIV-negative control tested positive; he had chronic leukaemia, a known risk factor for PML, and neurological abnormalities.

Hou (2000) reported a literature review which found that JC virus DNA can be detected by PCR in the circulating peripheral blood of 30% of people with HIV, compared with 5% of uninfected people. In patients with positive brain biopsies, only 41% were found to have JC virus DNA in their peripheral blood. Bone marrow biopsies showed the presence of JC virus DNA two and four years before they developed PML symptoms.

Garcia de Viedma (2002) measured JC viral load in the cerebrospinal fluid (CSF) of 12 HIV-infected people with PML. While JC viral load varied greatly, a viral load over 4.68 log was associated with a shorter survival time. There was no association between viral load and the amount of damaged brain tissue.

Gasnault (2004) found that early brainstem damage (symptoms include oculomotor palsies, stupor and clouding of consciousness, central vestibular syndrome or dysphagia) and CSF JC viral load over 4.5 log were independently associated with shorter survival in people on HAART. The use of cidofovir and CD4 cell count at baseline did not influence survival.

Sala (2001) studied two regions of the JC virus taken from 10 people with PML, 5 of whom responded to combination antiretroviral therapy (HAART). Both groups had extensive rearrangements in the genome but there was no evidence that specific genomic changes were associated with more virulent PML.

Giri (2001) reported that a single measure of JS viral load in the CSF can be used to inform prognosis.

Whiley (2001) reported that a PCR assay using a LightCycler platform to detect JC virus in urine was as accurate as a PCR assay, with a quicker turn around time.

Dubois (1996) reported that JC virus DNA could be detected in the plasma of 28.9% of a sample of 165 people with HIV, compared with 16.4% of an HIV-negative group. Viraemic individuals are being followed to see what proportion develop PML.

Research into PML and HAART

Wyen (2004) carried out a retrospective multicentre cohort study of PML in HIV-positive patients. 35 cases were identified, diagnosed by histology (9), detection of JC virus in CSF (17) and radiology (9). 15 patients had never received HAART and 11 had been on HAART for >6 months. 9 cases occurred in people on HAART for <6 months. 12 patients were treated concomitantly with cidofovir and had a shorted survival time (p = 0.03).

Berenguer (2003) studied survival, neurologic function and prognostic factors in 118 people diagnosed with PML. Average CD4 count at diagnosis was 85, viral load was 4.85. 39 people were diagnosed with PML after starting anti-HIV treatment: 9 experienced treatment failure, and 10 developed PML as a consequence of immune reconstitution, on average six weeks after starting HAART. The remaining 20 were thought to develop PML due to delayed immune recovery. 75 patients (63.6% of the cohort) were alive 2.2 years after diagnosis with PML. There were 36 PML-related deaths (30.5% of sample), and these occurred on average 12 weeks after diagnosis with PML. 7 patients died of conditions not associated with PML. Neurological function in survivors was categorised as a cure or improvement in 33 (44%) and as stabilisation or worsening in 40 (53%). CD4 cell count was the only factor which was predictive of prognosis. Amongst the patients who died, 71% had a CD4 cell count below 100 cells/mm³. Amongst survivors, 47% had a CD4 cell count below 100 cells/mm³.

Marzocchetti (2004) studied 44 patients (32 with PML and 12 controls) to determine whether a HAART-related increase in cerebrospinal fluid (CSF) levels of cytokines involved in inflammatory reactions/immune responses relate to survival. One cytokine, macrophage chemotactic protein (MCP-1), was significantly higher in PML patients than in controls (p <0.0001), while another, tumour necrosis factor, (TNF-alpha), was lower in those with PML than in controls (p = 0.022). Higher TNF-alpha levels were associated with lower CD4 counts <100 (p = 0.012). In those with PML and CD4 counts less than 100 cells/mm³, higher levels of MCP-1, but not other cytokines, were associated with longer survival (for each log increase, HR for death = 0.27; (95% CI: 0.08 to 0.96). Multivariate analysis confirmed the association of MCP-1 with longer survival, although cytokine levels did not predict neurological evolution at eight weeks.

