Several studies have documented that various agents can induce diabetes mellitus, such as steroids, thiazides, anti-psychotic agents, and anti-viral agents. Many antiviral agents are also reported to impair insulin resistance and induce diabetes mellitus in patients infected with human immunodeficiency virus (HIV). However, there are no reports of diabetes mellitus induced by clevudine, one of the antiviral agents used to treat chronic hepatitis B virus (HBV) infection. We report a case of diabetes mellitus induced by clevudine in a patient with chronic hepatitis B.
Antiviral Agents ; Arabinofuranosyluracil ; Diabetes Mellitus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; HIV ; Humans ; Insulin Resistance ; Steroids ; Thiazides ; Viruses

BACKGROUND: Clevudine (Revovir(R)) is a recently introduced antiviral drug, and clinical trials have demonstrated its potent, sustained antiviral activity without specific adverse events. However, several studies have found severe myopathy during clevudine therapy. Our study aimed to summarize the clinical and pathological features of clevudine-induced myopathy. METHODS: We analyzed the demographic data, clinical features, and pathologic findings of 18 consecutive hepatitis-B patients who developed skeletal myopathy during clevudine therapy. RESULTS: The 18 patients comprised 11 women and 7 men aged 48.2+/-14.0 years (mean+/-standard deviation; range 28-74 years). Each of the 18 patients was treated with clevudine for at least 5 months (range 5-20 months) before the development of symptoms. In all patients the main symptom was proximal muscular weakness that progressed slowly over several months. Elevated creatine kinase and myopathic patterns on electromyography were found. Muscle biopsies revealed severe myonecrosis associated with numerous ragged red fibers and cytochrome-c-oxidase-negative fibers, mitochondrial proliferation, and predominant type-II fiber atrophy. The muscle weakness gradually improved within 20 weeks after discontinuation of clevudine. CONCLUSIONS: Clevudine therapy can induce myopathy associated with mitochondrial toxicity. Careful clinical and laboratory monitoring of the skeletal muscle dysfunction is required in patients receiving clevudine therapy.
Aged ; Arabinofuranosyluracil ; Atrophy ; Biopsy ; Creatine Kinase ; Electromyography ; Female ; Hepatitis ; Humans ; Male ; Muscle Weakness ; Muscle, Skeletal ; Muscles ; Muscular Diseases

BACKGROUND/AIMS: The clinical effects of clevudine have been reported in patients with chronic hepatitis B virus infections (CHIs). In this investigation, we assessed whether clevudine induced biochemical and virological improvements in hepatocellular carcinoma (HCC) patients with CHI. METHODS: Fifty-four patients who received 30 mg clevudine for more than 24 weeks between 2007 and 2009 at the National Cancer Center Hospital, Korea, were enrolled. Among these cases, 39 had HCC (CHI/HCC group) and 15 did not (CHI group). RESULTS: In relation to the CHI group, the CHI/HCC group was older (55.5 years.) and had a higher liver cirrhosis rate (79.5%) (p<0.05). Median changes in serum hepatitis B virus (HBV) DNA levels from baseline at weeks 12, 24, and 36 of treatment in the CHI/HCC group were not significantly different from those of the CHI group (-2.3, -2.7, -2.6 vs -1.7, -1.8, -2.4, respectively). HBV DNA <2,000 copies/mL was achieved in 76.5% of the CHI/HCC group at 24 weeks. Rates of ALT normalization in the CHI/HCC and CHI groups were 62.5% and 66.7%, respectively (p>0.05). Liver function was preserved with clevudine treatment in patients displaying response or stable disease under anti-cancer therapy. Four patients (7.4%) developed viral resistance during clevudine therapy. Among these, one was naive, and three had previously received antiviral therapy. One CHI/HCC patient (1.9%) discontinued clevudine treatment due to symptomatic myopathy. CONCLUSIONS: Our findings clearly indicate that clevudine has comparable antiviral and biochemical effects in patients with CHI and with CHI/HCC and preserves the underlying liver function in HBV-related HCC patients.
Arabinofuranosyluracil ; Carcinoma, Hepatocellular ; DNA ; Hepatitis B virus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Korea ; Liver ; Liver Cirrhosis ; Viruses

No abstract available.
Antiviral Agents/*adverse effects ; Arabinofuranosyluracil/adverse effects/*analogs & derivatives ; Female ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B, Chronic/*drug therapy ; Humans ; Male ; Muscular Diseases/*chemically induced

