The Lancet Global Health

Ranking the most efficient human papillomavirus vaccination strategies in low-income and lower-middle income countries: a mathematical modelling analysis

One-dose vaccination and increased vaccine supply provide the opportunity for low-income countries (LICs) and lower-middle-income countries (LMICs) to extend human papillomavirus (HPV) vaccination to populations other than girls aged 9-14 years targeted by routine vaccination. The aim of our study was to use mathematical modelling to identify and rank HPV vaccination strategies according to their efficiency at reducing cervical cancer in LICs and LMICs. In this mathematical modelling analysis, we used HPV-ADVISE to model the efficiency of 162 vaccination strategies in 67 LICs and LMICs varying the following parameters: targeted populations (girls and women or gender neutral); age cohorts (routine vaccination at age 9 years or multi-age cohorts up to age 14 years, 20 years, 25 years, 30 years, and 35 years); number of doses (one or two); and vaccination coverage (40-90%), under different one-dose vaccine efficacy and duration assumptions. We measured efficiency using the number of doses needed to prevent one cervical cancer (ie, number needed to vaccinate [NNV]), obtained by dividing the incremental number of doses given by the incremental number of cervical cancers averted over 100 years. We ranked, incrementally, all strategies from most to least efficient. Globally, under our base-case assumptions (80% vaccination coverage, non-inferior one-dose vaccine, and unfeasibility of increasing vaccination coverage), the model projects that, following routine vaccination of girls aged 9 years with one dose, the most efficient strategies (efficiency frontier) would be, in order: multi-age cohort vaccination of girls aged 10-14 years with one dose (NNV 48); multi-age cohort vaccination of girls aged 15-20 years with one dose (NNV 64); multi-age cohort vaccination of women aged 21-25 years with two doses (NNV 369); routine and multi-age cohort vaccination of boys aged 9-20 years with one dose (NNV 512); multi-age cohort vaccination of women aged 26-30 years (NNV 640) and 31-35 years (NNV 771) with two doses. Under all scenarios investigated (varying vaccination coverage, one-dose vaccine assumptions, and country characteristics), the model projects that the most efficient strategies would be to vaccinate girls up to age 20 years with one dose. The next most efficient strategies depend on the vaccination coverage that can be achieved and the cervical cancer incidence in a given country. Our study suggests that the most efficient vaccination strategy to prevent cervical cancer in LICs and LMICs is to vaccinate girls aged up to 20 years with a single-dose vaccine with high vaccination coverage, before adding boys or providing a second dose to girls. The choice of additional populations to vaccinate will depend on the characteristics and prioritisation goals of a country. WHO, Canadian Institute of Health Research, and the Gates Foundation.

Achieving cervical cancer elimination: an ecological assessment of global determinants using a policy determinant model

Countries must implement and scale up effective programmes to achieve the WHO 2030 cervical cancer elimination targets; however, systemic challenges exist. This study aimed to determine key economic, political, sociocultural, and health-system determinants associated with achieving target coverage of human papillomavirus vaccination and screening, cancer treatment, and areas of opportunity for policy reform and health system strengthening. In this ecological study, we developed a policy determinant model (PDM) to assess key policy determinants of interest using the following conceptual frameworks: social determinants of health, WHO building blocks, and universal health coverage. Core framework domains were operationalised within the PDM through identification of direct or proxy variables located in publicly available global datasets. The PDM was applied with cervical cancer as the disease focus, using an ecological approach. Kendall's and Pearson's correlation coefficients measured the strength of associations between policy indicators and indicators measuring WHO elimination target coverage for vaccination, screening, and treatment. Data from 155 countries across 39 policy determinant indicators were analysed. Indicators measuring equity-focused economic, social, and public policies had large positive associations, with higher values reported for country-level screening and treatment coverage, per WHO targets. Assessment of indicators measuring health system performance likewise showed core health system capability and availability to be associated with progress in cervical cancer elimination. National cancer control planning had low or no associations with achieving target coverage, indicating ineffective implementation. Social, economic, cultural, and environmental policies, in conjunction with health system performance and equitable access to care play integral roles in country capacity to achieve the 2030 elimination targets. In harnessing the cervical cancer elimination agenda, nations have the opportunity to leverage global momentum and funding to drive broader health system strengthening, investment, and policy reform. Australian National Health and Medical Research Centre.