Antinori (2001) analysed the incidence of PML in the pre-HAART and HAART eras. The introduction of HAART had not impacted on the incidence of PML but those diagnosed with PML in the HAART era lived for longer after diagnosis (245 vs 66 days). PML which occurred in people taking HAART generally developed during the first six months of treatment. JC DNA viral load in the CSF above 4.7 log copies/ml was associated with poorer outcomes. JC viral load at week 4 and complete clearance of JC from the CSF were associated with better outcomes. Of all neurological conditions associated with AIDS studied in the Italian IRINA study, PML had the lowest rate of survival at one year.

Geschwind (2001) retrospectively analysed 97 people with HIV-associated PML attending the John Hopkins HIV Neurology Program between 1985-2000. While one or 2 antiretroviral drugs did not impact on survival, HAART was associated with longer survival. Interferon alfa had no impact on survival independent of HAART.

Cinque (2001) found no factors predictive of poor outcome among people with AIDS-related PML. Survival improved in 1996-1997 when highly active antiretroviral therapy (HAART) was first used. Poor PML outcome was seen in HAART-naive and HAART-experienced patients. In some instances, PML was associated with commencement of HAART and was deemed to be an immune reconstitution illness.

Miralles (2001) reviewed clinical records and neuroimaging of 28 people with PML who were treated with HAART. Stabilisation or improvement occurred in 17 people. CD4 count at diagnosis was predictive of outcome. Average CD4 count among those who responded to HAART was 144 and 78 among patients whose health had deteriorated. Neurological condition deteriorated in 3 people (at weeks 4, 4 and 7). Brain biopsies showed blood vessel inflammation. Overall, 4/9 people on HAART had blood vessel inflammation in the brain compared with 1 of 19 on dual therapy or monotherapy. The authors suggested an immune recovery syndrome was affecting response to HAART.

Dworkin (1999) conducted an observational study of 415 HIV-infected people diagnosed with PML between 1990-1997. Average survival was one month. A CD4 count below 20 was associated with reduced survival time. Factors associated with increased survival after diagnosis were protease inhibitor prescription (relative risk 0.2); other antiretroviral prescription (RR 0.6); and alcoholism (RR 0.7).

Tantisiriwat (1999) reported 3 people who developed PML while on HAART. Time of HAART was between 4-11 months, and viral loads were low. HAART was switched in 2 with detectable viral load when PML developed, and HIV viral load declined. However, symptoms did not improve. In the one person with undetectable viral load when PML occurred, symptoms improved when interferon alfa was added to treatment.

Guidici (2000) reported that CSF JC virus DNA disappeared in 5/6 patients with HIV-related PML treated with HAART. Four developed antibodies to JCV in the CSF and the neuroradiological picture improved or stabilised after 12 months of HAART.

Albrecht (1998) conducted a retrospective analysis of 29 patients with PML, of whom 14 never received or stopped antiretroviral therapy after diagnosis, 10 were treated with nucleoside analogues only and five received a protease inhibitor. Median survival after diagnosis was 123 days, 127 days and over 500 days respectively.

Vago (2002) reported that the prevalence of HIV encephalitis and brain lesions fell significantly during the 1990s, as antiretroviral therapies were introduced.

Use of single antiretroviral drugs in the early days of antiretroviral treatment rarely had a significant effect on PML (Allegre 1993; Berger 1992a; Conway 1990; Singer 1994; Lortholary 1995).

Research into cidofovir for PML

Marra (2002) presented results of the pilot study ACTG 363 - a prospective, non-randomised study of cidofovir for HIV-associated PML in 24 people. Cidofovir was given 5mg/kg IV weekly for 2 weeks, then fortnightly with dose adjustments for renal function. Baseline statistics were: median CD4 count 62, viral load 2,941, Karnofsky 60, and mean neurological score 8.04. 17 people were taking highly active antiretroviral therapy (HAART). 54% of patients were alive at 12 weeks follow-up. 2 people experienced a 25% improvement in neurological examination scores at week 8, although overall people with undetectable HIV viral load showed greater improvement. Cidofovir had no impact on survival. Factors associated with survival were a higher CD4 count at diagnosis and a lower viral load. Fewer people on antiretroviral therapy died (2/7 vs 10/17) but this difference was not significant (p=0.52).

