宫颈癌疫苗对宫颈癌防治作用有效性的循证医学研究

发布时间：2018-01-22 21:38

本文关键词： 宫颈癌人乳头瘤病毒疫苗有效性 META分析　出处：《吉林大学》2014年硕士论文　论文类型：学位论文

【摘要】：背景及目的：宫颈癌是女性恶性肿瘤中危害妇女健康生命安全的第二大杀手，全球范围内每年大概有270,000万人死于宫颈癌及相关并发症。高危型人乳头瘤病毒持续感染是宫颈病变发生发展的主要原因之一，世界范围内HPV16和HPV18感染占全部HPV相关性宫颈病变的70%。二价和四价宫颈癌疫苗的相继问世，及国外大规模临床随机双盲对照试验对宫颈癌疫苗安全性有效性的探究，为宫颈癌的一级预防指明了方向。本文旨在通过循证医学meta分析的方法对目前已经进入临床研究的宫颈癌疫苗对HPV16及HPV18持续6个月感染的预防作用，及对HPV相关性宫颈病变预防作用有效性进行分析。为宫颈癌疫苗临床大规模使用提供询证医学证据。方法: （1）实验研究设计：计算机检索2000年1月至2013年11月以来发表的关于人乳头瘤病毒（HPV）疫苗用于预防HPV持续感染以及宫颈病变的随机对照试验研究。（2）研究对象（participants）：健康未孕女性。年龄介于12岁至25岁之间。受试者国籍种族不限。（3）干预措施（interventions）：实验组受试者接受HPV预防性疫苗。（4）对照组（comparisons）：以受试者接受安慰剂或者是其他疫苗为对照。（5）结局（outcomes）：①HPV感染持续存在（HPV感染持续6个月及以上）。②宫颈上皮内瘤变I级（CINⅠ）及以上的发病率。③宫颈上皮内瘤变Ⅱ级（CINⅡ）及以上发病率。对入选文献提取数据后应用RevMan5.2软件进行meta分析。结果: 1.人乳头瘤病毒疫苗对宫颈HPV16持续6个月感染的meta分析：入选5项研究共纳入17815人次。其中干预组8893人，对照组8883人。干预组与对照组HPV16持续6个月感染的相对危险度如图4.1（a）。纳入的研究异质性检验结果提示P=0.97，I2=0%，说明各研究之间同质性好，应用固定效应模型，合并计算相对危险度为0.05，即疫苗有效性为95%，可信区间为[0.03,0.09]。图示4.1（a）森林图显示各研究的置信区间均不包括0，表明各研究的效应量均有统计学意义，Z=10.61（P＜0.00001），表明人乳头瘤病毒疫苗对HPV16持续6个月的感染有预防作用。图示4.1（b）漏斗图图形对称，说明研究资料的无发表偏倚。 2.人乳头瘤病毒疫苗对宫颈HPV18持续6个月感染的meta分析：共纳入的3项研究试验人数共计13921人次。其中干预组6967人，对照组6954人。干预组与对照组HPV18持续6个月感染的相对危险度如图4.2（a）。纳入的研究异质性检验结果提示P=0.51，I2=0%，说明各研究之间同质性好，应用固定效应模型，合并计算相对危险度为0.22，即疫苗有效性为78%，可信区间为[0.13,0.39]。图示4.2（a）森林图显示各菱形完全位于中线左侧未与中线相交，Z=5.51（P＜0.00001），表明人乳头瘤病毒疫苗对HPV18持续6个月的感染有预防作用。图示4.2（b）漏斗图图形对称，说明研究资料的无发表偏倚。 3.人乳头瘤病毒疫苗对宫颈上皮内瘤变I级及以上发病率预防作用的meta分析：共纳入文献8篇。参加实验人数共计26601人次。其中干预组13290人，对照组13311人。干预组与对照组发生宫颈上皮内瘤变的相对危险度如图4.3.1（a）。纳入的研究异质性检验结果提示P=0.02，I2=58%，说明各研究之间存在异质性，应用随机效应模型，合并计算相对危险度为0.18，即疫苗有效性为82%，可信区间为[0.08,0.37]。图示4.3（a）森林图显示各菱形完全位于中线左侧未与中线相交，Z=4.64（P＜0.00001），表明人乳头瘤病毒疫苗对CINI级及以上发病有预防作用。图示4.3.1（b）漏斗图图形对称尚可，说明研究资料不存在发表偏倚。 4.二价人乳头瘤病毒疫苗对宫颈上皮内瘤变I级及以上的预防作用的meta分析：共纳入4篇文献，总人数为20222，其中干预组10114人，对照组10108人。纳入的研究异质性检验结果提示P=0.12，I2=49%，说明各研究之间异质性较小，应用固定效应模型，合并计算相对危险度为0.34，即疫苗有效性为66%，可信区间为[0.28,0.42]。图示4.3.2.1（a）森林图显示各菱形完全位于中线左侧未与中线相交，Z=10.54（P＜0.00001），表明二价人乳头瘤病毒疫苗对宫颈上皮内瘤变I级及以上有预防作用。图示4.3.2.1（b）漏斗图图形对称性良好，说明研究资料的不存在发表偏倚。 5.四价人乳头瘤病毒疫苗对宫颈上皮内瘤变I级及以上的预防作用的meta分析：分析共纳入4篇文献，总人数为6379，其中干预组3176人，对照组3203人。纳入的研究异质性检验结果提示P=0.46，I2=0%，说明各研究之间无异质性，应用固定效应模型，合并计算相对危险度为0.09，即疫苗有效性为91%，可信区间为[0.04,0.21]。