Christine M. Hunt

Prevalence and Clinical Correlates of YMDD Variants during Lamivudine Therapy for Patients with Chronic Hepatitis B

YMDD variants of hepatitis B virus (HBV) emerge in some patients with chronic hepatitis B who receive lamivudine. YMDD variants were examined in 794 patients in 4 controlled studies of 1 years duration. The long-term effects of YMDD variants were examined in a subset of patients treated up to 4 years. YMDD variants were detected by polymerase chain reaction (PCR) and restriction fragment-length polymorphism assays. After 1 year, YMDD variants were detected in 81 (24%) of 335 patients. In these patients, the median serum HBV DNA concentration at 1 year was <20% of the baseline level, and serum alanine transaminase (ALT) levels and liver histologic findings had significantly improved. In patients with YMDD variants who were treated for up to 4 years, median HBV DNA and ALT levels showed improvements. Sex, baseline body mass index, and HBV DNA level were associated with emergence of YMDD variants. Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.

Effect of age and gender on the activity of human hepatic CYP3A.

Many pharmacokinetic investigations in the elderly population reveal decreased clearance of lipophilic drugs metabolized by the cytochrome P450 enzymes; however, few studies have evaluated aging-dependent or gender-related changes in specific cytochrome P450 enzymes. The clearance of quinidine, midazolam, triazolam, erythromycin, and lidocaine declines with age; these drugs are metabolized by the isoform, CYP3A. To determine whether these metabolic effects are due to changes in CYP3A, the effects of age and gender on CYP3A activity were examined. The activity of the human hepatic cytochrome P450, CYP3A, was quantified in vitro as erythromycin N-demethylation in microsomes prepared from forty-three resected human liver specimens obtained from patients, age 27 to 83, with normal liver function. Erythromycin N-demethylation varied 5-fold in human liver microsomes. CYP3A activity was 24% higher in females than males (P = 0.027). CYP3A activity did not correlate with age, smoking status, ethanol consumption or percent ideal body weight. Large interindividual differences and a small female-specific increase in CYP3A activity were obtained. However, CYP3A activity was unaffected by age over the range of 27-83 years, suggesting that the aging-related alteration in the clearance of CYP3A substrates is secondary to changes in liver blood flow, size, or drug binding and distribution with aging.

Case Definition and Phenotype Standardization in Drug-Induced Liver Injury

Drug‐induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

Effect of interferon-α treatment of chronic hepatitis C on health-related quality of life

Studies of interferon-α (IFN-α)therapy for chronic hepatitis C have focused on viralclearance; however, few have evaluated patientshealth-related quality of life during therapy. Thisstudy evaluates health-related quality of life and theprevalence of anxiety and depression in patients withchronic hepatitis C before, during, and followingIFN-α therapy. Patients undergoing IFN-αtherapy for chronic hepatitis C were asked to completehealth status measures as well as anxiety and depressioninventories before, during, and following IFN-αtherapy. These measures were compared to the results of healthy adults in the general US population.Thirty-eight of forty-eight eligible patients (79%) withchronic hepatitis C completed the questionnaires.Respondents demonstrated a significant increase in depression during the sixth month ofinterferon therapy in comparison to pretreatmentresults. Anxiety scores improved significantly after onemonth of IFN-α in comparison to pretreatmentresults. Scores on the health status measures did notvary with IFN-α therapy. Patient responses wereanalyzed with respect to biochemical response(normalized transaminases) to IFN-α. IFN-αresponders, who were aware of their transaminase results,exhibited lower scores on anxiety subscales during andafter therapy (P = 0.02-0.04). Scores on the healthstatus subscale, role emotional, improved in IFN-α responders compared to nonresponders during thesixth month of therapy (P = 0.02). Response toIFN-α therapy was not associated with any otherdifferences on subscale analysis. Patients with chronichepatitis C exhibited health perceptions similar to thegeneral US population, and these were unchanged duringIFN-α therapy. However, the incidence ofdepression significantly increased during the sixthmonth of IFN-α therapy. IFN-α respondersexhibited fewer emotional problems as well as a lowerincidence of anxiety during and followingtherapy.

Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase Unified List Based on International Collaborative Work

Background: Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans.Objective: (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase™).Data Sources and Extraction: (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase™, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, ‘overall liver injury’ and ‘ALF’. EBGM of ≥2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of ‘overall liver injury’ and ‘ALF’ calculated from VigiBase™.Data Synthesis: After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase™, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of ‘overall liver injury’ and 83.1% were associated with at least one reported case of ALF.Conclusions: This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol

The N‐demethylation of erythromycin and 6β‐hydroxylation of Cortisol are both functions of the glucocorticoid‐inducible CYP3A in human liver microsomes. To determine whether 6β‐hydroxylation and erythromycin N‐demethylation are catalyzed by similar or distinct CYP3A isoforms, erythromycin N‐demethylase activity, as reflected by the recently described 14[C]‐erythromycin breath test, was compared with urinary 6β‐hydroxycortisol/cortisol ratios, a measure of Cortisol 6β‐hydroxylase activity, in nine patients. Erythromycin N‐demethylation varied fourfold and 6β‐hydroxycortisol/cortisol ratios varied sevenfold among the subjects; no correlation was found between these activities (r2 = 0.065). New noninvasive tests of CYP3A strongly suggest Cortisol 6β‐hydroxylation and erythromycin N‐demethylation are performed by distinct CYP3A isoforms.

