Efficacy of pegylated interferon α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy

Zhang et al. Virology Journal 2013, 10:21 http://www.virologyj.com/content/10/1/21 RESEARCH Open Access Efficacy of pegylated interferon α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy Xu-Qing Zhang*, Hui-Yan Zhang, Jian-Ping You and Qing Mao* Abstract Background: Improving the HBe seroconversion rate of patients without HBeAg loss after long-term lamivudine therapy has become an urgent clinical problem that we have to face. Unfortunately, there is no consensus on the mananement of these patients. The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. Methods: Fifty patients with chronic hepatitis B without the loss of HBeAg after ≥96 weeks of lamivudine treatment were enrolled to withdraw from treatment to induce a biochemical breakthrough. Patients who achieved a biochemical breakthrough within 24 weeks received 48-weeks of PEG-IFN α2a therapy, and were then assessed during a subsequent 24-week follow-up period. Results: Forty-three (86.0%) patients achieved a biochemical breakthrough within 24 weeks of lamivudine withdrawal. The rates of combined response (both undetectable HBV DNA and HBeAg loss) and HBsAg loss were alone 51.2% and 20.9%, respectively after 48 weeks of PEG-IFN α2a therapy, and 44.2% and 18.6%, respectively, at 24 weeks after treatment cessation. The end-of-treatment combined response rate was 65.4% among patients with a baseline HBsAg <20,000 IU/mL, which was significantly higher than 29.4% of patients with HBsAg ≥20,000 IU/mL (P=0.031). For patients with HBsAg levels <1,500 IU/mL at 12 and 24 weeks therapy, the end-of-treatment combined response rate was 68.2% and 69.0%, which were both significantly higher than patients with HBsAg ≥1,500 IU/mL (33.3% and 14.3%; P=0.048 and 0.001). The end-of-treatment combined response rate was significantly higher among patients with HBV DNA<105 copies/mL (76.2%) compared to patients with HBV DNA ≥105 copies/mL (27.3%) after 24 weeks of therapy (P=0.004). Conclusion: Retreatment with PEG-IFN α2a was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. HBsAg levels at the baseline, 12 and 24 weeks of therapy, and HBV DNA levels at 24 weeks of therapy, can predict the effect of PEG-IFN α2a after 48 weeks of therapy. Keywords: Chronic hepatitis B, Pegylated interferon α2a, Lamivudine, Biochemical breakthrough Background Chronic infection with hepatitis B virus (HBV) is a major global health problem, which affects more than 400 million people worldwide [1,2]. Approximately 15– 40% of infected patients develop cirrhosis, liver failure or hepatocellular carcinoma (HCC). Appropriate antiviral treatment has been confirmed to be effective in * Correspondence: ; Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China preventing advanced liver disease and reducing the number of HBV-related deaths. The current treatment options for chronic HBV infection consist of interferon-α (IFN-α) and nucleos(t) ide analogues (NUCs), such as lamivudine, adefovir, entecavir and telbivudine. Since lamivudine was initially approved for the treatment of chronic HBV infection in China, several million affected patients have received long-term antiviral treatment with NUCs to prevent disease progression. Most patients hope that the period of antiviral treatment is temporary. In HBeAg- positive © 2013 Zhang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Virology Journal 2013, 10:21 http://www.virologyj.com/content/10/1/21 patients, durable HBe seroconversion is a satisfactory end-point as it is associated with an improved prognosis [1]. However, it is very difficult for most HBeAg positive patients to meet the criteria for the cessation of lamivudine treatment. In these patients, the rate of HBe seroconversion with lamivudine treatment has been reported to be 16-17% at 48 weeks, 17-29% at 96 weeks, 23-40% at 144 weeks, and 28-47% at 192 weeks [1-4]. Unfortunately, extended treatment with lamivudine is associated with the development of drug resistance. The cumulative incidence of HBV resistance to lamivudine is 24% at 1 year, 38% at 2 years, 49% at 3 years, 67% at 4 years, and 70% at 5 years. Therefore, it is very important to institute new treatment strategies to improve the rate of HBeAg loss or HBe seroconversion for patients without HBeAg loss after long-term lamivudine treatment. However, there are no definitive guidelines regarding whether lamivudine therapy should be continued or a new treatment should be commenced and the optimal stopping point for receiving lamivudine treatment has yet to be determined. IFN-α exerts an antiviral effect by degrading viral mRNA and proteins, and upregulates the immunological response to HBV by enhancing human leukocyte antigen class I expression on hepatocytes, its use has been confirmed as effective in the treatment of chronic HBV infection [1,5-8]. The use of pegylated interferon (PEGIFN) α has certain advantages over NUCs, which include the absence of resistance, higher rates of HBeAg loss and seroconversion, and higher rates of both sustained off-treatment virological responses and HBsAg loss [1]. For HBeAg-positive patients with PEG-IFNα, higher rates of HBeAg loss or seroconversion are associated with higher pre-treatment serum alanine aminotransferase (ALT) levels. Additionally, post-treatment ALT flares with viral proliferation often occur following the withdrawal of lamivudine. Thus, a new retreatment strategy that involves switching from lamivudine during a withdrawal-induced ALT flare to PEG-IFN α2a therapy is a reasonable protocol for patients without HBeAg loss after long-term lamivudine treatment. However, neither the efficacy nor safety of this new treatment strategy has been fully demonstrated. The aim of our study was to evaluate the use of PEG-IFN α2a therapy for the retreatment of patients with chronic HBV infection after a lamivudine withdrawal-induced biochemical breakthrough. These patients were without HBeAg loss after more than 96 weeks lamivudine treatment. Methods Selections of patients and study design Inclusion criteria included: i) age 18–60 years; ii) continuous lamivudine treatment >96 weeks; iii) serum HBV DNA levels <103 copies/mL;iv) positive for HBsAg Page 2 of 9 and HBeAg, but negative for anti-HBs and anti-HBe;v) normal liver function tests;vi) no history of liver failure or cirrhosis,and the lack of cirrhosis confirmed by a computed tomography scan; vii) neutrophil count ≥ 1.5×109/L and platelet count ≥100×109 (...truncated)