Changes in incidence of HPV-related cancers in South Africa (2011–21): a cross-sectional analysis of the South African National Cancer Registry

Understanding human papillomavirus (HPV)-related cancer epidemiology in South Africa is crucial for informing cancer prevention in this high-burden country. We aimed to describe HPV-related cancer incidence in South Africa between 2011 and 2021. For this cross-sectional study, we obtained data on cancer incidence from the South African National Cancer Registry and population estimates from Statistics South Africa. We calculated age-standardised incidence per 100 000 person-years for cervical carcinoma, and vulvar, vaginal, penile, oropharyngeal, and anal squamous cell carcinoma among people aged 15 years and older by sex, year, age, and race. Average annual percentage changes (AAPCs) were calculated using the Joinpoint Regression Program. Between Jan 1, 2011 and Dec 31, 2021, the overall cervical carcinoma incidence was 30·4 cases per 100 000 person-years (95% CI 30·2 to 30·6), which was highest in females aged 55-64 years (58·5 cases per 100 000 person-years [57·5 to 59·5]); incidence was stable between 2011 and 2016 and began to decline in 2016 (AAPC -2·7% [95% CI -10·8 to -0·2]). The incidence of vulvar squamous cell carcinoma (2·3 cases per 100 000 person-years [2·2 to 2·4]), vaginal squamous cell carcinoma (0·7 cases per 100 000 person-years [0·7 to 0·7]), and female-anal squamous cell carcinoma (0·6 cases per 100 000 person-years [0·6 to 0·7]) increased between 2011 and 2021 (AAPC 8·0% [95% CI 5·3 to 13·9] for vulvar squamous cell carcinoma; 3·2% [0·5 to 6·6] for vaginal squamous cell carcinoma; and 8·5% [2·0 to 23·2] for anal squamous cell carcinoma). The largest increase in vulvar squamous cell carcinoma between 2011 and 2021 was observed among females aged 15-44 years (AAPC 10·0% [8·2 to 13·4]) and 45-54 years (AAPC 10·7% [8·2 to 14·1]). The incidence of penile squamous cell carcinoma (1·4 cases per 10 000 person-years [1·3 to 1·4]) and anal squamous cell carcinoma in males (0·4 cases per 100 000 person-years [0·4 to 0·5]) increased between 2011 and 2021 (AAPC 6·9% [3·8 to 10·7] for penile squamous cell carcinoma; 9·3% [6·7 to 12·7] for anal squamous cell carcinoma). For both sexes, oropharyngeal squamous cell carcinoma trends were stable. The incidence of cervical carcinoma, vulvar squamous cell carcinoma, and vaginal squamous cell carcinoma was highest among Black females; penile squamous cell carcinoma was highest among Black males; anal squamous cell carcinoma in males was similar by race; and oropharyngeal squamous cell carcinoma was highest among White and Coloured individuals. The incidence of non-cervical anogenital cancers is rapidly increasing in South Africa. The incidence of most HPV-related cancers is high among Black individuals, especially for cervical and vulvar cancers, potentially due to disproportionately high HPV-HIV co-infection prevalence among young Black females. HIV prevention and continued HPV vaccination efforts are crucial for reducing HPV-driven cancers in the future. South African National Health Laboratory Services and US National Cancer Institute Intramural Research Program.

Performance of an artificial intelligence-based tool for cervical precancer screening in five countries in Africa: a prospective, observational, diagnostic accuracy study

