Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy : AIDS

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Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy

Albrecht, Helmut1,2,5; Hoffmann, Christian2; Degen, Olaf2,4; Stoehr, Albrecht3; Plettenberg, Andreas3; Mertenskötter, Thomas4; Eggers, Christian2; Stellbrink, Hans-Jürgen2

Author Information

1Emory University, Atlanta, Georgia, USA

2University Clinic Eppendorf, Hamburg, Germany

3St Georg Hospital, Hamburg, Germany

4Bernhard-Nocht Institute, Hamburg, Germany.

5Requests for reprints to: Dr Helmut Albrecht, Emory University, Department of Medicine, Division of Infectious Diseases, 69 Butler Street SE, Atlanta, GA 30303, USA.

H.A. and C.H. are joint first authors of this study.

Sponsorship: The study was a local project of the German AIDS Study Group (GASG/IDKF) supported by grant RKI 415-4476-09/25 BMG.

Note: Preliminary results have been presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, October 1997, the 35th Annual Meeting of the Infectious Diseases Society of America, San Francisco, September 1997, and the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection, Hamburg, September 1997.

Date of receipt: 17 October 1997; revised: 5 March 1998; accepted: 11 March 1998.

AIDS 12(10):p 1149-1154, July 9, 1998.
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Abstract

Objective: 

To evaluate the impact of different antiretroviral therapies on the prognosis of AIDS patients affected by progressive multifocal leukoencephalopathy (PML).

Methods: 

A retrospective analysis of all HIV-infected patients admitted to hospital between 1988 and 1996 found 29 patients (25 men) with histologically or PCR- confirmed PML. Their mean age was 39.3 years. The median CD4 cell count was 40 × 106/l (mean, 106 × 106/l). Six patients had CD4 cell counts > 200 × 106/l. Fourteen patients never received or stopped antiretroviral therapy following diagnosis (group A), 10 patients were treated with nucleoside analogues alone (group B), and five patients started highly active antiretroviral therapy (HAART) including protease inhibitors (group C).

Results: 

The median survival following the onset of symptoms was 131 days, but differed significantly between the three groups: group A, 127 days; group B, 123 days; group C, > 500 days (P < 0.0002 for the difference between group C versus group A and B, stratified log-rank test). As of July 1997, four out of five patients on HAART were still alive 391, 500, 543, and 589 days after diagnosis of PML and have either experienced a resolution of the symptoms (three patients) or had progressed very slowly (one patient). A multivariate analysis using Cox regression found younger age at diagnosis to be the only other variable associated with improved survival (P < 0.02). CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, or interferon-α did not affect survival in this cohort (P > 0.1).

Conclusion: 

This study of a large cohort of patients with confirmed PML indicates that AIDS patients with PML may benefit significantly from HAART. All patients with PML should be offered optimal antiretroviral combination therapy.

Introduction

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive AIDS-defining disease of the central nervous system. It is caused by the infection and destruction of oligodendrocytes and perhaps other brain cells by the JC virus, a ubiquitous polyomavirus, resulting in multifocal demyelination. PML affects up to 8% of patients with AIDS and in most cases is fatal within 3–5 months [1–3]. Existing treatment options have not proven effective. Anecdotal case reports have recently suggested that highly active antiretroviral therapy (HAART) may improve survival in patients with PML [4–7]. The diagnosis of PML in two [4,5] of these case reports, however, was solely based on clinical and radiological criteria and not confirmed histologically or virologically. In the other two patients, follow-up was relatively short [6,7]. We present a large cohort of patients with confirmed PML. The purpose of the study was to evaluate the impact of antiretroviral therapy on the prognosis of affected patients.

