Famvir
Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation.

Tillmann HL, Trautwein C, Bock T, Boker KH, Jackel E, Glowienka M, Oldhafer K, Bruns I, Gauthier J, Condreay LD, Raab HR, Manns MP.

Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.

Famciclovir (FCV) and lamivudine (LAM) reduce viral replication in patients with recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). Eighteen of 20 patients with insufficient response to FCV were treated with 100 mg LAM daily after OLT. These patients had shown nonresponse (n = 5), partial response (n = 7), or breakthrough (n = 6) during FCV therapy. Despite passive immunoprophylaxis with hepatitis B immunoglobulin after liver transplantation, HBV reinfection had occurred in 14 of 15 transplanted patients. HBV-DNA levels and the regions A to E of the HBV-DNA polymerase gene were analyzed before and after treatment failure to either therapy. Within 4 weeks on LAM, all but 1 patient showed a 95% average reduction of the HBV-DNA level. As with FCV, we did not observe any severe side-effects attributable to LAM. However, 7 patients developed a breakthrough within 12, 29 (n = 2), 32, 37, 54, and 145 weeks under treatment with LAM associated with the methionine-to-valine signature mutation (M552V) in the YMDD motif in all. With FCV, no unique, but a dominant, resistance pattern with the L528M mutation was identified for patients with breakthrough under FCV. In contrast, nonresponders or patients with partial response to FCV did not exhibit such mutations. Our results indicate that the L528M mutation is a risk factor for LAM breakthrough, because breakthrough during LAM occurred earlier in patients with this mutation (50 +/- 10 weeks vs. 120 +/- 21 weeks). Because breakthrough on either treatment is frequent for this specific group of patients, the use of combination therapy should be explored.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10385663&dopt=Abstract famciclovir Famvir



Famvir
Evaluation of anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]- guanine (A-5021) in mice.

Iwayama S, Ohmura Y, Suzuki K, Ono N, Nakazawa H, Aoki M, Tanabe I, Sekiyama T, Tsuji T, Okunishi M, Yamanishi K, Nishiyama Y.

Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan.

The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guani ne (A-5021) was evaluated in murine cells and in several murine models of herpes simplex virus (HSV) infection. Against HSV type 1 (HSV-1), A-5021 was 15-30- and 30-60-fold more active, and against HSV type 2 (HSV-2), it was 2- and 8-fold more active than acyclovir and penciclovir in Balb/3T3 cells, respectively. When antiviral compounds were administered orally (once daily) to mice infected intraperitoneally with HSV-1 (Tomioka), A-5021 was more active than acyclovir or famciclovir in spite of its relatively low oral bioavailability. A-5021 was as active as penciclovir when the antiviral compounds were given intravenously (three times daily) to mice infected intraperitoneally with HSV-2 (186). In mice with a cutaneous HSV-1 (KOS) infection, three times daily oral therapy with A-5021 at 25 mg/kg per day produced more significant reduction in severity of skin lesions than equivalent treatment with acyclovir or famciclovir. In mice infected intracerebrally with HSV-1 (Tomioka), complete survival was observed in the group treated intravenously with A-5021 at 25 mg/kg per day (three times daily), while more than 50% of mice died in the groups treated intravenously with acyclovir of up to 100 mg/kg per day (three times daily). Moreover, A-5021 was more effective than acyclovir in clearing infectious virus from the brain. These findings demonstrate that A-5021 has potent anti-HSV activity in several murine models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10389656&dopt=Abstract famciclovir Famvir



Famvir
[Treatment of patients with chronic hepatitis B virus infect ion with lamivudine combined with famciclovir]

[Article in Chinese]

Wang HF, Li L, Su HB, Ji W.

The Sixth Department of Infectious Diseases, The 302nd Hospital of the PLA, Beijing 100039, China.

OBJECTIVE: To evaluate the clinical efficacy of combined treatment with lamivudine and famciclovir on chronic hepatitis B virus (HBV) infection. METHODS: Ninety patients with chronic HBV infection were divided into 3 groups. Group one had 28 patients and was treated with combination of lamivudine (0.1 g/d, PO) and famciclovir (1.5 g/d,PO) for 24 weeks. Group two and three had 30 and 32 cases, respectively, and were treated with lamivudine 100 mg/day PO and famciclovir (1.5 g/d,PO) alone. All the patients had positive markers of HBsAg, HBeAg and anti-HBcAg in serum assayed by ELISA and of HBV DNA tested by PCR. RESULTS: Three strategies of treatment had no different effects on the change of patients' ALT levels. The serum HBV DNA became negative after treatment in 89.3% (25/28) of patients treated with combination of lamivudine and famciclovir, 66.7% (20/30) of patients treated with lamivudine, and 40.6% (13/32) of patients treated with famciclovir. The rate of serum HBeAg loss in 3 groups were 28.6% (8/28), 23.3% (7/30) and 21.9% (7/32), respectively. CONCLUSIONS: The combination treatment of lamivudine and famciclovir for chronic HBV infection is safer than and superior to that of either drug alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12870005&dopt=Abstract famciclovir Famvir



Famvir
Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials.

