Progressive Multifocal Leukoencephalopathy - Cidofovir

5/15/2004

Question: What is the efficacy of Cidofovir in the treatment of progressive multifocal leukoencephalopathy in patients undergoing highly active antiretroviral therapy ( HAART )?.

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Unique Identifier:12218391

Authors: Marra CM. Rajicic N. Barker DE. Cohen BA. Clifford D. Donovan Post MJ. Ruiz A. Bowen BC. Huang ML. Queen-Baker J. Andersen J. Kelly S. Shriver S. Adult AIDS Clinical Trials Group 363 Team.

Institution: Department of Neurology and Medicine, University of Washington School of Medicine, Seattle, WA, USA.

Title: A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS.[erratum appears in AIDS. 2003 Jan 24;17(2):281.].

Source: AIDS. 16(13):1791-7, 2002 Sep 6.

Abstract: OBJECTIVE: To assess the safety, tolerability and effect of cidofovir for HIV-1 associated progressive multifocal leukoencephalopathy. DESIGN: Prospective, open-label study in nine AIDS Clinical Trials Units. PATIENTS AND METHODS: Twenty-four HIV-1-infected individuals, with neuroimaging and clinical findings consistent with PML, and symptoms for 90 days or less, whose diagnosis was confirmed by the detection of JC virus DNA in the cerebrospinal fluid or brain biopsy, received cidofovir 5 mg/kg intravenously at baseline and 1 week, followed by infusions every 2 weeks with the dose adjusted for renal function. Follow-up continued to 24 weeks. The safety of cidofovir and changes in neurological examination scores between baseline and week 8 were assessed. RESULTS: Seventeen subjects were receiving potent antiretroviral agents. Survival at 12 weeks was 54%. The CD4 cell count at entry was significantly associated with survival (P = 0.02). Five subjects discontinued treatment because of toxicity: a 50% or greater decrease in intraocular pressure in either eye in four, and proteinuria in one. Overall, magnetic resonance imaging abnormalities and neurological examination scores worsened. Only two subjects experienced a 25% or greater improvement in neurological examination scores at week 8, which were significantly better in subjects with HIV-1-RNA levels of 500 copies/ml or less at entry compared with those with HIV-1-RNA levels over 500 copies/ml (P = 0.05). CONCLUSION: Cidofovir did not improve neurological examination scores at week 8. However, such scores were significantly better in subjects who entered with suppressed plasma HIV-1-RNA levels, which could be the result of control of HIV-1 infection itself or cidofovir. Copyright 2002 Lippincott Williams & Wilkins CAS Registry/EC Number 0 (Antiviral Agents). 0 (Organophosphorus Compounds). 113852-37-2 (cidofovir). 71-30-7 (Cytosine).

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Unique Identifier:11517420

Authors: Gasnault J. Kousignian P. Kahraman M. Rahoiljaon J. Matheron S. Delfraissy JF. Taoufik Y.

Institution: Neuro-AIDS Rehabilitation Unit, Department of Internal Medicine, INSERM E109, Faculte de Medecine Paris Sud, Le Kremlin-Bicetre, France. jacques.gasnault@bct.ap-hop-paris.fr

Title: Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: a monocenter observational study with clinical and JC virus load monitoring.

Source: Journal of Neurovirology. 7(4):375-81, 2001 Aug.

Abstract: A monocenter observational study was conducted to determine the clinical and virological effects of cidofovir added to highly active anti-retroviral therapy (HAART) in AIDS-associated progressive multifocal leukoencephalopathy (PML). Exposure to other anti-viral drugs or late initiation of cidofovir were exclusion criteria. Of the 53 consecutive patients with virologically proven PML admitted at the NeuroAIDS Unit of Bicetre Hospital between May 1996 and July 2000 and having received HAART with or without cidofovir, 46 met the inclusion criteria. Cidofovir was initiated in most cases on compassionate grounds. The 22 patients treated with HAART only (HAART group) were compared to the 24 patients treated with HAART and cidofovir (CDV group). Survival, neurological outcome assessed by the expanded disability status scale (EDSS), and monitoring of the JC virus (JCV) load in CSF were investigated prospectively. At baseline (date of initiation or intensification of HAART), both groups were similar regarding CD4 cell count, plasma HIV load, CSF JCV load, EDSS, and demographic features. Both groups had similar response to HAART in terms of plasma HIV load and CD4 cell count. At month 6, CSF-JCV load was below the detection level in 8 out of 24 (33%) patients from the CDV group and 7 out of 18 (39%) patients from the HAART group (P = 0.71). One-year cumulative probability of being alive was 62% in the CDV group and 53% in the HAART group (P = 0.72). However, an additional benefit with respect to survival was observed in patients who were given cidofovir after adjustment to the following baseline variables (CSF-JCV load, CD4 cell count, and EDSS). Despite the addition of cidofovir to HAART, no significant benefit had been observed in neurological outcome, particularly in patients with an early worsening. CAS Registry/EC Number 0 (Antiviral Agents). 0 (Organophosphorus Compounds). 113852-37-2 (cidofovir). 71-30-7 (Cytosine).

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Unique Identifier:11517418

Authors: De Luca A. Giancola ML. Ammassari A. Grisetti S. Cingolani A. Larussa D. Alba L. Murri R. Ippolito G. Cauda R. Monforte A. Antinori A.

Institution: Department of Clinical Infectious Diseases, Universita Cattolica del S Cuore, Rome, Italy. andeluc@tin.it

Title: Potent anti-retroviral therapy with or without cidofovir for AIDS-associated progressive multifocal leukoencephalopathy: extended follow-up of an observational study.