A 40-year-old man with chronic hepatitis B complained of progressive weakness of the proximal muscles and edema of both legs. He had been receiving long-term clevudine (nucleoside analogue reverse transcriptase inhibitor, NRTI) therapy for his hepatitis. The serum creatine kinase level was increased on the laboratory tests. His electromyography showed a generalized myopathic process. The muscle biopsy showed numerous ragged-red fibers, degenerating myofibers with variable sized cytoplasmic bodies, the prominence of type 1 fibers with type 2 fiber atrophy and an endomysial mononuclear cell infiltration. The electron microscopic examination revealed necrotic myofibers, including extremely dysmorphic mitochondria with extensive loss, blunting and focal clumping of the cristae and concentric cristae. Although clevudine is known to be a less cytotoxic agent among the various NRTIs, careful clinical attention should be paid to the patients who are receiving long-term clevudine therapy for the occurrence of myopathy.
Adult ; Arabinofuranosyluracil ; Atrophy ; Biopsy ; Creatine Kinase ; Cytoplasm ; Edema ; Electromyography ; Electrons ; Hepatitis ; Hepatitis B, Chronic ; Humans ; Leg ; Mitochondria ; Mitochondrial Myopathies ; Muscles ; Muscular Diseases ; RNA-Directed DNA Polymerase

A 47-year-old woman underwent orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related end-stage liver cirrhosis. The patient received hepatitis B immunoglobulin prophylaxis after OLT. Despite the protective level of the serum anti-hepatitis-B surface antibody, HBV recurred at 22 months post-OLT and induced subacute hepatic failure. The pre-OLT HBV genome contained a complex mutation pattern in overlapping frame regions of the surface (S) and polymerase (P) genes, which is the same mutation pattern as seen in post-OLT HBV DNA. G145R and K141R mutations in the "a" determinant were detected only in the post-OLT sample. Clevudine (30 mg once daily) was administered for recurrent hepatitis B. Hepatitis B was reactivated with a flare-up, and a M204I mutation (YIDD mutant type) appeared with a higher viral load at 9 months after clevudine treatment. We report here a case of a YIDD mutation that developed in recurrent hepatitis B after OLT induced by an S-escape mutant.
Arabinofuranosyluracil ; DNA ; Female ; Genome ; Hepatitis ; Hepatitis B ; Hepatitis B virus ; Humans ; Immunoglobulins ; Liver ; Liver Cirrhosis ; Liver Failure ; Liver Transplantation ; Middle Aged ; Viral Load

BACKGROUND/AIMS: Entecavir (ETV) and clevudine (CLV) are potent inhibitors of hepatitis B virus (HBV) DNA polymerase and have demonstrated clinical efficacy. No comparative study has reported on these two medications among patients with naive chronic hepatitis B (CHB). We assessed the clinical outcome of CHB patients treated with either ETV or CLV. METHODS: A nonrandomized comparative study was conducted retrospectively. The clinical results from treatments of either 0.5 mg ETV (n=56) or 30 mg CLV (n=45) were analyzed during a 1 year period. The median reduction in serum HBV DNA, undetectable HBV DNA, HBeAg seroconversion, and normalization of alanine transaminase (ALT) were compared between the two groups. RESULTS: After 1 year on antiviral therapy, the median reduction in serum HBV DNA from baseline to the endpoint was greater in patients in the ETV group than in those in the CLV (5.73 vs. 4.5 log copies/mL, p=0.009) group. ALT normalization occurred in 85.5% (47/55) of the ETV cases and 77.3% (34/40) of the CLV cases (p=0.215). HBV DNA was undetectable in 80.0% (44/55) of the ETV group and 78.0% (32/41) of the CLV group (p=0.505). HBeAg seroconversion occurred in 15.4% (6/39) of those administered ETV and in 14.3% (4/28) administered CLV (p=0.593). Within 12 months, a virological breakthrough was documented in three patients undergoing CLV treatment, and CLV-related myopathy developed in three other patients. CONCLUSIONS: ETV and CLV showed excellent antiviral effects in patients with CHB. ETV was superior for viral suppression and showed fewer side effects than CLV.
Alanine Transaminase ; Arabinofuranosyluracil ; DNA ; Guanine ; Hepatitis B e Antigens ; Hepatitis B virus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Muscular Diseases ; Retrospective Studies