Sarisky RT, Bacon TH, Boon RJ, Duffy KE, Esser KM, Leary J, Locke LA, Nguyen TT, Quail MR, Saltzman R.

Virology Department, Metabolic and Viral Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania, USA. rsarisky cntus.jnj.com

Asusceptibility testing program was established to determine the prevalence of resistance to penciclovir among herpes simplex virus isolates collected from patients participating in 11 world-wide clinical trials involving penciclovir (topical or intravenous formulations) or famciclovir, the oral prodrug of penciclovir. These trials represented nine randomised double blind, placebo or aciclovir-controlled studies and two open-label studies. Groups surveyed included immunocompetent or immunocompromised patients receiving 2 to 12 months chronic suppressive therapy for genital herpes, immunocompetent patients with recurrent herpes labialis treated for four days, and immunocompromised patients with mucocutaneous herpes simplex virus (HSV). Another subset of patients had been identified as non-responders to aciclovir or to valaciclovir. This program assessed the susceptibility profile for a total of 2145 herpes simplex virus isolates from 913 immunocompetent and 288 immunocompromised patients treated with penciclovir, famciclovir, aciclovir or placebo (depending on trial design). HSV isolates were tested for susceptibility to penciclovir using the plaque reduction assay (PRA) in MRC-5 cells. Resistance was defined as an IC(50)>or=2.0 microg/ml or an IC(50)> 10-fold above the wild type control virus IC(50) within that particular assay. Penciclovir-resistant HSV was isolated from 0.22% immunocompetent patients, and 2.1% of immunocompromised patients overall and therefore the frequency of penciclovir-resistant herpes simplex virus in the immunocompetent population approximates that of aciclovir-resistant herpesvirus reported previously. Penciclovir-resistant HSV isolates were more common in isolates from immunocompromised patients, consistent with aciclovir clinical experience. Treatment with penciclovir (intravenous formulation) was associated with the development of resistant HSV in only one severely immunocompromised patient (day 7 isolate IC(50) = 2.01 microg/ml), although treatment was effective and resulted in the complete clearance of the lesion by day 8. No patients receiving topical penciclovir developed treatment-associated penciclovir-resistant HSV, and a single immunocompromised patient developed resistant HSV upon treatment with oral famiciclovir.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14505088&dopt=Abstract famciclovir Famvir



Famvir
Detection of hepatitis B virus variants resistant to lamivudine and famciclovir among randomly selected chronic carriers from Spain.

Leon P, Pozo F, Echevarria JM.

Diagnostic Microbiology Department, National Center for Microbiology. Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.

BACKGROUND: Treatment for chronic hepatitis B with lamivudine is often hampered by the emergence of point mutations in the YMDD motif of the HBV DNA polymerase gene that confer drug resistance. This usually occurs after several months of therapy, but early detection of lamivudine-resistant mutants has been reported among patients in South Korea. Data from Japan and France suggest that naturally occurring, lamivudine-resistant hepatitis B virus (HBV) variants can be found among chronic carriers who have never received lamivudine treatment. Famciclovir can be used as an alternative when lamivudine-resistant variants emerge, though the substitute treatment may also give rise to the emergence and selection of drug-resistant variants. METHODS: The presence of mutations related with lamivudine and famciclovir resistance was studied in serum samples from 79 randomly selected Spanish HBV carriers, using a line probe assay (LiPA) on HBV genome fragments amplified by polymerase chain reaction. Data concerning antiviral therapy prior to sampling were available for these patients. RESULTS: Mutations related with resistance to either drug were detected in ten patients. Three of them (3.8% of the 79 carriers studied) had no record of prior lamivudine or famciclovir treatment at the time of sampling. Wild-type strains together with either the rtM204I (M552I) or rtV207I (V555I) point mutation were found in two of these cases, and the rtV207I mutation alone was detected in the third. CONCLUSIONS: These findings seem to indicate that lamivudine and famciclovir-resistant variants circulate among Spanish HBV carriers. Since it is expected that antiviral therapy will be ineffective when drug-resistant variants are present before the beginning of treatment, it could be beneficial to test for these variants as an additional routine procedure when designing antiviral therapy on an individual basis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14987532&dopt=Abstract famciclovir Famvir