图示4.3.2.2（a）森林图显示各菱形完全位于中线左侧未与中线相交，Z=5.57（P＜0.00001），表明四价人乳头瘤病毒疫苗对宫颈上皮内瘤变I级及以上有预防作用。图示4.3.2.2（b）漏斗图图形对称良好，说明研究资料不存在发表偏倚。 6．人乳头瘤病毒疫苗对宫颈上皮内瘤变Ⅱ级及以上预防作用的meta分析：共纳入文献11篇。参加实验人数共计75490人次。其中干预组37727人，对照组37763人。如4.4.1（a）纳入的研究异质性检验结果提示P＜0.00001，I2=82%，说明各研究之间存在明显异质性，应用随机效应模型，合并计算相对危险度为0.07，即疫苗有效性为93%，可信区间为[0.02,0.22]。图示4.4.1（a）森林图显示各菱形完全位于中线左侧未与中线相交，Z=4.73（P＜0.00001），表明人乳头瘤病毒疫苗对CINⅡ级及以上发病率有预防作用。图示4.4.1（b）漏斗图图形对称较好，说明研究资料不存在发表偏倚。 7.二价人乳头瘤病毒疫苗对宫颈上皮内瘤变CINⅡ级及以上的预防作用：共纳入6篇文献，总人数为53471，其中干预组26733人，对照组26738人。纳入的研究异质性检验结果提示P＜0.00001，I2=87%，，说明各研究之间存在明显异质性，应用随机效应模型，合并计算相对危险度为0.09，即疫苗有效性为91%，可信区间为[0.042,0.38]。图示4.4.2.1（a）森林图显示各菱形完全位于中线左侧未与中线相交，Z=3.32（P=0.0009），表明二价人乳头瘤病毒疫苗对宫颈上皮内瘤变Ⅱ级及以上有预防作用。图示4.4.2.1（b）漏斗图图形对称良好，说明研究资料不存在发表偏倚。 8.四价人乳头瘤病毒疫苗对宫颈CINⅡ+的预防作用分析：共纳入5篇文献，总人数为22019，，其中干预组10994人，对照组11025人。纳入的研究异质性检验结果提示P=0.84，I2=0%，应用固定效应模型，合并计算相对危险度为0.04，即疫苗有效性为96%，可信区间为[0.01,0.11]。图示4.4.2.2（a）森林图显示各菱形完全位于中线左侧，Z=5.96（P＜0.00001），表明四价人乳头瘤病毒疫苗对宫颈上皮内瘤变Ⅱ级及以上有预防作用。图示4.4.2.2（b）漏斗图图形对称良好，说明研究资料不存在发表偏倚。结论： 1.人乳头瘤病毒预防性疫苗可以降低HPV16及HPV18持续感染的风险。 2.人乳头瘤病毒预防性疫苗可以降低CINⅠ级及以上宫颈病变患病率的风险。 3.人乳头瘤病毒预防性疫苗可以降低CINⅡ级及以上宫颈病变患病率的风险。
[Abstract]:Background and objective: cervical cancer is endangering the life safety of the second women's health killer of women malignant tumor, there are about 2 billion 700 million people died of cervical cancer and related complications worldwide. HPV infection is one of the main reasons for the occurrence and development of cervical lesions, one after another in the world accounted for the relationship between cervical HPV in 70%., two divalent and tetravalent vaccine against cervical cancer HPV16 and HPV18 infection, and foreign large-scale clinical randomized controlled trial on cervical cancer vaccine safety and effectiveness, and pointed out the direction for the primary prevention of cervical cancer. This paper aims to prevent evidence based analysis method of meta medicine has now entered the clinic study on the cervical cancer vaccine of HPV16 and HPV18 infection in 6 months, and for HPV associated cervical lesions were analyzed. The preventive effect is effective for cervical cancer The large-scale use of the vaccine provides evidence of medical evidence.