De Luca (2001) reported an observational study of 27 individuals with PML treated with HAART alone and 16 treated with HAART and cidofovir (5mg/kg per week for 2 weeks and then every second week). Overall, 26% experienced neurological improvement and 57% eradicated JC virus from the CSF. 9 people developed PML after starting HAART. Survival at 12 months was 61% in those treated with HAART and cidofovir, versus 29% in those who received HAART alone (p=0.02). Cidofovir was independently associated with reduced risk of death.

Berenguer (2003, above) reported that cidofovir was added to HAART in 44 of 118 people diagnosed with PML. Treatment with cidofovir was not found to have an effect on prognosis.

Brosgart (1997) treated two men who had PML with cidofovir (5 mg/kg weekly for two weeks followed by 5 mg/kg every two weeks). Highly active antiretroviral therapy (HAART) had been introduced 4 and 9 months previously, and one of the two had achieved undetectable viral load. After 2 months of treatment, both individuals regained use of all extremities and were living independently. MRI showed stability or improvement of all lesions, and both patients remained stable 7 and 9 months later.

Gasnault (2001) studied PML in 46 people attending the Bicetre Hospital in Paris. 22 received HAART alone and 24 received HAART plus cidofovir. At baseline, there were no significant differences between the groups in terms of CD4 count, HIV viral load, JC CSF viral load, response to HAART at 6 months, disability scale or demographic features. JC viral load in the CSF was undetectable in 33% of the cidofovir group and 39% of the HAART group at 6 months (non-significant). Survival at one year was 62% vs 53% in the cidofovir and HAART groups respectively (non-significant), although cidofovir showed some benefit when controlling for baseline variables.

Research into other PML treatments

Fong (1995) studied the natural history of 28 patients with proven PML. 16 presented with PML as the AIDS-defining event and their mean survival after presentation was 7.5 +/- 7.6 months. Among the 12 people with a prior AIDS diagnosis, mean survival was 3.2 +/- 2.8 months. Mean survival for people with CD4 counts above 90 at presentation was 9.4 +/- 8.7 months, compared with 3.6 +/- 1.8 months for those with CD4 counts below 90. No clinical or survival benefit was seen in 9 people treated with cytarabine alone or in combination with interferon alfa.

Hall (1998) randomised 62 people with PML to receive 24 weeks of treatment with either antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine in the study ACTG 243. The study was terminated after an interim analysis revealed no difference in survival between the arms. Toxicities were marginally significantly higher among those receiving antiretroviral therapy alone.

Dupont (2001) administered topotecan by 21-day continuous infusion every 28 days as a treatment for HIV-related PML in 10 individuals. 3/10 responded both clinically and radiologically and survived for over 80 weeks. However, the overall survival was on 17 weeks. Toxicities were common including 6 cases of grade 4 neutropenia, 2 cases of grade 4 thrombocytopenia and 5 cases of grade 3-4 anaemia.

There had been many anecdotal reports of the use of intravenous or intrathecal cytarabine for treating PML, some with positive results (Britton 1992; Portegies 1991; Lidman 1991; Nicoli 1992) and some with negative results (De Truchis 1993; Antinori 1994).

Blick (1998) reported a case study in which an individual with PML achieved prolonged remission during treatment with cidofovir plus cytarabine. This finding has been disputed by Chocarro Marinez (2000).

Huang (1998) reported that in a retrospective review of 104 individuals with PML, median survival of untreated individuals was 121 compared with 325 days in those received interferon alfa for at least 3 weeks. Prolonged remissions were observed in 7/21 interferon alfa recipients and 4 showed clear-cut MRI improvement.

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