To our knowledge, this is the most detailed modelled evaluation of cervical cancer screening to be conducted in China. The analysis incorporated setting-specific information on the risks of HPV infection, screening and management procedures and the costs associated with screening, diagnosis and treatment. The screening alternatives considered were based on extensive consultation with local key opinion leaders about the practical options for organising screening in rural China. We evaluated the predicted outcomes resulting from various screening alternatives, including once or twice-lifetime screening at ages 35 and/or 45 years by mobile screening units; and routine screening at 5-yearly, 10-yearly and IARC-recommended intervals within a program of regular screening. Depending on the test technology used, and assuming a participation rate of ~70%, we found that once-lifetime screening at age 35 years would reduce age-standardised cervical cancer mortality in the population by 8-12% over the long term, with a CER of $557-959 per LYS. Regular screening at a feasible age-standardised participation rate of 62% in women aged 30-59 years would reduce cervical cancer mortality by 19-54%, with a CER of $665-2,269 per LYS. Although these findings imply that all strategies would be considered cost-effective in relation to no intervention, testing with careHPV is predicted to lead to greater absolute benefits when compared to visual inspection tests.
The screening participation rate used in the evaluation was informed by a government-sponsored VIA/VILI screening demonstration project. Although the assumed participation rate may seem relatively high in context of developed country programs, it has been demonstrated to be achievable locally, in the context of a high level of population enumeration and high compliance with government initiatives. We found that in this population in rural China a single round of screening can potentially be extended from 35 year old women to women aged up to 50 years without loss of effectiveness. This finding is important for the practical realisation of single round screening strategies as it implies that a reasonably wide age range of women can be included whilst still maximising long term benefits. However, we found that the lifetime benefits of once-off screening may be lower than previously estimated for other populations . A previous study of the cost-effectiveness of cervical screening in five developing countries (not including China) concluded that once-lifetime screening at age 35 years could reduce the cumulative lifetime risk of invasive cervical cancer in screened women by between 25-36%, depending on the screening strategy and technology used . After taking into account a population rather than an individual perspective, local information on the sensitivity of screening tests, the local requirement for colposcopic confirmation of all screening test results with consequent diagnostic accuracy loss, and other factors, our analysis for rural China identified more attenuated benefits. Our findings are complementary to that of a recent randomised trial in rural India which found that a single round of HPV screening was associated with a reduction by approximately 50% in the hazard ratio for the development of advanced cervical cancer and cervical cancer death over the following eight years . Over a lifetime, the relative protective effect of a single HPV test in screened versus unscreened women is expected to be reduced as some new HPV infections and new cancer cases accrue in both groups over time. Our study supplements the trial findings by providing a measure of the benefits of a single round of screening but considered from the standpoint of long term (lifetime) follow-up.
Our finding that careHPV screening can be cost-effective in rural China is consistent with that of a prior analysis by Levin et al . However, we focused on the differential outcomes and cost-effectiveness associated with visual inspection methods and careHPV testing, considering the differential effects associated with varying the HPV test threshold or adjusting the visual methodology to include Lugol's iodine. In contrast, prior work considered careHPV testing in relation to HC2 testing and cervical cytology, which may not be readily practicable alternatives in this setting. Therefore, the current paper extends the findings of the related previous work [27, 31] in two important ways - it provides more detail for this particular setting, and it compares the performance of careHPV screening to the other currently viable test alternatives in this setting.
Visual inspection methods have been proposed as low cost screening solutions in less developed countries [7, 30, 32]. However, problems with accuracy and test standardisation may have hindered the widespread adoption of visual testing modalities, and a round of VIA screening was not associated with any significant reduction in the risk of advanced cancer or death over eight years of follow-up in a recent large scale trial in India . It has been suggested that in some diagnostic accuracy studies of visual inspection methods the sensitivity of the test may have been overestimated by up to 20 absolute percentage points due to verification bias when colposcopically-directed biopsy is used as the gold standard . In order to increase the sensitivity of visual testing, the addition of VILI has been proposed as a secondary test for VIA-negative women . The VIA/VILI combined procedure may moderately increase the sensitivity of visual inspection modalities  and has been shown to be logistically feasible within a government-sponsored large-scale demonstration project at 42 sites across China, which was rolled out from 2006 . However, limited data are available on the accuracy of VIA/VILI as a combined procedure. Based on re-analysis of follow-up data from a previous study [5, 16], we assumed that in this setting the addition of VILI would increase sensitivity but would decrease the overall specificity of visual inspection testing, which may not uniformly be the case . Therefore, more data on the accuracy of combined VIA/VILI testing is required, and our results for this combined test modality should be considered provisional.
This analysis has several limitations. Firstly, the model which was used is based upon CIN natural history states rather than states that directly reflect type-specific HPV infection persistence and progression. It should be noted that there are considerable uncertainties about the natural history of HPV (and thus modelled analysis of primary HPV testing) in populations such as the one we studied in rural China, in which the rates of infections at older ages are comparable or higher to those at younger ages. The relative proportion of new versus re-emerging latent or persisting HPV infections in women over 35 years of age in this population is not known. Furthermore, the progressive potential of new infections in older women in this population is difficult to characterise. We did not have direct information on male sexual behaviour and thus could not estimate the total rate of new exposures in older women; therefore we took a fitting approach to modelling the observed pattern of female HPV infection by incorporating survey data on female behaviour and estimating male behaviour patterns. In general terms, if infections in women aged 35 years or older have a low potential to progress to CIN3 (and then to invasive cancer), then the efficacy of once-lifetime HPV screening at age 35 would be higher. In our baseline analysis we assumed that some new infections would progress to CIN3 after a once-lifetime screening event. However, under the extreme assumption that all HPV infections occurring in older women that have the potential to progress to CIN 3 are potentially detectable (and treatable) at the time of the screening event, the average reduction in cumulative lifetime incidence and mortality associated with once-lifetime HPV screening would increase. This implies that from the perspective of the cost-effectiveness of once-lifetime primary HPV screening, our evaluation has taken a conservative approach.
