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Abstract & Commentary
Treatment of HHV-8-related Disease with Antivirals
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is a speaker for Cubist Pharmaceuticals and GSK, and is a consultant for Siemens Diagnostics.
Synopsis: A pilot study of 14 HIV-infected patients with KHSV-associated multicentric Castleman's disease (MCD) was conducted. A regimen of valganciclovir (VGCV) plus high-dose zidovudine (AZT) appeared to produce clinical response. A second study treated 5 HIV-negative patients with classic Kaposi sarcoma (KS) with conventional doses of valganciclovir and there was no evidence of response.
Sources: Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: A pilot study of virus-activated cytotoxic therapy. Blood 2011 April 12; Epub ahead of print; Krown SE, Dittmer DP, Cesarman E, et al. Pilot study of oral valganciclovir therapy in patients with classic Kaposi sarcoma. J Infect Dis 2011;203:1082-1086..
Uldrick et al performed a pilot study in which 14 HIV-infected patients with symptomatic MCD received high-dose AZT (600 mg PO Q6 hours) and VGC (900 mg PO Q12 hours). Eighty-six percent of patients attained major clinical responses (defined as resolution of symptoms and at least partial resolution of lymphandenopathy). Fifty percent attained major biochemical responses (normalization of hemoglobin, platelet count, albumin, sodium, and CRP). Median progression-free survival was 6 months and overall survival was 86% at 12 months. In patients who responded, levels of IL-6, IL-10, and KHSV viral load also were reduced. Hematologic toxicities were common.
Krown et al performed a pilot study in which 5 HIV-negative patients with classic KS were treated with VGCV for up to six, 4-week cycles. KS progressed in 4 patients after 1-4 cycles and remained stable in 1 patient after 6 cycles. KS biopsies showed minimal lytic KS antigen and gene expression at baseline and post-treatment.
KSHV (HHV-8), like Epstein-Barr Virus (EBV), is a gamma herpesvirus. Both viruses generally have a lytic replication cycle in the oropharynx. In the case of EBV, a latent replication cycle where episomal DNA is associated with B-cell proliferation occurs. Examples of EBV disease include oral hairy leukoplakia (lytic infection predominates) and diseases where almost exclusively latent EBV replication is present (infectious mononucleosis, post-transplant lymphoproliferative disorder, and many cases of B-cell non-Hodgkin lymphoma). In the case of KHSV, three major clinical syndromes have been described: MCD, primary effusion lymphoma (PEL), and KS. Of these KHSV-associated syndromes, only MCD has been shown to possess significant lytic cycle KHSV.
Ganciclovir (and its prodrug, valganciclovir), as well as other acyclic nucleoside analogues, has been shown to be active against the lytic replication cycle of both EBV and KHSV, but not against latent (episomal) cycle. This basic understanding of gamma herpesvirus biology seems to be lacking in many ID specialists who insist on treating diseases such as PTLD and KS with ganciclovir or VGCV despite the significant hematologic toxicities of these agents and lack of clinical evidence of efficacy. It should be noted that Uldrick and colleagues did not use AZT and VGCV for their antiviral effects, but rather designed this regimen as antineoplastic/cytotoxic agents based on the observation that in MCD two KHSV lytic genes, ORF36 and ORF21, phosphorylate GCV and AZT, respectively, to cytotoxic metabolites. The positive results of their pilot study appear to validate this rationale and suggest the desirability of larger randomized comparative trials of treatment for MCD, recognizing that MCD is a very rare disease.
Similarly, Krown's small pilot study of VGCV treatment in classic KS support our understanding of KHSV biology. GCV and VGCV have no place in the treatment of KS (or PEL), but may have a role in treatment of MCD related to their targeted activation as cytotoxic agents, not as antivirals.