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Cidofovir Treatment of Progressive Multifocal Leukoencephalopathy in a Patient Receiving Highly Active Antiretroviral Therapy

      Progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating disease caused by JC virus, occurs as an opportunistic infection in patients with acquired immunodeficiency syndrome. Curative therapy has been elusive, but recent reports suggest its improvement after institution of highly active antiretroviral therapy (HAART). We describe a case of PML that developed 6 months after the patient, a 55-year-old man, began to receive HAART. The PML progressed despite good virologic and immunologic response to HAART. Substantial symptomatic and radiographic improvement occurred after the addition of cidofovir to the treatment regimen. We reviewed the scientific literature on this rare occurrence of PML after institution of HAART and describe the patient characteristics, potential pathogenesis, and therapeutic options, including the successful use of cidofovir as an adjunctive agent.

      Abbreviations:

      AIDS (acquired immunodeficiency syndrome), CSF (cerebrospinal fluid), HAART (highly active antiretroviral therapy), HIV (human immunodeficiency virus), JCV (JC virus), MRI (magnetic resonance imaging), PCR (polymerase chain reaction), PI (protease inhibitor), PML (progressive multifocal leukoencephalopathy)
      Progressive multifocal leukoencephalopathy (PML), a demyelinating brain disease caused by the polyoma JC virus (JCV), is a devastating illness that causes serious morbidity and mortality among patients with the acquired immunodeficiency syndrome (AIDS). It occurs in 4% to 5% of patients with AIDS and is frequently fatal. In untreated individuals median survival is 4 months after the onset of symptoms. Recent reports of the efficacy of highly active antiretroviral therapy (HAART) on the outcome of PML have been promising.
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      However, successful treatment for PML remains elusive because HAART alone may not be effective in all patients despite good virologic and immunologic response.
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      Cidofovir, an acyclic nucleoside phosphonate derivative, is highly active against polyoma-viruses in vitro and may be an effective adjunct to HAART in these patients.
      • Andrei G
      • Snoeck R
      • Vandeputte M
      • De Clercq E
      Activities of various compounds against murine and primate polyomaviruses.
      We report a case of PML that developed and progressed while the patient had an undetectable human immunodeficiency virus (HIV) RNA load (<50 copies/mL) and an adequate CD4 cell count (>0.35 × 109/L) 6 months after institution of treatment with zidovudine, lamivudine, and efavirenz. His condition improved clinically and radiographically after institution of adjunctive cidofovir treatment.

      REPORT OF A CASE

      A 55-year-old man was diagnosed as having AIDS in March 2000 after presenting with profound neutropenia and bacterial gingivitis. He had an HIV RNA load of 3372 copies/mL and a CD4 cell count of 0.18 × 109/L. He was started on a regimen of zidovudine, lamivudine, and efavirenz. Because of his neutropenia (absolute neutrophil count of 0.26 × 109/L), he was placed on a maintenance dose of granulocyte colony-stimulating factor given subcutaneously twice a week. Two months later, his CD4 cell count had increased to 0.44 × 109/L, and his HIV RNA load was undetectable (<50 copies/mL).
      In September 2000, while the patient continued to receive HAART, he complained of gait instability, slurred speech, weakness, and double vision. Magnetic resonance imaging (MRI) of his brain performed at another institution reported increased T2 signal–associated lesions in the cerebellum and left cerebellar peduncle, the midbrain, the pons, and the basal ganglia. His cerebrospinal fluid (CSF) showed a normal cell count and protein and glucose levels. It was negative for viral, bacterial, fungal, and mycobacterial cultures. His CD4 cell count was measured at 0.40 × 109/L, and his HIV RNA load was less than 50 copies/mL. His medications were switched to zidovudine, lamivudine, and nevirapine over concerns that the neurologic symptoms were “aggravated by efavirenz.”
      In November 2000, he presented to our institution with subacute progression of his symptoms. He complained of diplopia, slurred speech, ataxic gait, and numbness and clumsiness on the left side of his body. Neurologic examination revealed an alert and oriented man with ataxic dysarthria and ataxic gait. He had limb dysmetria of the left side. There was minimal nystagmus on left lateral gaze. Diffuse hyperreflexia was present, but there were no Babinski signs. Findings on the rest of his examination were normal.
      He had a peripheral white blood cell count of 12.7 × 109/L (reference range, 3.5–10.5 × 109/L), a hemoglobin level of 14.7 g/dL (13.5–17.5 g/dL), and platelet count of 263 × 109/L (150–450 × 109/L). Results of serum chemistries were normal. His CD4 cell count was 0.39 × 109/L, and his HIV RNA load was less than 400 copies/mL. Brain MRI with axial fluid-attenuated inversion recovery sequences showed asymmetric, nonenhancing, patchy, and confluent areas of increased T2 signal involving the cerebellum, pons, medulla, and midbrain with no marked mass effect (Figure 1, A). The CSF analysis revealed a clear fluid with total nucleated cell count of 2.0/mL (96% lymphocytes, 4% monocytes), glucose level of 59 mg/dL (blood glucose, 103 mg/dL), and protein level of 104 mg/dL. Microbiologic cultures were negative. Qualitative CSF JCV polymerase chain reaction (PCR) assays demonstrated the presence of JCV DNA.
      Figure thumbnail gr1
      Figure 1Magnetic resonance images of the brain obtained at baseline (A) and after 3 weeks (B) and 14 weeks (C) of combination cidofovir and highly active antiretroviral therapy.
      The patient began to take cidofovir, 5 mg/kg per dose weekly for the first 2 doses and every 2 weeks thereafter. Three weeks later, he reported mild symptomatic improvement with diminished weakness and numbness of his left side, resolution of his diplopia, and improved speech. Brain MRI showed slight improvement in the signal abnormalities (Figure 1, B). He continued to take cidofovir and was maintained on zidovudine, lamivudine, and efavirenz. Six weeks later, his speech normalized, and he became independently ambulatory using a cane. Twelve weeks later, he was able to ambulate independently without any assistive device, and his brain MRI continued to show improvement (Figure 1, C). At that time, an attempt was made to decrease his cidofovir to once-monthly infusion, but this was complicated by a progression of the right pontomedullary lesion. He completed 6 months of adjunctive cidofovir therapy. Three months after completion of cidofovir treatment, he was able to perform his activities of daily living without assistive devices. Mild residual weakness of the left shoulder persisted.

