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 HIVinfected 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 highdose 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.

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

“…28,29,32 A recent report described MCD remission in a multiple myeloma patient undergoing treatment with the proteosome inhibitor bortezomib. 33 Finally, herpesvirus-directed treatments using inhibitors of the viral DNA polymerase have shown promise, 34,35 consistent with the involvement of lytic phase replication in MCD; however, as for chemotherapy, the benefits are transient and long-term use is complicated by dose-limiting toxicities of these agents.…”

“…Originally developed to treat herpes simplex virus infection, they also inhibit KSHV in vitro 60,[64][65][66] and have displayed activity against KSHV-associated disease based on reductions in viral oropharyngeal shedding 67,68 and clinical relief of MCD symptoms. 34,35 At the outset, we considered three alternatives: (1) ganciclovir and the immunotoxin might display additive anti-KSHV activities; (2) they might detected on a small subpopulation of induced cells; this pattern was not observed on uninduced cells (data not shown). The mean fluorescent intensity of the entire population of induced cells was 24.9 with mAb 4C3 compared with 8.0 with control IgG1.…”

“…In one case study, ganciclovir was associated with reduction in the frequency of active MCD episodes, 34 although in another report cidofovir was found to be ineffective 76 despite its strong anti-KSHV activity in vitro. In a recent pilot study, 35 high-dose zidovudine plus valganciclovir produced significant clinical, biochemical and virologic responses in symptomatic potentiate one another through their differential mechanisms of inhibiting production of infectious virus during the lytic phase of KSHV replication; (3) ganciclovir might compromise immunotoxin activity by suppressing expression of the gpK8.1A target antigen. 60,66 We therefore examined the activities of each agent alone and in combination over wide concentration ranges.…”

Pulmonary manifestations of human herpesvirus-8 during HIV infection

“…Cidofovir has no effect on MCD. A recent series showed transient remission with high-dose zidovudine and valganciclovir, but only 23% were long-term responders [87,88].…”

KSHV: forgotten but not gone

“…In this issue of Blood, for the first time, Uldrick et al describe a long overdue approach to MCD therapy based on direct targeting of KSHV. 4 There are now 7 known human cancer viruses but only scattered efforts to developed drugs specifically targeting them. The successes of the human papillomavirus and hepatitis B virus vaccines make clear that virusoriented therapies have the potential to be major success stories in cancer management.…”