Robert P. Perrillo

Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States

BACKGROUND AND METHODS Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

A Randomized, Controlled Trial of Interferon Alfa-2b Alone and after Prednisone Withdrawal for the Treatment of Chronic Hepatitis B

Abstract Background and Methods. Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment. Results. Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P<0.001); the difference between those given 1 million units of interferon (7 of 41; 17 percent) and the controls was not significant. The strongest indep...

Long-Term Mortality after Transfusion-Associated Non-A, Non-B Hepatitis

Abstract Background. Acute non-A, non-B hepatitis after blood transfusion often progresses to chronic hepatitis and sometimes culminates in cirrhosis or even hepatocellular carcinoma. However, the frequency of these sequelae and their effects on mortality are not known. Methods. We traced patients with transfusion-related non-A, non-B hepatitis who had been identified in five major prospective studies conducted in the United States between 1967 and 1980. We matched each patient with two control subjects (identified as the first and second controls) who received transfusions but who did not have hepatitis. The mortality rates in the three groups were determined with use of data from the National Death Index and Social Security Death Tapes. Cause-specific mortality was determined by reviewing death certificates. Results. Vital status was established for over 94 percent of the 568 patients who had had non-A, non-B hepatitis and the two control groups (526 first controls and 458 second controls). After an ave...

Pathological diagnosis of chronic hepatitis C: A multicenter comparative study with chronic hepatitis B

BACKGROUND Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain. METHODS In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens. RESULTS Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1). CONCLUSIONS These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.

Hepatitis B virus genotypes in the United States: results of a nationwide study

BACKGROUND & AIMS Hepatitis B virus (HBV) genotypes may be related to severity of liver disease and treatment response. The aims of this nationwide study were to determine the prevalence of HBV genotypes in the United States and the association between HBV genotypes and patient demographics, mode of infection, and clinical status. METHODS A total of 694 consecutive chronic HBV-infected patients seen in 17 U.S. liver centers during a 1-year period were enrolled. Demographic, clinical, and laboratory data were collected. Sera were tested for HBV genotyping, precore, and core promoter variants by line-probe assays. RESULTS All 7 HBV genotypes (A-G) were found, with genotypes A and C the most common. The prevalence of HBV genotypes was different in different regions of the United States. A strong correlation was found between HBV genotypes and ethnicity. HBV genotype A was prevalent among white and black patients, whereas genotypes B and C were most common among Asian patients. The predominant genotype among patients born in the United States, Europe, the Far East, and Southeast Asia were A, D, C, and B, respectively. Genotypes A and C were associated with a higher prevalence of hepatitis B e antigen. Precore variant was detected in 27% of patients and core promoter variant in 44% of patients. CONCLUSIONS Our study suggests that the epidemiology of HBV infection in the United States may have changed over time as a result of immigration from countries with a high prevalence of HBV infection. HBV genotypes may account for the heterogeneity in disease manifestations among patients with chronic HBV infection.

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

Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus

BACKGROUND & AIMS Interferon therapy has been associated with a number of severe side effects when administered to patients with decompensated cirrhosis caused by chronic hepatitis B. The safety and potential efficacy of a low-dose, titratable regimen of interferon alfa-2b in patients with decompensated liver disease caused by chronic hepatitis B virus infection were studied. METHODS Twenty-six patients were treated at five medical centers. Five patients had Childs class A status, 15 had Childs B status, and 6 had Childs C status. Treatment was continued for 24 weeks whenever possible. Dose adjustments were made according to predefined safety criteria. RESULTS All patients with Childs A status responded with a sustained loss of serum hepatitis B virus DNA, reduction in aminotransferase activity, and clinical stabilization. Only 5 patients with Childs B (33%) and no patients with Childs C status reached similar end points. The probability of survival was greater in responders than in nonresponders (P = 0.017). Three patients each developed serious infections or greater than twofold increases in serum aminotransferase levels during therapy. CONCLUSIONS Low-dose, titratable interferon therapy is safer than previously reported regimens. Nonetheless, serious infections were observed relatively frequently, and this therapy should be reserved for individuals with mild to moderate hepatic decompensation, preferably patients with Childs A status.

