干扰素中和抗体对慢性乙型肝炎抗病毒应答的影响

Clinical significance of neutralizing anti-interferon antibodies in chronic hepatitis B patients treated with recombinant interferon-alpha

目的 观察干扰素中和抗体(NA)对重组α干扰素(rIFN-α)治疗慢性乙型肝炎时病毒学应答的影响。方法 181例经肝穿刺活检证实的慢性乙型肝炎患者,给予rIFN-α 1b治疗,每次5MU,每周3次,疗程6～37个月(中位数10个月),疗程中每1～3个月以抗病毒生物中和法检测NA、以聚合酶链反应荧光定量测定HBV DNA、以Abbott EIA试剂检测乙型肝炎e抗原。结果 NA产生率为33.7％。阳性者治疗结束时完全应答率显著低于阴性者(27.9％对45.0％,x^2(?)4.979,P(?)0.026),NA出现时间对疗效无显著影响,但NA出现时已获部分应答者(35例)完全应答率显著高于未获部分应答者(26例)(45.7％对3.8％,x^2(?)11.009,P(?)0.001),NA出现时血清HBV DNA水平低于20 pg/ml且近3个月下降幅度超过60％者(16例)完全应答率显著高于NA出现时血清HBV DNA水平高于20 pg/ml或虽低于20 pg/ml但近3个月下降幅度不足60％者(45例)(56.3％对20.0％,x^2(?)7.457,P(?)0.006)。结论 NA可削弱或抵消rIFN-α抗HBV应答,NA出现时已获部分应答者及血清HBV DNA水平低于20pg/ml且近3个月下降幅度超过60％者完全应答率较高。

Objective To investigate the clinical significance of neutralizing anti-interferon-alpha antibodies (NA) in chronic hepatitis B patients treated with recombinant interferon-alpha(rlFN-alpha). Methods One hundred and eighty-one patients (128 male and 53 female) with histological proven chronic hepatitis B were treated with 5 MU recombinant interferon-alpha 1b (rIFN-alpha 1b) subcutaneously thrice weekly for 6~37 (median 10) months. For each patient, Specific detection of serum HBV DNA level with fluorescent-quantitative PCR, HBeAg with enzymoimmunoassay and NA with an antiviral neutralizing biological assay were performed during therapy. Results NA was found in 61 (33.7%) of 181 patients. At the end of treatment, complete-response was achieved in 17 (27.9%) of 61 patients with NA and in 54 (45.0%) of 120 patients without NA, respectively ( x2 = 4.979, P = 0.026). For NA positive patients, the complete-response rate was significantly lower in those who had not achieved partial-response prior to or at the same time as NA occurred than in those who did (3.8%, 1/26, vs 45.7%, 16/35, x2= 7.457, P = 0.006). Moreover, it was lower in patients who either had 20pg/ml of serum HBV DNA or above or HBV DNA had being reduced by less than 60% recent 3 months, but higher in those who had less than 20 pg/ml of HBV DNA and HBV DNA had being reduced by 60% or above (20.0%, 9/45, vs 56.3%, 9/16, x2= 11.009, P = 0.001. Conclusion NA may negate the antiviral effects of rlFN-alpha in chronic hepatitis B patients treated with rlFN-alpha, especially if they appear before partial-response or at the occasion at which serum HBV DNA level was not below 20 pg/ml or HBV DNA had being reduced by less than 60% recent 3 months.