      DISCUSSION

      Despite the dramatic decrease in the mortality and incidence of other opportunistic infections in the era of antiretroviral therapy,
      • Moore RD
      • Chaisson RE
      Natural history of HIV infection in the era of combination antiretroviral therapy.
      • Palella Jr, FJ
      • Delaney KM
      • Moorman AC
      • HIV Outpatient Study Investigators
      • et al.
      Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.
      • Ledergerber B
      • Egger M
      • Erard V
      • et al.
      AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study.
      PML continues rarely to afflict individuals with AIDS. The precise reason for PML occurrence despite fewer other opportunistic infections remains obscure. In addition, the predictors of its occurrence in the face of effective HAART remain ill defined.
      Through a MEDLINE search to identify reports of PML that occurred while patients were receiving HAART, we found 19 additional cases with adequate clinical characteristics for our analysis (Table 1).
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      • Tantisiriwat W
      • Tebas P
      • Clifford DB
      • Powderly WG
      • Fichtenbaum CJ
      Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy.
      • Mayo J
      • Collazos J
      • Martinez E
      Progressive multifocal leukoen-cephalopathy following initiation of highly active antiretroviral therapy [letter].
      • Sadler M
      • Chinn R
      • Healy J
      • Fisher M
      • Nelson MR
      • Gazzard BG
      New treatments for progressive multifocal leukoencephalopathy in HIV-1-infected patients [letter].
      • Blick G
      • Whiteside M
      • Griegor P
      • Hopkins U
      • Garton T
      • LaGravinese L
      Successful resolution of progressive multifocal leukoencephalopathy after combination therapy with cidofovir and cytosine arabinoside.
      All patients presented with compatible clinical and radiographic findings; the majority (75%) of cases were confirmed by the demonstration of JCV DNA in the CSF and/or characteristic histology on brain biopsy. After exclusion of the 9 patients described by De Luca et al
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      for whom specific age and sex were not reported, the remaining 11 patients were men between 34 and 55 years of age (mean age, 43 years). The interval between the institution of HAART and the onset of PML symptoms ranged from 2 weeks to 1 year (mean, 5 months). The antiretroviral regimens consisted mostly of dual nucleoside reverse transcriptase inhibitor and a single protease inhibitor (PI). The mean CD4 cell count at the time of PML diagnosis was 0.22 × 109/L (range, 0.03–0.40 × 109/L), and the HIV RNA load ranged from fewer than 50 to 8003 copies/mL. Among the 6 reported patients with available CD4 cell count data prior to the institution of HAART, the observed mean CD4 cell count increased 460% from baseline (range, 50%-1176%) at or prior to the onset of PML symptoms. In addition to these cases, Clifford et al
      • Clifford DB
      • Yiannoutsos C
      • Glicksman M
      • et al.
      HAART improves prognosis in HIV-associated progressive multifocal leu-koencephalopathy.
      reported 15 cases of PML in patients receiving HAART, suggesting that this opportunistic pathogen remains a serious concern among AIDS patients in the era of HAART.
      Table 1Characteristics of Patients Who Developed PML While Receiving HAART
      HAART = highly active antiretroviral therapy; NR = not reported; PML = progressive multifocal leukoencephalopathy.
      SourcePatient No.Age (y)/sexDisease onsetCD4 cell count (×109/L)HIV RNA copies/mLHAART regimen at time of diagnosisHAART regimen after diagnosisAdjunctive treatmentOutcome
      De Luca et al
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      Values are mean (range).
      1–9NR9 wk (3–28 wk)0.13NRNRNRCidofovir
      Number of patients taking cidofovir not specified.
      1 improved, others stable
      Tantisiriwat et al
      • Tantisiriwat W
      • Tebas P
