Robert G. Gish

American Gastroenterological Association Institute Guideline on the Prevention and Treatment of Hepatitis B Virus Reactivation During Immunosuppressive Drug Therapy

Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina; Division of Infectious Diseases, Brigham & Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, Connecticut; and Division of Gastroenterology and Hepatology, Department of Medicine, Case and VA Medical Center, Case Western Reserve University, Cleveland, Ohio

Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil

Abstract Background & aims: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of adefovir dipivoxil. Antiviral efficacy of adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. Methods: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). Results: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Conclusions: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.

Severe Hepatotoxicity Associated with Nevirapine Use in HIV-Infected Subjects

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Two subjects died of hepatic failure. Independent risk factors were body-mass index (BMI) <18.5, female sex, serum albumin level <35 g/L, mean corpuscular volume >85 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L. The use of nevirapine in female patients with a low BMI should be discouraged.

Influence of hepatitis B virus genotypes on the intra-and extracellular expression of viral DNA and antigens

Various genotypes of the hepatitis B virus (HBV) induce liver disease of distinct severity, but the underlying virological differences are not well defined. Huh7 cells were transfected with plasmids carrying 1.24‐fold the HBV genome of different genotypes/subgenotypes (2 strains each for Aa/A1, Ae/A2, Ba/B2 and D; 3 each for Bj/B1 and C). HBV DNA levels in cell lysates, determined by Southern hybridization, were the highest for C followed by Bj/Ba and D/Ae (P < .01), and the lowest for Aa (P < .01), whereas in culture media, they were the highest for Bj, distantly followed by Ba/C/D and further by Ae/Aa (P < .01). The intracellular expression of core protein was more than 3‐fold lower for Ae/Aa than the others. Hepatitis B e antigen (HBeAg) was excreted in a trend similar to that of HBV DNA with smaller differences. Secretion of hepatitis B surface antigen (HBsAg) was most abundant for Ae followed by Aa, Ba, Bj/C and remotely by D, which was consistent with mRNA levels. Cellular stress determined by the reporter assay for Grp78 promoter was higher for C and Ba than the other genotypes/subgenotypes (P < .01). Severe combined immunodeficiency mice transgenic for urokinase‐type plasminogen activator (uPA/SCID), with the liver replaced for human hepatocytes, were inoculated with virions passed in mouse and recovered from culture supernatants. HBV DNA levels in their sera were higher for C than Ae by 2 logs during 4–7 weeks after inoculation. In conclusion, virological differences among HBV genotypes were demonstrated both in vitro and in vivo. These differences may influence HBV infections with distinct genotypes in clinical and epidemiological settings. (HEPATOLOGY 2006;44:915–924.)

Cost effectiveness of peginterferon α-2b plus ribavirin versus interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C

Background: Peginterferon α-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. Aims: To estimate the cost effectiveness of treatment with peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Methods: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. Results: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon α-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11 800 and 6600 per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. Conclusions: Peginterferon α-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.

Hepatitis C-related hepatocellular carcinoma in the United States: Influence of ethnic status

OBJECTIVES:The incidence of hepatocellular carcinoma (HCC) seems to be rising in the United States (US), and considerable variability in the incidence and etiology of HCC has been noted among different racial and ethnic groups in this country. The aim of this study was to evaluate the influence of racial and ethnic status in the viral etiology of HCC in the US.METHODS:Retrospective surveys were conducted at liver transplantation centers in the US. Respondents were asked to review the charts of all patients with HCC seen at their institution for the 2-yr period between July, 1997, and June, 1999, and provide information about the racial and ethnic distribution of cases and their serological status with regard to hepatitis B and C markers.RESULTS:Complete information was available on 691 patients who formed the basis of this study, comprising 59% whites, 14% blacks, 16% Asians, and 11% other racial groups. Of the patients, 107 patients (15.4%) were positive for hepatitis B surface antigen (HBsAg), 322 had antibodies to hepatitis C virus (anti-HCV) (46.5%), 33 (4.7%) had both HBsAg and anti-HCV), and 229 (33.1%) had neither marker present. Clear differences were seen among racial groups. Anti-HCV positivity was the most frequent risk factor in both blacks and whites, whereas HBsAg positivity was the most frequent etiological factor in Asians with HCC.CONCLUSION:HCV infection seems to be the major risk factor for HCC in the US, particularly among individuals of white and black ethnicity, whereas hepatitis B remains the main risk factor among patients of Asian ethnicity. These preliminary findings indicate the need for a more detailed study of ethnic variability in the pathogenesis of HCC.

