Therapy for HDV Based on Inhibition of the Helper Hepadnavirus

There is currently no generally accepted effective therapy for type D hepatitis (see Niro et al. 2005 for a review), and liver transplantation is the only option for the associated end-stage liver disease (Wright and Pereira 1995). The dependence of HDV on HBV could suggest that successful treatment of HDV infection would follow successful treatment of the supporting HBV infection. Unfortunately, this does not always appear to be the case. Although treatment of chronic HBV carriers with lamivudine (b-L-2',3'-dideoxy-3'-thiacytidine, 3TC) leads to decreased levels of HBV in serum and improved liver histology (Dienstagetal. 1995;Laietal. 1998;Nevensetal. 1997),in patients with chronic delta hepatitis prolonged lamivudine therapy neither lowers HDV RNA levels nor ameliorates disease activity, even though HBV viremia is reduced (Lau et al. 1999; Wolters et al. 2000). Similarly, treatment with famciclovir was not effective against HDV infection (Yurdaydin et al. 2002). The most likely explanation for the failure of these treatments to affect HDV is that HDV requires the HBsAg function of HBV, and lamivudine treatment does not typically reduce HBsAg levels.

The nucleoside analogL-FMAU [2'-fluoro-5-methyl-p-l-arabinofuranosyl-uridine, clevudine] has substantial antiviral activity against WHV replication in chronically infected woodchucks (Menne et al. 2002; Peek et al. 2001; Zhu et al. 2001), and has recently exhibited potent activity in HBV-infected patients in a phase II clinical trial (Marcellin et al. 2004). Of particular interest, about 75% of animals treated with 10 mg/kg of clevudine exhibited 100-fold or greater decreases in serum levels of WHsAg (Korba et al. 2004; Peek et al. 2001). The reason for the different patterns of WHsAg response is not clear, but may be related to the effects of clevudine treatment on hepatic levels of WHV covalently closed circular DNA (Peek et al. 2001). Because of the high frequency of substantial reductions in surface antigen levels in woodchucks treated with clevudine, we sought to determine whether clevudine therapy could be effective in reducing levels of HDV viremia in chronically infected woodchucks.

Four woodchucks chronically infected with HDV for at least 11 months were given 10 mg/kg clevudine (L-FMAU) orally, once daily for 20 weeks. As expected, all four animals exhibited marked decreases in serum WHV DNA after 4 weeks of treatment (>107-fold reduction). Consistent with the effects of clevudine on WHsAg levels observed in other studies (Korba et al. 2004; Peek et al. 2001), there was an approximate 1,000-fold decrease in WHsAg levels in three of the four treated animals by 12 weeks of treatment. In all three of these animals HDV RNA became undetectable by 16 weeks of treatment. Of particular note, in the one animal that did not exhibit decreased levels of WHsAg, HDV RNA remained at high levels. Thus, there was a strong temporal correlation between the decrease in the levels of WHsAg and the drop in HDV viremia.

The correlation of the suppression of HDV viremia with the reduction of surface antigen in individual animals is consistent with the concept that targeting surface antigen expression is a useful antiviral strategy for HDV. Thus, we suggest that any therapy that lowers WHV or HBV surface antigen levels sufficiently maybe useful as a therapeutic option to control chronic HDV infection. Although HBsAg levels were not measured in previous reports of lamivudine therapy of chronic HDV carriers (Lau et al. 1999; Wolters et al. 2000), treatment was unsuccessful most likely because HBsAg was not reduced. Indeed, neither lamivudine nor adefovir dipovoxil, the two nucleoside analogues currently licensed for the treatment of HBV infection, routinely have a significant effect on circulating levels of HBsAg, even though both reduce HBV replication sufficiently to ameliorate HBV-induced disease (Dienstaget al. 1995; Feld and Locarnini 2002; Lai et al. 1998; Nevens et al. 1997).

There is no long-standing cellular repository for HDV as there is for HBV (Smedile et al. 1998), and the half-life of HDV-infected cells may be brief; in mice infected cells survive for as little as 2 weeks (Netter et al. 1993). While in this study it was not possible to determine the long term outcome of clevudine therapy on the course of chronic HDV infection or disease, the sustained reduction of HDV to undetectable levels by therapy with this potent nucleoside analog suggests that HDV disease in clinical patients would be reduced and that treatment has the potential to eliminate HDV infection in chronically infected individuals. In this regard, it is important to note that a recent phase II clinical trial indicated potent activity of clevudine in HBV-infected patients, although effects on HBsAg levels were not reported (Marcellin et al. 2004).

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