      • Clifford DB
      • Powderly WG
      • Fichtenbaum CJ
      Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy.
      1051/M1 y0.188003Lamivudine, stavudine, saquinavirDidanosine, lamivudine, indinavir, nevirapineNoneDied
      1145/M9 mo0.044047Stavudine, lamivudine, indinavirDidanosine, nevirapine, ritonavir, saquinavirNoneDied
      1237/M12 wkNR2593Stavudine, lamivudine, saquinavir, ritonavirStavudine, lamivudine, saquinavir, ritonavirInterferon alfaImproved
      Mayo et al
      • Mayo J
      • Collazos J
      • Martinez E
      Progressive multifocal leukoen-cephalopathy following initiation of highly active antiretroviral therapy [letter].
      1336/M2 wk0.06NRZidovudine, lamivudine, indinavirZidovudine, lamivudine, indinavirNoneImproved
      1440/M8 wk0.30460Zidovudine, lamivudine, indinavirZidovudine, lamivudine, indinavirNoneImproved
      1537/M5 wk0.331220Lamivudine, stavudine, ritonavirLamivudine, stavudine, ritonavirNoneImproved
      Sadler et al
      • Sadler M
      • Chinn R
      • Healy J
      • Fisher M
      • Nelson MR
      • Gazzard BG
      New treatments for progressive multifocal leukoencephalopathy in HIV-1-infected patients [letter].
      1641/MNR0.17<500Lamivudine, stavudine, ritonavirLamivudine, stavudine, ritonavirCidofovirImproved
      1741/M7 mo0.03NRZidovudine, lamivudine, indinavirZidovudine, lamivudine, indinavirCidofovirImproved
      1851/M8 mo0.27<500Lamivudine, stavudineLamivudine, stavudine, abacavirNoneImproved
      Blick et al
      • Blick G
      • Whiteside M
      • Griegor P
      • Hopkins U
      • Garton T
      • LaGravinese L
      Successful resolution of progressive multifocal leukoencephalopathy after combination therapy with cidofovir and cytosine arabinoside.
      1934/M4 wk0.251940Lamivudine, stavudine, saquinavirLamivudine, stavudine, saquinavirCidofovirImproved
      Present case2055/M6 mo0.40<50Lamivudine, zidovudine, nevirapineLamivudine, stavudine, efavirenzCidofovirImproved
      * HAART = highly active antiretroviral therapy; NR = not reported; PML = progressive multifocal leukoencephalopathy.
      Values are mean (range).
      Number of patients taking cidofovir not specified.
      Recent reports on improved survival of patients with PML after institution of HAART have been promising.
      • Clifford DB
      • Yiannoutsos C
      • Glicksman M
      • et al.
      HAART improves prognosis in HIV-associated progressive multifocal leu-koencephalopathy.
      However, this may be a limited response since many such patients demonstrated only cessation of PML disease progression, and few actually showed clinical improvement. These cases illustrate the need for a more direct therapy against JCV.
      Before such direct therapy can be successful, the pathogenesis of this disease needs to be elucidated. Several theories suggested to explain the occurrence of PML in the face of HAART include immune reconstitution, partial immune recovery, and the existence of a more virulent JCV strain. Among these, PML occurring as a product of immune reconstitution phenomenon has received the most interest. It is believed that the improved immunologic function mediated by HAART induces the evolution of latent infection into symptomatic disease. Reports of worsening infections after institution of HAART, including Mycobacterium avium-intracellulare lymphadenitis and Pneumocystis carinii pneumonia, have been attributed to this phenomenon. The JCV may exist in the central nervous system as a latent infection.
      • Quinlivan EB
      • Norris M
      • Bouldin TW
      • et al.
      Subclinical central nervous system infection with JC virus in patients with AIDS.
      As such, the sudden reconstitution of the immune system after HAART would drive an inflammatory response to this incubating subclinical infection and induce the development and progression of neurologic symptoms with continued immune reconstitution. While the absence of inflammatory changes is characteristic on the gadolinium-enhanced MRI scans of PML patients with AIDS, a recent report