Changes in haemoglobin during interferon alpha‐2b plus ribavirin combination therapy for chronic hepatitis C virus infection

Interferon alpha and ribavirin (RBV) combination therapy is associated with decreases in haemoglobin (Hb) concentrations and anaemia. The aim of this analysis was to better characterize the magnitude and frequency of Hb changes and risk factors. This retrospective analysis evaluated treatment‐related changes in Hb in 677 patients who participated in either of two interferon alpha‐2b plus RBV studies for chronic hepatitis C virus (HCV) infection. Study 1 included 192 interferon alpha‐naïve patients randomized to receive RBV 1000–1200 mg/day plus interferon alpha‐2b 3 million IU daily or three times weekly for 48 weeks. Study 2 included 485 interferon alpha‐experienced patients randomized to receive RBV 1000‐1200 mg daily plus interferon alpha‐2b 3 million IU daily or three times weekly for 4 weeks, followed by three times weekly dosing for 44 weeks. More than 50% of all patients experienced a decrease in Hb ≥30 g/L. Women were 4.4 times as likely as men to experience a Hb level of <100 g/L; however, men were at a 40% higher risk to experience a Hb decline of >30 g/L from baseline. Daily use of interferon alpha‐2b did not impact the magnitude of Hb decrease. In this pooled analysis, RBV dose reduction resulted in increases in Hb concentration of approximately 10 g/L. Lower baseline creatinine clearance, higher baseline Hb levels and increased age were independently associated with increased risk of Hb decreases of >27.7%. Lower baseline weight was not associated with increased risk of Hb decrease. Substantial Hb decreases occur frequently with interferon alpha/RBV combination therapy. Sex, the magnitude of the Hb decline and renal function are potentially important factors to consider in patients receiving RBV. Further research is needed to determine the impact on virological response and to develop strategies to manage the medical consequences.

Keratin 8 mutations in patients with cryptogenic liver disease.

Background About 10 percent of patients who undergo liver transplantation have cryptogenic liver disease. In animal models, the absence of heteropolymeric keratins 8 and 18 or the presence of mutant keratins in hepatocytes causes or promotes liver disease. We have previously described a mutation in the keratin 18 gene in a patient with cryptogenic cirrhosis, but the importance of mutations in the keratin 8 and keratin 18 genes in such patients is unclear. Methods We tested for mutations in the keratin 8 and keratin 18 genes in purified genomic DNA isolated from 150 explanted livers and 89 peripheral-blood specimens from three groups of patients: 55 patients with cryptogenic liver disease; 98 patients with noncryptogenic liver disease, with causes that included alcohol use, autoimmunity, drug use, and viral infections; and 86 randomly selected inpatients and outpatients who provided blood to the hematology laboratory. Results Of the 55 patients with cryptogenic liver disease, 3 had glycine-to-cysteine muta...

Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C

Increased rates of apoptosis (programmed cell death) have been demonstrated in many hepatic diseases including chronic hepatitis C. IDN‐6556 is a potent inhibitor of caspases, the proteases that execute apoptosis. In a prior phase 1 study, IDN‐6556 lowered aminotransferase activity in a small number of patients with liver impairment. The purpose of this study was to further explore the effect of IDN‐6556 in patients with liver disease in a multicenter, double‐blind, placebo‐controlled, dose‐ranging study with a 14‐day dosing period. A total of 105 patients were enrolled in the study; 79 received active drug; 80 patients had chronic hepatitis C and 25 had other liver diseases including nonalcoholic steatohepatitis (NASH), hepatitis B, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). IDN‐6556 doses ranged from 5 mg to 400 mg daily, given from 1 to 3 times per day. In the HCV patients, all doses of IDN‐6556 significantly lowered ALT and AST (P = 0.0041 to P < 0.0001 for various dosing groups in Wilcoxon tests comparing IDN‐6556 to placebo), with the exception of the lowest dose. Declines in aminotransferase activity were also seen in patients with NASH but effects were not apparent in the small number of other liver diseases. Adverse experiences were not different between IDN‐6556 and placebo. There were no clinically meaningful changes in other laboratory parameters. In particular, mean HCV RNA levels did not show significant changes. Conclusion: Oral IDN‐6556, given for 14 days, significantly lowered aminotransferase activity in HCV patients and appeared to be well tolerated. Longer studies to assess potential effects of IDN‐6556 on liver inflammation and fibrosis are merited. (HEPATOLOGY 2007.)

Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV partners study.

The efficiency of hepatitis C virus (HCV) transmission by sexual activity remains controversial. We conducted a cross‐sectional study of HCV‐positive subjects and their partners to estimate the risk for HCV infection among monogamous heterosexual couples. A total of 500 anti–HCV‐positive, human immunodeficiency virus–negative index subjects and their long‐term heterosexual partners were studied. Couples were interviewed separately for lifetime risk factors for HCV infection, within‐couple sexual practices, and sharing of personal grooming items. Blood samples were tested for anti‐HCV, HCV RNA, and HCV genotype and serotype. Sequencing and phylogenetic analysis determined the relatedness of virus isolates among genotype‐concordant couples. The majority of HCV‐positive index subjects were non‐Hispanic white, with a median age of 49 years (range, 26‐79 years) and median of 15 years (range, 2‐52 years) of sexual activity with their partners. Overall, HCV prevalence among partners was 4% (n = 20), and nine couples had concordant genotype/serotype. Viral isolates in three couples (0.6%) were highly related, consistent with transmission of virus within the couple. Based on 8,377 person‐years of follow‐up, the maximum incidence rate of HCV transmission by sex was 0.07% per year (95% confidence interval, 0.01‐0.13) or approximately one per 190,000 sexual contacts. No specific sexual practices were related to HCV positivity among couples. Conclusion: The results of this study provide quantifiable risk information for counseling long‐term monogamous heterosexual couples in which one partner has chronic HCV infection. In addition to the extremely low estimated risk for HCV infection in sexual partners, the lack of association with specific sexual practices provides unambiguous and reassuring counseling messages. (HEPATOLOGY 2013)