Method:
(1) experimental research design: computer search for a randomized controlled trial of human papillomavirus (HPV) vaccine used to prevent HPV persistent infection and cervical lesions since January 2000 to November 2013.
(2) study object (participants): healthy unpregnant women. Age between 12 and 25 years. The nationality of the subjects is not limited.
(3) intervention (interventions): the subjects in the experimental group received HPV prophylactic vaccine.
(4) the control group (comparisons): the subjects received placebo or other vaccines as control.
(5) outcome (outcomes): (1) HPV infection persisted (HPV infection lasted for 6 months or more). 2. The incidence of cervical intraepithelial neoplasia I grade (CIN I) and above. 3. The incidence of cervical intraepithelial neoplasia grade II (CIN II) or above.
After extracting the data from the selected literature, the RevMan5.2 software was used for meta analysis.
Result:
1. human papilloma virus vaccine for cervical HPV16 persistent infection: analysis of 6 months of meta: a total of 5 studies were included in the intervention group of 17815 people. 8893 people, 8883 people in the control group. The intervention group and the control group HPV16 infection 6 months relative risk as shown in Figure 4.1 (a). In the study of heterogeneity test results indicated that P=0.97, I2=0%, explains the study between homogeneity, using fixed effect model, and calculate the relative risk of 0.05, vaccine effectiveness was 95%, 4.1 confidence interval [0.03,0.09]. diagram (a) shows the confidence interval of the forest research doesn't include the 0, the study indicates that the effect of the amount of statistical significance, Z=10.61 (P < 0.00001), shows that human papillomavirus vaccines have a preventive effect on HPV16 for 6 months of infection. Figure 4.1 (b) funnel plot symmetry, no publication bias of the data.
2. human papilloma virus vaccine for cervical HPV18 persistent infection: analysis of 6 months of meta: 3 studies were included in the total number of 13921 people. In the intervention group of 6967 people, 6954 people in the control group. The intervention group and the control group HPV18 infection 6 months relative risk as shown in Figure 4.2 (a) into. The study of heterogeneity test showed that P=0.51, I2=0%, explains the study between homogeneity, using fixed effect model, and calculate the relative risk of 0.22, vaccine effectiveness was 78%, 4.2 confidence interval [0.13,0.39]. diagram (a) shows the diamond forest located in the midline and left without completely intersecting line, Z=5.51 (P < 0.00001), shows that human papillomavirus vaccines have a preventive effect on HPV18 for 6 months of infection. Figure 4.2 (b) funnel plot symmetry, no publication bias of the data.
Analysis of 3. human papilloma virus vaccine I level and above, the incidence of preventive effect on cervical intraepithelial neoplasia meta: a total of 8 articles were included in the experiment. A total of 26601 people. In the intervention group of 13290 people, 13311 people in the control group. The intervention group and the control group had cervical intraepithelial neoplasia relative risk figure 4.3.1 (a). The study included heterogeneity test showed that P=0.02, I2=58%, indicating the existence of heterogeneity between the studies and application of random effect model, and calculate the relative risk of 0.18, vaccine effectiveness was 82%, 4.3 confidence interval [0.08,0.37]. diagram (a) shows the forest located in the midline of each diamond completely on the left side and not intersecting line, Z=4.64 (P < 0.00001), shows that human papillomavirus vaccines have a preventive effect on CINI level and above 4.3.1 (b). The incidence of funnel plot symmetry can, explain the research data do not exist to express bias.
