Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for persistent infection of hepatocytes. The aim of this study was to determine changes in intrahepatic cccDNA in patients with chronic hepatitis B (CH-B) during 48 weeks of antiviral therapy and its correlation to virological, biochemical, and histological parameters. Twenty-six HBsAg-positive CH-B patients received combination treatment with pegylated interferon alpha-2b (peg-IFN) and adefovir dipivoxil (ADV) for 48 weeks. Paired liver biopsies from before and at the end of treatment were analyzed for intrahepatic HBV-DNA. Median serum HBV-DNA had decreased by -4.9 log10 copies/mL at the end of treatment and was undetectable in 13 individuals (54%). Median intrahepatic total HBV-DNA and cccDNA had decreased by -2.2 and -2.4 log10, respectively. Changes in intracellular HBV-DNA positively correlated with HBsAg serum reduction and were accompanied by a high number of serological responders. Eight of 15 HBeAg-positive patients lost HBeAg, and five developed anti-HBe antibodies during treatment. These eight patients exhibited lower cccDNA levels before and at the end of therapy than did patients without HBeAg loss. Four patients developed anti-HBs antibodies. ALT normalized in 11 patients. The number of HBs-antigen- and HBc-antigen-positive hepatocytes was significantly lower after treatment, suggesting the involvement of cytolytic mechanisms. In conclusion, combination therapy with peg-IFN and ADV led to marked decreases in serum HBV-DNA and intrahepatic cccDNA, which was significantly correlated with reduced HBsAg.
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PMID:Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. 1694 93

In patients with chronic hepatitis B virus (HBV), 2 predominant precursor dendritic cell (DC) subtypes, the myeloid dendritic cell (mDC) and the plasmacytoid dendritic cell (pDC), were recently found to be functionally impaired. HBV DNA was found to be present in the DC subtypes, but no viral replication could be detected. The question remains whether simply the presence of the virus and viral proteins causes this dysfunction of DCs. To address this issue, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the number and functionality of circulating DCs was studied during 6 months of treatment. Treatment resulted in a mean 5 log(10) decrease in the viral load and normalization of alanine aminotransferase within 3 months. The number of mDCs, but not of pDCs, increased significantly over 6 months of treatment to a level comparable to that of uninfected healthy controls. The allostimulatory capacity of isolated and in vitro matured mDCs increased significantly after 3 months of treatment. Accordingly, mDCs exhibited an increased capacity to produce tumor necrosis factor alpha and interleukin-12 after 3-6 months of treatment. There was no change in interferon alpha production by pDCs during treatment. In conclusion, adefovir treatment results in an improvement in the number and functionality of mDCs, but not of pDCs. Our findings provide clues for the reasons why current antiviral therapy does not lead to consistently sustained viral eradication.
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PMID:Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV. 1700 7

Thirty-eight chronic hepatitis C (CHC) Egyptian patients with persistently elevated serum alanine aminotransferase (ALT) for 6 months were randomly allocated into 2 groups: Group I (19 patients) received 3 million units (MU) of interferon alpha - 2b (Intron-A) subcutaneously thrice weekly for 6 months. In group I, complete response (normalization of ALT by the end of treatment) was achieved in 8 patients (42.1%), partial response (decrease of ALT by at least 50% of the pretreatment values) in 7 patients (36.8%) and no response in 4 (21.1%). Sustained response for 6 months after the end of therapy was attained in 4 of the 8 (50%) complete responders. Thus attaining an overall sustained response in 4 of the 19 patients (21.1%). In group II, spontaneous normalization of ALT was established in 1 patient (5.3%). Repeat liver biopsies in 16 patients of the interferon group, revealed moderate improvement in the degree of lobular inflammation, hepatocyte necrosis and portal inflammation. We conclude from this study that treatment of CHC with 3 MU of IFN-alfa 2b thrice weekly for 6 months is associated with a low response rate (21.1%). To improve the results, escalation of the IFN dose and/or prolongation of the treatment period should be considered.
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PMID:Controlled trial with interferon alfa 2-b in chronic hepatitis C patients. 1721 3

Twenty-nine HCV-infected patients were treated with pegylated interferon alpha. Diagnosis was based on serum HCV RNA-PCR positive results and liver biopsy. All patients had elevated serum levels of alanine aminotransferase at the time of the study, but liver disease was compensated. Patients were evaluated at baseline treatment and after 4 and 12 weeks of antiviral treatment with the Medical Outcomes Study 36-item Short-Form Health Survey. The Mini-International Neuropsychiatric Interview was used to exclude previous or current psychiatric diagnoses. Both patients and psychiatrists were blind to the HCV RNA status, and serum HCV RNA test results only became available after the visit at week 12. After antiviral treatment, 16 patients (55.2%) were classified as nonresponders and 13 (44.8%) were classified as responders. When compared to nonresponders, responders had a greater improvement in the HRQOL scores for the mental health domain (P < .019). Differences in other domains were not significant. The present study confirms that active viral infection is one possible reason for the poor Health-Related Quality of Life in this population.
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PMID:The effect of early virological response in health-related quality of life in HCV-infected patients. 1820 11

