对E抗原阴性病人派罗欣优于拉米(20040915HIV&HBV)

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Sept. 15, 2004 ?Peginterferon alfa-2a (PegIF) is superior to lamivudine for controlling chronic hepatitis B e antigen (HBeAg)-negative hepatitis B virus (HBV), and lamivudine does not add to the benefit of interferon, according to the results of a randomized trial published in the Sept. 16 issue of the New England Journal of Medicine. "Available treatments for HBeAg-negative chronic hepatitis B are associated with poor sustained responses," write Patrick Marcellin, MD, from H魀ital Beaujon in Clichy, France, and colleagues from the HBeAg-Negative Chronic Hepatitis B Study Group. "As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications." Current consensus guidelines recommend interferon-alfa or nucleoside or nucleotide analogues as first-line therapy for HBeAg-negative chronic HBV. However, the suboptimal pharmacokinetics of conventional interferon-alfa require inconvenient dosing, and drug resistance associated with lamivudine increases with extended use. PegIF has better pharmacokinetics than conventional interferon-alfa, allowing once-weekly dosing. In this study, 177 patients with HBeAg-negative chronic HBV were randomized to receive PegIF (180 礸 once weekly) plus placebo, 179 patients to PegIF plus lamivudine (100 mg daily), and 181 patients to receive lamivudine alone. Treatment duration was 48 weeks, and patients were followed up for an additional 24 weeks. After 24 weeks of follow-up, normalization of alanine aminotransferase (ALT) levels occurred in 59% of patients treated with PegIF monotherapy, in 60% of those treated with PegIF plus lamivudine, and in 44% of those treated with lamivudine monotherapy (P = .004). HBV DNA levels decreased below 20,000 copies/mL in 43%, 44%, and 29%, respectively (P = .003). Rates of sustained suppression of HBV DNA to below 400 copies/mL were 19% with PegIF monotherapy, 20% with combination therapy, and 7% with lamivudine alone (P < .001 for both peginterferon groups vs lamivudine alone). Loss of HBV B surface antigen (HBsAg) occurred in 12 patients receiving PegIF alone or in combination and in none of the patients receiving lamivudine alone. Compared with patients receiving PegIF monotherapy or combination therapy, patients receiving lamivudine monotherapy had fewer adverse events, including pyrexia, fatigue, myalgia, and headache. "Our data demonstrate the possibility of achieving HBsAg loss or seroconversion in patients with HBeAg-negative chronic hepatitis B with the use of peginterferon alfa-2a and therefore support the use of this agent as a first-line therapy for HBeAg-negative chronic hepatitis B," the authors write. "The ability of this agent to improve and sustain biochemical, virologic, and HBsAg response rates constitutes a therapeutic advance over current treatments, which are associated with poor rates of sustained response after the cessation of therapy." Roche supported this study, employs two of its authors, and has various financial arrangements with seven other authors, who also report various financial arrangements with Bristol-Myers Squibb, Gilead Sciences, Bayer, Novartis, Vertex Pharmaceuticals, Valeant Pharmaceuticals, Schering-Plough, and/or GlaxoSmithKline. N Engl J Med. 2004;351:1206-1217 Learning Objectives for This Educational Activity Upon completion of this activity, participants will be able to:Compare the effects of PegIF alone, lamivudine alone, and the combination of both drugs in patients with HBeAg-negative chronic HBV. List adverse events associated with the treatments.Clinical Context HBeAg-negative chronic HBV is a late phase of hepatitis B infection representing progressive viral damage and complications include liver failure, hepatocellular carcinoma, and cirrhosis. It has a poor prognosis and spontaneous sustained remissions are rare. Available therapies include interferon-alfa or nucleosides or nucleoside analogues as first-line treatment. However, interferon-alfa has an inconvenient dosing regimen while lamivudine is associated with drug resistance. PegIF has a dual immunomodulatory and antiviral action with convenient once weekly dosing and has been associated with superior clinical outcomes in patients with chronic hepatitis C and HBeAg-positive chronic HBV. The authors of this partially double-blind international multicenter