Hepatic cytochrome P-4503A (CYP3A) activity in the elderly

Elderly patients exhibit decreased clearance of multiple drugs biotransformed by the hepatic cytochromes P-450. The cytochromes P-450 are a superfamily of enzymes, which comprise a central component of phase I drug metabolism. Distinct isoforms metabolize specific drugs. In human liver microsomes, the glucocorticoid-inducible cytochrome P-450IIIA, CYP3A, catalyzes the N-demethylation of erythromycin. To examine the activity of hepatic CYP3A in elderly males and females, erythromycin N-demethylation was examined, as reflected by the recently described [14C]erythromycin breath test in 24 healthy volunteers, age 70-88. The [14C]erythromycin breath test was measured in normal elderly males and females to: (a) determine persistence of the gender-related dimorphism (evident in younger subjects) of CYP3A activity in the elderly population, (b) examine the effect of % ideal body weight, age, diet, and medication use on the activity of human hepatic CYP3A, and (c) compare breath test results obtained in normal geriatric volunteers with published results obtained in younger subjects, to determine aging-related alterations in CYP3A enzyme activity. Erythromycin N-demethylation varied fivefold among these patients. Similar to earlier studies examining erythromycin N-demethylation in younger subjects, CYP3A activity was found to vary with gender in the geriatric cohort. [14C]Erythromycin N-demethylation at 60 min was 3.14% +/- 0.75 (n = 13) in females and 2.15% +/- 0.77 (n = 11) in males (P = 0.005). In evaluating the role of % ideal body weight and % dietary fat using multivariable linear regression analyses, [14C]erythromycin N-demethylation, was found to decline significantly as % ideal body weight increased (P = 0.001). This was not confounded by gender. [14C]Erythromycin N-demethylation was not related to dietary fat intake (P less than 0.13). [14C]Erythromycin N-demethylation in the elderly volunteers was similar to values reported for subjects aged 20-60. Performance of a new non-invasive test of the human hepatic glucocorticoid-inducible CYP3A in a geriatric cohort suggests that: (a) the gender-related heterogeneity in function of the glucocorticoid inducible human CYP3A persists during normal aging, (b) that the activity of CYP3A may decrease in obesity, and (c) that the activity of CYP3A is stable throughout normal ageing.

Hepatitis C in pregnancy

Objective To review the epidemiology and clinical course of hepatitis C virus (HCV) infection, to examine current data on the vertical transmission of HCV to neonates, and to develop recommendations for intrapartum and postpartum follow-up of neonates born to HCV-infected mothers. Data Sources The English-language medical literature from 1988 to 1996 was reviewed through MEDLINE. Methods of Study Selection Case series evaluating vertical transmission of HCV infection in neonates, determined by HCV RNA testing, after delivery and breast-feeding were reviewed and summarized. Tabulation, Integration, and Results Vertical transmission of HCV infection was examined with respect to maternal human immunodeficiency virus (HIV) status (as heterosexual transmission of HCV is enhanced in HIV-positive patients) and chronicity of HCV infection. Vertical transmission of HCV from HIV-negative mothers with chronic hepatitis C ranged from 0 to 18%. The risk of HCV vertical transmission from HIV-negative mothers with acute hepatitis C may be higher than that from mothers with chronic HCV infection. Vertical transmission of HCV was proportional to maternal HCV RNA levels; no transmission was noted in women without HCV RNA, whereas the greatest transmission was noted in women with HCV RNA greater than 1 million copies/mL. Vertical transmission of HCV from HIV-positive mothers with chronic hepatitis C ranged from 6 to 36%. In colostrum, HCV RNA was found to be present in low titers. No studies have documented transmission of HCV infection to infants via breast-feeding. Conclusion Vertical transmission of HCV complicates up to 18% of pregnancies in HCV-positive, HIV-negative women and 6–36% in HCV-positive, HIV-positive women. The highest rates of vertical transmission of HCV were noted in women with high HCV RNA or concurrent HIV infection. Breast-feeding has not been associated with vertical transmission of HCV infection.

Tetracycline-induced bile duct paucity and prolonged cholestasis

Acute self-limited liver disease has been associated with tetracycline use. However, severe prolonged cholestatic hepatitis and bile duct paucity have not been previously attributed to tetracyclines. Hepatitis, characterized by prolonged jaundice, severe pruritus, and moderate increased transaminase values, occurred within 2 months of ingesting tetracyclines in two female patients. Serum bilirubin levels normalized 12 and 34 months after tetracycline ingestion. Liver histology revealed bile duct paucity, severe cholestasis, and minimal necrosis and inflammation. Tetracyclines may infrequently induce bile duct paucity and prolonged, severe, and reversible cholestasis.

Drug-induced liver injury following positive drug rechallenge

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury. Positive rechallenge with suspect drug was reported in 770 of 36,795 hepatic adverse events. A total of 88 cases met inclusion criteria for analysis. Mean age was 44 years (range 0.5-83) and 56% were male. A broad spectrum of suspect drugs were identified. Many patients exhibited hepatitis symptoms or jaundice on the initial and rechallenge liver event. Twelve patients (14%) exhibited clinically worrisome severe hepatocellular injury and jaundice on either initial or rechallenge event and two died, reflecting a 2.3% fatality rate in those with positive rechallenge. The two fatalities developed severe hepatocellular injury with jaundice only upon rechallenge. Liver injury recurred in most rechallenges. Improved identification and communication of possible drug-induced liver injury is needed to avoid potentially serious and/or fatal drug rechallenges. Clinicians should generally avoid such rechallenges.