| Background:Cervical cancer is one of gynecological tumors with the heaviest disease burden,and high-risk human papillomavirus(HR-HPV)persistent infection is the prerequisite of cervical cancer.HPV vaccination is the best measure for primary prevention of cervical cancer,however,there is disagreement on whether vaccination is necessary for sexually active women aged 27-45 years.The domestic HPV vaccines were licensed,which makes wide coverage of HPV vaccination possible in China.Is it recommended to vaccination for women aged 27-45 years?It is imminent to develop HPV vaccination strategy.Mathematical modelling has been used to estimate the costeffectiveness of HPV vaccination,which requires realistic assumptions for HR-HPV infection natural process.HPV Cross-sectional studies have showed that the epidemiology of HPV infection in China is different from those of the developed countries.In developed countries,the prevalence of HR-HPV infection peak shortly after the debut of sexual activity,and then quickly decrease and keep at low rate.While in Chinese women,the age-specific prevalence of HR-HPV presents as bimodal distribution,the prevalence reaches its second peak in older women.The characteristics of persistence,clearance and clinical outcome after HR-HPV infection remain unknown,and prospective cohort studies are urgently needed to elucidate this important issue.Objectives:To investigate the characteristics of HR-HPV infection in women aged 1826 years and women aged 27-45 years in China,including the prevalence,incidence,and clearance of HR-HPV infection,proportion of HR-HPV persistent infection,the duration of persistence,and the cumulative incidences of developing to CIN from prevalent or newly acquired HR-HPV infection.The burden of disease associated with HR-HPV infection would be studied in women aged 18-26 years and in women aged 27-45 years.Also,to evaluate the protection against HPV-16/18 infection of naturally acquired antibodies.The data from this study would support making the cervical cancer screening policies and immunization policies suitable for Chinese women.Methods:From November 2012 to April 2013,a total of 7372 healthy women aged 18-45 years were recruited from five study sites in China for a phase III clinical trial of the HPV-16/18 bivalent vaccine.This study was conducted in the control arm cohort of the clinical trial,which included 3683 women with 1862 women aged 18-26 years and 1821 women aged 27-45 years.All participants were followed-up with 6-month interval for first 30 months and with 12-month interval for last 36 month in a 66-month followup period.At each follow-up visit,gynecologic examination was performed with collection of endocervical swab samples for Papanicolaou testing and HPV DNA testing.In addition,blood samples were collected once a year for HPV antibody detection.Participants with abnormal cytology(except ASC-US and HC2 negative)were subjected to colposcopy,and tissue biopsy and pathological diagnosis were performed according to clinical practice.χ2-test or the Fisher’s exact test were used to compare the prevalence of HR-HPV infection,cervical lesions and proportion of persistent infection in different age groups.COX regression model was used to calculate the Hazard ratio of incidence of HR-HPV infection,HR-HPV related disease between different age groups,to calculate the Hazard ratio of clearance,recurrence and cumulative incidences of developing to CIN between different age groups,and to calculate the Hazard ratio of incidence of HPV-16/18 infection among different serostatus groups.The Kaplan-Meier method and Log-rank tests were used to construct and compare the cumulative incidence,clearance of HR-HPV infections by age group,and to construct and compare the cumulative incidence of HPV-16/18 infection by baseline serostatus of HPV-16/18.Results:1.Prevalence of HR-HPV infection and cervical abnormalities in Chinese healthy women aged 18-45 yearsThe age-specific prevalence of HR-HPV infection presents as U-shaped bimodal distribution,there was no significant difference of HR-HPV infection between women aged 18-26 years and women aged 27-45 years(14.8%vs 14.2%).Detection of a single HR-HPV genotype was the most common finding in HR-HPV positive women,and there was no significant difference in the distribution of single or multiple infection between women aged 18-26 years and women aged 27-45 years.The prevalence of cervical abnormalities in women aged 27-45 years was 6.4%,which was higher than that of women aged 18-26 years(5.4%),however,the prevalence of CIN2+was nonsignificantly higher than that in women aged 18-26 years(1.6%vs 1.0%).In both women aged 18-26 years and women aged 27-45 years,HPV-52 was most common finding in samples of normal cytology,abnormal cytology,and CIN1,while