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ENGLISH ABSTRACT
外用红色诺卡菌细胞壁骨架治疗子宫颈高危型HPV持续感染的有效性及安全性研究
陈飞
狄文
胡元晶
李长忠
王飞
段华
刘军
姚书忠
张友忠
郭瑞霞
王建东
王建六
张玉泉
王敏
林仲秋
郎景和
作者及单位信息
·
DOI： 10.3760/cma.j.cn112141-20230331-00154
Evaluation of the efficacy and safety of Nocardia rubra cell wall skeleton immunotherapy for cervical high-risk HPV persistent infection
Chen Fei
Di Wen
Hu Yuanjing
Li Changzhong
Wang Fei
Duan Hua
Liu Jun
Yao Shuzhong
Zhang Youzhong
Guo Ruixia
Wang Jiandong
Wang Jianliu
Zhang Yuquan
Wang Min
Lin Zhongqiu
Lang Jinghe
Authors Info & Affiliations
Chen Fei
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, National Clinical Medical Research Center for Obstetrics and Gynecology, Beijing 100730, China
Di Wen
Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200001, China
Hu Yuanjing
Department of Gynecological Oncology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin 300199, China
Li Changzhong
Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan 250021, China
Wang Fei
Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan 250021, China
Duan Hua
Gynecological Minimally Invasive Surgery Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100006, China
Liu Jun
Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China
Yao Shuzhong
Department of Gynecology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Zhang Youzhong
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, China
Guo Ruixia
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Wang Jiandong
Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100006, China
Wang Jianliu
Department of Obstetrics and Gynecology, Peking University People′s Hospital, Beijing 100044, China
Zhang Yuquan
Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong 226001, China
Wang Min
Department of Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
Lin Zhongqiu
Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510289, China
Lang Jinghe
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, National Clinical Medical Research Center for Obstetrics and Gynecology, Beijing 100730, China
·
DOI： 10.3760/cma.j.cn112141-20230331-00154
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摘要

目的评估外用红色诺卡菌细胞壁骨架（Nr-CWS）治疗子宫颈高危型人乳头状瘤病毒（HPV）持续感染的有效性及安全性。

方法本研究为前瞻性、随机、双盲、多中心临床试验。征集2017年12月至2020年12月于全国13家医院门诊确诊为常见14种高危型HPV亚型持续感染的患者共688例。将临床及病理确诊为子宫颈高危型HPV感染的患者，分为3个亚组，（1）第一亚组：单纯性高危型HPV感染持续12个月及以上者；（2）第二亚组：子宫颈上皮内瘤变（CIN）Ⅰ伴高危型HPV感染持续12个月及以上者；（3）第三亚组：CINⅡ或CIN Ⅲ（CINⅡ/Ⅲ）手术后高危型HPV阳性亚型与术前相同，且经阴道镜和子宫颈活检确诊为非CINⅡ及以上病变（CINⅡ +）者。3个亚组以2∶1随机分入试验组与对照组，试验组受试者于子宫颈局部使用Nr-CWS冻干粉，对照组使用不含Nr-CWS的安慰剂冻干粉。分别于治疗后的1、4、8、12个月进行治疗后疗效包括消除HPV的有效率及各型高危型HPV（主要为HPV 16、18、52、58型）转阴率的评估，并比较治疗前、后安全性指标的差异。

结果（1）本研究共纳入子宫颈高危型HPV感染患者555例（试验组368例、对照组187例），其年龄为（44.1±10.0）岁。两组受试者的基线特征包括年龄、汉族占比、体重、高危型HPV亚型构成、各亚组占比分别比较，差异均无统计学意义（ P均>0.05）。（2）治疗后12个月，试验组和对照组受试者消除HPV的有效率分别为91.0%（335/368）和44.9%（84/187），两组比较，差异有统计学意义（ χ 2=142.520， P<0.001）。治疗后12个月，试验组受试者HPV16、18、52、58型感染的转阴率分别为79.2%（84/106）、73.3%（22/30）、83.1%（54/65）、77.4%（48/62），对照组分别为21.6%（11/51）、1/9、35.1%（13/37）、20.0%（8/40），两组分别比较，差异均有统计学意义（ P均<0.001）。（3）试验组与对照组受试者在治疗前及治疗后1、4、8、12个月的生命体征（体重、体温、呼吸、心率、收缩压、舒张压等）、实验室常规指标（血、尿常规检查）分别比较，差异均无统计学意义（ P均>0.05）；两组受试者与试验药物相关的不良反应发生率比较，差异无统计学意义［分别为8.7%（32/368）、8.0%（15/187）； χ 2=0.073， P=0.787］。

