hepwatch 2004.11

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HEPATITIS B VIRUS (HBV) TREATMENT TRIALS

Peginterferon alfa-2a versus lamivudine in HBeAg-negative patients. HBeAg-negative chronic hepatitis B is a late stage of infection characterized by progressive liver disease. Current consensus guidelines recommend treatment with interferon alfa or nucleoside/nucleotide analogues. However, these therapies are associated with poor sustained response rates and/or the development of resistance. Peginterferon alfa-2a has yielded superior outcomes to interferon alfa in patients with HBeAg-positive chronic hepatitis B (Cooksley, J Viral Hepatitis, 2003). The current multicenter, partially double-blind study conducted by Patrick Marcellin and others randomized HBV patients who had been negative for HBeAg for at least 6 months to receive either peginterferon alfa-2a (180 ug once weekly) plus placebo (n = 177), peginterferon alfa-2a plus lamivudine (100 mg daily) (n = 179), or lamivudine alone (n = 181). Patients were treated for 48 weeks and followed for another 24 weeks. Sustained suppression of HBV DNA to <400 copies/mL occurred in 19%, 20%, and 7% of patients treated with peginterferon alfa-2a plus placebo, combination therapy, and lamivudine alone, respectively (p <0.001 for both peginterferon vs. lamivudine and combination therapy vs. lamivudine). A significantly greater percentage of peginterferon-treated patients had normalization of alanine aminotransferase (ALT) levels compared to patients treated with lamivudine alone. In addition, 12 patients who received peginterferon versus no patients in the lamivudine alone treatment group had loss of HBsAg. This study showed that patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a had higher sustained response rates than those receiving lamivudine. Moreover, the addition of lamivudine to peginterferon therapy did not improve the sustained response rate. Additional follow-up is needed to determine the durability of response. (Marcellin P, et al. N Engl J Med 2004; 351:1206-1217)

Dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic HBV infection. Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against HBV in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity and pharmacokinetics were assessed in 43 adults with HBeAg-positive chronic hepatitis B. This placebo-controlled, dose-escalation trial investigated 6 telbivudine dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks’ follow-up. Marked dose-related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800 mg/d cohort, the mean HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a 99.98% reduction viral load. Correspondingly, post-treatment return of viral load was slowest in the high-dose groups. Telbivudine was well tolerated at all dosing levels, with no dose-related or treatment-related clinical or laboratory adverse events. These results support expanded clinical studies of this new agent for the treatment of chronic hepatitis B. (Lai C-L et al. Hepatology 2004; 40:719-26)

NATURAL HISTORY OF HBV INFECTION

Follow-up of patients from an early stage of HBV infection. Natural history studies of patients with chronic HBV infection have reported hepatitis relapse rates of 5% to 15% and annual rates of progression to cirrhosis of 2% to 6%. C.M. Chu and colleagues at the Chang Gung Memorial Hospital (Taipei, Taiwan) reviewed the clinical course of HBeAg to anti-HBe seroconversion in 240 HBeAg-positive carriers who had normal ALT levels at baseline to provide natural history data beginning at an early phase of HBV infection. The mean age at study entry was 27.6 ± 6.2 years. Prior to seroconversion, 29% of patients experienced an increase in ALT levels to ≥200 U/L and 3% had serum bilirubin levels ≥2.0 mg/dL. The mean age at which anti-HBe seroconversion occurred was 31.3 ± 7.0 years. Hepatitis recurred in 36 (15%) patients at an annual rate of 2.2%. Cirrhosis developed in 13 (5%) patients at an annual rate of 0.5%. The cumulative probability of cirrhosis after 17 years was 12.6%. Multivariate analysis identified age at anti-HBe seroconversion and relapse of hepatitis to be independent risk factors for the development of cirrhosis. The authors suggest that following these patients from an early stage of HBV infection may have decreased the effects of referral bias on the clinical data. The findings indicate that this cohort of chronic HBV patients had a less severe clinical course than that reported in previous natural history studies. (Chu CM, et al. Am J Med 2004; 116:829-834)

LIVER TRANSPLANTATION (OLT)

Improved outcome. During the 1990s important innovations, such as the use of hepatitis B immune globulin (HBIG) and lamivudine, have improved the outcome of patients undergoing OLT for HBV-related disease. In order to examine the effects of these innovations, Ray Kim et al. at the Mayo Clinic in Rochester performed a retrospective analysis of data collected by the United Network for Organ Sharing for all adult patients who underwent primary OLT in the US between 1987 and 2002. Patients were divided into the following 3 eras: Era 1, 1987-1991 (n = 6,708 [675 with HBV]); Era 2, 1992-1996 (n = 13,995 [1,005 with HBV]); and Era 3, 1997-2002 (n = 20,730 [1,723 with HBV]). The survival of HBV patients was greater in Era 2 versus Era 1 and in Era 3 versus Era 2. No difference in survival was detected between patients with HBV infection and those with all other diagnoses. Multivariate analysis identified the effect of these eras to independently predict survival. Fulminant disease and Asian race had no effect on patient survival. These findings demonstrate the importance of the implementation of therapeutic innovations over the past 15 years for HBV patients undergoing OLT. (Kim WR, et al. Liver Transpl 2004;10: 968-974)