Source: Journal of Neurovirology. 7(4):364-8, 2001 Aug.

Abstract: To analyze the clinical efficacy of cidofovir combined with highly active anti-retroviral therapy (HAART) in AIDS-related progressive multifocal leukoencepalopathy (PML), a multicenter observational study was performed. Consecutive HIV-positive patients with histologically or virologically proven PML and at least 4 weeks of treatment after diagnosis were examined: 27 patients were treated with HAART, whereas 16 patients were treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and every other week thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. Baseline virologic, immunologic, and clinical characteristics as well as HIV RNA and CD4 responses to HAART were homogeneous between the groups. The median follow-up was 132 weeks. In one case (6%), cidofovir was permanently discontinued because of severe proteinuria. One-year cumulative probability of survival was 0.61 with cidofovir and 0.29 without (log rank test P = 0.02). After adjusting for baseline CD4 counts, JC viral load in CSF, Karnofsky, and use of HAART prior to the onset of PML, the use of cidofovir was independently associated with a reduced risk of death (hazard ratio, 0.21, 95% confidence interval, 0.07-0.65; P = 0.005). A randomized study will definitively establish whether cidofovir confers significant advantage over HAART alone in AIDS-related PML. CAS Registry/EC Number 0 (Antiviral Agents). 0 (Organophosphorus Compounds). 113852-37-2 (cidofovir). 71-30-7 (Cytosine).

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Unique Identifier:11408993

Authors: Segarra-Newnham M. Vodolo KM.

Institution: Veterans Affairs Medical Center, West Palm Beach, FL, USA. marisel.segarra-newnham@med.va.gov

Title: Use of cidofovir in progressive multifocal leukoencephalopathy. [Review] [26 refs]

Source: Annals of Pharmacotherapy. 35(6):741-4, 2001 Jun.

Abstract: BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating illness caused by the JC virus, a polyomavirus that occurs in 4-5% of HIV-positive patients. Mortality is high, and no useful therapy has been identified. Highly active antiretroviral therapy (HAART) has been reported to be effective in halting progression of the disease in some, but not all, patients. Cidofovir has been shown to be active against polyomaviruses. OBJECTIVE: To review data on the use of cidofovir to treat PML. DATA SOURCES: English-language case reports and clinical studies were located through a literature search (MEDLINE and AIDSLINE, 1995-July 2000). STUDY SELECTION AND DATA EXTRACTION: Relevant case reports and studies describing the use of cidofovir for PML were reviewed. DATA SYNTHESIS: Most case reports describing the use of cidofovir have shown that the drug is effective in the treatment of PML. Some patients were also receiving HAART concurrently; therefore, it is not clear which treatment modality had a greater impact on PML. However, cidofovir may be effective in patients whose disease has progressed despite HAART or who are-unable to tolerate these regimens. A pilot study of cidofovir for treating PML has completed enrollment, but preliminary results showed no benefit. CONCLUSIONS: Cidofovir may be the most reasonable treatment option for PML in HIV-infected individuals who fail to improve with HAART or who are unable to tolerate these regimens. Patients who receive cidofovir should be monitored for renal and ocular toxicity. [References: 26] CAS Registry/EC Number 0 (Antiviral Agents). 0 (Organophosphorus Compounds). 113852-37-2 (cidofovir). 71-30-7 (Cytosine).

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Unique Identifier:11061646

Authors: De Luca A. Giancola ML. Ammassari A. Grisetti S. Cingolani A. Paglia MG. Govoni A. Murri R. Testa L. Monforte AD. Antinori A.

Institution: Istituto di Clinica delle Malattie Infettive, Universita Cattolica, Roma, Italy.

Title: Cidofovir added to HAART improves virological and clinical outcome in AIDS-associated progressive multifocal leukoencephalopathy.

Source: AIDS. 14(14):F117-21, 2000 Sep 29.

Abstract: OBJECTIVES: To analyse the virological and clinical efficacy of cidofovir combined with highly active antiretroviral therapy (HAART) in AIDS-related progressive multifocal leukoencephalopathy (PML). DESIGN: Multicentre observational study of consecutive HIV-positive patients with histologically or virologically-proven PML. Group A, 26 patients treated with HAART; group B, 14 patients treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and alternate weeks thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. RESULTS: Baseline virological, immunological and clinical characteristics were homogeneous between the groups. In one case cidofovir was discontinued because of severe proteinuria. There was no significant difference in HIV RNA responses and changes in the number of CD4 cells between group A and B. After 2 months of therapy, five out of 12 (42%) patients from group A and seven out of eight (87%) from group B reached undetectable JC virus DNA in the CSF (Chi-square P = 0.04); moreover, 24% of group A and 57% of group B patients showed neurological improvement or stability (P = 0.038). One-year cumulative probability of survival was 0.67 with cidofovir and 0.31 without (log-rank test, P = 0.01). Variables independently associated with longer survival were the use of cidofovir, HAART prior to the onset of PML, a baseline JC virus DNA load in CSF < 4.7 log10 copies/ml, and a baseline Karnofsky performance status > or = 60. CONCLUSIONS: In AIDS-related PML, cidofovir added to HAART is associated with a more effective control of JCV replication, with improved neurological outcome and survival compared with HAART alone. CAS Registry/EC Number 0 (Anti-HIV Agents). 0 (DNA, Viral). 0 (Organophosphorus Compounds). 0 (RNA, Viral). 113852-37-2 (cidofovir). 71-30-7 (Cytosine).