Correspondence
Progressive Multifocal Leukoencephalopathy, HIV, and Highly Active Antiretroviral Therapy
N Engl J Med 1998; 339:848-849September 17, 1998
- Article
To the Editor:
The results of AIDS Clinical Trials Group Study 243, reported by Hall et al. (May 7 issue),1 show that neither cytarabine nor regimens of one or two reverse-transcriptase inhibitors affect the course of progressive multifocal leukoencephalopathy in patients infected with the human immunodeficiency virus (HIV). Recent case reports have indicated that neurologic conditions and survival may improve in patients with progressive multifocal leukoencephalopathy who receive highly active antiretroviral therapy, including protease inhibitors.2-4 Protease inhibitors became widely available only after the cytarabine trial.1
We evaluated survival and the presence or absence of JC virus DNA in cerebrospinal fluid in a group of 10 selected patients attending three infectious-disease clinics in northern Italy between July 1996 and November 1997 who had not previously received protease inhibitors and in whom highly active antiretroviral therapy was initiated within 90 days of the onset of symptoms of progressive multifocal leukoencephalopathy. All the patients had clinical and radiologic findings suggestive of progressive multifocal leukoencephalopathy. In all 10 patients, the diagnosis was confirmed by the detection of JC virus DNA in cerebrospinal fluid with a polymerase-chain-reaction (PCR) assay.5 At base line, the median HIV type 1 (HIV-1) RNA level was 150,000 copies per milliliter (range, 74,000 to 330,000), and the median CD4-positive cell count was 67 per cubic millimeter (range, 8 to 162).
All 10 patients were still alive a median of 430 days (range, 207 to 669) after the diagnosis had been made. Neurologic conditions improved substantially in six patients, remained stable in three, and worsened in one. In five patients, JC virus DNA was no longer detectable in a second cerebrospinal fluid sample, obtained 112 to 365 days after the diagnosis. After 180 days of therapy, HIV-1 RNA was undetectable in nine patients, and the median CD4-positive cell count had increased to 110 per cubic millimeter (range, 43 to 419).
Ten HIV-infected patients with progressive multifocal leukoencephalopathy, matched for age, sex, and CD4-positive cell count at base line (median, 54 per cubic centimeter; range, 3 to 180), were observed before June 1996 and were either untreated or received antiretroviral monotherapy, cytarabine, or both. The median survival in this group was 105 days (range, 14 to 360; P<0.001 by the Mann–Whitney test for the comparison with the group receiving highly active antiretroviral therapy). We did not observe a reversion from detectable to nondetectable JC virus DNA in follow-up cerebrospinal fluid specimens obtained 15 to 210 days after diagnosis from 2 patients in the control group and in 14 other patients observed during the same period.
Highly active antiretroviral therapy may halt the progression of progressive multifocal leukoencephalopathy in HIV-infected patients. This effect, together with the clearance of JC virus DNA from the cerebrospinal fluid, may have important implications for diagnosis, as well as for the design of future trials of new drugs for the treatment of JC virus infection.
5 ReferencesPaola Cinque, M.D.
San Raffaele Hospital, 20127 Milan, ItalySalvatore Casari, M.D.
Davide Bertelli, M.D.
