Lennox J. Jeffers

Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection

OBJECTIVES:Needle liver biopsy has been shown to have a high rate of sampling error in patients with diffuse parenchymal liver diseases. In these cases, the sample of liver tissue does not reflect the true degree of inflammation, fibrosis, or cirrhosis, despite an adequate sample size. The aim of this study was to determine the rate and extent of sampling error in patients with chronic hepatitis C virus infection, and to assess the intraobserver variation with the commonly used scoring system proposed by Scheuer and modified by Batts and Ludwig.METHODS:A total of 124 patients with chronic hepatitis C virus infection underwent simultaneous laparoscopy-guided biopsies of the right and left hepatic lobes. Formalin-fixed paraffin-embedded sections were stained with hematoxylin and eosin and with trichrome. The slides were blindly coded and randomly divided among two hepatopathologists. Inflammation and fibrosis were scored according to the standard grading (inflammation) and staging (fibrosis) method based on the modified Scheuer system. Following the interpretation, the slides were uncoded to compare the results of the right and left lobes. Fifty of the samples were blindly resubmitted to each of the pathologists to determine the intraobserver variation.RESULTS:Thirty of 124 patients (24.2%) had a difference of at least one grade, and 41 of 124 patients (33.1%) had a difference of at least one stage between the right and left lobes. In 18 patients (14.5%), interpretation of cirrhosis was given in one lobe, whereas stage 3 fibrosis was given in the other. A difference of two stages or two grades was found in only three (2.4%) and two (1.6%) patients, respectively. Of the 50 samples that were examined twice, the grading by each pathologist on the second examination differed from the first examination in 0% and 4%, and the staging differed in 6% and 10%, respectively. All observed variations were of one grade or one stage.CONCLUSIONS:Liver biopsy samples taken from the right and left hepatic lobes differed in histological grading and staging in a large proportion of chronic hepatitis C virus patients; however, differences of more than one stage or grade were uncommon. A sampling error may have led to underdiagnosis of cirrhosis in 14.5% of the patients. These differences could not be attributed to intraobserver variation, which appeared to be low.

Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation

BACKGROUND Orthotopic liver transplantation for end-stage hepatitis-B-virus (HBV) infection is commonly complicated by recurrence of HBV. Lamivudine, a cytosine nucleoside analogue, has been shown to suppress HBV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver disease secondary to hepatitis B. METHODS Two of the patients received lamivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an attempt to prevent HBV recurrence after transplantation. The three patients initially responded well to treatment, but viral recurrence occurred after 9-10 months of treatment in all patients. HBV DNA was amplified from serum and sequenced through a conserved polymerase domain-the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed the susceptibility of HBV to lamivudine by infecting primary human hepatocytes with serum taken before the start of treatment and after recurrence in varying concentrations of lamivudine. FINDINGS DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all patients during lamivudine treatment. In hepatocyte cultures infected with pretreatment serum, HBV DNA concentrations were reduced to less than 6% of those in control cultures by addition of lamivudine in concentrations as low as 0.03 mumol/L. By contrast, in cultures treated with serum taken after recurrence, HBV DNA concentrations did not fall below 20% of control values, even with lamivudine at 30 mumol/L. INTERPRETATION Resistance to lamivudine has been reported in HIV patients with mutations in the YMDD locus of the polymerase gene. Our findings indicate a common mechanism of lamivudine resistance for HIV and HBV that involves similar point mutations in homologous domains of the viral polymerases.

Peginterferon alfa‐2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1

Black Americans (blacks) have a high prevalence of chronic hepatitis C virus (HCV) infection and respond poorly to therapy with interferon alfa‐based regimens, but they have been underrepresented in clinical trials. The aim of this study was to assess the rate of sustained virological response (SVR) to peginterferon alfa‐2a (40 kd) in combination with ribavirin in black patients chronically infected with HCV genotype 1. In a prospective, multicenter, open‐label trial, 78 black and 28 white American interferon‐naïve patients were enrolled to receive once weekly subcutaneous injections of 180 μg peginterferon alfa‐2a plus oral ribavirin (1000 mg/d for patients weighing less than 75 kg and 1200 mg/d for patients weighing 75 kg or more) for 48 weeks. Pre‐ and post‐treatment liver biopsies were evaluated for necroinflammation and fibrosis. SVR, defined as undetectable (<50 IU/mL) HCV RNA, was 26% in the black group and 39% in the white group. Although the SVR rate was lower in blacks than in whites, the SVR of 26% represents an improvement over previously reported SVR rates from smaller, retrospective studies of black patients. We also observed improvement in fibrosis in 25% of the black patients. No unexpected adverse events occurred. In conclusion, this prospective study evaluating responses of black patients with chronic hepatitis C to peginterferon alfa‐2a/ribavirin has demonstrated that treatment can be safely offered to such individuals with reasonable antiviral and histological benefit. (HEPATOLOGY 2004;39:1702–1708.)

Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C

BACKGROUND/AIMS It has been reported that hepatic iron concentration (HIC) may influence response to therapy in chronic viral hepatitis. The aim of this study was to determine the relationship between HIC and response to interferon alfa therapy in patients with chronic hepatitis C. METHODS HIC was measured in liver biopsy specimens from 58 patients with chronic hepatitis C treated at three centers. Three patients had mild chronic hepatitis C, 35 had moderate to severe chronic hepatitis C, and 20 had active cirrhosis. Serum ferritin levels were measured in 51 of these 58 patients. Response to therapy was defined as normalization of alanine aminotransferase levels at the end of treatment. RESULTS Twenty-four patients (41%) responded to therapy. HICs were generally within the normal range (< 1500 micrograms/g). The mean HIC in nonresponders (860 +/- 100 micrograms/g; range, 116-2296 micrograms/g) was significantly higher than in responders (548 +/- 85 micrograms/g; range, 29-1870 micrograms/g) (P < 0.05). Eighty-eight percent of patients with an HIC of > 1100 micrograms/g and 87% of patients with an elevated serum ferritin concentration did not respond to interferon alfa therapy. CONCLUSIONS HIC seems to influence response to interferon alfa therapy among patients with chronic hepatitis C. A subgroup of patients with chronic hepatitis C has been identified for which an HIC of > 1100 micrograms/g predicted nonresponse in 88% of patients.

The role of laparoscopy in the diagnosis of cirrhosis

BACKGROUND A definitive diagnosis of cirrhosis is important in the prognosis and management of patients with chronic liver disease. The diagnosis of cirrhosis is made either by histologic examination of a biopsy specimen or upon visualization of a diffusely nodular and firm surface of the liver at laparotomy or laparoscopy. A liver biopsy, however, may not demonstrate the histologic features of cirrhosis in some cirrhotic patients. Our goal in this study was to compare the accuracy of liver descriptions made during laparoscopy with liver histology found by laparoscopic biopsy in patients with chronic liver disease. METHODS A retrospective review of paired laparoscopy and histology reports was performed on 434 consecutive patients who underwent laparoscopy between 1992 and 1994. (M:F ratio, 1.3:1; mean age, 48 +/- 14 years). ETIOLOGY 52% hepatitis C, 8% hepatitis B, 8% fatty liver, 4% primary biliary cirrhosis, 3% autoimmune hepatitis, and 25% miscellaneous (cancer patients were excluded). RESULTS One hundred sixty-nine patients had laparoscopic evidence of cirrhosis; 115 were confirmed by histology, representing a 32% sampling error. Two of 265 patients with histologic evidence of cirrhosis (0.8%) had no macroscopic evidence of cirrhosis at laparoscopy. CONCLUSIONS (1) There was a 32% histologic sampling error among patients documented to have cirrhosis by laparoscopy. (2) Using laparoscopy as a gold standard, the sensitivity of liver biopsy was 68% and the specificity was 99%.

Early Hepatitis B Virus DNA Reduction in Hepatitis B e Antigen-Positive Patients with Chronic Hepatitis B : A Randomized International Study of Entecavir Versus Adefovir

This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside‐naïve adults with chronic hepatitis B (CHB). Sixty‐nine nucleoside‐naïve CHB patients with baseline HBV DNA of 108 copies/mL or more were randomized 1:1 to open‐label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (−6.23 log10 copies/mL versus −4.42 log10 copies/mL, respectively; mean difference −1.58 log10 copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV−ADV difference estimate: −0.66 log10 copies/mL; 95% CI [−0.30, −0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir‐treated than adefovir‐treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV‐treated versus 15 (47%) ADV‐treated patients had HBV DNA of 105 copies/mL or more. Both antivirals were well tolerated. Conclusion: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside‐naïve HBeAg‐positive patients with CHB. (HEPATOLOGY 2009;49:72‐79.)

