Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B

BACKGROUND & AIMS: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. METHODS: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). RESULTS: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was -5.11 log(10) copies/mL for entecavir-treated patients and -0.48 log(10) copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. CONCLUSIONS: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile.     

恩替卡韦分散片治疗慢性乙型肝炎临床研究

目的评价恩替卡韦分散片治疗慢性乙型肝炎（chronic hepatitisB,CHB）的抗病毒疗效及安全性。方法采用随机、双盲、双模拟、阳性药物恩替卡韦片（博路定）平行对照试验方法。120例CHB患者按2：1的比例随机双盲分成2组,其中试验组80例,对照组40例。24周的双盲治疗期间,试验组13服恩替卡韦分散片0．5mg／d及不含恩替卡韦片的模拟剂1片,d,对照组口服恩替卡韦片0．5mg／d及不含恩替卡韦分散片的模拟剂1片／d;接着2组均接受24周的开放治疗,13服恩替卡韦分散片0．5mg／d。结果治疗12周时试验组和对照组血清HBVDNA水平分别下降4．98、4．73log10治疗24周时分别下降5．45、5．0010‰,治疗48周时分别下降5．19、5．01log10,2组比较差异均无统计学意义。治疗12周时试验组与对照组血清HBVDNA水平完全抑制（〈1×10^2U／m1）率分别为41．33％和51．43％,治疗24周时分别为83．10％和74．19％,治疗48周时分别为76．47％和67．74％,2组比较差异均无统计学意义。治疗12周和24周时试验组和对照组血清HBVDNA水平较基线水平下降≥2log10的比例均为100．00％,治疗48周时分别为95．59％和100．00％,2组比较差异均无统计学意义。治疗12周时试验组和对照组的ALT复常率分别为92．00％和82．86％,治疗24周时分别为97．18％和93．55％,治疗48周时分别为83．82％和90．32％,2组比较差异均无统计学意义。试验组和对照组均未发生任何严重不良事件。结论恩替卡韦分散片在治疗CHB方面具有显著的抗病毒作用,疗效与恩替卡韦片相当,是一种安全有效的抗乙肝病毒药物。     

恩替卡韦:一种有希望的抗慢性乙型肝炎药物

目前全球有20多亿人感染乙型肝炎(乙肝)病毒,其中有约3.5亿人为慢性感染(终生感染)者.这些感染者可能死于肝硬化及肝癌的几率很高[1].这3.5亿人当中,75%居住在亚洲[2].原发性肝癌或肝细胞癌(HCC)在许多亚洲国家位列癌症死因的前3名.根据世界卫生组织(WHO)的数据显示,全球每年有超过50万人死于原发性肝癌,而80%的肝癌起因于乙型肝炎(乙肝)[3].我国是全球乙肝和肝癌负担最沉重的国家,HBV流行率最高,HBV病毒携带者占全球总数的1/3以上.据估计约有1.2亿～1.3亿乙肝病毒携带者.     

恩替卡韦联合苦参素治疗慢性乙型肝炎48周疗效观察

目的：观察恩替卡韦联合苦参素治疗慢性乙型肝炎患者48周的临床疗效。方法选择慢性乙型肝炎患者100例,随机分为两组。治疗组52例应用恩替卡韦片联合苦参素片治疗;对照组48例仅服用恩替卡韦片,观察48周。结果在治疗48周时,联合组患者血清 ALT 复常率、HBeAg 转阴率和 HBV DNA 转阴率分别为80.77%、82.69%和82.67%,均优于对照组的72.92%、58.33%和62.50%,差异均具有统计学意义（P〈0.05）。结论恩替卡韦联合苦参素治疗慢性乙型肝炎具有协同作用,且无不良反应。     

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

Purpose This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and safety of entecavir in Chinese patients with lamivudine-refractory chronic hepatitis B. Methods One hundred forty-five lamivudine-refractory patients with chronic hepatitis B were randomized to double-blind treatment with oral entecavir 1 mg (n = 116) or placebo (n = 29) daily for 12 weeks, followed by 36 weeks of open-label entecavir treatment. The primary efficacy endpoint was the mean change from baseline in serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) assay at week 12. Results At week 12, the mean change from baseline in serum HBV DNA by PCR assay was –4.30 log₁₀ copies/ml for patients on entecavir compared to –0.15 log₁₀ copies/ml for patients on placebo (P < .0001). Among patients with baseline serum alanine aminotransferase (ALT) >1 × upper limit of normal (ULN), a higher proportion of entecavir than placebo patients (68% vs. 6%, respectively) achieved ALT normalization by week 12 (P < .0001). After 48 weeks of entecavir treatment, the mean change in HBV DNA by PCR assay was –5.08 log₁₀ copies/ml, and 85% of patients with baseline ALT >1 × ULN had achieved ALT normalization. The safety profile of entecavir was similar to that of placebo during the first 12 weeks of blinded dosing. Entecavir was also well tolerated during 36 weeks of open-label treatment. Conclusions Lamivudine-refractory chronic hepatitis B patients treated with entecavir demonstrated marked HBV DNA reduction and normalization of ALT in most cases. Entecavir treatment for 48 weeks was well tolerated. This clinical trial was sponsored by Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT, USA.     