Methods

A retrospective analysis of 29 consecutive patients (25 men) with histologically or PCR-confirmed PML diagnosed at one of the three participating centers in Hamburg, Germany between 1988 and 1996 was performed. The mean age was 39.3 years (range, 21–54 years). Sixteen patients (55%) had previously suffered from another AIDS-defining condition. The median CD4 cell count at diagnosis was 40 × 106/l (mean, 106 × 106/l; range, 0–450 × 106/l). Six patients had CD4 cell counts > 200 × 106/l. The majority of patients (n = 22, 76%) had acquired HIV infection through homosexual contacts. Two patients each had received contaminated blood transfusions or factor VIII preparations. One patient had acquired HIV through heterosexual contacts, and another through injecting drug use. The mode of HIV transmission of one patient was unknown.

Fourteen patients never received or stopped antiretroviral therapy following diagnosis (group A), 10 patients were treated with nucleoside analogues alone (group B), and five patients were started on HAART including protease inhibitors (group C).

Statistical analyses were performed by Prof. J. Berger (Department of Mathematics in Medicine, University Clinic Eppendorf, Hamburg, Germany) using SPSS software (SPSS, Inc., Chicago, Illinois, USA). Cox regression analysis was used to determine the influence of predefined parameters [age, CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, interferon (IFN)-α, or antiretrovirals] on the patient survival. Because the covariate matrix was unstable and some coefficients did not converge, significant parameters were retested using a stratified and unstratified log-rank test. Survival was plotted using the Kaplan–Meier method.

Results

JC virus infection was diagnosed histologically in 14 patients. Ten patients were diagnosed at autopsy and four patients were diagnosed using stereotactic brain biopsy. The remaining 15 patients had clinical symptoms and radiological signs suggestive of PML, and JC viral DNA was detected by PCR in the cerebrospinal fluid using a PCR technique described previously [8]. Three patients with positive JC virus PCR died and diagnosis was confirmed at autopsy, increasing the number of histologically verified cases to 17. The prevalence of the most important PML-associated symptoms are summarized in Table 1.

T1-6
Table 1:
. Symptoms in patients with confirmed progressive multi-focal leukoencephalopathy (PML).

Neuroradiological imaging studies were performed in all patients. Nineteen patients had both computed tomography (CT) and magnetic resonance imaging (MRI) scans (Table 2). In five of these 19 patients, solitary or multiple lesions were documented on MRI that had not been visualized on CT. Grey matter involvement was documented in 13 (46.4%) out of 28 patients in whom lesions were visualized. Perifocal contrast or gadolinium enhancement was evident in four (14.3%) out of 28 patients.

T2-6
Table 2:
. Comparison of computed tomography (CT) and magnetic resonance imaging (MRI) in 19 patients undergoing both tests.

Cerebrospinal fluid (CSF) samples of 17 patients were examined for the presence of JC viral DNA using PCR. Viral DNA was detected in the first sample of 12 (71%) patients and in the second sample of three (17%) patients. No JC viral DNA was detected in two patients (12%) with autopsy-confirmed PML. CSF protein was normal in 61% of patients, and often only slightly elevated in the remaining patients (median, 450 mg/l; range, 160–1330 mg/l). A CSF pleocytosis of more than 10 × 106 white blood cells/l was found in only 8% of patients (median, 5 × 106/l; range, 1–164 × 106/l).

The median survival for the entire cohort was 131 days (range, 18 to >589 days). The median survival of patients that never received or stopped antiretroviral therapy following diagnosis (group A, 14 patients) was 127 days (mean, 132 ± 75 days; range, 18–268 days). Patients who continued to take or were switched to antiretroviral regimes consisting of nucleoside analogues alone (group B, 10 patients) had a median survival of 123 days (mean, 118 ± 55 days; range, 28–231 days). Five patients were started on HAART including protease inhibitors (group C). Their median survival was > 500 days (mean, 461 ±111 days; range, 283 to > 589 days). As of July 1997, four of the five patients treated with protease inhibitors were still alive 391, 500, 543 and 589 days after the onset of their first symptoms. In all other patients, death was confirmed by review of death certificates. The difference in survival between group C and the other two groups was statistically significant (P < 0.0002, for the difference between group C versus group A and B, log-rank test stratified by age; Table 3, Fig. 1). In a multivariate analysis using the Cox regression model, younger age at diagnosis was the only other variable associated with improved survival (P = 0.011), whereas CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, or IFN-α did not significantly affect survival in this cohort (P > 0.1; Table 3).

