BACKGROUND & AIMS There is no satisfactory way to identify patients who will maintain a response after discontinuation of nuleos(t)ide analogue therapy for chronic hepatitis B virus (HBV) infection. We investigated whether patients with negative results from tests for HBV DNA and HBV RNA (double negative) at the end of treatment maintain a long-term response to treatment. METHODS We performed a post-hoc analysis of data from a 2-year multi-center randomized controlled trial, and its long-term extension trials, on 130 patients with chronic HBV infection who were positive for the HB e antigen (HBeAg-positive; mean age, 30.8 ± 6.9 years; 72.3% male) and received telbivudine with or without adefovir and stopped therapy after they had HBeAg seroconversion and levels of HBV DNA <300 copies/mL for at least 48 weeks (evaluation cohort). Clinical and laboratory assessments were made every 12 or 16 weeks until clinical relapse (defined as HBV DNA > 2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) or until 4 years off treatment. We validated our findings in a cohort of 40 HBeAg-positive patients (36.5 ± 9.4 years old; 72.5% male) treated with entecavir or tenofovir, and followed after discontinuation for up to 5.5 years. Patients were considered to be negative for HBV DNA if it was not detected in the COBAS Taqman assay. Patients were considered to be negative for HBV RNA if it was not detected by quantitative real-time PCR with 2 different pairs of primers. RESULTS After 4 years off treatment, in the evaluation cohort, 30.8% of patients had a clinical relapse, 54.7% had virologic relapse (HBV DNA >2000 IU/mL in 2 tests), and 16.8% had reappearance of HBeAg in 2 tests (reversion). A significantly lower proportion of double negative patients had a clinical relapse 4 years later (2/35; 8.0%) than of patients who tested positive for either HBV DNA or RNA (32/102; 31.4%; P = .018). In the validation cohort, after 5.5 years of follow up, a lower proportion of double negative patients had clinical relapse (2/13; 15.4%) than of patients who tested positive for either HBV DNA or RNA at the end of treatment (9/27; 33.3%; P = .286) CONCLUSIONS: In an analysis of data from 2 independent cohorts, we associated negative results from tests for HBV DNA and RNA (double negative) at the end of treatment with continued response 4 or more years after discontinuation of therapy in HBeAg-positive patients. These results might be used to identify the best candidates for discontinuation of nuleos(t)ide analogue therapy.

中文翻译：

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HBV DNA 和 RNA 检测的阴性结果与停止核（酸）类似物治疗后反应持久性之间的关联。

背景和目的 没有令人满意的方法来确定在停止治疗慢性乙型肝炎病毒 (HBV) 的核苷（酸）类似物治疗后仍能保持反应的患者。我们调查了治疗结束时 HBV DNA 和 HBV RNA（双阴性）检测结果为阴性的患者是否对治疗保持长期反应。方法 我们对 130 名 HB e 抗原阳性（HBeAg 阳性；平均年龄，30.8 ± 6.9 岁；72.3% 男性），接受替比夫定联合或不联合阿德福韦治疗，并在 HBeAg 血清学转换和 HBV DNA 水平 <300 拷贝/mL 至少 48 周后停止治疗（评估队列）。每 12 或 16 周进行一次临床和实验室评估，直至临床复发（定义为 HBV DNA > 2000 IU/mL 且丙氨酸转氨酶水平超过正常上限的 2 倍）或直至停止治疗 4 年。我们在 40 名 HBeAg 阳性患者（36.5 ± 9.4 岁；72.5% 男性）接受恩替卡韦或替诺福韦治疗的队列中验证了我们的发现，并在停药后进行了长达 5.5 年的随访。如果在 COBAS Taqman 检测中未检测到 HBV DNA，则认为患者的 HBV DNA 为阴性。如果使用 2 对不同的引物进行定量实时 PCR 检测未检测到 HBV RNA，则认为患者的 HBV RNA 为阴性。结果 停止治疗 4 年后，在评估队列中，30.8% 的患者出现临床复发，54.7% 出现病毒学复发（2 项检测中 HBV DNA > 2000 IU/mL），16 例。8% 在 2 次测试中再次出现 HBeAg（逆转）。双阴性患者在 4 年后临床复发的比例 (2/35；8.0%) 显着低于 HBV DNA 或 RNA 检测呈阳性的患者 (32/102；31.4%；P = .018)。在验证队列中，经过 5.5 年的随访，双阴性患者临床复发的比例（2/13；15.4%）低于治疗结束时 HBV DNA 或 RNA 检测呈阳性的患者（9/ 27；33.3%；P = .286) 结论：在对 2 个独立队列的数据进行分析时，我们将治疗结束时 HBV DNA 和 RNA 检测的阴性结果（双阴性）与治疗后 4 年或更长时间的持续反应联系起来。 HBeAg 阳性患者停止治疗。