title: High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy.
abstract: Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Uldrick
authors.forename: Mark N
authors.initials: MN
authors.lastname: Polizzotto
authors.forename: Karen
authors.initials: K
authors.lastname: Aleman
authors.forename: Deirdre
authors.initials: D
authors.lastname: O'Mahony
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wyvill
authors.forename: Victoria
authors.initials: V
authors.lastname: Wang
authors.forename: Vickie
authors.initials: V
authors.lastname: Marshall
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.forename: Denise
authors.initials: D
authors.lastname: Whitby
authors.forename: Richard F
authors.initials: RF
authors.lastname: Little
authors.forename: Robert
authors.initials: R
authors.lastname: Yarchoan
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005871:Castleman Disease / Q000150:complications / Q000188:drug therapy* / Q000821:virology*; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006566:Herpesviridae Infections / Q000150:complications / Q000821:virology; D019288:Herpesvirus 8, Human / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011494:Protein Kinases / Q000737:chemistry; D016019:Survival Analysis; D000077562:Valganciclovir; D019562:Viral Load / Q000187:drug effects; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014775:Virus Activation / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D014764:Viral Proteins; D015215:Zidovudine; D011494:Protein Kinases; C492430:ORF36 protein kinase, Kaposi's sarcoma herpesvirus; D000077562:Valganciclovir; D015774:Ganciclovir