Spedali Civili, 25125 Brescia, Italy1
Hall CD ,Dafni U ,Simpson D , et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 1998;338:1345-1351
Full Text | Web of Science | Medline2
Power C ,Nath A ,Aoki FY ,Del Bigio M . Remission of progressive multifocal leukoencephalopathy following splenectomy and antiretroviral therapy in a patient with HIV infection. N Engl J Med 1997;336:661-662
Full Text | Web of Science | Medline3
Elliot B ,Aromin I ,Gold R ,Flanigan T ,Mileno M . 2.5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy. Lancet 1997;349:850-850
CrossRef | Web of Science | Medline4
Domingo P ,Guardiola JM ,Iranzo A ,Margall N . Remission of progressive multifocal leucoencephalopathy after antiretroviral therapy. Lancet 1997;349:1554-1555
CrossRef | Web of Science | Medline5
Cinque P ,Scarpellini P ,Vago L ,Linde A ,Lazzarin A . Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS 1997;11:1-17
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Cinque et al. that the clinical outlook for HIV-infected patients with progressive multifocal leukoencephalopathy may be improving with the advent of highly active antiretroviral therapy. The research group involved in the study of the effects of cytarabine has continued to evaluate sequential cases of progressive multifocal leukoencephalopathy, and we have reported the preliminary results elsewhere.1 Patients are eligible if they have a clinical presentation compatible with the diagnosis and either brain-biopsy confirmation of disease or a positive PCR test for JC virus DNA in cerebrospinal fluid. To date, 37 patients have received maximal antiretroviral therapy, with no other specific treatment for progressive multifocal leukoencephalopathy.
We have found no relation between HIV systemic viral load at entry and survival. In the patients who did not have a reduced viral load in response to therapy, the survival (median, 14 weeks) was similar to that in the cytarabine study. Patients who had a reduction in the viral load in response to therapy had significantly prolonged survival. A preliminary review of the data in the cytarabine study also supports a negative correlation between cerebrospinal fluid JC virus DNA and survival. These results are similar to the findings of Cinque et al. and indicate that control of HIV should be the aim in HIV-infected patients presenting with progressive multifocal leukoencephalopathy. Trials of agents that may, in addition, directly reduce the burden of JC virus are under way.
1 ReferencesColin D. Hall, M.B., Ch.B.
University of North Carolina School of Medicine, Chapel Hill, NC 27599-7025Constantin Yiannoutsos, Ph.D.
Harvard School of Public Health, Boston, MA 02115David B. Clifford, M.D.
Washington University, St. Louis, MO 63110- Citing Articles (17)
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Norman P. Markowitz, Mark L. Rosenblum. (2007) Neurological manifestations of acquired immunodeficiency syndrome. Journal of Neurosurgery 107:6, 1251-1252
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Mark T M Roberts. (2005) AIDS-Associated Progressive Multifocal Leukoencephalopathy. CNS Drugs 19:8, 671-682
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David M. Aboulafia, Lynne Taylor. (2002) Vacuolar Myelopathy and Vacuolar Cerebellar Leukoencephalopathy: A Late Complication of AIDS After Highly Active Antiretroviral Therapy-Induced Immune Reconstitution. AIDS Patient Care and STDs 16:12, 579-584
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D. J. Skiest. (2002) Focal Neurological Disease in Patients with Acquired Immunodeficiency Syndrome. Clinical Infectious Diseases 34:1, 103-115
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J. Portilla, V. Boix, F. Román, S. Reus, E. Merino. (2000) Progressive Multifocal Leukoencephalopathy Treated with Cidofovir in HIV-infected Patients Receiving Highly Active Anti-retroviral Therapy. Journal of Infection 41:2, 182-184
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Kimon C Zachary. (2000) Systemic manifestations of HIV infection. Clinics in Dermatology 18:4, 441-446
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B. Giudici, B. Vaz, S. Bossolasco, S. Casari, A. M. Brambilla, W. Luke, A. Lazzarin, T. Weber, P. Cinque. (2000) Highly Active Antiretroviral Therapy and Progressive Multifocal Leukoencephalopathy: Effects on Cerebrospinal Fluid Markers of JC Virus Replication and Immune Response. Clinical Infectious Diseases 30:1, 95-99
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Jean-Michel Tassie, Jacques Gasnault, Michèle Bentata, Jacqueline Deloumeaux, François Boué, Eric Billaud, Dominique Costagliola. (1999) Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. AIDS 13:14, 1881-1887
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David Orentlicher, Michael K. Hehir. (1999) Advertising Policies of Medical Journals: Conflicts of Interest for Journal Editors and Professional Societies. The Journal of Law, Medicine & Ethics 27:2, 113-121
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