Cervical cancer kills 300 000 women annually, almost entirely in low-income and middle-income countries. Visual inspection of the cervix using acetic acid (VIA) remains a common method of screening but has suboptimal accuracy. Automated visual evaluation (AVE) is an internally validated artificial intelligence (AI)-based tool designed to assist health workers to improve VIA and to aid diagnostic accuracy. We aimed to measure sensitivity and specificity of AVE for detection of histology-confirmed cervical intraepithelial neoplasia 2 or greater (CIN2 +) in real-world clinical settings, including testing its performance relative to naked-eye VIA. This prospective diagnostic accuracy study took place in government health facilities in Malawi, Rwanda, Senegal, Zambia, and Zimbabwe convenience-sampled between March 17, 2022, and Jan 13, 2023. Eligible participants were women attending routine cervical screening. Women who were pregnant; less than 6 weeks postpartum; had a previous hysterectomy or removal of the cervix; previous treatment for cervical precancer or cancer; and impaired visualisation of the cervix due to inflammatory changes associated with acute infection were excluded. Participants formed a consecutive series. The index test was the previously validated AI-based AVE system. The reference test was histopathology assessment of cervical tissue sample. Among 24  447 eligible women, 9559 (39·1%) were women living with HIV and 11 635 (47·6%) women were positive on at least one test: 7695 (31·5%) on HPV, 5610 on AVE (22·9%), and 2314 (9·6%) on VIA. Of 18  086 women with confirmed final status, 526 (2·9%) had CIN2 +. AVE was found to have sensitivity of 60·1% (95% CI 55·5-64·5) for CIN2 + and specificity of 81·9% (81·3-82·5) for less than CIN2. VIA was found to have sensitivity of 36·6% (32·2-41·1) and specificity of 94·2% (93·8-94·5). Improved sensitivity of AVE over VIA was statistically significant (p<0·0001). AVE-assisted VIA, considering a participant positive when either VIA or AVE is positive, was found to have sensitivity of 71·8% (67·6-75·8) and specificity of 79·0% (78·3-79·6). HPV sensitivity was 90·4% (87·4-92·9) and specificity was 80·1% (79·5-80·7). AVE showed increased sensitivity compared to VIA, with moderate loss in specificity. This method could potentially increase detection of cervical precancerous lesions. High HPV and CIN2 + positivity, influenced by high HIV positivity among participants, underscore the importance of scaling up population-based screening programmes in resource-limited settings to support cervical cancer elimination. Unitaid and Global Health Labs.

Global and regional estimates of genital human papillomavirus prevalence among men: a systematic review and meta-analysis

The epidemiology of human papillomavirus (HPV) in women has been well documented. Less is known about the epidemiology of HPV in men. We aim to provide updated global and regional pooled overall, type-specific, and age-specific prevalence estimates of genital HPV infection in men. We conducted a systematic review and meta-analysis to assess the prevalence of genital HPV infection in the general male population. We searched Embase, Ovid MEDLINE, and the Global Index Medicus for studies published between Jan 1, 1995, and June 1, 2022. Inclusion criteria were population-based surveys in men aged 15 years or older or HPV prevalence studies with a sample size of at least 50 men with no HPV-related pathology or known risk factors for HPV infection that collected samples from anogenital sites and used PCR or hybrid capture 2 techniques for HPV DNA detection. Exclusion criteria were studies conducted among populations at increased risk of HPV infection, exclusively conducted among circumcised men, and based on urine or semen samples. We screened identified reports and extracted summary-level data from those that were eligible. Data were extracted by two researchers independently and reviewed by a third, and discrepancies were resolved by consensus. We extracted only data on mucosal α-genus HPVs. Global and regional age-specific prevalences for any HPV, high-risk (HR)-HPV, and individual HPV types were estimated using random-effects models for meta-analysis and grouped by UN Sustainable Development Goals geographical classification. We identified 5685 publications from database searches, of which 65 studies (comprising 44 769 men) were included from 35 countries. The global pooled prevalence was 31% (95% CI 27-35) for any HPV and 21% (18-24) for HR-HPV. HPV-16 was the most prevalent HPV genotype (5%, 95% CI 4-7) followed by HPV-6 (4%, 3-5). HPV prevalence was high in young adults, reaching a maximum between the ages of 25 years and 29 years, and stabilised or slightly decreased thereafter. Pooled prevalence estimates were similar for the UN Sustainable Development Goal geographical regions of Europe and Northern America, Sub-Saharan Africa, Latin America and the Caribbean, and Australia and New Zealand (Oceania). The estimates for Eastern and South-Eastern Asia were half that of the other regions. Almost one in three men worldwide are infected with at least one genital HPV type and around one in five men are infected with one or more HR-HPV types. Our findings show that HPV prevalence is high in men over the age of 15 years and support that sexually active men, regardless of age, are an important reservoir of HPV genital infection. These estimates emphasise the importance of incorporating men in comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases. Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020. For the Spanish and French translations of the abstract see Supplementary Materials section.

Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative

Tracking progress and providing timely evidence is a fundamental step forward for countries to remain aligned with the targets set by WHO to eliminate cervical cancer as a public health problem (ie, to reduce the incidence of the disease below a threshold of 4 cases per 100 000 women-years). We aimed to assess the extent of global inequalities in cervical cancer incidence and mortality, based on The Global Cancer Observatory (GLOBOCAN) 2020 estimates, including geographical and socioeconomic development, and temporal aspects. For this analysis, we used the GLOBOCAN 2020 database to estimate the age-specific and age-standardised incidence and mortality rates of cervical cancer per 100 000 women-years for 185 countries or territories aggregated across the 20 UN-defined world regions, and by four-tier levels of the Human Development Index (HDI). Time trends (1988-2017) in incidence were extracted from the Cancer Incidence in Five Continents (CI5) plus database. Mortality estimates were obtained using the most recent national vital registration data from WHO. Globally in 2020, there were an estimated 604 127 cervical cancer cases and 341 831 deaths, with a corresponding age-standardised incidence of 13·3 cases per 100 000 women-years (95% CI 13·3-13·3) and mortality rate of 7·2 deaths per 100 000 women-years (95% CI 7·2-7·3). Cervical cancer incidence ranged from 2·2 (1·9-2·4) in Iraq to 84·6 (74·8-94·3) in Eswatini. Mortality rates ranged from 1·0 (0·8-1·2) in Switzerland to 55·7 (47·7-63·7) in Eswatini. Age-standardised incidence was highest in Malawi (67·9 [95% CI 65·7 -70·1]) and Zambia (65·5 [63·0-67·9]) in Africa, Bolivia (36·6 [35·0-38·2]) and Paraguay (34·1 [32·1-36·1]) in Latin America, Maldives (24·5 [17·0-32·0]) and Indonesia (24·4 [24·2-24·7]) in Asia, and Fiji (29·8 [24·7-35·0]) and Papua New Guinea (29·2 [27·3-31·0]) in Melanesia. A clear socioeconomic gradient exists in cervical cancer, with decreasing rates as HDI increased. Incidence was three times higher in countries with low HDI than countries with very high HDI, whereas mortality rates were six times higher in low HDI countries versus very high HDI countries. In 2020 estimates, a general decline in incidence was observed in most countries of the world with representative trend data, with incidence becoming stable at relatively low levels around 2005 in several high-income countries. By contrast, in the same period incidence increased in some countries in eastern Africa and eastern Europe. We observed different patterns of age-specific incidence between countries with well developed population-based screening and treatment services (eg, Sweden, Australia, and the UK) and countries with insufficient and opportunistic services (eg, Colombia, India, and Uganda). The burden of cervical cancer remains high in many parts of the world, and in most countries, the incidence and mortality of the disease remain much higher than the threshold set by the WHO initiative on cervical cancer elimination. We identified substantial geographical and socioeconomic inequalities in cervical cancer globally, with a clear gradient of increasing rates for countries with lower levels of human development. Our study provides timely evidence and impetus for future strategies that prioritise and accelerate progress towards the WHO elimination targets and, in so doing, address the marked variations in the global cervical cancer landscape today. French Institut National du Cancer, Horizon 2020 Framework Programme for Research and Innovation of the European Commission; and EU4Health Programme.

HPV vaccines: when one plus one equals three

Point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation for the early detection and treatment of cervical pre-cancer in women in Papua New Guinea: a prospective, single-arm intervention trial (HPV-STAT)