HPV-16 was most common finding in tissue samples of CIN2+.2.Incidence of HR-HPV infection and HR-HPV related cervical abnormalities in Chinese healthy women aged 18-45 yearsThe incidences of HR-HPV infection,persistent infection(>6 month,6mPI),and persistent infection(>12 month,12mPI)in women aged 27-45 years were all no significantly lower than those of women aged 18-26 years(infection:64.1/1000 personyear vs 71.1/1000 person-year,6mPI:24.2 vs 29.2,12mPI:18.3 vs 21.1).The risk of HR-HPV infection was still high in Chinese women aged 27-45 years.Among HRHPV genotypes,the incidence of HPV-52 was highest in both women aged 18-26 years and women aged 27-45 years.The incidences of HR-HPV related CIN1+and CIN2+in women aged 18-26 years were 1.76 and 1.98 times higher than in those of women aged 27-45 years,respectively.3.Clinical outcome of HR-HPV infection in Chinese healthy women aged 18-45 years(1)Clearance:the clearance rate and median time to clearance of both prevalent and newly acquired HR-HPV infection were similar in women aged 18-26 years and women aged 27-45 years,the clearance rates of prevalent HR-HPV infection were 60.5/100 person years and 57.0/100 person years,and of newly acquired HR-HPV infection were 69.1/100 person years and 71.0/100 person years in women aged 18-26 years and women aged 27-45 years,respectively.The median time to clearance of prevalent HRHPV infection were 12.5 and 12.6 months,and those of newly acquired HR-HPV infection were both 12.9 months in women aged 18-26 years and women aged 27-45 years.Coinfection with LR-HPV(HR:1.25,95%CI:1.05,1.48)or presence of LRHPV related CIN1+(HR:9.25,95%CI:6.51,13.15)increase the chance of clearance,while concomitant CIN1+associated with the same HPV type diminished the chance(HR:0.01,95%CI:0,0.09),and previous cervical HPV infection would take more time to clear.(2)Recurrence:regardless of prevalent or the newly acquired HR-HPV infection,the recurrence rates were no significant difference in women aged 18-26 years and women aged 27-45 years.The recurrence rates of prevalent HR-HPV infection were 37.0/1000 person years and 44.4/1000 person years in women aged 1826 years and women aged 27-45 years,and those of newly acquired HR-HPV infection were 49.7/1000 person years and 44.4/1000 person years,respectively.(3)Persistence:For newly acquired HR-HPV infections,the proportions of 6mPI and 12mPI were similar in women aged 18-26 years and women aged 27-45 years.The proportions of 6mPI,12mPI were 38.6%and 38.7%,25.0%and 26.8%in women aged 18-26 years and women aged 27-45 years,respectively.The median duration of 6mPI was no significant difference in women aged 18-26 years and 27-45 years(1 1.8 months vs 12.3 months).(4)Progression:the risk of progression from prevalent HR-HPV infection to CIN1+and CIN2+were no significantly difference between women aged 18-26 years and women aged 27-45 years,whereas the risk of progression from newly acquired HRHPV infection to CIN1+in women aged 18-26 years was higher than in women aged 27-45 years(HR:1.69,95%CI:1.04,2.74),and the risk of progression from newly acquired HR-HPV infection to CIN2+was no significantly higher than older women(HR:1.92,95%CI:0.96,3.85).The risk of progression from both prevalent and newly acquired HR-HPV 6mPI to CIN1+and CIN2+were no significantly difference between women aged 18-26 years and women aged 27-45 years.4.Naturally acquired HPV-16/18 antibodies against subsequent homotypic infectionFor the persistent HPV-16/18 infection(>6 months)endpoints,naturally acquired HPV16/18 neutralizing antibodies significantly reduced the risk of subsequent 6-month infection by 84%(HR:0.16,95%CI:0.04,0.65),while the binding IgG antibodies modestly and non-significantly lowered the risk by 34%(HR:0.66,95%CI:0.40,1.09).Conclusions:1.The characteristics of HR-HPV infection,including the incidence,clearance of HR-HPV infection,proportion of HR-HPV persistent infection,and the duration of persistence were no significant difference in Chinese women aged 18-26 years and women aged 27-45 years.The risk of HR-HPV infection in Chinese women aged 27-45 years was still higher.The risk of progression from HR-HPV infection to CIN1+and CIN2+,and the incidences of HR-HPV related CIN1+and CIN2+in women aged 18-26 years was higher than women aged 27-45 years.However,the prevalences of cervical cytology abnormalities and CIN2+were higher in women aged 27-45 years.Thus,HPV vaccination and cervical cancer screening should be actively promoted for prevention and control of cervical cancer.2.Naturally acquired antibodies are associated with a substantially reduced risk of subsequent homotypic infection.Neutralizing antibodies are a highly specific indicator for HPV protective natural immunity. |
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