Benefits, harms and cost-effectiveness of cervical screening and treatment in 78 low-income and lower-middle income countries for women in the general population: modelling to support updated WHO cervical screening and treatment guidelines to prevent cervical cancer
Authors: Simms Kate , Keane Adam , Nguyen TND , Caruana Michael , Hall Michaela , Lui Gigi , Gauvreau Cindy , Demke Owen , Arbyn Marc , Basu Partha , Wentzensen Nicolas , Lauby-Secretan Beatrice , Ilbawi André , Hutubessy Raymond , Almonte Maribel , DeSanjose Silvia , Kelly Helen , Dalal Shona , Eckert Lindo , Santesso Nancy , Broutet Nathalie , Canfell Karen 
Published: December 2022

Abstract
A strategy for the elimination of cervical cancer as a public health problem, through the scale-up of human papillomavirus (HPV) vaccination, cervical screening and precancer/cancer treatment, was launched by the World Health Organisation (WHO) in November 2020. To support the strategy, WHO published updated cervical screening and treatment guidelines in 2021. A modelled assessment of the benefits, harms and cost-effectiveness of screening approaches for the general population across 78 low-and lower-middle income countries (LMICs) informed the updated guidelines. With the support of the WHO Guidelines Development Group for Screening and Treatment to Prevent Cervical Cancer, we used an established modelling platform, Policy1-Cervix, to evaluate the impact of seven screening algorithms based on primary visual inspection with acetic acid (‘VIA’), primary cytology, and primary HPV DNA (‘primary HPV’) with no triage, or triage using HPV16/18 genotyping, colposcopy, cytology, or VIA. Screening intervals of 3 and 5 years were considered for primary VIA and cytology, and intervals of 5 and 10 years were considered for primary HPV. Screening and triage test performance was informed by updated systematic review evidence. For this normative analysis informing guidelines in screened populations, we assumed 70% of women attended each routine screen, and 90% complied with follow-up or treatment. Outcomes included reduction in cancer incidence and mortality, number of precancer treatments needed to prevent a death (NNT) and preterm delivery events directly due to precancer treatment and cost-effectiveness (US$/Health-Adjusted Life Year Saved [HALYS]). A range of assumptions were considered in sensitivity and supplementary analyses. We found that primary HPV DNA testing approaches, regardless of triaging method, were the most effective and cost-effective screening approaches and they appear on, or near to, the cost-effectiveness frontier. Primary HPV DNA testing without triage every 5 years for ages 30–50 years could result in a 64% reduction in cervical cancer mortality rates, compared to no screening. This strategy was associated with an NNT of 54 to prevent one death and was associated with an incremental cost-effectiveness ratio (ICER) of US$530/HALY saved (69/78[88%] of LMICs have a GDP-per-capita of > = US$518). Strategies involving primary HPV with triage of HPV positive women before treatment were almost as effective, reducing overall cervical cancer mortality rates by 60–63%, had a similar position on the cost-effectiveness frontier, but had an improved benefits-to-harms profile compared to HPV screening without triage, with an NNT of 26–37 to prevent a death. Compared to VIA screening, primary HPV screening, even without triaging, generated at least 60% fewer precancer treatment events and had 47% fewer additional preterm delivery events. In conclusion, primary HPV testing approaches were the most effective, optimised benefits-to-harms, and were cost-effective compared to primary VIA or cytology. If loss-to-follow-up after triage is limited, triaging HPV positive women before treatment reduces precancer treatments and preterm delivery events with minimal loss in effectiveness, and thus further improves the benefits-to-harms. Based on these findings, WHO now recommends primary HPV screening with or without triage for women in the general population. Going forward, country-specific analyses will continue to have an important role because they will be able to consider local factors that influence follow-up options and feasible triage testing approaches.