WHO recommends human papillomavirus (HPV) testing and same-day treatment for cervical screening in low-income and middle-income countries (LMICs); however, few published data exist on the validity of the strategy. We aimed to evaluate the clinical performance, treatment completion rates, adverse events profile, and acceptability of a fully integrated strategy, comprising point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation, for screening of cervical cancer in women in Papua New Guinea. HPV-STAT was a large-scale, prospective, single-arm intervention trial conducted at two clinical sites in Papua New Guinea. Cervical screening clinics with an on-site consultant gynaecologist were selected in consultation with national and provincial health authorities, church health services, and local stakeholders. Eligible participants were women aged 30-59 years attending cervical screening services at the two clinics, who were willing to comply with study procedures and able to provide written informed consent. Women self-collected vaginal specimens for point-of-care GeneXpert testing (Cepheid, Sunnyvale, CA, USA) for oncogenic HPV types. Women testing positive for HPV underwent pelvic examination followed by same-day thermal ablation or referral for gynaecology review. All HPV-positive women and a 15% random sample of HPV-negative women provided a clinician-collected cervical specimen for liquid-based cytology. The primary outcome was clinical performance (ie, sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of the strategy for the detection of high-grade squamous intraepithelial lesion (HSIL) or worse. This trial is registered with ISRCTN, ISRCTN13476702. Between June 5, 2018, and Jan 6, 2020, we recruited 4285 women, 3638 (84·9%) of whom tested negative for HPV and 647 (15·1%) tested positive for one or more oncogenic HPV type. Sensitivity of the algorithm to detect HSIL or worse was 85·4% (95% CI 81·0-89·6), with specificity 89·6% (88·6-90·6), PPV 35·2% (31·6-39·0), and NPV 98·9% (98·6-99·2). Among HPV-positive women, 602 (93·0%) received same-day thermal ablation and 42 (6·5%) were referred for gynaecology review, 37 (88·1%) of whom attended. Acceptability was high among both HPV-positive and HPV-negative women. Among the 329 HPV-positive women who attended a 3-month follow-up visit, 51 (15·5%) reported mild adverse symptoms that resolved in all cases by the follow-up visit. There were no serious adverse events. We conducted the first real-world evaluation of a fully integrated point-of-care HPV self-collect, test, and treat strategy for same-day cervical screening in a LMIC and found it to be effective, acceptable, and safe when implemented at scale in primary health-care facilities in Papua New Guinea. Our findings support the introduction and scale-up of HPV screening and treatment for the control and elimination of cervical cancer in LMICs, as recommended by WHO. Australian National Health and Medical Research Council.

Domestic HPV vaccine price and economic returns for cervical cancer prevention in China: a cost-effectiveness analysis

Coinciding with the release of the first Chinese domestic human papillomavirus (HPV) vaccine Cecolin in 2019, and the substantial advancements in cervical cancer screening technology, we aimed to evaluate the cost-effectiveness of the combined strategies of cervical cancer screening programmes and universal vaccination of girls (aged 9-14 years) with Cecolin in China. We did a cost-effectiveness analysis in China, in which we developed a Markov model of cervical cancer to evaluate the incremental cost-effectiveness ratios of 61 intervention strategies, including a combination of various screening methods at different frequencies with and without vaccination, and also vaccination alone, from a health-care system perspective. We did univariate and probabilistic sensitivity analyses to assess the robustness of the model's findings. Compared with no intervention, various combined screening and vaccination strategies would incur an additional cost of US$6 157 000-22 146 000 and result in 691-970 quality-adjusted life-years (QALYs) gained in a designated cohort of 100 000 girls aged 9-14 years over a lifetime. With a willingness-to-pay threshold of three times the Chinese per-capita gross domestic product (GDP), careHPV screening (a rapid HPV test) once every 5 years with vaccination would be the most cost-effective strategy with an incremental cost-effectiveness ratio of $21 799 per QALY compared with the lower-cost non-dominated strategy on the cost-effectiveness frontier, and the probability of it being cost-effective (44%) outperformed other strategies. Strategies that combined screening and vaccination would be more cost-effective than screening alone strategies when the vaccination cost was less than $50 for two doses, even with a lower willingness-to-pay of one times the per-capita GDP. careHPV screening once every 5 years with vaccination is the most cost-effective strategy for cervical cancer prevention in China. A reduction in the domestic HPV vaccine price is necessary to ascertain a good economic return for the future vaccination programme. The findings provide important evidence that informs health policies for cervical cancer prevention in China. National Natural Science Foundation of China.