Analysis of 4. valence two HPV vaccine I level and preventive effect of above of cervical intraepithelial neoplasia meta: a total of 4 articles were included, the total number of 20222, including 10114 in the intervention group and the control group of 10108 people. The research into the heterogeneity test results suggest that P=0.12, I2=49%, the study of heterogeneity the application of small, fixed effect model, and calculate the relative risk of 0.34, vaccine effectiveness was 66%, CI [0.28,0.42]. icon 4.3.2.1 (a) showed that the forest map completely on the left side of the center line with diamond intersecting line, Z=10.54 (P < 0.00001), showed that the two price of HPV vaccine for cervical epithelium neoplasia of I and above have a preventive role. The 4.3.2.1 (b) funnel plot symmetry, explains the research data there is no publication bias.
Analysis of 5. quadrivalent human papillomavirus vaccine I and preventive effect of above of cervical intraepithelial neoplasia meta analysis: a total of 4 articles were included, the total number of 6379, including 3176 in the intervention group and the control group of 3203 people. The research into the heterogeneity test results suggest that P=0.46, I2=0%, explains the heterogeneity Study on the application, fixed effect model, and calculate the relative risk of 0.09, vaccine effectiveness was 91%, CI [0.04,0.21]. icon 4.3.2.2 (a) showed that the forest map completely on the left side of the center line with diamond intersecting line, Z=5.57 (P < 0.00001), indicated that quadrivalent human papillomavirus vaccine for cervical intraepithelial neoplasia grade I and above have a preventive role. The 4.3.2.2 (b) funnel plot symmetry is good, there is no data of publication bias.
6. human papilloma virus vaccine of cervical intraepithelial neoplasia grade II and above the preventive effect of meta: a total of 11 articles were included in the experiment. A total of 75490 people. Among them 37727 in the intervention group and the control group of 37763 people. Such as 4.4.1 (a) into the study of heterogeneity test showed that P < 0.00001, I2=82% that shows significant heterogeneity between the studies and application of random effect model, and calculate the relative risk of 0.07, vaccine effectiveness was 93%, CI [0.02,0.22]. icon 4.4.1 (a) showed that the forest map completely on the left side of the center line with diamond intersecting line, Z=4.73 (P < 0.00001), showed that human papilloma virus vaccines have a preventive effect on CIN II and above. The incidence of 4.4.1 (b) the funnel plot symmetry is good, that does not exist on information publication bias.
7. two price of HPV vaccine for cervical intraepithelial neoplasia grade CIN and preventive effect of more than 6 articles were included, the total number of 53471, including 26733 in the intervention group and 26738 in the control group. Test results indicate that the heterogeneity of P < 0.00001, I2=87% included, indicating that there exist obvious heterogeneity the study, using a random effects model, and calculate the relative risk of 0.09, vaccine effectiveness was 91%, CI [0.042,0.38]. icon 4.4.2.1 (a) showed that the forest map completely on the left side of the center line with diamond intersecting line, Z=3.32 (P=, 0.0009) showed that the two price of human papillomavirus vaccine prevention the role of cervical intraepithelial neoplasia grade II and above. The 4.4.2.1 (b) funnel plot symmetry is good, there is no data of publication bias.
Analysis of preventive effect of 8. quadrivalent HPV vaccine for cervical CIN + II: a total of 5 articles were included, the total number of 22019, including 10994 in the intervention group and the control group of 11025 people. The research into the heterogeneity test results suggest that P=0.84, I2=0%, using fixed effect model, and calculated relative risk was 0.04 that is, vaccine effectiveness was 96%, CI [0.01,0.11]. icon 4.4.2.2 (a) showed that the diamond forest map completely on the left side of the center line, Z=5.96 (P < 0.00001), indicated that quadrivalent human papillomavirus vaccine to prevent cervical intraepithelial neoplasia grade II and above. The 4.4.2.2 (b) funnel plot symmetry well, there is no data of publication bias.
Conclusion:
The 1. human papillomavirus prophylactic vaccine can reduce the risk of persistent infection of HPV16 and HPV18.
The 2. human papillomavirus prophylactic vaccine can reduce the risk of CIN grade I and above the prevalence of cervical lesions.
The 3. human papillomavirus prophylactic vaccine can reduce the risk of the prevalence of CIN class II and above cervix.

【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.33

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