T3-6
Table 3:
. Survival of patients with confirmed progressive multifocal leukoencephalopathy (PML).
F1-6
Fig. 1:
. Survival of patients with progressive multifocal leukoencephalopathy (PML). HAART, Highly active anti-retroviral therapy.

Clinical characteristics of patients on HAART

One patient, a 51-year-old man who presented with a CD4 cell count of 370 × 106/l and a plasma HIV viral load of 159 000 copies/ml had serial determinations of HIV copy numbers in CSF. The pretreatment CSF viral load was 59 500 copies/ml. One month later, his CD4 cell count was 440 × 106/l, plasma viraemia was < 200 RNA copies/ml, and HIV RNA copy number in CSF was also < 200 RNA copies/ml. A limited improvement of clinical symptoms was noted, but there was no evidence of regression of cerebral lesions on MRI. CSF and plasma viral load remained below the limit of detection at days 207, 266 and 433. JC virus PCR, however, remained positive during follow-up. His CD4 cell count stabilized at more than 600 × 106/l. After initial clinical improvement, however, his symptoms started to worsen again after approximately 350 days, which was accompanied by expansion of preexisting lesions. Subcutaneous interleukin-2 was added to the antiretroviral regimen without beneficial effect. The patient was alive 500 days after diagnosis of PML, but had been bedridden for at least 8 weeks.

One patient with cortical amaurosis and hemiparesis experienced substantial improvement of clinical symptoms, which was accompanied by a regression of preexisting lesions on MRI (Fig. 2). Her initial viral load was 293 000 copies/ml and remained below the level of detection throughout the entire course of therapy. CD4 cell counts increased from 40 to 280 × 106/l. Two other patients, one who initially presented with paresis and severe cognitive dysfunction and another who presented with paresis, tremor and dyplopia, improved dramatically and had only minimal residual symptoms at the close of the study. The fifth patient had previously failed multiple nucleoside analogues before he was diagnosed with PML. After HAART, the disease continued to progress slowly and the patient died 9 months later.

F2-6
Fig. 2:
. Brain magnetic resonance imaging of a patient with progressive multifocal leukoencephalopathy (a) before and (b) after 6 months of highly active antiretroviral therapy demonstrating a partial resolution of the lesions in the T2-weighted scans.

Discussion

The reported prevalence of PML in AIDS patients varies between 0.7 and 3.8% [1,2,9,10]. More recent data cite higher figures of 5.3–8% [11–14]. It is not clear whether the prevalence of the disease continues to increase, or whether the increasing numbers reflect the more widespread availability of improved diagnostic methods [8,11,14]. PML was the AIDS-defining illness for 45% of our patients, similar to that reported by other authors [1,3,12,15].

Clinically, PML is characterized by variable but rapidly progressive neurological impairments, depending on the location of the cerebral lesions. Gross dementia, paralysis and loss of all senses often mark the end stages of disease [14,16]. The range of symptoms observed in this cohort was similar to those reported in other series. The differential diagnosis of cerebral lesions in HIV-infected patients is broad, the clinical and radiological signs of PML are non-specific, and other viral encephalitis, especially HIV encephalitis, can mimic PML [12,14,16,17]. Reliable confirmation of the diagnosis is therefore mandatory when evaluating treatment responses.