Treatment of Hepatitis B e Antigen-Positive Chronic Hepatitis with Telbivudine or Adefovir: A Randomized Trial

BACKGROUND The efficacy of nucleoside and nucleotide analogues for hepatitis B has been linked to the magnitude and durability of hepatitis B virus (HBV) suppression. OBJECTIVE To compare the antiviral efficacy of telbivudine and adefovir dipivoxil, and the effects of switching from adefovir to telbivudine, in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B. DESIGN Randomized, controlled, open-label trial. SETTING 16 outpatient clinics. PATIENTS 135 treatment-naive, HBeAg-positive adults with chronic hepatitis B. INTERVENTION Patients were randomly assigned in a 1:1:1 ratio to 52 weeks of telbivudine (group A) or adefovir (group B), or 24 weeks of adefovir and then telbivudine for the remaining 28 weeks (group C). One hundred thirty-one patients completed 52 weeks of treatment. MEASUREMENTS The primary efficacy comparison was serum HBV DNA reduction at week 24, with a secondary comparison at week 52. RESULTS At week 24, mean HBV DNA reduction was greater in group A than in pooled groups B and C (-6.30 vs. -4.97 log10 copies/mL; difference, -1.33 log10 copies/mL [95% CI, -1.99 to -0.66 log(10) copies/mL]; P < 0.001), and more patients in group A were polymerase chain reaction-negative (39% vs. 12%; odds ratio, 4.46 [CI, 1.86 to 10.72]; P = 0.001). At week 52, the mean residual HBV DNA level was lower in group A and group C than in group B (3.01 log10 copies/mL [group A] and 3.02 log10 copies/mL [group C] vs. 4.00 log10 copies/mL [group B]; difference, -0.99 log10 copies/mL [CI, -1.67 to -0.32 log10 copies/mL] and -0.98 log10 copies/mL [CI, -1.64 to -0.32 log10 copies/mL]; P = 0.004). Adverse events were similar across groups; the most common were upper respiratory symptoms, headache, back pain, and diarrhea. LIMITATIONS The trial was open-label and was not of sufficient size or duration to compare clinical outcomes and long-term efficacy. CONCLUSION Telbivudine demonstrated greater and more consistent HBV DNA suppression than adefovir after 24 weeks of treatment. After 52 weeks, HBV DNA suppression was greater in patients who had received continuous telbivudine or were switched to telbivudine after 24 weeks than in those who received continuous adefovir.

Peginterferon Alfa-2a and Ribavirin in Latino and Non-Latino Whites with Hepatitis C

BACKGROUND Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. METHODS In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. RESULTS Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. CONCLUSIONS Treatment with peginterferon alfa-2a and ribavirin for 48 weeks resulted in rates of sustained virologic response among patients infected with HCV genotype 1 that were lower among Latino whites than among non-Latino whites. Strategies to improve the sustained virologic response in Latinos are needed. (ClinicalTrials.gov number, NCT00107653.)

Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: A randomized, open‐label study

A randomized, open‐label comparative study of entecavir versus adefovir therapy was performed in subjects with chronic hepatitis B who had hepatic decompensation (Child‐Turcotte‐Pugh score ≥7). Adult subjects were randomized and treated (n = 191) with entecavir 1.0 mg or adefovir 10 mg daily for up to 96 weeks from the date of last subject randomization. Subjects were positive or negative for hepatitis B e antigen and experienced or naive for treatment with nucleos(t)ide analogues. The primary efficacy endpoint was the mean reduction in serum hepatitis B virus (HBV) DNA, as determined by polymerase chain reaction, at week 24, adjusted for baseline HBV DNA and lamivudine resistance status by linear regression analysis. Entecavir demonstrated superiority to adefovir for this endpoint (treatment difference 1.74 log10 copies/mL [95% confidence interval −2.30, −1.18]; P < 0.0001). The entecavir group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved HBV DNA < 300 copies/mL at weeks 24 (entecavir 49%; adefovir 16%; P < 0.0001) and 48 (entecavir 57%; adefovir 20%; P < 0.0001). Approximately two‐thirds of subjects in both groups showed improvement/stabilization in Child‐Turcotte‐Pugh status. Model for End‐Stage Liver Disease score change at week 48 was −2.6 for entecavir and −1.7 for adefovir. Adverse event rates were comparable between groups. Cumulative hepatocellular carcinoma rates were 12% for entecavir and 20% for adefovir. Cumulative death rates were 23% for entecavir and 33% for adefovir. Week 24 mortality rates were 12% for both groups. Conclusion: Entecavir demonstrated superior virologic efficacy to adefovir in a population of patients with chronic hepatitis B who had hepatic decompensation. Biochemical and clinical benefits were also demonstrated. Entecavir was well tolerated, and early mortality rates were consistent with rates observed in similar populations treated with lamivudine. (HEPATOLOGY 2011;)

Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection

BACKGROUND:Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.METHODS:We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.RESULTS:Overall, 32.2% (95% CI, 30.8–33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2–42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24–25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85–13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70–13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42–16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0–78.3%) agreed to be treated and multivariable analysis showed that persons ≥50 yr of age (OR = 1.37; 95% CI, 1.07–1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08–1.93) were more likely to decline treatment.CONCLUSIONS:The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.