Interferon-based treatment of chronic hepatitis D

Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon-alfa for more than three decades. First studies to treat HDV-infected patients with type 1 interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one-quarter to one-third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long-term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon-alfa will still have an important role in the management of hepatitis D – either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon-based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development.     

恩替卡韦联合胸腺素α1治疗慢性乙型肝炎患者疗效及其外周血T淋巴细胞亚群的变化

目的 探讨恩替卡韦联合胸腺素α1治疗慢性乙型肝炎患者疗效及其外周血T淋巴细胞亚群的变化。方法 2014年3月~2015年12月我院诊治的慢性乙型肝炎患者76例,被随机分为观察组38例和对照组38例,分别给予恩替卡韦联合胸腺素α1或恩替卡韦治疗,观察48 w。结果 在治疗48 w末,观察组患者外周血CD4+和CD8+细胞百分比分别为（38.5±5.0）%和（27.6±4.7）%,显著高于对照组的（23.4±4.2）%和（22.3±4.2）%,差异具有统计学意义（P<0.05）;观察组血清AST水平为（23.8±4.2） U/L,显著低于对照组的（46.4±6.2） U/L,差异具有统计学意义（P<0.05）;观察组血清 HBeAg 阴转率为 26.3%,显著高于对照组的15.8%（P<0.05）。结论 恩替卡韦联合胸腺素α1治疗慢性乙型肝炎患者能够有效地提高血清HBeAg阴转率,可能与改善了患者免疫功能有关。     

恩替卡韦治疗慢性乙型肝炎的临床研究

目的评价恩替卡韦治疗慢性乙型肝炎(CHB)的疗效和安全性。方法72例CHB患者随机分配到治疗组和对照组,治疗组(30例)予恩替卡韦0.5mg/d;对照组(42例)予拉米夫定100mg/d疗程均48周,基础治疗相似。结果治疗组和对照组在治疗24周、48周时:血清HBV-DNA水平比基线值(log10copies/ml)平均下降分别为5.48、6.87和2.84、5.38;病毒应答率分别为53%、67%和21%、43%。均P<0.001,两组均有显著差异。ALT复常率分别为67%、77%和60%、67%,血清HBeAg阴转率、HBsAg消失率、不良事件发生率,均P>0.05,差异无统计学意义。无严重不良反应发生。结论恩替卡韦治疗慢性乙型肝炎,可在病毒学及生物化学方面取得显著疗效,且安全性良好,无耐药发生。     

Entecavir up-regulates dendritic cell function in patients with chronic hepatitis B

AIM： To investigate the in vitro effect of entecavir （ETV on the function of dendritic cells （DCs） derived from chronic hepatitis B （CHB） patients. METHODS： Mononuclear cells were isolated from peripheral blood of patients with CHB. DCs wer incubated with RPMI-1640 medium supplemented wit fetal bovine serum, IL-4, granulocyte-macrophag colony-stimulating factor （GM-CSF）. DCs were treate with or without ETV on the fourth day. Cell surfac molecules, including CD1a, CD80, CD83 and HLA-DR were assessed by flow cytometry. Concentrations of IL- and IL-12 in the supernatant were assayed by enzyme linked immunosorbent assay （ELISA）. The ability of th generated DCs to stimulate lymphocyte proliferation wa observed. RESULTS： Compared with CHB control group, th expression levels of CD1a （29.07 ± 3.20 vs 26.85 ± 2.80 CD83 （25.66 ± 3.19 vs 23.21 ± 3.10）, CD80 （28.00 ± 2.7 vs 25.75 ± 2.51） and HLA-DR （41.96 ± 3.81 vs 32.20 ± 3.04） in ETV-treated group were higher （P 〈 0.05）. ETV treated group secreted significantly more IL-12 （157.6 ± 26.85 pg/mL vs 132.60 ± 22.00 pg/mL （P 〈 0.05） an had a lower level of IL-6 in the culture supernatant （83.0 ± 13.88 pg/mL vs 93.60 ± 13.61 pg/mL, P 〈 0.05） tha CHB control group. The ability of DCs to stimulate th proliferation of allogeneic lymphocytes was increase in ETV-treated group compared with CHB control grou （1.53 ± 0.09 vs 1.42 ± 0.08, P 〈 0.05）.CONCLUSION： Entecavir can enhance the biological activity of DCs derived from CHB patients.     