      Miralles P, Berenguer J, Lacruz C, et al. Paradoxical worsening of AIDS-associated progressive multifocal leukoencephalopathy following HAART [abstract]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, Ill. Abstract 598. Available at: www.retroconference.org/2001/abstracts/abstracts/abstracts/598.htm. Accessibility verified July 25, 2001.

      suggested the paradoxical worsening of the MRI lesions (with gadolinium enhancement in 1 patient) that is accompanied by inflammatory changes on brain biopsy in patients who develop PML after institution of HAART. These findings suggest that the pathogenesis of PML in patients receiving HAART may be distinct from its occurrence among patients not receiving HAART, and this may be mediated by immune reconstitution.
      Partial immune recovery with no substantial protection against JCV or the presence of a more virulent JCV strain are 2 other theories that have been proposed to explain the development of PML in patients receiving HAART. While possible, 2 studies demonstrating lower levels of JCV DNA in the CSF and its continued quantitative drop in patients who develop PML while receiving HAART negates these latter theories and favors the immune reconstitution phenomenon.
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      • Yiannoutsos CT
      • Major EO
      • Curfman B
      • et al.
      Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.
      Additionally, the quantitation of JCV DNA in CSF has been evaluated as a prognostic factor for survival among patients with PML.
      • Yiannoutsos CT
      • Major EO
      • Curfman B
      • et al.
      Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.
      Lower CSF JCV DNA load at baseline is correlated with better outcome and higher CD4 cell counts.
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      • Yiannoutsos CT
      • Major EO
      • Curfman B
      • et al.
      Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.
      • Meylan PR
      • Vuadens P
      • Maeder P
      • Sahli R
      • Tagan MC
      Monitoring the response of AIDS-related progressive multifocal leukoencepha-lopathy to HAART and cidofovir by PCR for JC virus DNA in the CSF.
      A JCV DNA threshold of 50 to 100 copies/µL has been proposed to identify patients at risk of worse out-come.
      • Yiannoutsos CT
      • Major EO
      • Curfman B
      • et al.
      Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.
      In our case, the qualitative CSF JCV DNA PCR assay was positive in only 2 of the 4 PCR assays suggesting a lower CSF JCV DNA load. Our hypothesis is supported by the report of decreased assay sensitivity and reproducibility on samples with fewer than 1600 copies/mL.
      • De Luca A
      • Giancola ML
      • Ammassari A
      • et al.
      The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.
      Thus, since the levels of JCV DNA in the CSF are relatively lower among patients who develop PML while receiving HAART, it may be necessary to repeat the assay, when results are initially negative (or suspected to be falsely negative), if laboratory diagnosis is necessary to confirm clinical suspicion.
      While the pathogenesis of PML in patients receiving HAART is being evaluated, it is clear that a consensus on an effective treatment strategy is needed. Some cases of PML improved over time with just the maintenance of or intensification of the HAART regimen (Table 1). However, there are also patients, such as the one described here, whose symptoms continued to worsen even with good response to HAART. Since time is essential in the preservation of neurologic function, adjunctive therapy is necessary to maximize neurologic stability and recovery among these patients. The early institution of this effective anti-JCV treatment could curtail the continued damage on the nervous system that may prove to be irreversible.
      Cidofovir is an antiviral agent with broad activity against the Herpesviridae family and has been approved by the Food and Drug Administration for the treatment of cytomegalovirus retinitis. Interestingly, it is also reported to be a potent antipolyomavirus drug.
      • Andrei G
      • Snoeck R
      • Vandeputte M
      • De Clercq E
      Activities of various compounds against murine and primate polyomaviruses.
      However, it has not been proven to be particularly effective for JCV.
      • Hou J
      • Major EO
      The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line.
      Its clinical efficacy for the treatment of PML has been suggested mostly by case reports (Table 1). In this particular case report, our patient had symptomatic improvement within 2 weeks and started to show radiographic improvement as early as 3 weeks after the start of therapy. In addition, the slight worsening of his pontomedullary lesions following a reduction of cidofovir infusion attests to the direct effect of the drug on the outcome of PML. While all these reports are anecdotal, it calls to attention the potential benefit of this agent. Recently, 2 contrasting observations were reported concerning the efficacy of cidofovir use for the treatment of PML. The open-label nonrandomized trial conducted by AIDS Clinical Trials Group 363

