Reduction in HPV16/18 prevalence among young women with high-grade cervical lesions following the Japanese HPV vaccination program

Abstract

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, P_trend < .0001) and CIN2-3/AIS (83.3% to 45.0%, P_trend = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch-up vaccination (P = .04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government's suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.

Keywords: adenocarcinoma in situ; cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; vaccination.

Figure 1

Changes in the registered numbers of women with cervical intraepithelial neoplasia grade 2‐3 (CIN2‐3)/adenocarcinoma in situ (AIS) and invasive cervical cancer (ICC) by age group. Year‐on‐year trends (dotted lines) of the registered number of Japanese women with CIN2‐3/AIS (A) and (ICC) (B) are shown for 4 age groups (20‐24 [red], 25‐29 [blue], 30‐34 [green], and 35‐39 [black] y). Although all newly diagnosed cases of these diseases each year at the 21 participating institutions were registered, we could not find any significant trends in the number of CIN2‐3/AIS or ICC cases in women aged 20‐24 y between 2013 and 2017

Figure 2

Changes in human papillomavirus type 16 or 18 (HPV16/18) prevalence among Japanese women with cervical intraepithelial neoplasia grade 1 (CIN1) or CIN2‐3/adenocarcinoma in situ (AIS) by age group. A, B, Year‐on‐year trend of HPV16/18 prevalence (dotted lines) among Japanese women with CIN1 (A) and CIN2‐3/AIS (B) are shown for 4 age groups (20‐24 [red], 25‐29 [blue], 30‐34 [green], and 35‐39 [black] y). Among women aged 20‐24 y, HPV16/18 prevalence decreased from 50.0% to 0.0% for CIN1 (P _trend < .0001) (A) and from 83.3% to 45.0% for CIN2‐3/AIS (P _trend = .07) (B) during a 6‐year period. No similar decline was observed for older age groups. C, D, Year‐on‐year trend of HPV16/18 prevalence (dotted lines) and estimated prevalence trends (solid lines) among Japanese women with CIN1 (C) and CIN2‐3/AIS (D) shown for 2 age groups (20‐24 [red] and ≥25 [green] y). Using a linear regression model, the difference in linear trends of HPV16/18 prevalence between women aged 20‐24 and ≥25 y was statistically significant for CIN1 (P = .001) (C) and marginally significant for CIN2‐3/AIS (P = .06) (D)

Figure 3

Attribution of human papillomavirus type 16 or 18 (HPV16/18) to cervical intraepithelial neoplasia grade 2‐3 (CIN2‐3)/adenocarcinoma in situ (AIS) by age at first vaccination. Prevalence of HPV16/18 in CIN2‐3/AIS was 12.5% for women who received their first dose at ages 12‐16 y (n = 16), 14.3% for those aged 17‐20 y at first vaccination (n = 7), 35.3% for those aged 21‐25 y at first vaccination (n = 17), 39.4% for those aged >25 y at first vaccination (n = 66), and 47.8% for those unvaccinated (n = 3213). Among vaccinated women, attribution of HPV16 and HPV18 to CIN2‐3/AIS was significantly lower among those aged 13‐20 y at first vaccination than among those aged >20 y at first vaccination (P = .02)