Assessing the diagnostic value of Xpert HPV – Authors' reply

Assessing the diagnostic value of Xpert HPV

Cervical cancer and HIV in Zambian women

Cervical cancer screening outcomes in Zambia, 2010–19: a cohort study

Globally, cervical cancer is the fourth leading cause of cancer-related death among women. Poor uptake of screening services contributes to the high mortality. We aimed to examine screening frequency, predictors of screening results, and patterns of sensitisation strategies by age group in a large, programmatic cohort. We did a cohort study including 11 government health facilities in Lusaka, Zambia, in which we reviewed routine programmatic data collected through the Cervical Cancer Prevention Program in Zambia (CCPPZ). Participants who underwent cervical cancer screening in one of the participating study sites were considered for study inclusion if they had a screening result. Follow-up was accomplished per national guidelines. We did descriptive analyses and mixed-effects logistic regression for cervical cancer screening results allowing random effects at the individual and clinic level. Between Jan 1, 2010, and July 31, 2019, we included 183 165 women with 204 225 results for visual inspection with acetic acid and digital cervicography (VIAC) in the analysis. Of all those screened, 21 326 (10·4%) were VIAC-positive, of whom 16 244 (76·2%) received treatment. Of 204 225 screenings, 92 838 (45·5%) were in women who were HIV-negative, 76 607 (37·5%) were in women who were HIV-positive, and 34 780 (17·0%) had an unknown HIV status. Screening frequency increased 65·7% between 2010 and 2019 with most appointments being first-time screenings (n=158 940 [77·8%]). Women with HIV were more likely to test VIAC-positive than women who were HIV-negative (adjusted odds ratio 3·60, 95% CI 2·14-6·08). Younger women (≤29 years) with HIV had the highest predictive probability (18·6%, 95% CI 14·2-22·9) of screening positive. CCPPZ has effectively increased women's engagement in screening since its inception in 2006. Customised sensitisation strategies relevant to different age groups could increase uptake and adherence to screening. The high proportion of screen positivity in women younger than 20 years with HIV requires further consideration. Our data are not able to discern if women with HIV have earlier disease onset or whether this difference reflects misclassification of disease in an age group with a higher sexually transmitted infection prevalence. These data inform scale-up efforts required to achieve WHO elimination targets. US President's Emergency Plan for AIDS Relief.

Maximising the potential of HPV vaccines

Effects of updated demography, disability weights, and cervical cancer burden on estimates of human papillomavirus vaccination impact at the global, regional, and national levels: a PRIME modelling study

The Papillomavirus Rapid Interface for Modelling and Economics (PRIME) has been used around the world to assess the health impact and cost-effectiveness of human papillomavirus (HPV) vaccination in girls. We updated PRIME with new data and methods for demography, disability weights, and cervical cancer burden, and generated revised estimates of the health impact of HPV vaccination at the global, regional, and national levels for 177 countries. PRIME was updated with population demography of the UN World Population Prospects (UNWPP) 2019 revision, disability weights of the Global Burden of Disease (GBD) 2017 study, and cervical cancer burden from the Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2018 database. We estimated the lifetime health benefits for bivalent or quadrivalent and nonavalent vaccination of 9-year-old and 12-year-old girls at 90% coverage during 2020-29 in 177 countries. Health impact was presented in terms of cervical cancer cases, deaths, or disability-adjusted life-years (DALYs) averted per 1000 vaccinated girls in comparison with the counterfactual scenario of no vaccination, and the number of girls needed to be vaccinated to prevent a single case, death, or DALY. In estimating the health impact of HPV vaccination of 9-year-old girls, the combined updates to demography, disability weights, cervical cancer burden estimates resulted in a 26% increase in the estimated number of cases averted, a 51% increase in deaths averted, and a 72% increase in DALYs averted per 1000 vaccinated girls for both the bivalent or quadrivalent and nonavalent vaccines, compared with previous estimates. With the updated model, the bivalent or quadrivalent HPV vaccine was estimated to avert 15 cases, 12 deaths, and 243 DALYs per 1000 vaccinated girls, and the nonavalent HPV vaccine was estimated to avert 19 cases, 14 deaths, and 306 DALYs per 1000 vaccinated girls. The health benefits of vaccination of 12-year-old girls were estimated to be similar but slightly decreased in comparison with vaccination of 9-year-old girls. HPV vaccination provides greater health benefits and is more cost-effective than was previously estimated. The demography update, which incorporates population aging, has the largest effect on the health impact estimates. The WHO African region is expected to gain the greatest health benefits and should be prioritised for HPV vaccination. Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation.

Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study

HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat. We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results. We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women. More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. Supported by the National Cancer Institute UH2/3 CA189908.