结论外用Nr-CWS治疗子宫颈高危型HPV持续感染具有良好的疗效和安全性。

人乳头状瘤病毒感染;宫颈疾病;佐剂，免疫;细胞壁骨架;黏蛋白质类;诺卡氏菌属
ABSTRACT

ObjectiveTo evaluate the efficacy and safety of Nocardia rubra cell wall skeleton (Nr-CWS) in the treatment of persistent cervical high-risk human papillomavirus (HR-HPV) infection.

MethodsA randomized, double blind, multi-center trial was conducted. A total of 688 patients with clinically and pathologically confirmed HR-HPV infection of the cervix diagnosed in 13 hispital nationwide were recruited and divided into: (1) patients with simple HR-HPV infection lasting for 12 months or more; (2) patients with cervical intraepithelial neoplasia (CIN) Ⅰ and HR-HPV infection lasting for 12 months or more; (3) patients with the same HR-HPV subtype with no CINⅡ and more lesions after treatment with CINⅡ or CIN Ⅲ (CINⅡ/CIN Ⅲ). All participants were randomly divided into the test group and the control group at a ratio of 2∶1. The test group was locally treated with Nr-CWS freeze-dried powder and the control group was treated with freeze-dried powder without Nr-CWS. The efficacy and negative conversion rate of various subtypes of HR-HPV were evaluated at 1, 4, 8, and 12 months after treatment. The safety indicators of initial diagnosis and treatment were observed.

Results(1) This study included 555 patients with HR-HPV infection in the cervix (included 368 in the test group and 187 in the control group), with an age of (44.1±10.0) years. The baseline characteristics of the two groups of subjects, including age, proportion of Han people, weight, composition of HR-HPV subtypes, and proportion of each subgroup, were compared with no statistically significant differences (all P>0.05). (2) After 12 months of treatment, the effective rates of the test group and the control group were 91.0% (335/368) and 44.9% (84/187), respectively. The difference between the two groups was statistically significant ( χ 2=142.520, P<0.001). After 12 months of treatment, the negative conversion rates of HPV 16, 18, 52, and 58 infection in the test group were 79.2% (84/106), 73.3% (22/30), 83.1% (54/65), and 77.4% (48/62), respectively. The control group were 21.6% (11/51), 1/9, 35.1% (13/37), and 20.0% (8/40), respectively. The differences between the two groups were statistically significant (all P<0.001). (3) There were no statistically significant differences in vital signs (body weight, body temperature, respiration, pulse rate, systolic blood pressure, diastolic blood pressure, etc.) and laboratory routine indicators (blood cell analysis, urine routine examination) between the test group and the control group before treatment and at 1, 4, 8, and 12 months after treatment (all P>0.05); there was no statistically significant difference in the incidence of adverse reactions related to the investigational drug between the two groups of subjects [8.7% (32/368) vs 8.0% (15/187), respectively; χ 2=0.073, P=0.787].

ConclusionExternal use of Nr-CWS has good efficacy and safety in the treatment of high-risk HPV persistent infection in the cervix.

Papillomavirus infections;Uterine cervical diseases;Adjuvants, immunologic;Cell wall skeleton;Mucoproteins;Nocardia
Lang Jinghe, Email: mocdef.labiamtohhjgnal

Chinese Clinical Trial Registry，ChiCTR2100050129

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引用本文

陈飞,狄文,胡元晶,等. 外用红色诺卡菌细胞壁骨架治疗子宫颈高危型HPV持续感染的有效性及安全性研究[J]. 中华妇产科杂志,2023,58(07)：536-545.

