Valganciclovir and Human Herpesvirus–8
The possibility that ganciclovir or valganciclovir might inhibit HHV‐8 replication and prevent development of Kaposi sarcoma in HIV‐infected patients was suggested by the observation that patients who received 4.5 g daily of orally administered ganciclovir to prevent development of CMV retinitis in the eye without an ocular ganciclovir implant also had a lower incidence of Kaposi sarcoma in a large clinical trial. This suggested the intriguing possibility that replicating HHV‐8 expressed lytic proteins or stimulated cellular cytokines, which contributed to the development of Kaposi sarcoma. It has been suggested that in KS lesions, the lytic cycle gene products may be involved in proliferation of neighboring cells, contributing to pathogenesis. One attractive candidate is an early lytic protein of HHV‐8 that might contribute to oncogenesis is the viral‐encoded G‐protein–coupled receptor of HHV‐8 (ORF74). This protein has been shown to be a viral oncogene and angiogenesis activator. The expression of ORF74 induces an angiogenesis phenotype by secretion of vascular endothelial growth factor, an angiogenesis growth factor. The HHV‐8 ORF74 can also activate mitogen-activated protein kinase, which indicates that the viral protein has a molecular specificity to trigger signaling cascades that are activated by inflammatory cytokines. Another viral protein that may be a candidate for contributing to pathogenesis is the HHV‐8 homologue of human IL‐6, the vIL‐6 protein. Thus, prevention of HHV‐8 replication might provide therapeutic benefits in human disease.
This study by Casper et al. provides evidence that valganciclovir is the first antiviral agent that has been shown to reduce HHV‐8 replication in a randomized clinical trial. The study design was a double blind, placebo‐controlled crossover trial in which 26 HHV‐8 infected men were randomized to receive 8 weeks of valganciclovir or placebo (900 mg once per day administered orally). After a 2‐week washout period, participants received the other study drug for 8 additional weeks. Oral swab samples were taken daily and analyzed for HHV‐8 DNA and CMV DNA by real time PCR. Sixteen HIV‐positive men and 10 HIV‐negative men completed the study. Valganciclovir administered orally effectively inhibited mucosal HHV‐8 replication, as detected by a sensitive PCR assay for HHV‐8 DNA. The antiviral effect of valganciclovir reduced the frequency and quantity of HHV‐8 that was detected in the oropharynx; this effect was prompt and occurred independently of the reduction in CMV replication. The Casper et al. study also provided evidence that HHV‐8 replication occurs independently of CMV replication in immunocompromised patients. The hematologic, renal, and hepatic toxicities of valganciclovir were similar to those of placebo in this short trial of low‐dose valganciclovir.
The Casper et al. study provides important new quantitative data that valganciclovir suppresses replication and oropharyngeal shedding of HHV‐8 and sets the stage for additional research to determine whether valganciclovir prevents Kaposi sarcoma in patients at high risk due to immunosuppression. The effects of valganciclovir on other HHV‐8 associated malignancies, such as primary effusion lymphoma and multicentric Castleman disease, should also be carefully evaluated.