Use of Antiherpes Drugs and the Risk of Kaposi's Sarcoma: Data from the Multicenter AIDS Cohort Study

Abstract

To determine if use of antiherpes drugs protects against the development of AIDS-associated Kaposi's sarcoma (KS), data from 935 homosexual men with AIDS from the Multicenter AIDS Cohort Study were analyzed. In nested case-control analysis, neither acyclovir use for human immunodeficiency virus infection (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.56-1.26; P = .39) nor acyclovir use for any indication (OR, 1.02; 95% CI, 0.76-1.38; P = .89) was associated with a reduced risk of KS as initial AIDS diagnosis. In longitudinal analysis, acyclovir was also not protective against developing KS as a late manifestation of AIDS (after initial non-KS AIDS diagnosis). Among men with cytomegalovirus disease, ganciclovir use (relative risk [RR], 0.56; 95% CI, 0.22-1.44; P = .23) and foscarnet use (RR, 0.40; 95% CI, 0.051-3.10; P = .38) were associated (although not significantly) with a reduced risk of KS. Thus, acyclovir use does not appear to reduce the risk of KS, but further study of other antiherpes drugs such as ganciclovir and foscarnet is warranted.

Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy.

“…Acyclovir routinely has had no beneficial effect (14,32,33), while ganciclovir has had in some cases no effect (14,33) but in others a modest protective benefit (32). Foscarnet has shown the greatest potential, with both case reports of KS remissions after treatment (34) and larger observational studies describing associations between treatment and the inhibition of KS development (14,32). (However, the potential benefit of foscarnet remains controversial [33].)…”

Kaposi's Sarcoma-Like Tumors in a Human Herpesvirus 8 ORF74 Transgenic Mouse

“…Several lines of evidence suggest that HHV-8 pathogenesis in KS is mediated indirectly by paracrine factors produced by cells that undergo lytic phase viral replication but that act on uninfected or latently infected cells. Treatment with drugs that target lytic replication has been reported to result in regression of KS (19,27,30), although this has not been a universal finding. Cultured primary endothelial cells can be transformed and converted into spindle cells by infection with HHV-8 (9,13,35).…”

KSHV Paracrine Effects on Tumorigenesis

“…Fourth, KS lesions show a substantial rate of spontaneous remission, observed after the introduction of HAART (J. Gill et al, 2002;Ledergerber et al, 1999), cessation of immunosuppression (Kondo et al, 2000;Nagy et al, 2000), or treatment with ganciclovir or foscarnet, which selectively inhibits lytic KSHV replication (Glesby et al, 1996;Mocroft et al, 1996). Together, these features imply that KS is not a true malignancy, but rather a polyclonal reactive hyperplasia.…”

“…First, KS is typically observed in patients with higher circulating KSHV loads, indicating that lytic expression is necessary for the recruitment and de novo infection of cells (Campbell et al, 2000;Whitby et al, 1995). Second, ganciclovir and foscarnet have been shown to mediate the long-term remission of KS (Glesby et al, 1996;Mocroft et al, 1996), again indicating that ongoing lytic replication is necessary for lesion formation. Third, immunosuppression favours KS development, and this is connected with KSHV reactivation and lytic replication D.F.…”