      Marra CM, Rajicic N, Barker DE, Cohen B, Clifford D, ACTG 363 Team. Prospective pilot study of cidofovir for HIV-associated progressive multifocal leukoencephalopathy (PML) [abstract]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, Ill. Abstract 596. Available at: www.retroconference.org/2001/abstracts/abstracts/abstracts/596.htm. Accessibility verified July 25, 2001.

      did not show a beneficial effect of cidofovir on the overall survival of the 24 patients enrolled in the study, while the report by Berenguer et al

      Berenguer J, Miralles P, Arrizabalaga J, et al, GESIDA 11/99 Study Group. Clinical course and prognostic factors of AIDS-associated progressive multifocal leukoencephalopathy (PML) in patients treated with HAART (GESIDA 11/99) [abstract]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, Ill. Abstract 10. Available at: www.retroconference.org/2001/abstracts/abstracts/abstracts/10.htm. Accessibility verified July 25, 2001.

      that evaluated 118 patients suggested a strong association between cidofovir use and patient survival.
      Furthermore, the mechanism of action of cidofovir for the treatment of PML needs to be defined further. Cidofovir has demonstrated antipolyomavirus activity,
      • Andrei G
      • Snoeck R
      • Vandeputte M
      • De Clercq E
      Activities of various compounds against murine and primate polyomaviruses.
      but if the neurologic damage in PML after HAART is mediated by immune reconstitution and not primarily from a continued direct damage by JCV, one wonders whether cidofovir has an unrecognized anti-inflammatory activity as well.
      It is also important to note that most patients with PML were treated with a PI-containing HAART regimen. Our case is unique because we continued to use a PI-sparing antiretroviral regimen. One may argue that our patient may have improved without cidofovir, if a PI medication was added. While this seems reasonable, we thought that the addition of PI would not contribute much to his immunologic function and virologic control, and instead, the addition of cidofovir was warranted in an effort to prevent further neurologic damage.
      In conclusion, PML remains a devastating complication in AIDS patients even in the era of HAART. Further research is warranted to define its pathogenesis, including the intriguing role of immune reconstitution. Its continued threat to the success of present HIV care emphasizes the urgent need for an effective therapeutic strategy. While we recognize that our observations are subject to bias that is inherent to uncontrolled and small studies, our case contributes to the growing body of data on the successful use of cidofovir, making it a candidate drug for adjunctive treatment of this opportunistic infection.

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      1. Miralles P, Berenguer J, Lacruz C, et al. Paradoxical worsening of AIDS-associated progressive multifocal leukoencephalopathy following HAART [abstract]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, Ill. Abstract 598. Available at: www.retroconference.org/2001/abstracts/abstracts/abstracts/598.htm. Accessibility verified July 25, 2001.

        • Yiannoutsos CT
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        • Meylan PR
        • Vuadens P
        • Maeder P
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        Monitoring the response of AIDS-related progressive multifocal leukoencepha-lopathy to HAART and cidofovir by PCR for JC virus DNA in the CSF.
        Eur Neurol. 1999; 41: 172-174
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      2. Marra CM, Rajicic N, Barker DE, Cohen B, Clifford D, ACTG 363 Team. Prospective pilot study of cidofovir for HIV-associated progressive multifocal leukoencephalopathy (PML) [abstract]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, Ill. Abstract 596. Available at: www.retroconference.org/2001/abstracts/abstracts/abstracts/596.htm. Accessibility verified July 25, 2001.

      3. Berenguer J, Miralles P, Arrizabalaga J, et al, GESIDA 11/99 Study Group. Clinical course and prognostic factors of AIDS-associated progressive multifocal leukoencephalopathy (PML) in patients treated with HAART (GESIDA 11/99) [abstract]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, Ill. Abstract 10. Available at: www.retroconference.org/2001/abstracts/abstracts/abstracts/10.htm. Accessibility verified July 25, 2001.