Liu Yuanyuan, Pei Zhiyan, Ma Aidi, Li Yongfang, Lu Fengmin, Zhang Lingyi
Department of Hepatology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Transl Pediatr. 2025 Jul 31;14(7):1726-1732. doi: 10.21037/tp-2025-250. Epub 2025 Jul 25.
rtM204I mutation is commonly associated with resistance to nucleos(t)ide analog (NA) therapy for hepatitis B virus (HBV), often resulting in virological breakthrough and treatment failure. Owing to unique immunological and virological characteristics of HBV, achieving a functional cure in pediatric patients is easier than in adults, and cases involving concurrent drug-resistant mutations are rare.
A 4-year-old boy infected with HBV through mother-to-child transmission experienced virological rebound (HBV DNA, 4.66×107 IU/mL) after 12 months of lamivudine (LAM) monotherapy. Resistance testing revealed rtM204I mutation. The treatment regimen was adjusted to tenofovir disoproxil fumarate (TDF) combined with pegylated interferon α-2a (PegIFNα-2a). At 12 weeks of treatment, there was a significant decline in hepatitis B surface antigen (HBsAg) levels accompanied by positive antibody to hepatitis B surface antigen (anti-HBs), thus presenting an atypical serological pattern of double positivity for HBsAg and anti-HBs. By week 24, HBsAg was negative, but hepatitis B e antigen (HBeAg) remained positive, demonstrating an atypical serological pattern of response dissociation whereby HBsAg disappeared before HBeAg. TDF combined with PegIFNα-2a was administered until week 36, resulting in persistent HBsAg negativity and a significant increase in anti-HBs levels. PegIFNα-2a was discontinued, and TDF monotherapy was continued for 10 months. During this period, HBsAg negativity and anti-HBs positivity were maintained, HBeAg became negative, and alanine aminotransferase levels remained normal. These results indicate achievement of a functional cure.
This case indicated that in children with rtM204I mutation, optimizing antiviral therapy combined with PegIFNα-2a can achieve a functional cure despite atypical serological response patterns. Long-acting interferons have significant therapeutic value in pediatric patients with drug-resistant mutations.
rtM204I突变通常与乙型肝炎病毒（HBV）对核苷（酸）类似物（NA）治疗的耐药性相关，常导致病毒学突破和治疗失败。由于HBV独特的免疫学和病毒学特征，在儿科患者中实现功能性治愈比在成人中更容易，且并发耐药突变的病例很少见。
一名通过母婴传播感染HBV的4岁男孩，在接受拉米夫定（LAM）单药治疗12个月后出现病毒学反弹（HBV DNA，4.66×107 IU/mL）。耐药性检测显示rtM204I突变。治疗方案调整为替诺福韦酯（TDF）联合聚乙二醇化干扰素α-2a（PegIFNα-2a）。治疗12周时，乙型肝炎表面抗原（HBsAg）水平显著下降，同时出现乙型肝炎表面抗原抗体（抗-HBs）阳性，从而呈现出HBsAg和抗-HBs双阳性的非典型血清学模式。到第24周时，HBsAg呈阴性，但乙型肝炎e抗原（HBeAg）仍为阳性，显示出一种非典型的反应解离血清学模式，即HBsAg在HBeAg之前消失。TDF联合PegIFNα-2a持续给药至第36周，导致HBsAg持续阴性，抗-HBs水平显著升高。停用PegIFNα-2a，继续TDF单药治疗10个月。在此期间，维持HBsAg阴性和抗-HBs阳性，HBeAg变为阴性，丙氨酸氨基转移酶水平保持正常。这些结果表明实现了功能性治愈。
该病例表明，在rtM204I突变的儿童中，优化抗病毒治疗联合PegIFNα-2a尽管血清学反应模式不典型，但仍可实现功能性治愈。长效干扰素在有耐药突变的儿科患者中具有显著的治疗价值。
