Comparison of Anti HIV Drugs Used Alone or in Combination With Cytosine Arabinoside to Treat Progressive Multifocal Leukoencephalopathy (PML) in HIV-Infected Patients

Condition(s) targeted: HIV Infections; Leukoencephalopathy, Progressive Multifocal

Intervention: Filgrastim (Drug); Cytarabine (Drug); Zidovudine (Drug); Zalcitabine (Drug); Didanosine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Hall C, Study Chair
Timpone J, Study Chair

To compare the safety and efficacy of antiretroviral therapy (zidovudine plus either didanosine or dideoxycytidine) versus antiretroviral therapy plus intravenous cytarabine (Ara-C) versus antiretroviral therapy plus intrathecal Ara-C in the maintenance or improvement of neurological function over 6 months in HIV-infected individuals who have developed progressive multifocal leukoencephalopathy (PML). To compare the effect of these three treatment regimens on Karnofsky score and MRI studies.

The effectiveness of Ara-C in the treatment of PML, caused by a human DNA papovavirus (designated JC virus) infection, has not been determined, although the most encouraging results have occurred with intrathecal administration of the drug.

Official title: A Phase II Multicenter Study Comparing Antiretroviral Therapy Alone to Antiretroviral Therapy Plus Cytosine Arabinoside (Cytarabine; Ara-C) for the Treatment of Progressive Multifocal Leukoencephalopathy (PML) in Human Immunodeficiency Virus (HIV)-Infected Subjects

Study design: Treatment

Detailed description: The effectiveness of Ara-C in the treatment of PML, caused by a human DNA papovavirus (designated JC virus) infection, has not been determined, although the most encouraging results have occurred with intrathecal administration of the drug.

Patients are randomized to receive antiretroviral therapy alone (AZT plus ddI or ddC), antiretroviral therapy plus intravenous Ara-C, or antiretroviral therapy plus intrathecal Ara-C. All patients receive 24 weeks of antiretroviral therapy. Beginning at week 2, patients on the intravenous Ara-C arm receive daily infusions of Ara-C over 5 days, with cycles repeating every 21 days. Patients on the intrathecal Ara-C arm receive single administrations of Ara-C at weeks 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24. A brain biopsy confirmation or in situ hybridization will be required within 7 days after study entry. Patients are followed every 4 weeks.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria

Concurrent Medication:

Allowed:

- Local intralesional chemotherapy for mucocutaneous Kaposi's sarcoma.

- Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for

treatment of mucosal and esophageal candidiasis.

- Foscarnet for newly developed CMV infection, only after discussion with the protocol

chair.

- Prophylactic and maintenance therapy for other opportunistic infections, provided

patients are considered clinically stable.

- No more than 1000 mg/day acyclovir for herpes simplex.

- Antibiotics for bacterial infections as clinically indicated.

- Antipyretics, analgesics, and antiemetics.

Concurrent Treatment:

Allowed:

- Local radiation therapy for mucocutaneous Kaposi's sarcoma.

Patients must have:

- HIV infection.

- Confirmed PML.

- No other current active opportunistic infections requiring systemic therapy.

- Life expectancy of at least 3 months.

NOTE:

- A durable power of attorney is recommended where severe neurologic or psychiatric

impairment can be foreseen while the patient is on study.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

- Current active cryptococcal meningitis, cytomegaloviral encephalitis, toxoplasmosis

encephalitis, CNS lymphoma, or neurosyphilis.

NOTE:

- Patients on maintenance therapy for cryptococcal meningitis or toxoplasmosis

encephalitis that has been stable for 4 months are permitted.

- Conditions that seriously increase risk of a surgical procedure (e. g., coagulopathy,

severe thrombocytopenia).

- Any other disease that would interfere with evaluation of the patient.

- Other life-threatening complications likely to cause death in < 3 months.

Concurrent Medication:

Excluded:

- Ganciclovir.

- Interferon.

- Systemic chemotherapy other than Ara-C (unless specifically allowed).

- Antiretroviral medications other than AZT, ddI, or ddC.

Patients with the following prior conditions are excluded:

History of allergy or intolerance to G-CSF.

Prior Medication:

Excluded:

- Any prior Ara-C.

Excluded within 14 days prior to study:

- Ganciclovir or foscarnet.

- Interferon.

- Antiretroviral medications other than AZT, ddI, or ddC.

- Experimental medications for treatment of PML.

San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco, California 941102859, United States

Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States

Yale Univ / New Haven, New Haven, Connecticut 065102483, United States

Georgetown Univ Med Ctr, Washington, District of Columbia 20007, United States

Univ of Miami School of Medicine, Miami, Florida 331361013, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Johns Hopkins Hosp, Baltimore, Maryland 21287, United States

Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, United States

Univ of Rochester Medical Center, Rochester, New York 14642, United States

Mount Sinai Med Ctr, New York, New York 10029, United States

Columbia Presbyterian Med Ctr, New York, New York 100323784, United States

Adirondack Med Ctr at Saranac Lake, Albany, New York 122083479, United States

Mid - Hudson Care Ctr, Albany, New York 122083479, United States

Albany Med College / Division of HIV Medicine A158, Albany, New York 122083479, United States

Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States

Univ of Kentucky Lexington, Cincinnati, Ohio 45267, United States

Julio Arroyo, West Columbia, South Carolina 29169, United States

Univ of Washington, Seattle, Washington 981224304, United States

Click here for more information about Zidovudine

Click here for more information about Zalcitabine

Click here for more information about Didanosine

Related publications:

[No authors listed] Cytarabine nixed for PML. GMHC Treat Issues. 1996 Nov;10(11):9. No abstract available.

Post MJ, Yiannoutsos C, Simpson D, Booss J, Clifford DB, Cohen B, McArthur JC, Hall CD. Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team. AJNR Am J Neuroradiol. 1999 Nov-Dec;20(10):1896-906.

Hall C, Timpone J, Dafni I, Antonijevic Z, Millar L, Booss J, Clifford D, Cohen B, McArthur J, Hollander H. ARA-C treatment of PML in AIDS patients. Conf Retroviruses Opportunistic Infect.1997 Jan 22-26;4th:66 (abstract no 8)PMID: 97926517

Yiannoutsos CT, Major EO, Curfman B, Jensen PN, Gravell M, Hou J, Clifford DB, Hall CD. Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol. 1999 Jun;45(6):816-21.

Hall CD, Dafni U, Simpson D, Clifford D, Wetherill PE, Cohen B, McArthur J, Hollander H, Yainnoutsos C, Major E, Millar L, Timpone J. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med. 1998 May 7;338(19):1345-51.

Last updated: June 23, 2005