Treatment of hepatitis B virus (HBV) with lamivudine is effective in suppressing virus replication and results in reduced inflammatory activity. However, the emergence of lamivudine-resistant mutant virus, with amino acid substitution in the YMDD motif of DNA polymerase, has been reported. We report the emergence and takeover of YMDD mutant and re-takeover by wild type during and after long-term lamivudine therapy. YMDD mutants were detected in five patients who showed DNA breakthrough (HBV DNA becoming detectable after a period of DNA negativity), which occurred after 9 to 14 months of lamivudine therapy. Four of five mutants had amino acid sequence YIDD, and the remaining mutant had YVDD. Patients with high HBV-DNA titer and/or hepatitis B e antigen tended to develop breakthrough (P ؍ .038). Using a sensitive and specific polymerase chain reaction (PCR)-based method developed in this study, the emergence of YMDD mutants was detected 1 to 4 months before DNA breakthrough, but not detected in any of the pretreatment sera. The mutants were predominant at breakthrough, but were replaced by wild-type virus 3 to 4 months after cessation of therapy in the two patients who discontinued therapy. One of these patients had a relapse of hepatitis. Mutant continued to replicate in the remaining three patients who continued to receive treatment, and relapse occurred in only one of these patients. Our results suggest that the replication of YMDD mutant viruses is less than wild type and is re-overtaken by wild type after cessation of therapy. Re-administration of lamivudine, possibly combined with other antiviral therapy, might be useful in some patients experiencing hepatitis with lamivudine-resistant variants. (HEPATOLOGY 1998;27: 1711-1716.)is a potent inhibitor of RNA-dependent DNA polymerase of hepatitis B virus (HBV), as well as human immunodeficiency virus (HIV) reverse transcriptase. [1][2][3][4][5][6][7][8][9][10] The in vivo antiviral activity of lamivudine has been reported in animal studies as well as in humans. [11][12][13][14][15][16][17][18][19][20][21][22] However, the emergence of lamivudineresistant HBV strains was initially noticed in patients who received orthotopic liver transplantation and immunosuppressive therapy. [23][24][25][26][27][28] Such resistant viruses show a characteristic mutation of the 550th amino acid methionine in the YMDD motif of DNA polymerase to isoleucine (YIDD mutant) or valine (YVDD mutant). Honkoop et al. 29 recently showed the emergence of such mutant viruses in 5 of 14 (36%) immunocompetent patients who were treated with lamivudine over 26 weeks. However, in a larger placebo-controlled study in 358 Asian patients with HBV infection treated for 52 weeks, the rate of detection of lamivudine-resistant variants by polymerase chain reaction (PCR) was 19 of 134 (14%) in patients treated with 100 mg daily. 30 To our knowledge, there is no report that describes the presence of mutant viruses in the serum before administration of lamivudine. The low incidence and late emergence of YM...
biochemical and histological improvement. 3,4 Several factors Hepatitis C virus (HCV) genotype 1b and high precan predict a poor response to interferon therapy, e.g., high treatment virus load are predictive factors of poor repretreatment virus load, genotype 1b, advanced histological sponse to interferon therapy in patients with chronic changes, lower serum ferritin level, and a high degree of hepatitis C. To further examine the factors predicting amino acid substitutions of the hypervariable region (for rethe response to interferon in patients with genotype 1b view, see Davis 5). infection, we analyzed 110 consecutive patients withRecently, Enomoto et al. 6 compared amino acid sequences HCV who were treated with a total of 624 million units of of interferon-sensitive and -resistant quasispecies by analyzlymphoblastoid interferon alfa. Thirty-six patients (33%) ing serum samples of three patients infected with genotype were responders, while the remaining 74 patients (67%)1b HCV before and after interferon therapy. They identified were nonresponders. Multivariate analysis showed that in the interferon-sensitive strains of HCV clusters of amino a high virus titer (assessed by serum core protein level, acid substitutions in the carboxyl terminal half of the NS5A P Å .0021) and the presence of more than two amino acid region (codon 2154-2383). They also detected multiple missubstitutions in the interferon sensitivity-determining sense mutations exclusively in a 40-amino acid stretch (coregion (ISDR) (P Å .0036) correlated significantly with don 2209-2248) in interferon-sensitive HCV isolates. 6,7 In the response to interferon therapy. Because mutations contrast, the sequences of interferon-resistant HCV strains analyzed by direct sequencing of polymerase chain reacwere identical to those of prototype genotype 1b. They desigtion (PCR) products may reflect artifacts of direct senated the region with these amino acid substitutions as the quencing, we further analyzed quasispecies of HCV in interferon sensitivity-determining region (ISDR) 6 and this region by cloning and sequencing. Although PCRshowed, by multivariate analysis, that the substitution in based analysis of responders with multiple amino acid the ISDR was the best predictive factor of the response to substitutions in the ISDR showed the presence of a small interferon therapy. 7 These results were potentially of great amount of wild-type strain in their serum, the results importance but were based on relatively few patients treated obtained by direct sequencing and cloning were essenwith varying regimens of interferon. To provide further evitially the same. A longitudinal study of quasispecies in dence for or against the predictive power of amino acid substi-2 patients who showed a dramatic change in the virus titer showed no conversion from wild type to mutant or tutions in the ISDR, we used a large sample of patients with vice versa. Our results indicate that amino acid substitu-HCV genotype 1b seen in our unit who were treated with a tions and virus ...