恩替卡韦治疗慢性重型乙型肝炎疗效观察

目的观察恩替卡韦治疗慢性重型乙型肝炎的疗效和安全性。方法36例慢性重型乙型肝炎患者随机分为2组。对照组16例给予常规的综合治疗;治疗组20例,在常规综合治疗的基础上,加用恩替卡韦0.5mg,每日一次,口服4周。分别观察2组治疗前后肝功能和凝血酶原活动度（PTA）、血清HBVDNA水平变化及疗效情况。结果治疗组的总有效率为85.0%,对照组为50.0%,P〈0.01。治疗后4周,与对照组相比,治疗组存活患者的总胆红素降低,凝血酶原活动度（PTA）升高、血清HBVDNA水平降低具有统计学意义P〈0.01。未发现明显的毒副作用。结论恩替卡韦治疗慢性重型乙型肝炎具有较好的疗效和安全性。     

Entecavir as treatment for reactivation of hepatitis B in immunosuppressed patients

AIM: To study the efficacy and safety of entecavir (ETV) as first-line therapy for hepatitis B virus (HBV) reactivation due to immunosuppression. METHODS: Four patients that were treated with different immunosuppressive regimens for hematological malignancies, who presented with HBV reactivation were treated with ETV. Clinical outcome, biochemical and virological factors, including quantitative hepatitis B surface antigen (HBsAg) were studied. RESULTS: In all patients, ETV induced suppression of HBV, and rapid clinical improvement without side effects. In one patient with an alanine aminotransferase (ALT) flare, tenofovir was added after 3 mo of treatment. Until death from disease progression at 6 mo after treatment initiation, this patient did not clear HBV infection. Retrospectively, it is highly probable that thepatient had been non-adherent. In the other three patients, the virological responses were associated with an expeditious decrease in quantitative HBsAg titers with negativity after 2 mo, and all three had HBsAg seroconversion. In one patient, HBV DNA reached a plateau after 3 mo, before becoming undetectable after 1 year, despite early ALT normalization and undetectable quantitative HBsAg. CONCLUSION: ETV seems to be effective and safe treatment for HBV reactivation. Monitoring of quantitative HBsAg might be an additional useful tool to monitor treatment response.     

Treatment of chronic hepatitis D

Summary.  Despite recent advances in the treatment of chronic viral hepatitis, therapy of chronic hepatitis D is not yet satisfactory. The only option currently available is interferon-α (IFN), whose efficacy is related to the dose and duration of treatment. However, the rate of sustained hepatitis D virus (HDV) clearance after a 1-year course with high doses of standard IFN is low. Better results have recently been reported with pegylated IFN both in IFN-naïve and in previous nonresponders to standard IFN, suggesting the use of pegylated IFN as a first-line therapy in chronic hepatitis D. Nucleoside analogues that inhibit hepatitis B virus (HBV) are ineffective against HDV and combination therapy with lamivudine or ribavirin has not shown significant advantages over monotherapy with either standard or pegylated IFN. Because the ultimate goal of treatment is eradication of both HDV and HBV, in responders IFN therapy should be continued as long as possible until the loss of hepatitis B surface antigen, adjusting the dose to patient tolerance. However, because side-effects are common, continuous monitoring is mandatory. Although the first results obtained with pegylated IFN have been encouraging, the rate of sustained virological response is still low and the rate of relapse high, emphasizing the need for developing novel classes of antivirals specifically interfering with the life cycle of this unique virus.     

Ribavirin treatment for chronic hepatitis D: a pilot study

To assess whether therapy with Ribavirin may affect the course of chronic delta hepatitis, nine Italian patients with this disease received the drug orally at a dosage of 15 mg/kg daily for 16 weeks. At the end of the therapy period, all patients were followed for 12 additional months. Seven patients completed the trial. Two patients were withdrawn: one developed hemolytic anemia, and the other intractable itching. At the end of treatment HD viremia was reduced in one patient, had cleared in another, and was unchanged in the remaining five patients. None of the patients decreased their alanine transferase (ALT) levels by more than 50%. At the doses given in this study. Ribarivin did not show significant antiviral effects in chronic hepatitis D, and was not effective in reducing the biochemical markers of liver inflammation and necrosis.