Famvir
In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance.

Xiong X, Yang H, Westland CE, Zou R, Gibbs CS.

Gilead Sciences, Foster City, CA 94404, USA. shelly_xiong gilead.com

Several mutations (V521L, P525L, L528M, T532S, and V555I) in the gene for hepatitis B virus (HBV) polymerase have been identified in HBV isolated from patients that displayed break-through viremia during famciclovir treatment. To determine whether these mutations cause phenotypic resistance to famciclovir, we compared the inhibition constants (K(i)) of penciclovir triphosphate (PCVTP, the active metabolite of famciclovir) for recombinant wild-type and mutant HBV polymerases containing these mutations. In in vitro enzymatic assays, the V555I mutation displayed the most resistance (with K(i) increased by 6.2-fold) to PCVTP. The V521L and L528M mutations showed moderately decreased sensitivity to PCVTP (K(i) increased by >3-fold). We also analyzed the cross-resistance profiles of these variants for adefovir and lamivudine, two other antiviral agents that also inhibit DNA replication by HBV polymerase. All 5 famciclovir-associated mutations were sensitive to adefovir diphosphate (ADVDP) in in vitro enzymatic assays (<2.3-fold decreased sensitivity). The V521L, L528M, and T532S mutations were also sensitive to lamivudine triphosphate (LAMTP); however, the P525L and V555I mutations displayed moderately decreased sensitivity to LAMTP in enzymatic assays (3.6-fold decreased sensitivity). The lamivudine-resistant mutations M552I, M552V, and L528M+M552V, which were previously shown to display 8- to 25-fold resistance to LAMTP, were less resistant (< or = 3.1-fold) to PCVTP.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10613749&dopt=Abstract famciclovir Famvir



Famvir
Famciclovir as antiviral prophylaxis in laser resurfacing procedures.

Wall SH, Ramey SJ, Wall F.

Plastic Surgery LLP, Shreveport, LA, USA. swallmd aol.com

Latent herpes simplex virus (HSV types I and II) may be reactivated by laser resurfacing procedures, presenting serious postoperative complications in approximately 9 percent of patients. Perioperative prophylactic administration of nucleoside analog antiviral agents has been shown to decrease the duration and severity of postsurgical herpes infection and to prevent recurrence. This study was conducted to assess the efficacy of famciclovir in preventing orofacial herpes virus reactivation and primary infection in patients undergoing laser resurfacing. HSV history was obtained from a total of 121 patients undergoing the procedure. Antiviral prophylaxis with famciclovir was begun 1 to 2 days before surgery and continued for 5 days after surgery. Patients with no history of orofacial herpes (n = 94) received 125 mg of famciclovir twice daily. Those with a history of orofacial herpes (n = 27) received 250 mg of famciclovir twice daily. Postsurgical HSV infection rates in patients receiving famciclovir prophylaxis were compared with those from a similar historical control group of HSV-positive patients (n = 127) who received no prophylaxis. In patients receiving famciclovir prophylaxis, one patient (1.1 percent) in the HSV-negative history group and no patients in the HSV-positive history group had postsurgical herpes infection. Famciclovir significantly reduced postsurgical herpes infection when compared with the 9.4 percent rate of herpes reactivation in patients who received no prophylaxis (p = 0.003). This study suggests that twice-daily famciclovir prophylaxis markedly reduces orofacial herpes virus infection in patients undergoing laser resurfacing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10654754&dopt=Abstract famciclovir Famvir



Famvir
Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy.

Mutimer D, Pillay D, Cook P, Ratcliffe D, O'Donnell K, Dowling D, Shaw J, Elias E, Cane PA.

Public Health Laboratory Service Antiviral Susceptibility Reference Unit, Divisions of Medical Sciences, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom.

Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations. The latter mutation has not been associated with famciclovir resistance. Thus, the addition of famciclovir to lamivudine therapy in persons with group 2 lamivudine resistance may lead to virus suppression. The effect of lamivudine/famciclovir combination therapy on HBV infection was monitored in 5 lamivudine-resistant patients by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus. No patients treated with combination therapy had a decline in HBV load >1 log10. Continual evolution of the viral polymerase was detected in association with virologic resistance to both drugs. Cloning experiments identified the preexistence of these multidrug-resistant virus variants as minority species prior to addition of famciclovir therapy. HBV resistance to lamivudine monotherapy is associated with a complex mixture of variants that limit the efficacy of second-line nucleoside-analogue therapy. First-line potent combination therapy may reduce the emergence of HBV drug resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10669360&dopt=Abstract famciclovir Famvir



Famvir
Persistence of viral replication after anti-HBe seroconversion during antiviral therapy for chronic hepatitis B.

Pichoud C, Berby F, Stuyver L, Petit MA, Trepo C, Zoulim F.

INSERM Unit 271, Hotel Dieu, Lyon, France.

BACKGROUND/AIMS: Hepatitis B virus genome mutants may be selected during the immune-mediated clearance of infection or during long-term nucleoside analog administration and may escape both antiviral pressures. The pattern of anti-HBe seroconversion was analyzed in patients receiving new nucleoside analogs, lamivudine or famciclovir, in comparison with patients treated with interferon alpha. METHODS: Eighteen consecutive patients who seroconverted to anti-HBe were included in the study. Serial serum samples were studied with the quantitative determination of HBV DNA by the branched DNA assay (Chiron) and by a quantitative PCR assay (Roche diagnostics), determination of pre-S1 Ag, the genetic analysis of the viral genome with the determination of pre-core promoter or pre-core region mutations with a line probe assay (Innogenetics) and, in selected samples of polymerase gene mutations. RESULTS: The quantitative PCR assay was found to be more sensitive than the bDNA assay, allowing a 25-log decrease in viral DNA levels to be demonstrated after anti-HBe seroconversion. Viral persistence after anti-HBe seroconversion induced by interferon, lamivudine or famciclovir, was often associated with circulating HBV genomes harboring mutations in the precore promoter. The clinical significance of these findings was demonstrated by the observation of reversion to HBeAg in two patients treated with interferon and one with lamivudine. CONCLUSION: Persistence of significant levels of viremia that are not detected by the branched DNA assay may be observed after anti-HBe seroconversion. A precise monitoring of viremia levels with more sensitive assays and HBV mutant strains is warranted in patients undergoing antiviral therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10707872&dopt=Abstract famciclovir Famvir



Famvir
Early therapy with valaciclovir or famciclovir reduces but does not abrogate herpes simplex virus neuronal latency.

Field HJ, Thackray AM.

Centre for Veterinary Science, Cambridge University Veterinary School.

Mice were infected via the ear pinna using a recombinant strain of HSV-1 expressing the beta-gal gene under the LAT promoter. Mice were treated continuously with valaciclovir or famciclovir, from 1 day before or 1 day after virus inoculation for 10 days. Ipsilateral and contralateral trigeminal and cervical ganglia were later assessed by co-cultivation or for X-Gal-positive or LAT-positive neurons. Latency was markedly reduced by early therapy, however, a basal level of HSV-1-positive neurons was detected in all mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10772727&dopt=Abstract famciclovir Famvir