Enrollment and follow-up characteristic of women after cervical surgery
168(vaccine, n = 87; control, n = 81) performed excisional treatment for a first cervical lesion in this clinical trial. 166 had been followed up and were categorized based on cytological results and HPV status at enrollment. Comparison of analytical cohort stratified by study arm revealed the balance regarding to cytology results, and HPV status (HPV type) at enrollment (Table 1).
Women who undergone cervical surgery had a median of 9 study visits after treatment (HPV arm: 9, IQR: 5–12; control arm: 8, IQR: 5–11) and were followed for a median of 50.0 months after treatment (HPV arm: 49.5, IQR: 32.0–64.0; control arm: 50.0, IQR: 30.3–63.5). The median number of months between enrollment and treatment was 17 for those in the HPV arm (IQR:4.0–30.0 months) and 17 for women in the control arm (IQR:6.0–34.8 months).
Impact of vaccination on rate of HPV infections and abnormal cytological results after excision treatment
In infection-level analysis, 10 women (vaccine, n = 5; placebo, n = 5) were excluded because of no follow-up (Fig. 1). Finally, 158 women (vaccine, n = 82; placebo, n = 76) were included in the analysis. The woman is included in analysis from the day when the women underwent an excisional procedure [loop electrosurgical excision procedure (LEEP) or cone] for a first cervical lesion to the day of their last follow-up visit, due to the women could be infected HPV or had abnormal cytological results for several times after excisional treatment. Among all the infections that treated women had, 71.06% were oncogenic infection and of these 52.49% were the result of new infections. We observed significant effect of vaccination on rates of 14 types oncogenic HPV infection (VE 27.0%; 95%CI 4.9%, 44.0%), and a nonsignificant but positive vaccine efficacy estimate of 28.1% (95% CI -62.9%,68.3%) for HPV-16/18 infections after excision treatment (Table 2). Vaccine efficacy estimates against new infections after treatment for 14 types oncogenic HPV infection were 32.0% (95%CI 1.8%,52.8%), and for HPV-16/18 infections were consistently positive in this restricted analysis but didn’t reach statistical significance.
Then, we evaluated whether rates of viral clearance or HPV persistent rate differed by vaccination status. Results were shown in Fig. 2. We found no evidence that vaccination lead to faster clearance or had effect on the persistent infection rate. The accumulative clearance rate of the vaccine group and placebo group were 88.9%, 81.6% for HPV16/18 infection(P = 0.345), 81.3%, 80.0% for HPV31/33/45 infections( P༞0.999), 63.4%, 48.7% for 14 types oncogenic HPV infection(P = 0.062), respectively. And there were no significant difference for the persistent rate of HPV16/18(4.4% vs 2.6%,P༞0.999), HPV31/33/45(18.8% vs 10.0%,P = 0.637),14 types oncogenic HPV infection(20.7% vs 17.1%,P = 0.561) between the two groups.
When LSIL + was examined as the outcome, we observed a nonsignificant but positive vaccine efficacy estimate of 45.5% (95%CI -15.5%, 74.2%) for 14 types oncogenic HPV infection, a nonsignificant positive vaccine efficacy estimate of 85.1% (95% CI -23.5%, 98.2%) for newly detected outcome after treatment. Similar patterns were observed when we evaluated HPV-16/18 infection.
Impact of vaccination on occurrence of LSIL + and subsequent histopathologically confirmed disease
15 women (vaccine, n = 7; placebo, n = 8) were excluded because of no cytological results (Fig. 1). Finally, 153 women were included in the final analysis (vaccine, n = 80; placebo, n = 73). In this analysis, the follow-up time is from the day of excisional procedure to the day of ascertainment of the subsequent disease end point (LSIL + incidence), for the women without a subsequent disease end point, until the day of their last follow-up visit. Median follow-up time was 46.0 months among women who were treated. The median follow-up time for vaccine group and placebo group were 48.5 months, 44.0 months, respectively. The vaccine efficacy for the occurrence of LSIL + was 55.3% (95%CI -12.1%, 82.2%), irrespective of HPV DNA types. There were no significant difference (P = 0.088, Fig. 3).
In vaccine group, there was one woman who detected vulvar intraepithelial neoplasia 2 (VAIN2), one women with VAIN1, and one women with CIN1 post-surgery. Of the two women in the control group, one developed CIN2 and one had CIN1 after treatment. The one CIN2 case in the placebo group (Case 4: Fig. 4) occurred in a woman who, at visit3 (6month), was HPV-16, 31, 33 DNA positive, with HSIL predicted by cytology at gynecological examination. She underwent cold knife conization treatment at visit 3(6 months) and CIN3 was diagnosed; the margins of the excisional material were disease-free. After six months she had ASCH predicted by cytology and was referred for colposcopy. CIN2 (HPV-31,33 DNA positive) was diagnosed on punch biopsy. The one VAIN2 case in the vaccine group (Case 2: Fig. 4) occurred in a woman who, at baseline (visit1), was HPV-16 DNA positive, with HSIL predicted by cytology. She underwent LEEP treatment at baseline (visit1) and CIN3 was diagnosed; the margins of the excisional material were disease-free. At 12 months, she had ASCUS predicted by cytology and was referred for colposcopy. VAIN2 (HPV-16 DNA positive) was diagnosed on punch biopsy.