Point-of-care HPV molecular diagnostics for a test-and-treat model in high-risk HIV populations

Evidence for the path to cervical cancer elimination

Effect of Brazil's national human papillomavirus vaccination programme on the incidence of cervical cancer and cervical intraepithelial neoplasia grade 3 in women aged 20–24 years: a population-based study

Studies from high-income countries have shown significant reductions in cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3) after implementing the human papillomavirus (HPV) vaccination. However, evidence from low-income and middle-income countries remains limited. Therefore, we aimed to evaluate the impact of the Brazilian HPV vaccination programme on the incidence of cervical cancer and CIN3. In this population-based study, we analysed cervical cancer and CIN3 incidence among women aged 20-24 years between 2019 and 2023, using data from the diagnosis, treatment, and hospitalisations (ie, admittance to hospital) databases from Brazil. Birth cohorts were categorised according to the year of birth. The primary outcome was the diagnosis of cervical cancer (ICD-10 code C53) and CIN3 (code D06). Incidence rate ratios were estimated using Bayesian negative binomial regression, adjusting for calendar year, age, and trimester of diagnosis. We used breast cancer as a negative control outcome. The main analysis was conducted using the data from the Painel Oncologia (diagnosis and treatment database). We analysed 60·6 million women-years of follow-up for women aged 20-24 years. 1318 cervical cancer and 2132 CIN3 cases were recorded. The incidence rate ratios comparing the 2001-03 birth cohort to the 1994-98 birth cohort were 0·42 (95% credible interval 0·27-0·66) for cervical cancer and 0·33 (0·20-0·53) for CIN3. The negative control outcome and exposure showed values close to the null with wider credible intervals. Sensitivity analyses using hospitalisation data showed similar results. Brazil's HPV vaccination programme reduced cervical cancer and CIN3 incidence in women aged 20-24 years. These findings underscore the vaccine's potential to reduce health disparities and contribute to the elimination of cervical cancer in low-income and middle-income populations. Royal Society and Conselho Nacional de Desenvolvimento Científico e Tecnológico.

Single dose HPV vaccine in achieving global cervical cancer elimination

Quantitative estimates of preventable and treatable deaths from 36 cancers worldwide: a population-based study

Cancer is a leading cause of premature mortality globally. This study estimates premature deaths at ages 30-69 years and distinguishes these as deaths that are preventable (avertable through primary or secondary prevention) or treatable (avertable through curative treatment) in 185 countries worldwide. For this population-based study, estimated cancer deaths by country, cancer, sex, and age groups were retrieved from the International Agency for Research on Cancer's GLOBOCAN 2020 database. Crude and age-adjusted cancer-specific years of life lost (YLLs) were calculated for 36 cancer types. Of the estimated all-ages cancer burden of 265·6 million YLLs, 182·8 million (68·8%) YLLs were due to premature deaths from cancer globally in 2020, with 124·3 million (68·0%) preventable and 58·5 million (32·0%) treatable. Countries with low, medium, or high human development index (HDI) levels all had greater proportions of YLLs at premature ages than very high HDI countries (68·9%, 77·0%, and 72·2% vs 57·7%, respectively). Lung cancer was the leading contributor to preventable premature YLLs in medium to very high HDI countries (17·4% of all cancers, or 29·7 million of 171·3 million YLLs), whereas cervical cancer led in low HDI countries (26·3% of all preventable cancers, or 1·83 million of 6·93 million YLLs). Colorectal and breast cancers were major treatable cancers across all four tiers of HDI (25·5% of all treatable cancers in combination, or 14·9 million of 58·5 million YLLs). Alongside tailored programmes of early diagnosis and screening linked to timely and comprehensive treatment, greater investments in risk factor reduction and vaccination are needed to address premature cancer inequalities. Erasmus Mundus Exchange Programme and the International Agency for Research on Cancer. For the German, French, Spanish and Chinese translations of the abstract see Supplementary Materials section.

Human papillomavirus vaccine effect against human papillomavirus infection in Rwanda: evidence from repeated cross-sectional cervical-cell-based surveys