DOI:10.3760/cma.j.cn112141-20230331-00154

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子宫颈癌是常见的威胁妇女生命健康的恶性肿瘤之一。2020年，全球子宫颈癌新发病例约60.4万例，其中88.1%发生在中低收入国家，且其死亡率居育龄期妇女恶性肿瘤的第2位 ［ 1 , 2 ］ ；我国子宫颈癌的新发病例10.9万例、死亡病例5.9万例，近年仍呈上升趋势 ［ 3 ］ 。人乳头状瘤病毒（human papillomavirus，HPV）感染是子宫颈癌发生的主要原因，99.7%的子宫颈癌患者合并HPV感染 ［ 4 ］ 。然而，绝大多数HPV感染被自体免疫系统清除，不会引起病变；部分HPV感染发展成子宫颈上皮内瘤变（cervical intraepithelial neoplasia，CIN）；只有少数HPV感染成为“转化型CIN（transforming CIN）”，其特征是HPV E6和E7基因的表达改变且形态学表现出CINⅡ或CIN Ⅲ（CINⅡ/Ⅲ） ［ 5 ］ 。大多数HPV持续感染后3~5年进展为CINⅡ/Ⅲ，而进一步进展为子宫颈癌可能需要10~30年，WHO子宫颈癌前病变筛查和治疗指南（第2版） ［ 6 ］ 推荐，HPV DNA检测作为首选的子宫颈癌筛查方法可有效筛选出子宫颈癌前病变和子宫颈癌，对于WHO倡议的2030年全球消除子宫颈癌具有重大意义 ［ 7 ］ 。
接种预防性HPV疫苗使人体内产生抵抗HPV的有效免疫应答，是目前预防子宫颈癌的一级措施。通过肿瘤抗原或提升免疫微环境的免疫干预药物（如免疫检查点抑制剂或治疗性HPV疫苗） ［ 8 , 9 , 10 ］ ，激活或增强免疫系统功能，可达到治疗子宫颈癌前病变及子宫颈癌的目的。红色诺卡菌细胞壁骨架（Nocardia rubra cell wall skeleton，Nr-CWS）是一种非特异性免疫调节剂，可提高HPV感染患者子宫颈组织中CD 4 +和CD 8 + T淋巴细胞表达水平，抑制细胞程序性死亡受体1（programmed cell death protein 1，PD-1）/细胞程序性死亡配体1（programmed cell death ligand 1，PD-L1）信号通路，增强树突状细胞（dendritic cell，DC）表面的甲酰肽受体3表达并激活辅助性T淋巴细胞1（T helper cell 1，Th1）型免疫反应，促进HPV感染和CIN患者的局部免疫功能 ［ 11 , 12 , 13 ］ 。已有研究显示，外用Nr-CWS冻干粉治疗子宫颈病变的临床效益良好 ［ 14 , 15 , 16 ］ ，且治疗过程无创，是有生育要求或有保留子宫颈结构和功能愿望女性可选择的方法之一。本研究主要在全国13家医院进行外用Nr-CWS冻干粉的前瞻性、随机、双盲的多中心临床试验，评价外用Nr-CWS冻干粉治疗子宫颈高危型HPV持续感染的疗效及安全性，为临床使用Nr-CWS提供循证医学的证据。
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备注信息
A
郎景和，Email： mocdef.labiamtohhjgnal
B

陈飞、狄文：临床方案设计、病例入组与治疗、采集和分析数据、文章撰写；胡元晶、李长忠、王飞、段华、刘军、姚书忠、张友忠、郭瑞霞、王建东、王建六、张玉泉、王敏、林仲秋：病例入组与治疗、采集数据；郎景和：临床方案设计

C

中国临床试验注册中心，ChiCTR2100050129

D
陈飞, 狄文, 胡元晶, 等. 外用红色诺卡菌细胞壁骨架治疗子宫颈高危型HPV持续感染的有效性及安全性研究[J]. 中华妇产科杂志, 2023, 58(7): 536-545. DOI: 10.3760/cma.j.cn112141-20230331-00154.
E
所有作者声明无利益冲突
F
北京协和医院中央高水平医院临床科研专项 (2022-PUMCH-D-003)
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