We administered a 24 week cycle of recombinant interferon alpha (r-IFNa) treatment (6 MU twice per week) to 18 patients over 50 years and 20 patients under 50 years affected by chronic hepatitis C without cirrhosis in order to evaluate the efficacy of, and tolerance to r-IFNa. Liver histology and serum alanine aminotransferase (ALT) values prior to treatment were overlapping in the two groups. Complete response was achieved in 2 patients of the first group (11%) and 12 of the second (60%, p < 0.01) and was defined as normalization of ALT values during treatment. Sustained response was defined as persisting normal ALT values 6 months after the end of treatment and was observed in 2 patients of the group above 50 years of age and in 8 patients of the younger group. Partial response was observed in 8 patients (44.5%) of the older group and 2 patients (10%) of the younger group; it was defined as a more than 50% ALT reduction compared to the values before the treatment. No statistically significant correlation was observed between the pretreatment histological picture and type of response. Tolerance to treatment was good in both group and none of the patients presented side effects necessitating suspension of treatment.
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PMID:Recombinant interferon alpha therapy in elderly patients with chronic hepatitis C without cirrhosis. 1865 51

Interferon-alpha (IFNalpha) is a critical mediator of immunity to hepatitis B virus (HBV) infection. Although IFN has been used in the treatment of viral hepatitis for more than a decade, the role of IFN-alpha-receptor in HBV infection has not been intensively studied. We have evaluated the impact of two variants of the IFNAR1 gene on the outcome of HBV infection. Four hundred and fifty eight HBV-infected Vietnamese patients, with well-characterised clinical profiles including all forms of hepatic disease, and 160 non-infected, healthy Vietnamese individuals were enrolled in the study. Of these patients, 54 had acute hepatitis B, 88 had chronic hepatitis B, 118 had liver cirrhosis, 146 had a hepatocellular carcinoma and 52 were asymptomatic carriers of HBV. We analysed two SNPs for unequal distribution between these groups. The first SNP, rs1012335 is situated in intron 3 of the interferon alpha receptor 1 (IFNAR1). A C at position 17470 in the IFNAR1 on both chromosomes was detected more frequently in HBV-infected patients compared to healthy controls (OR: 2.6; 95% CI: 1.46-4.72, p < 0.001). The same homozygosity is also associated with higher concentrations of AST and ALT (aspartate and alanine amino-transferase) in the plasma of the patients. The second SNP (rs2257167) is situated in exon 4, causing a change of amino acids from Val (GTT) to Leu (CTT). Subjects having GTT on both chromosomes were more frequent in the healthy control group (OR: 0.54, 95% CI: 0.35-0.84, p = 0.004) and had lower plasma ALT concentrations. The findings indicate that two variants of the IFNAR1 gene are associated with the clinical presentation of HBV infection.
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PMID:Association of two variants of the interferon-alpha receptor-1 gene with the presentation of hepatitis B virus infection. 1910 27

Chronic viral hepatitis B and C are diseases worldwide. At present, the number of effective and safe drugs for treatment of HBV and HCV is still limited. In order to develop novel anti-viral hepatitis drug, a number of analogues of the active component schizandrin C from Fructus Schiznadrae, a Chinese herb used in the therapy of viral hepatitis, were synthesized. Bicyclol, one of the analogues, was demonstrated to have actions of anti-hepatitis virus replication in duck hepatitis model and 2.2.15 cell line, anti-experimental liver injury induced by hepatotoxins such as CCl4, acetaminophen and ConA, and anti-liver fibrosis in rats and mice. The active mechanism of bicyclol might be anti-apoptosis of hepatocytes through multiple signaling pathways mainly inducing the expressions of hepatic heat shock proteins (HSP27 and HSP70), molecular chaperons. Clinical trial was performed by double blind, randomized and positive control or placebo method in multi-medical centers in China. Patients received bicyclol 25mg thrice daily for six months, then stopped treatment and followed up for 3 months. Oral administration of bicyclol normalized the elevated serum transaminases (ALT, AST) by approximately 50% in chronic viral hepatitis B and C, and also showed certain level of inhibiting HBV and HCV replication. No noticeable adverse reaction has been observed. In combination therapy of bicyclol with interferon alpha, lamivudine and adefovir dipivoxil in HBV or HCV, bicyclol may potentiate the anti-viral efficacy and reduce YMDD mutant and side effects. In 2004 China FDA issued license to manufacture bicyclol. Since then bicyclol has been widely used to treat chronic HBV and HCV in China.
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PMID:Bicyclol: a novel drug for treating chronic viral hepatitis B and C. 1914 48

Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.
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PMID:Natural history and clinical management of chronic hepatitis B virus infection in children. 1966 96

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of entecavir for the treatment of chronic hepatitis B (CHB) in adults based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from five randomised controlled trials (RCTs), of good methodological quality and measuring a range of clinically relevant outcomes, comparing entecavir with lamivudine. After 1 year of treatment entecavir was statistically superior to lamivudine in terms of the proportion of patients achieving hepatitis B virus (HBV) DNA suppression, alanine aminotransferase (ALT) normalisation and histological improvement, but not in terms of the proportion of patients achieving hepatitis B e antigen (HBeAg) seroconversion. The incidence of adverse or serious adverse events was similar for both treatments. The results of the manufacturer's mixed treatment comparison (MTC) model to compare entecavir with the comparator drugs in nucleoside-naive patients were considered to be uncertain because of concerns over its conduct and reporting. For the economic evaluation the manufacturer constructed two Markov state transition models, one in HBeAg-positive and one in HBeAg-negative patients. The modelling approach was considered reasonable subject to some uncertainties and concerns over some of the structural assumptions. In HBeAg-positive patients the base-case incremental cost-effectiveness ratios (ICER) for entecavir compared with lamivudine and pegylated interferon alpha-2a were 14,329 pounds and 8403 pounds per quality-adjusted life-year (QALY) respectively. Entecavir was dominated by telbivudine. In HBeAg-negative patients the base-case ICERs for entecavir compared with lamivudine, pegylated interferon alpha-2a and telbivudine were 13,208 pounds, 7511 pounds and 6907 pounds per QALY respectively. In HBeAg-positive lamivudine-refractory patients entecavir dominated adefovir added to lamivudine. In one-way deterministic sensitivity analysis on all key input parameters for entecavir compared with lamivudine in nucleoside-naive patients, ICERs generally remained under 30,000 pounds per QALY. In probabilistic sensitivity analysis in nucleoside-naive HBeAg-positive patients the probability of the ICER for entecavir being below 20,000 pounds per QALY was 57%, 82% and 45% compared with lamivudine, pegylated interferon alpha-2a and telbivudine respectively. In nucleoside-naive HBeAg-negative patients the probabilities were 90%, 100% and 96% respectively. The manufacturer's lifetime treatment scenario for HBeAg-negative patients and the ERG's 20-year treatment scenario for HBeAg-positive patients increased the ICERs, particularly in the latter case. Amending the HBeAg-negative model so that patients with compensated cirrhosis would also receive lifetime treatment gave probabilities of entecavir being cost-effective at a willingness to pay of 20,000 pounds and 30,000 pounds of 4% and 40% respectively. The NICE guidance issued in August 2008 as a result of the STA states that entecavir is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated.
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PMID:Entecavir for the treatment of chronic hepatitis B infection. 1984 26

The aim of this study was to evaluate the efficacy of interferon alpha (IFN-alpha) and long-term lamivudine therapy in children with chronic hepatitis B and to determine the optimal duration of lamivudine therapy. Thirty-eight HBeAg-positive children simultaneously received IFN-alpha2a 5 MU/m2 to 10 MU/m2 for six months and lamivudine (4 mg/kg/day). Lamivudine was administered until anti-HBe seroconversion and was continued for six months in responders. During the five-year study period, we evaluated the efficacy of treatment, occurrence of YMDD mutants and adverse effects. During the study period, alanine aminotransferase (ALT) normalization, clearance of hepatitis B virus (HBV) DNA, HBeAg/anti-HBeAb, HBsAg/anti-HBsAb seroconversion, and histological response were noted in 27 (71.1%), 14 (36.8%), 13 (34.2%), 2 (5.2%) and 10 (47.9%) patients, respectively. Complete response was determined in 34.2% (13/38), and in 69.2% of these responders, response was achieved within 18 months. Breakthrough and YMDD mutant rates were 65.8% and 55.2%, respectively. Breakthrough time was a median 24 months and was associated with low baseline ALT level (p < 0.01). In conclusion, although lamivudine was used for a longer period, the response rate was not higher than in previous reports. We suggest that 18 months' duration of lamivudine treatment is sufficient for combination therapy.
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PMID:Efficacy of combined interferon alpha and long-term lamivudine therapy in children with chronic hepatitis B. 2143 29


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