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Quantifying the Effects of Medical Examination and Possible Risk Factors against the Incidence of Cervical Cancer in a Low Human Papillomavirus Vaccination Coverage: An Ecological Study in Japan

喩 悦銘 広島大学

2022.03.23

概要

1. Introduction
Cervical cancer (CC) is one of the most common gynecological malignancies in females, mainly caused by human papillomavirus (HPV). Unlike other cancers, CC can be prevented by early use of the HPV vaccine and may potentially be eradicated entirely. Since the first approval of HPV vaccine in 2006, public health organizations in many countries and the World Health Organization have been urging the use of HPV vaccines and raising awareness of the advantage of vaccination. Despite their proven efficacy, some countries have not yet implemented an HPV vaccine strategy. For instance, the vaccination coverage in Japan is less than 1% for females born after 2002 (as of 20 June 2021).

Under such a low vaccine coverage, i) decrease the exposure to risk factors and ii) increase of the medical examination rate (i.e., screening rate and detailed examination rate) can be effective measures to decrease the incidence of CC at population level. The main route of HPV transmission is considered to be sexual contact, co-infection between HPV and other STDs, such as Chlamydia and Herpes-simplex virus infection, may occur along with infection of HPV through risky sexual behavior and increase the persistence of HPVs in the cervix. Furthermore, smoking, economic status, and education level have been reported as factors closely linked to the incidence of CC. Therefore, in this study, we aimed to elucidate how STD incidence, smoking rate, income, education level, screening rate, and detailed examination rate are associated with the incidence rate of CC, quantifying the effect of medical examination rate toward the decrease of CC incidence in Japan.

2. Materials and Methods
We collected the yearly data on CC incidence (2013–2017), incidence of sexually transmitted diseases (STDs; Chlamydia, Herpes, Condyloma, and Gonorrhea; 1993–2012), screening and detailed examination rate against CC (2013–2016), smoking rate (2001–2013), economic status (disposable income and economic surplus; 2014–2015), and education status (2015). All data are Japan’s Prefectural level data.

Subsequently, we examined the associations among them by checking the bivariate associations by Pearson correlation coefficients (rs). Finally, we developed generalized linear models (GLMs) with negative binomial error to predict the incidence of cervical cancer by setting the female population in each prefecture as offset with taking a 5-20 year time-lag between incidences of STDs and the CC incidence. The female population in each prefecture was set as an offset. We presented four types of models based on different use of STD data: (i) incidence rate of each STD in the population, (ii) incidence rate of STD in female only, (iii) incidence rate of STD in male only, and (iv) incidence rates of STD in both sexes. In addition, we used the single-year STD incidence data and the moving average of the STD incidences from 2 to 16 years for the analyses. The model selection was performed using Akaike information criterion (AIC). Using the selected models, we predicted the effect of medical examination rates on decreasing CC incidence.

3. Results
Correlation coefficients between the incidence rates of each STD and those of CC showed either positive or negative values. Between medical examination rates and the CC incidence rate, negative correlations were coherently observed regarding the screening rate. On the other hand, positive and negative correlations were observed regarding the detailed examination rate between socio-demographic factors and the CC incidence rates. Negative correlations were coherently observed regarding disposable income, average economic surplus, and smoking rate. Education level showed either positive correlations or negative correlations with the incidence rates of CC.

Among all the constructed GLMs, the lowest AIC (2146.5) was obtained in the model with the “single-year STD data of both male and female” setting, with “15-year time-lag between the STD incidences and the CC incidences”. The positive contribution of Chlamydia in females (0.0028, 95%CI: 0.0011–0.0044) and that of Gonorrhea in males (0.0061, 95%CI: 0.0039–0.0084) were observed against the increase of CC incidence. In contrast, the negative contribution of Condyloma in female (−0.0207, 95%CI: −0.0330–−0.0084) was observed. As for other selected variables, negative contributions by average economic surplus (−0.0025, 95%CI: −0.0034–−0.0016) and smoking rate (−0.0043, 95%CI: −0.0052–−0.0034) were observed. Among the factors related to the medical examination, only the screening rate was selected, showing a negative contribution to the incidences of CC and was estimated to be −0.0101 (95%CI: −0.0150–−0.0053).

4. Discussion
The compatibility of positive correlation and negative correlation between the incidence of each STD and that of CC demonstrated the complex relationships between the STD infections and the development of CC. The positive contribution of Chlamydia in females and that of Gonorrhea in males that were observed in the result of GLM may also imply that improving people’s awareness to prevent the infection of these STDs (i.e., avoiding risky sexual behavior) may help to reduce the incidence rate of CC. In contrast, the negative contribution of Condyloma observed in our model can be linked to some previous studies which reported possible interference between the LRHPV (i.e., HPV 6 and 11, related to Condyloma) infection and the HRHPV (HPV 16 and 18, related to the development of CC) infection. The result in the present study suggests that past exposure to the LR-HPV may also decrease the incidence of CC in Japan.

Concerning the medical examination, increasing in screening rate may contribute negatively to the increase of CC incidence. As the screening rate increased by 10%, the decreasing rates of CC incidences were predicted to be 9.6%. This implies that most of the potential patients (i.e., pre-cancerous patients) in the population newly tested by the screening test can be detected before the development of cervical cancer, which shows the effectiveness of the screening test. However, considering the difficulty for increasing the screening rate in current stiation, concurrent use of other effective preventive measures, such as HPV vaccine, should be implemented.

5. Conclusions
Increasing screening rate can help decrease CC incidence effectively, but not drastically. Not relying solely on the screening test, the combination of multiple countermeasures against CC prevention will be more effective.

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