Jenny Heathcote

Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B

BACKGROUND Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

Hepatocellular carcinoma (HCC): a global perspective

Peter Ferenci (chair) (Austria) Michael Fried (Switzerland) Douglas Labrecque (USA) J. Bruix (Spain) M. Sherman (Canada) M. Omata (Japan) J. Heathcote (Canada) T. Piratsivuth (Thailand) Mike Kew (South Africa) Jesse A. Otegbayo (Nigeria) S.S. Zheng (China) S. Sarin (India) S. Hamid (Pakistan) Salma Barakat Modawi (Sudan) Wolfgang Fleig (Germany) Suliman Fedail (Sudan) Alan Thomson (Canada) Aamir Khan (Pakistan) Peter Malfertheiner (Germany) George Lau (Hong Kong) F.J. Carillo (Brazil) Justus Krabshuis (France) Anton Le Mair (The Netherlands)

No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus

Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with potent activity against human immunodeficiency virus type 1 and hepatitis B virus (HBV). To date, no reports of HBV clinical resistance to TDF have been confirmed. In two phase 3 studies (GS‐US‐174‐0102 and GS‐US‐174‐0103), 375 hepatitis B e antigen–negative (HBeAg−) patients and 266 HBeAg+ patients with chronic hepatitis B (some nucleoside‐naive and some lamivudine‐experienced) were randomized 2:1 to receive TDF (n = 426) or adefovir dipivoxil (ADV; n = 215) for 48 weeks. After week 48, eligible patients received open‐label TDF with no interruption. The studies are being continued through week 384/year 8; week 144 data are presented here. Per protocol, viremic patients (HBV DNA level ≥ 400 copies/mL or 69 IU/mL) had the option of adding emtricitabine (FTC) at or after week 72. Resistance analyses of HBV polymerase/reverse transcriptase (pol/RT) were based on population dideoxy sequencing. Phenotypic analyses were conducted in HepG2 cells with recombinant HBV derived from patient serum. Most patients maintained TDF monotherapy treatment across both studies (607/641, 95%). A resistance analysis of HBV pol/RT was performed at the baseline for all patients, for viremic patients at week 144 or at the last time when they were on TDF monotherapy (34 on TDF and 19 on ADV‐TDF), and for patients who remained viremic after the addition of FTC (7/20 on TDF and 5/14 on ADV‐TDF). No patient developed amino acid substitutions associated with resistance to TDF. Virological breakthrough on TDF monotherapy was infrequent over 144 weeks (13/426, 3%) and was attributed to documented nonadherence in most cases (11/13, 85%). Persistent viremia (≥400 copies/mL) through week 144 was rare (5/641, 0.8%) and was not associated with virological resistance to TDF by population or clonal analyses. Conclusion: No nucleoside‐naive or nucleoside‐experienced patient developed HBV pol/RT mutations associated with TDF resistance after up to 144 weeks of exposure to TDF monotherapy. (HEPATOLOGY 2010)

A Prospective Controlled Trial of Azathioprine in Primary Biliary Cirrhosis

Between 1968 and 1974, azathioprine has been used in a controlled prospective trial to treat patients with symptomatic but precirrhotic primary cirrhosis. Forty-five patients were admitted, of whom 22 were given azathioprine in a dose of 2 mg per kg of body weight. During the 1st year, serum aspartate transaminase levels showed a significant change in favor of the treated group, but improvement did not continue. Throughout the trial, serum alkaline phosphatase, bilirubin, cholesterol, albumin and immunoglobulin M values showed no significant change. Titers of serum mitochondrial antibodies tended to become negative more often in the treated than the untreated. Pruritus cannot be assessed objectively, but seemed less in the treated than in controls. Serial hepatic biopsy specimens showed the development of cirrhosis equally in the two groups. Survival, as judged by the life table method, was similar for the first 5 years of the trial. There was, however, a significant difference in favor of the treated group in the 6th year, although the number of patients available for assessment at that time was extremely small.