study compared the efficacy and tolerability of monotherapy with either PegIF or lamivudine and the combination for 48 weeks of treatment and 24 weeks of follow-up in 537 patients with HBeAg-negative chronic HBV. Study Highlights Inclusion criteria were liver biopsy within 24 months consistent with chronic HBV, positive for anti-HBe antibody and HBsAg for at least 6 months, HBeAg-negative, HBV DNA level of more than 100,000 copies/mL, and serum ALT level of more than 1 and 10 times or less normal. Exclusion criteria were decompensated liver disease, serious medical or psychiatric problem, platelet count less than 90,000/mL, neutrophil count less than 1,500/mL, drug or alcohol abuse within one year, and coinfection with hepatitis C or D.179 patients received PegIF, 180 礸, once weekly, 181 received lamivudine, 100 mg, alone daily, and 177 received the combination for 48 weeks. Primary outcomes after 24 weeks of follow-up (at 72 weeks) were normalization of ALT and suppression of HBV DNA levels to below 20,000 copies/mL. Secondary outcomes were proportion with HBsAg loss, HBsAg seroconversion, histologic response, and suppression of HBV DNA to less than 400 copies/mL. Safety analysis included adverse events graded as mild, moderate, and severe. Resistance was determined by extracting mutations in the YMDD motif of the HBV polymerase gene.The study was powered at 80% to detect a primary response rate of 15% at a 0.025 significance level and secondary response rates at a 0.05 significance level. Intent-to-treat analysis was used.85% of patients were male, 60% were Asian, and 36% were white. Median age was 40 years, weight was 70 kg, ALT level was 65 IU/L, and HBV DNA level was 7 log copies/mL. One quarter had bridging fibrosis or cirrhosis on biopsy. At week 72, 59% of patients in the PegIF and 60% in the combination compared with 44% in the lamivudine group had significant ALT reductions (P = .004 and .003, respectively). During therapy, a significantly higher percentage of patients receiving PegIF (12%) compared with combination (4%) or lamivudine (6%) had ALT levels more than 10 times normal (P = .007 and .04, respectively). After completion of therapy, the percentage was higher for the lamivudine (14%) and the combination (15%) compared with the PegIF group (P = .03 and .02, respectively). At week 72, suppression of HBV DNA to below 20,000 copies/mL occurred in a greater percentage of patients receiving PegIF (43%) and combination (44%) than those taking lamivudine (29%); P = .007 and .003, respectively. At week 72, HBsAg loss occurred in 7 patients receiving PegIF, in 5 receiving combination, and in none receiving lamivudine. HBsAg seroconversion occurred in 5 receiving PegIF; 3, combination treatment; and none, lamivudine. Differences were significant at P = .007 and .03, respectively. Histologic response was similar in the 3 groups. There was a significant association between histologic improvement and virologic and biochemical response at week 72. Rate of adverse events were significantly less in the lamivudine group. The most common adverse events associated with the combination and the PegIF groups were pyrexia, fatigue, myalgia, and headache. Adverse events occurred in 5% of those receiving PegIF; 7%, combination; and 3%, lamivudine therapy. At week 48, 18% of patients receiving lamivudine compared with 1% of those in the combination group had YMDD mutations. Mean neutrophil and platelet counts were reduced during combination and PegIF treatment but returned to normal after treatment cessation. Pearls for Practice PegIF alone or in combination with lamivudine compared with lamivudine alone resulted in higher rates of sustained response in patients with HBeAg-negative chronic HBV. The addition of lamivudine to PegIF did not improve response rates. The most common adverse events with PegIF alone or in combination with lamivudine were pyrexia, fatigue, myalgia, and headache. To Post a message, send it to: [email protected] ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ To Unsubscribe, send a blank message to: [email protected] Yahoo! Groups Links <*> To visit your group on the web, go to: http://groups.yahoo.com/group/hepatitis-awareness/ <*> To unsubscribe from this group, send an email to: [email protected] <*> Your use of Yahoo! Groups is subject to: http://docs.yahoo.com/info/terms/