The Triage And Risk Management Of Cervical Cancer Screening And Cost-effective Analysis Of Vaccine

OBJECTIVESThe screening cohort with 1997 women aged 35 to 45 years old was built in 1999 in Xiangyuan County,Shanxi province(SPOCCS-I)and followed up for 15 years.This study aimed to evaluate the 15 years changing trends of high risk HPV(HR-HPV)prevalence,and the risks of cervical cancer and precancer lesions(CIN2+)in this Chinese rural screening cohort;to evaluate the risk stratification potency of HPV 16/18 E6 oncoprotein(E6)as a triage method for HPV positivity and to assess the cost-effectiveness of combined HPV vaccine and screening strategy in rural and urban settings in China.METHODS1.The triage methods and risk evaluation of screening:The screening cohort with 1997 women aged 35 to 45 years old was built in 1999 in Xiangyuan County,Shanxi province(SPOCCS-I)and followed up in the years of 2005,2010,2014.Participants were concurrently screened by HPV DNA testing(HC2),liquid based cytology(LBC),visual inspection with acetic acid(VIA),and referred to colposcopy and biopsy if any test was positive.OncoE6TM was performed on HR-HPV positive cervical samples collected from this cohort in 2005 and 2014.The changes of HR-HPV prevalence and the risks of cervical precancerous lesions with CIN2+ as the endpoints were analyzed during the past 15 years.The abilities of E6 in predicting the risk of CIN2+ or CIN3+ after five-and ten-year and the potential clinical performance in HPV positive triage were evaluated.2.The cost-effectiveness evaluation of HPV vaccination:After collecting the transprobability data by calculating the natural history of HPV infection from SPOCCS I,a Markov model was adapted to reflect the lifetime of a modelled 12 years old girls cohort in rural and urban settings in China.Input parameters were obtained from published literature,official reports and a two-round expert review panel.Clinical and economic outcomes of vaccination at age 12 with screening was compared to screening only.In the base case analysis,a 3%discount rate,the vaccine cost of 247 CNY,two rounds of screening in a life time and 70%coverage for both screening and vaccination were used.One-way,two-way and probabilistic sensitivity analyses were performed with different thresholds of cost-effectiveness to reflect the diversity of economic development in China.RESULTS1.The detection rates of HPV and CIN2+ were 22.3%and 4.3%in 2010 when the participants were around menopause,respectively.The cumulative risk of CIN2+ in HR-HPV positive women at baseline was significantly higher than HR-HPV negative(X2=408.021,P<0.01)during the 15-year follow-up.HPV better stratified risks than LBC and VIA.Among HPV positive women in 2005,E6 showed the lowest positive rate(9.9%)compared to LBC(48.4%)and VIA(28.0%),however,higher prevalence(10.3%)and ten-year cumulative incidence rate(53.0%)of CIN3+ were seen among women positive for E6,while only 4.2%and 2.9%women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005,23.0%and 16.5%developed to CIN3+ after ten-year,respectively.Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression(RRadjusted=40.0 and 21.2 respectively).2.Vaccination in addition to screening could prevent 60%more cervical cancer cases and deaths than screening only.The incremental cost effectiveness ratio varied largely when changing cost of vaccination and discount in one way analysis.Vaccination was very cost-effective when the vaccine cost ranged 87-630 CNY in rural and 87-750 CNY in urban;and remained cost-effective when the vaccine cost ranged 630-1,700 CNY in rural and 750-1,900 CNY in urban in two way analysis.Probabilistic sensitivity analyses showed that model results were robust.CONCLUSIONS1.HPV testing could stratify risks of CIN2+.Women aged 45-55 years old should still be considered as the target population in cervical cancer screening.The OncoE6TM Cervical Test could be a favorable option for triage in HPV DNA positive women,indicating a potential use in 'screen and treat'strategy.2.In both rural and urban areas,the vaccination cost and discounting were important factors determining the cost-effectiveness of HPV vaccination.In areas with a high burden of cervical cancer and limited screening activities,HPV vaccination should be prioritized.However,the vaccine cost needs to be reduced in particular in aresa with high screening coverage,low disease burden and low development.