Cell-Type Specific Gene Expression Signature in Liver Underlies Response to Interferon Therapy in Chronic Hepatitis C Infection

BACKGROUND & AIMS Chronic hepatitis C virus (CHC) infection is treated with interferon/ribavirin, but only a subset of patients respond. Treatment nonresponders have marked pretreatment up-regulation of a subset of interferon stimulated genes (ISGs) in their livers, including ISG15. We here study how the nonresponder gene expression phenotype is influenced by clinical factors and uncover the cellular basis of the phenotype through ISG15 protein expression. METHODS Seventy-eight CHC patients undergoing treatment were classified by clinical (gender, viral genotype, viral load, treatment outcome) and histologic (inflammation, fibrosis) factors and subjected to gene expression profiling on their pretreatment liver biopsies. An analysis of variance model was used to study the influence of individual factors on gene expression. ISG15 immunohistochemistry was performed on a subset of 31 liver biopsy specimens. RESULTS One hundred twenty-three genes were differentially expressed in the 78 CHC livers when compared with 20 normal livers (P < .001; fold change, > or =1.5-fold). Of genes influenced by a single factor, genotype (1 vs 2/3) influenced more genes (17) than any other variable; when treatment outcome was included in the analysis, this became the predominant influence (24 genes), and the effect of genotype was diminished. Treatment response was linked to cell-specific activation patterns: ISG15 protein up-regulation was more pronounced in hepatocytes in treatment nonresponders but in Kuppfer cells in responders. CONCLUSIONS Genotype is a surrogate marker for the nonresponder phenotype. This phenotype manifests as differential gene expression and is driven by activation of different cell types: hepatocytes in treatment nonresponders and macrophages in treatment responders.

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-alpha/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-alpha-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure.

Impact of Asian Race on Response to Combination Therapy With Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C

BACKGROUND:Prior investigation has identified factors associated with response to treatment in hepatitis C including viral genotype and titre, body weight, hepatic fibrosis, and adherence to therapy. The lower response rate of African-Americans relative to whites has been previously described, but studies of other racial or ethnic groups remain limited.OBJECTIVE:To determine whether Asian race is an independent marker for response to antiviral therapy in hepatitis C.METHODS:Data on treatment-naïve patients from a large multicenter study of combination therapy with peginterferon alfa-2a (180 μg SC each week) and ribavirin (800 mg daily) were analyzed retrospectively to identify factors associated with an SVR, defined as an undetectable serum HCV RNA at least 24 wk after completion of therapy.RESULTS:SVR occurred in 45% of 384 whites and 65% of 52 Asians (P = 0.0047) who were treatment naïve. In a multivariate logistic regression analysis that adjusted for all the aforementioned factors known to be associated with treatment response, Asian race was shown to be an independent predictor of achieving an SVR (OR 2.22, 95% CI 1.11–4.46). Other independent predictors of SVR include viral genotype, body mass index, degree of hepatic fibrosis, and adherence with ribavirin.CONCLUSIONS:Asians are more likely to achieve an SVR to treatment with peginterferon alfa-2a and ribavirin than whites with chronic hepatitis C, suggesting a genetic influence on the antiviral response.

Fulminant Hepatitis as a Consequence of Reactivation of Hepatitis B Virus Infection after Discontinuation of Low-Dose Methotrexate Therapy

Excerpt Development of liver disease in chronic hepatitis B virus carriers depends on the interplay between viral products and the host immune system. Although it is generally believed that the vir...

American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis

A group of multidisciplinary experts on primary biliary cirrhosis (PBC) and its complications convened on May 31, 2009, under the aegis of the American Association for the Study of Liver Diseases (AASLD) in order to identify the most appropriate design and endpoints for clinical trials of PBC based on current evidence and expert experience. The natural history of PBC was reviewed as well as current therapies. The current approaches to evaluating therapies for disease progression and symptoms as priorities were discussed. Appropriate aspects of trial design including entry criteria, study duration, and appropriate handling of issues such as stratification of subjects and use of ursodeoxycholic acid (UDCA), were identified and discussed. After a full day of presentations, in a consensus manner, appropriate endpoints for clinical efficacy trials regarding PBC and its complications were agreed upon and are reported in this summary.

Intrahepatic Cholestasis in Childhood

The apparent well-being of some children who as neonates were believed to have obstructive jaundice prompted us to study the clinical course, histologic features and possible etiologic factors in 17 children with cholestasis in the neonatal period. During a follow-up period of five months to 22 years, all had signs of chronic cholestasis, but only four died (two from nonhepatic causes); the others live remarkably normal lives. Serial hepatic biopsies in 11 showed a variety of initial lesions, which progressed to hypoplasia of the intrahepatic bile ducts, increasing portal fibrosis and eventual cirrhosis. Although evidence of possible viral infection was found in only 10 cases, a hepatitis, beginning either before or after birth, appears to be a likely original cause. The histologic changes seen may represent different stages of one process, starting as cholestasis with or without evidence of hepatitis and progressing to obliteration or failure of normal growth of the intrahepatic bile ducts.