PCR-based tests detecting JCV DNA in CSF have become the diagnostic method of choice, because they are easily repeatable and minimally invasive compared with brain biopsy. In recent years, primers with sensitivities of 80% and specificities approaching 100% have been developed [8,18,19]. With the primers used in this study [8] we have not yet encountered a false-positive result in more than 200 samples from HIV-infected patients with neurological symptoms or fever tested in our institutions for a specificity of 100% (data not shown). The sensitivity of the primers used was 71% in our cohort if only one sample was examined and approached 90% when multiple samples were evaluated. It has to be acknowledged, however, that only a minority of patients tested ultimately underwent autopsy or brain biopsy. The true sensitivity of the PCR test is therefore impossible to determine in our patient population because some cases of PML might have been missed.

The prognosis of PML is grave, and the median survival from the onset of first symptoms is 3.5–5.5 months. There are only few reports of patients with HIV-associated PML surviving more than 1.5 years [2,3,20–22]. In non-HIV-associated cases of PML, prolonged survival of up to 10 years is not uncommon, especially after withdrawal or dose reduction of immunosuppressive therapy [23–29].

Higher CD4 cell counts have been associated with prolonged survival in other studies [3,16,21]. In our cohort, there was no evidence that survival was significantly correlated with the initial CD4 cell count. Of the other parameters tested, only younger age at diagnosis and choice of antiretroviral therapy were associated with prolonged survival.

The therapeutic options for PML are extremely limited. No single drug or combination has been shown to be effective for PML in a controlled clinical trial. Therapeutic trials using cytarabine, IFN-α, foscarnet, steroids, heparin, vidarabine, idoxuridine, or different immune stimulators such as tilorin or levimasol have yielded conflicting or disappointing results [3,23,30–40].

AIDS Clinical Trials Group 243, the first well-controlled study performed in patients with PML, compared antiretroviral therapy alone with antiretroviral therapy plus cytarabine administered intravenously or intrathecally. The study was stopped in mid-1996 when an interim analysis found that at 24 weeks there were no differences in survival or neurological function between the three treatment arms [41]. Accordingly, cytarabine should no longer be used for treating persons with PML. In our study cohort, neither the use of cytarabine, IFN, nor foscarnet was associated with prolonged survival. New therapeutic approaches such as the use of camptothecin derivatives that inhibit topoisomerase I [28,42] or use of cidofovir are in early stages of evaluation [43].

Treatment with high-dose zidovudine has been reported to lead to responses [16,22,44,45]. In most cases, however, the magnitude and duration of the observed improvement has been less than satisfactory. Furthermore, a number of treatment failures have been reported [3,14,46]. The addition of other nucleoside analogues has not proven beneficial [3].

Recent anecdotal reports have documented some patients with PML that experienced regression of lesions and clinical remission after treatment with potent antiretroviral regimens including protease inhibitors [4–7]. The diagnosis in two patients, however, was based on clinical and radiological criteria only [4,5]. Follow-up for the other two patients was only 8 months, a time-span well within the life expectancy of patients with PML [6,7]. Of the five patients in our cohort that were treated with protease inhibitor-containing antiretroviral regimens, four are still alive more than 1 year after diagnosis. All five patients on HAART either experienced a significant improvement of symptoms (three patients) or an unusually slow progression of symptoms (two patients). A complete remission was not achieved in any of the patients, however, and in two patients remission was only intermittent and was followed by gradual deterioration. Nonetheless, the survival of patients treated with HAART was longer than that of all other patients in this cohort. Treatment with HAART therefore constitutes a major advance in the management of this devastating disease.

Although our results do not provide definitive proof that would obviate controlled trials and although the duration of the efficacy of the new regimens remains unclear, all patients with PML should be offered the best antiretroviral agents available, preferably drugs to which they are not already resistant.

Acknowledgements

The authors thank T. Weber and M. Martin for review of the manuscript and helpful suggestions. The authors also gratefully acknowledge the continuous support of this study by J. Berger, Director of the Department of Mathematics in Medicine of the University Clinic Eppendorf, Hamburg, Germany.

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Keywords:

Progressive multifocal leukoencephalopathy; highly active antiretroviral therapy; neurological manifestation; antiviral

© 1998 Lippincott Williams & Wilkins, Inc.