Famvir
Antiviral combination therapy for lamivudine-resistant hepatitis B reinfection after liver transplantation.

Seehofer D, Rayes N, Neuhaus R, Berg T, Muller AR, Bechstein WO, Neuhaus P.

Department of General-Visceral and Transplant Surgery, Humboldt University of Berlin, Germany.

Development of resistance is a major issue in antiviral treatment of hepatitis B reinfection after liver transplantation. Antiviral combination therapy is discussed for therapy or prevention of this breakthrough of viral replication. Eight patients were enrolled into this retrospective analysis after liver transplantation for chronic hepatitis B infection. All had reinfection of the graft and breakthrough of HBV during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy with lamivudine and interferon-alpha 2a (group I, n = 4) or lamivudine and famciclovir (group II, n = 4) was initiated. Combination therapy was started 61 months (group I) and 25 months (group II) after liver transplantation. It markedly reduced the viral replication rate in all patients despite lamivudine resistance. In group I three of four patients and in group II two of four patients became HBV-DNA negative. Two long-term responders were observed in group I, and none in group II. No patient became HBsAg negative or lost HbeAg. Pretreatment elevated ALT and AST levels were significantly reduced. No severe complications, and especially no rejection episodes, occurred. Lamivudine in combination with other antiviral agents, especially interferon-alpha, might be a therapeutic option for hepatitis B reinfection after liver transplantation. Suppression of virus replication to the point of undetectable values is possible even in patients with lamivudine-resistant virus mutations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11112032&dopt=Abstract famciclovir Famvir



Famvir
Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation.

Rayes N, Seehofer D, Hopf U, Neuhaus R, Naumann U, Bechstein WO, Neuhaus P.

Department of Surgery, Humboldt University, Berlin, Germany.

BACKGROUND: Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared. METHODS: A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3x500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied. RESULTS: A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis. CONCLUSIONS: Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11211203&dopt=Abstract famciclovir Famvir



Famvir
Famciclovir treatment in transplant recipients with HBV-related liver disease: disappointing results.

Berenguer M, Prieto M, Rayon M, Bustamante M, Carrasco D, Moya A, Pastor MA, Gobernado M, Mir J, Berenguer J.

Hepatogastroenterology Service, Hospital Universitario La Fe, Valencia, Spain.

OBJECTIVE: Long-term administration of hepatitis B immune globulin is effective as prophylaxis for hepatitis B virus (HBV) reinfection but is limited by cost, side effects, availability and a failure rate of 20%. Famciclovir has been shown to be effective in the treatment of hepatitis B in the immunocompetent patient. Fewer data exist in the liver transplant setting, particularly regarding its efficacy in de novo HBV infection. The aims of this pilot study were to determine the effectiveness and safety of long-term administration of famciclovir in recurrent (n = 3) and de novo (n = 3) HBV infection after liver transplantation. METHODS: Six patients with postransplant HBV infection (positivity of serum HBsAg and HBV DNA), four of whom were HBeAg positive, were treated with famciclovir (500 mg, 3 times a day) with a minimum follow-up period of 12 months. Biochemical, serological, virological (HBV DNA by hybridization assays and polymerase chain reaction), and histological (including HBV immunostaining) endpoints were evaluated. RESULTS: None of the patients had a complete biochemical response, with a near complete normalization of ALT levels being observed in 3/6 patients. There was a lack of correlation between virological and biochemical responses. None of the patients seroconverted to anti-HBs or anti-HBe. A virological clearance was observed in only two patients, whereas a moderate reduction in HBV DNA levels was present in one. HBV DNA levels were higher than levels during pretreatment in the three remaining patients. Histological improvement was only observed in one patient. CONCLUSION: Famciclovir alone appears of limited efficacy in the treatment of HBV infection after liver transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11232701&dopt=Abstract famciclovir Famvir



Famvir
Antiviral activities of penciclovir and famciclovir on duck hepatitis B virus in vitro and in vivo.

Offensperger WB, Offensperger S, Keppler-Hafkemeyer A, Hafkemeyer P, Blum HE.

Department of Medicine II, University of Freiburg, Germany.

Chronic hepatitis B virus (HBV) infection is a major health problem worldwide. Antiviral strategies available at present, including interferon-alpha, have only limited efficacy, leading us to analyse the antiviral effects of penciclovir and famciclovir in the duck hepatitis B virus (DHBV) model of HBV infection in vitro and in vivo. In DHBV-infected duck hepatocytes, penciclovir effectively inhibited viral replication, with a concentration giving half-maximal inhibition of 0.25 microM. Furthermore, in vivo, penciclovir and its orally administered prodrug famciclovir strongly inhibited DHBV replication. These data demonstrate that penciclovir and famciclovir both have strong antiviral activities, and suggest that these agents might be useful for treating HBV infection in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11322247&dopt=Abstract famciclovir Famvir



Famvir
Synthesis and evaluation of 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine mono- and diesters as potential prodrugs of penciclovir.

Kim DK, Lee N, Kim HT, Im GJ, Kim KH.

Life Science Research Center, SK Chemicals, Kyungki-Do, Korea. dkkim skchemicals.com

2-Amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7), and its mono- and diesters 8-15 were prepared and evaluated for their potential as prodrugs of penciclovir. Treatment of 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (5) with trimethylamine in THF followed by a reaction of the resulting trimethylammonium chloride salt 6 with KF in DMF afforded 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7) in 80% yield. Esterification of 7 with an appropriate acid anhydride [Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O] in DMF in the presence of a catalytic amount of DMAP produced the mono-esters 8-11 in 42-45% yields and diesters 12-15 in 87-99% yields. Of the prodrugs tested in rats, the monoisobutyrate 11 was the most efficiently absorbed and metabolized to 7, showing the mean maximum total concentration of penciclovir (5.5 microg/mL) and 7 (10.8 microg/mL) in the blood was much higher than the mean maximum concentration of penciclovir (11.5 microg/mL) from famciclovir. However, the mean concentrations of penciclovir from 11 were lower than those from famciclovir because of the limited conversion of a major metabolite 7 to penciclovir by adenosine deaminase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10220040&dopt=Abstract famciclovir Famvir