Another limitation of the study is that we could not account for variation in screening and diagnostic test performance over time, due to drift in clinical or laboratory practice (although we did include consideration of the need for quality control procedures in the costs associated with the screening strategies). Because of this limitation, we presented our main cost-effectiveness findings for each technology as a cost-effectiveness ratio compared to no intervention, since the relative test performance of visual inspection and HPV testing methodologies may vary over time in this setting in as-yet-unpredictable ways. Another limitation of the study is that we did not have extensive local data on health state preferences (utilities) or data from comparable populations to use in the calculation of QALYs, and therefore, the primary findings of the current analysis were based on the estimation of life years saved for the various screening strategies.
We have extensively reviewed the available local cervical cancer incidence and mortality data. Shanxi Province has been thought to be a "high risk" area for cervical cancer; but in practice the evidence for this appears to depend heavily on the findings of the earliest cancer mortality surveys conducted in China in the 1970s which found that rates were up to 83 per 100,000 women (according to the Segi World Standard Population [2, 33]; no information on the population according to Ahmad et al can be calculated because age-specific data are not available ). Two subsequent mortality surveys were performed in China [2, 34, 35] - the most recent in 2000-2005 included data from Xiangyuan county in Shanxi Province, finding a much lower mortality rate of 6.8 per 100,000 women [2, 35] (according to the Chinese standard population of 1982; again, age-specific data are not available to calculate rates according to the Ahmad et al standard population). Furthermore, perceptions of the region as "high risk" appear inconsistent with the relatively low rates of HPV infection observed in females overall (Figure 2A in our paper). There are no IARC-certified cancer registries in the region and so no up-to-date accurate registry information is available. In the absence of such information we have taken a conservative approach to the current evaluation, and assumed the lifetime risk of cancer and the average incidence rate are equivalent to the average rate of developing countries. It should be noted that this incidence rate is still much higher than the rate reported for China overall according to the most recent data from IARC's Cancer Incidence in Five Continents , which is less than 4 per 100,000 women and substantially less than many developed countries. If in fact cancer rates are higher than we assumed in this setting, this would have the effect of increasing the estimated cost-effectiveness of all screening strategies, but would be unlikely to change the relative costs and benefits of the various strategies, compared to no intervention.
Our objective in this study was to provide policy makers in China with the best available evidence on the relative benefits and costs of different screening strategies. Modelling is a commonly used approach, and here we have employed the techniques of modelling to integrate local evidence with international data. Modelling is an important complement to randomised clinical trials, but one of the advantages of modelling studies is that they can predict lifetime epidemiologic outcome and cost-effectiveness results. Additionally, a much greater range of potential strategies can be evaluated via modelled approaches. A total of 20 screening strategies were evaluated in our study, but such a large number of strategies are unlikely to be practical in a large-scale screening trial. Although randomised controlled trials are ultimately the "gold standard", in practice these are highly unlikely to be performed in every setting into which cervical cancer prevention initiatives are introduced. In the absence of such locally conducted trials, modelling studies provide local policy makers with the best available information with which to inform further decision making.
Our experience in working with local key opinion leaders and policy makers in China emphasises the importance of performing detailed evaluations of the viable alternative strategies taken in the context of local practices, feasible methods of screening organisation, and clinically acceptable options; rather than generically applying strategies that may be applicable in other settings. For example, although visual inspection with cryotherapy see-and-treat has previously been evaluated as cost-effective in other settings , this strategy would not be acceptable in China. This is because power supplies for LEEP would be available in the settings we considered; and the in context of local clinical practice it is felt that the lack of histological diagnosis after cryotherapy would potentially increase the risk of medical disputes and confusion about clinical management. The local preference for diagnostic confirmation followed by LEEP treatment is emphasised by the incorporation of this management strategy into a recently implemented large scale government demonstration project for VIA/VILI screening which has the objective of screening up to 10 million women . Our evaluation models the VIA/VILI management processes used in the demonstration project, but also gives local policy makers much more detailed information on the relative benefits of careHPV screening. In relation to the sampling method for HPV testing, we evaluated each method in context of the associated practically realisable method(s) of screening organisation, so that self-sampling (which is less costly than health provider sampling) was combined with community/village clinic-based once- or twice-lifetime screening. Health provider sampling was combined with county hospital-based regular screening, which would be viable in this more centralised approach. However, it should be noted that because the evidence suggests that both provider and self-sampling for careHPV testing has relatively high sensitivity , the effectiveness of the two sampling strategies are also expected to be similar.
The strengths of the current study lie in the detailed epidemiological modelling and the use of extensive local information on screening and diagnostic test accuracy and management practices, age-specific unsatisfactory rates, and costs. Our study takes into account measured patterns of sexual behaviour and HPV infection in this rural population. This has allowed us to characterise in detail the potential role of primary HPV screening in relation to other viable alternatives in this important low-resource setting.