We have previously reported a single nucleotide polymorphism (SNP) at nucleotide (nt) position –88 (G or T) within an interferon-stimulated response element-like sequence in the promoter region of the MxA gene, which correlated with responsiveness of hepatitis C patients to interferon. Upstream of it, we then identified another SNP (C or A at nt –123) and investigated whether this SNP also correlates with interferon responsiveness. The two SNPs showed a high linkage to each other: all the individuals having G at –88 had C at –123, and 73% of those having T at –88 had A at –123. As was expected from this observation, the SNP at –123 also exhibited a correlation with interferon responsiveness (C/C homozygotes were more frequent among nonresponders than among responders: 65% of 107 vs. 40% of 52, p = 0.0028). These in vivo data from patients were further supported by results from in vitro experiments. The MxA promoter sequence with A at –123 and T at –88 showed about 4-fold higher activity of upregulating the downstream reporter gene than that with C at –123 and G at –88, in a luciferase reporter assay.
SNPs in the promoter region of OPN may be useful as a marker to predict the efficacy of IFN-based therapies in patients with chronic hepatitis C, and further investigation regarding their real significance is warranted in a large series of patients.
The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 ,ug/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h, respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after (3-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9,-8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18 Nakamura, Chem. Abstr. 107:236733v, 1987) and ciprofloxacin (4) were synthesized in our laboratory as reported previously. Doses and concentrations of the drugs are expressed in terms of the free bases.Animals. The animals used were male Std-ddY mice weighing 22 to 38 g, male Wistar rats weighing 190 to 270 g, male beagle dogs weighing 11 to 13 kg, and male cynomolgus monkeys weighing 3.7 to 5.4 kg.Drug administration. For oral administration, AT-4140 was suspended in 0.2% carboxymethylcellulose sodium solution (for mice and rats) or 0.5% gum tragacanth solution (for monkeys) and ciprofloxacin was dissolved in deionized water to avoid its aggregation in 0.2% carboxymethylcellulose sodium solution (for mice). Both the drugs were packed in gelatin capsules for oral administration to dogs. For intravenous administration, the drugs were dissolved in physiological saline with an appropriate amount of NaOH if necessary. The drugs were administered once at a dose of 5 mg/kg to animals that had fasted overnight, unless otherwise specified.Preparation of assay samples. Blood was withdrawn by cardiac puncture from mice and rats under ether anesthesia at 0.25, 0.5, 1, 2, 4, 6, and 8 h postadministration and by * Corresponding author.venipuncture from dogs and monkeys at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration and 0.1, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after intravenous administration. Blood samples were centrifuged to separate the plasma. Organs and tissues were harvested from exsanguinated mice 0.5, 1, 2, 4, 6, and 8 h postadministration and from exsanguinated rats 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h postadministration. Spinal fluid was taken from the same rats by puncturing the atlanto-occipital membrane by the method of Yaksh and Rudy (17) before exsanguination. Tissue extracts were prepared as described previously (9). Bile was collected from rats through a polyethylene catheter introduced into the common bile duct by surgery and pooled for 0 to 3, 3 to 6, and 6 to 24...
-For the purpose of a side-effect monitoring of isoniazid (INH), we investigated the relationship between the genotypes of drug-metabolizing enzymes involved in INH metabolism and the serum concentrations of INH and its metabolites in 129 tuberculosis patients hospitalizing in the National Hospital Organization Chiba-East Hospital. Genotype distributions of N-acetyltransferase 2 (NAT2), CYP2E1*5B, CYP2E1*6, Glutathione-S-transferase (GST) M1 and GST T1 were similar to those already reported in Japanese populations. Acetylating pathway of INH to acetyl isoniazid (AcINH) tended to shift to the hydrolytic pathway generating hydrazine (Hz) with the increase of mutant alleles in NAT2 gene.tration of rifampicin (RFP) than in which RFP was not detected. The effect of CYP2E1 gene polymorphisms on the serum concentration of Hz was rarely observed, while that of GST gene polymorphism was observed in intermediate acetylators of NAT2. Hz tended to accumulate in patients with GST M1 null genotype. Therefore, it is conceivable that the risk factors of Hz accumulation are as follows: NAT2 slow acetylator phenotype, high concentration of serum RFP, and GST M1 null genotype. In these cases, we think it's necessary to pay attention to the development of hepatic disorder caused by Hz.
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