Sayan Murat, Buğdacı Mehmet Sait
Kocaeli University Medical Faculty Hospital, Central Laboratory, PCR Unit, Kocaeli, Turkey.
Mikrobiyol Bul. 2013 Jul;47(3):544-9. doi: 10.5578/mb.5442.
The hepatitis B virus (HBV) polymerase (pol) gene completely overlaps with the envelope (S) gene. Nucleos(t)ide analogue (NA) resistance mutations in the pol gene of HBV, either from selection of primary or secondary resistance mutations, typically result in changes in the overlapping hepatitis B surface antigen (HBsAg). Recent studies have conferred a new acronym to these HBV pol/S gene overlap mutants; ADAPVEMs, for antiviral drug-associated potential vaccine-escape mutants. The present report aimed to assess the determined multiple HBV vaccine-escape mutants in a Turkish patient with chronic hepatitis B (CHB), undergoing NAs treatment. The liver biopsy of HBsAg positive, HBeAg negative 53-year old female patient with CHB, revealed a score as histological activity index; 9 and fibrosis; 2 according to Ishak classification. NA treatment backgrounds consisted of 24 months lamivudine, followed by 18 months entacavir and lastly 3 months tenofovir monotherapies. Since HBV DNA load was determined as 7.030.000 IU/ml at the 4th month of tenofovir therapy, entecavir was added as current treatment regimen, and tenofovir + entecavir therapy decreased the HBV DNA load (400 IU/ml). Sequence analysis was performed for HBV pol/S gene and overlapping pol/S gene amino acid substitutions, primary/compensatory NA resistance mutations and antiviral drug-associated potential vaccine-escape mutations (ADAPVEM) were analysed. The patient isolate was identified as genotype D/subgenotype D1 of HBV. Primary drug resistance mutations (rtV173L + rtL180M + rtM204V) to lamivudine and telbivudine and a compensatory mutation (rtQ215H) to lamivudine and adefovir were described in the HBV pol gene sequence. However, multiple HBV vaccine-escape mutations (sS143T + sD144E + sG145R + sE164D + sI195M) have been determined on the HBV overlapping pol/S gene region. Lamivudine and telbivudine which are the frequently preferred drugs for the treatment of CHB in Turkey, have the potential to lead to ADAPVEMs. Thus ADAPVEMs should be monitored in infected and NA treated CHB patients and their public health risks should be assessed.
乙型肝炎病毒（HBV）聚合酶（pol）基因与包膜（S）基因完全重叠。HBV的pol基因中，无论是原发性还是继发性耐药突变的核苷酸类似物（NA）耐药突变，通常都会导致重叠的乙型肝炎表面抗原（HBsAg）发生变化。最近的研究为这些HBV pol/S基因重叠突变体赋予了一个新的首字母缩写词；ADAPVEMs，即抗病毒药物相关潜在疫苗逃逸突变体。本报告旨在评估一名接受NA治疗的土耳其慢性乙型肝炎（CHB）患者中确定的多种HBV疫苗逃逸突变体。这位53岁的HBsAg阳性、HBeAg阴性的CHB女性患者的肝活检显示，根据伊沙克分类，其组织学活动指数评分为9分，纤维化评分为2分。NA治疗背景包括24个月的拉米夫定治疗，随后是18个月的恩替卡韦治疗，最后是3个月的替诺福韦单药治疗。由于在替诺福韦治疗的第4个月时，HBV DNA载量测定为7,030,000 IU/ml，因此将恩替卡韦添加到当前治疗方案中，替诺福韦+恩替卡韦治疗降低了HBV DNA载量（400 IU/ml）。对HBV pol/S基因进行了序列分析，并分析了重叠的pol/S基因氨基酸取代、原发性/补偿性NA耐药突变以及抗病毒药物相关潜在疫苗逃逸突变（ADAPVEM）。患者分离株被鉴定为HBV基因型D/亚型D1。在HBV pol基因序列中描述了对拉米夫定和替比夫定的原发性耐药突变（rtV173L + rtL180M + rtM204V）以及对拉米夫定和阿德福韦的补偿性突变（rtQ215H）。然而，在HBV重叠的pol/S基因区域已确定了多种HBV疫苗逃逸突变（sS143T + sD144E + sG145R + sE164D + sI195M）。在土耳其，拉米夫定和替比夫定是治疗CHB最常用的药物，它们有可能导致ADAPVEMs。因此，应对感染且接受NA治疗的CHB患者监测ADAPVEMs，并评估其公共卫生风险。