Prednisone Withdrawal Followed by Recombinant Alpha Interferon in the Treatment of Chronic Type B Hepatitis: A Randomized, Controlled Trial

STUDY OBJECTIVE To determine the efficacy of a short course of prednisone followed by recombinant interferon treatment in patients with chronic type B hepatitis. DESIGN Randomized, controlled trial with a 5-month treatment phase and a 9-month observation period after treatment. SETTING Two referral-based university-affiliated medical centers. PATIENTS Thirty-nine clinically stable patients with chronic type B hepatitis, all of whom were positive for hepatitis B antigen, hepatitis B virus-associated-DNA (HBV-DNA), and DNA polymerase for at least 6 months before entry. Patients included 20 heterosexuals and 19 male homosexuals. INTERVENTIONS Eighteen patients were treated with a 6-week tapered regimen of prednisone, followed by 90 days treatment with recombinant interferon alpha-2b; 21 patients were untreated controls. Paired liver biopsy specimens of 27 patients (pretreatment and 9 months after treatment) were blindly evaluated. MEASUREMENTS AND MAIN RESULTS Nine treated patients had a sustained loss of HBV-DNA. In addition, eight treated patients lost hepatitis B e antigen and four became negative for hepatitis B surface antigen (HBsAg). When compared with controls the differences were statistically significant for clearance of HBV-DNA and HBsAg (P = 0.035 and 0.037, respectively). Treated patients who had a sustained loss of HBV-DNA had higher initial alanine aminotransferase lower initial DNA and DNA polymerase levels, and were more frequently heterosexual. Patients who responded to treatment with the disappearance of hepatitis B e antigen and HBV-DNA had normal liver function tests and markedly improved liver histology during follow-up. CONCLUSIONS The immunologic priming provided by a short course of prednisone used with alpha interferon may be an effective treatment for selected patients with chronic type B hepatitis.

Benefits and risks of interferon therapy for hepatitis B.

Alpha interferon is the only licensed drug for hepatitis B with immunomodulatory as well as viral inhibitory properties. Potential advantages of interferon compared to nucleoside analogs include a lack of drug resistance, a finite and defined treatment course, and a higher likelihood for hepatitis B surface antigen (HBsAg) clearance. Approximately 30% of hepatitis B e antigen (HBeAg)‐positive and 40% of HBeAg‐negative cases have a sustained virological response (when defined as HBeAg seroconversion and/or hepatitis B virus (HBV) DNA levels below 20,000 copies/mL, respectively) 6 months after completion of a 48‐week course of peginterferon alfa‐2a These responses remain durable in 80% and 50% of cases, respectively, when evaluated several years later. Recent studies have shown that changes in HBsAg and HBeAg concentration during treatment predict sustained virological response and serial monitoring of HBsAg is helpful in predicting HBsAg clearance. HBeAg‐positive patients with genotype A have higher rates of HBeAg and HBsAg clearance, whereas HBeAg‐negative patients with genotype D have the lowest rate of response to interferon therapy. Long‐term follow‐up of virological responders to either standard alpha interferon or peginterferon has demonstrated a progressive increase in the rate of HBsAg clearance, particularly in patients who were initially HBeAg‐positive. Future studies need to address if specific virological benchmarks during therapy can be used to tailor treatment duration. Conclusion: Peginterferon alfa has a place as first‐line therapy of hepatitis B in patients who are carefully selected on the basis of pretreatment serum HBV DNA and aminotransferase levels, safety considerations, and viral genotype. (HEPATOLOGY 2009;49:S103–S111.)

Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B☆

BACKGROUND/AIMS We aimed to evaluate nucleoside/nucleotide combination therapy in treatment-naïve HBeAg-positive patients with chronic hepatitis B (CHB). METHODS One hundred and fifteen HBeAg-positive patients received lamivudine 100 mg daily plus placebo (monotherapy) or lamivudine 100 mg plus adefovir dipoxil 10 mg daily (combination therapy) for 104 weeks in a randomized double-blind study. RESULTS Time-weighted average change in serum HBV DNA from baseline up to week 16 was -4.20 log(10)copies/mL for both groups (p=0.936). At week 104, median serum HBV DNA change from baseline (log(10)copies/mL) for monotherapy and combination therapy was -3.41 versus -5.22, respectively. HBV DNA breakthrough was detected in 44% of monotherapy and 19% of combination therapy patients. The M204V/I mutation was detected in 43% (15/35) and 15% (6/41) of each group, respectively. ALT normalization at week 100 and 104 was 34% (19/56) in the monotherapy group and 45% (23/51) in the combination therapy group (p=0.018). By week 104, HBeAg seroconversion occurred in 20% of monotherapy and 13% of combination therapy patients. Both regimens were well tolerated. CONCLUSIONS Lower rates of resistance to lamivudine, lower serum HBV DNA levels and higher rates of ALT normalization were seen in the combination therapy group after two years. However, serological outcomes were similar.