No abstract available.
Antiviral Agents/*therapeutic use ; Arabinofuranosyluracil/*analogs & derivatives/therapeutic use ; Drug Resistance, Viral ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/therapeutic use ; Practice Guidelines as Topic

The authors assessed the efficacy and antiviral resistance of 48-week clevudine therapy versus lamivudine in treatment of naive patients with HBeAg positive chronic hepatitis B. In this retrospective study, a total of 116 HBeAg positive patients, who received 30 mg of clevudine once daily (n=53) or 100 mg of lamivudine once daily (n=63) for 48 weeks, were included. At week 48, clevudine therapy produced a significantly greater mean reductions in serum HBV DNA levels from baseline than lamivudine therapy (-5.2 vs. -4.2 log(10)IU/mL; P=0.005). Furthermore, a significantly higher proportion of patients on clevudine achieved negative serum HBV DNA by PCR (<13 IU/mL) at week 48 (60.4% vs. 38.1%; P=0.025). The incidence of virologic breakthrough in the clevudine group was significantly lower than in the lamivudine group (9.4% vs. 25.4%; P=0.031). However, rates of alanine aminotransferase normalization and HBeAg loss or seroconversion were similar in the two groups (83.0% vs. 81.0%, 11.3% vs. 11.1%; P=0.813, 1.000, respectively). In conclusion, clevudine is more potent for viral suppression and lower for antiviral resistance at week 48 than lamivudine in treatment of naive patients with HBeAg positive chronic hepatitis B.
Adult ; Antiviral Agents/administration & dosage ; Arabinofuranosyluracil/administration & dosage/*analogs & derivatives ; Drug Resistance, Viral ; Female ; Hepatitis B e Antigens/*blood ; Hepatitis B, Chronic/diagnosis/*drug therapy/*immunology ; Humans ; Lamivudine/*administration & dosage ; Male ; Treatment Outcome

PURPOSE: The HSV1-tk gene has been extensively studied as a type of reporter gene. In hepatocellular carcinoma (HCC), only a small proportion of patients are eligible for surgical resection and there is limitation in palliative options. Therefore, there is a need for the develoopement of new treatment modalities and gene therapy is a leading candidate. In the present study, we investigated the usefulness of substrate, 2'-fluoro-2'-deoxy-1-beta-D-arabino-furanosyl-5-[124/125I]iodo- uracil ([124/125I]FIAU) as a non-invasive imaging agent for HSV1-tk gene therapy in hepatoma model using small animal PET. MATERIAL AND METHODS: With the Morris hepatoma MCA cell line and MCA-tk cell line which was transduced with the HSV1-tk gene, in vitro uptake and correlation study between [125I]FIAU uptake according to increasing numeric count of percentage of MCA-tk cell were performed. The biodistribution data and small animal PET images with [124I]FIAU were obtained with Balb/c-nude mice bearing both MCA and MCA-tk tumors. RESULTS: Specific accumulation of [125I]FIAU was observed in MCA-tk cells but uptake was low in MCA cells. Uptake in MCA-tk cells was 15 times higher than that of MCA cells at 480 min. [125I]FIAU uptake was linearly correlated (R2=0.964, p=0.01) with increasing percentage of MCA-tk numeric cell count. Biodistribution results showed that [125I]FIAU was mainly excreted via the renal system in the early phase. Ratios of MCA-tk tumor to blood acting were 10, 41, and 641 at 1 h, 4 h, and 24 h post-injection, respectively. The maximum ratio of MCA-tk to MCA tumor was 192.7 at 24 h. Ratios of MCA-tk tumor to liver were 13.8, 66.8, and 588.3 at 1 h, 4 h, and 24 h, respectively. On small aninal PET, [124I]FIAU accumulated in substantial higher levels in MCA-tk tumor and liver than MCA tumor. CONCLUSION: FIAU shows selective accumulation to HSV1-tk expressing hepatoma cell tumors with minimal uptake in normal liver. Therefore, radiolabelled FIAU is expected to be a useful substrate for non-invasive imaging of HSV1-tk gene therapy and therapeutic response monitoring of HCC.
Animals ; Arabinofuranosyluracil ; Carcinoma, Hepatocellular ; Cell Count ; Cell Line ; Genes, Reporter ; Genetic Therapy ; Herpes Simplex ; Herpesvirus 1, Human ; Humans ; Liver ; Liver Neoplasms, Experimental ; Methylmethacrylates ; Mice ; Polystyrenes ; Simplexvirus ; Statistics as Topic ; Uracil ; Ursidae