Rwanda was the first African country to implement national human papillomavirus (HPV) vaccination (against types HPV6, 11, 16, and 18). In 2011, a school-based catch-up programme was initiated to vaccinate girls aged younger than 15 years but it also reached older girls in schools. We aimed to estimate the population-level effect of HPV vaccination on HPV prevalence. Cross-sectional surveys were done between July, 2013, and April, 2014 (baseline), and between March, 2019, and December, 2020 (repeat), in sexually active women aged 17-29 years at health centres in the Nyarugenge District of Kigali, Rwanda. HPV prevalence was assessed in cervical cell samples collected by a health-care worker in PreservCyt solution (Cytyc, Boxbourough, MA, USA) and tested using a general primer (GP5+ or GP6+)-mediated PCR. Adjusted overall, total, and indirect (herd immunity) vaccine effectiveness was computed as the percentage of HPV detection among all women and among unvaccinated women. 1501 participants completed the baseline survey and 1639 completed the repeat survey. HPV vaccine-type prevalence in participants aged 17-29 years decreased from 12% (173 of 1501) in the baseline survey to 5% (89 of 1639) in the repeat survey, with an adjusted overall vaccine effectiveness of 47% (95% CI 31 to 60) and an adjusted indirect vaccine effectiveness of 32% (9 to 49). Among participants aged 17-23 years, who were eligible for catch-up vaccination, the adjusted overall vaccine effectiveness was 52% (35 to 65) and the adjusted indirect vaccine effectiveness was 36% (8 to 55), with important heterogeneity according to education (overall vaccine effectiveness was 68% [51 to 79] in participants with ≥6 years of school completed and 16% [-34 to 47] in those with <6 years) and HIV status (overall vaccine effectiveness was 55% [36 to 69] for HIV-negative participants and 24% [-62 to 64] for HIV-positive participants). In Rwanda, the prevalence of vaccine-targeted HPV types has been significantly decreased by the HPV vaccine programme, most notably in women who were attending school during the catch-up programme in 2011. HPV vaccine coverage and population-level impact is expected to increase in future cohorts who are eligible for routine HPV vaccination at age 12 years. Bill & Melinda Gates Foundation.

Impact of the human papillomavirus vaccine in low-resource settings

Cervical cancer elimination: actions needed in the COVID-19 era

The COVID-19 pandemic and disruptions to essential health services in Kenya: a retrospective time-series analysis

Public health emergencies can disrupt the provision of and access to essential health-care services, exacerbating health crises. We aimed to assess the effect of the COVID-19 pandemic on essential health-care services in Kenya. Using county-level data routinely collected from the health information system from health facilities across the country, we used a robust mixed-effect model to examine changes in 17 indicators of essential health services across four periods: the pre-pandemic period (from January, 2018 to February, 2020), two pandemic periods (from March to November 2020, and February to October, 2021), and the period during the COVID-19-associated health-care workers' strike (from December, 2020 to January, 2021). In the pre-pandemic period, we observed a positive trend for multiple indicators. The onset of the pandemic was associated with statistically significant decreases in multiple indicators, including outpatient visits (28·7%; 95% CI 16·0-43·5%), cervical cancer screening (49·8%; 20·6-57·9%), number of HIV tests conducted (45·3%; 23·9-63·0%), patients tested for malaria (31·9%; 16·7-46·7%), number of notified tuberculosis cases (26·6%; 14·7-45·1%), hypertension cases (10·4%; 6·0-39·4%), vitamin A supplements (8·7%; 7·9-10·5%), and three doses of the diphtheria, tetanus toxoid, and pertussis vaccine administered (0·9%; 0·5-1·3%). Pneumonia cases reduced by 50·6% (31·3-67·3%), diarrhoea by 39·7% (24·8-62·7%), and children attending welfare clinics by 39·6% (23·5-47·1%). Cases of sexual violence increased by 8·0% (4·3-25·0%). Skilled deliveries, antenatal care, people with HIV infection newly started on antiretroviral therapy, confirmed cases of malaria, and diabetes cases detected were not significantly affected negatively. Although most of the health indicators began to recover during the pandemic, the health-care workers' strike resulted in nearly all indicators falling to numbers lower than those observed at the onset or during the pre-strike pandemic period. The COVID-19 pandemic and the associated health-care workers' strike in Kenya have been associated with a substantial disruption of essential health services, with the use of outpatient visits, screening and diagnostic services, and child immunisation adversely affected. Efforts to maintain the provision of these essential health services during a health-care crisis should target the susceptible services to prevent the exacerbation of associated disease burdens during such health crises. Bill & Melinda Gates Foundation.

Cervical cancer screening programmes and age-specific coverage estimates for 202 countries and territories worldwide: a review and synthetic analysis

Cervical cancer screening coverage is a key monitoring indicator of the WHO cervical cancer elimination plan. We present global, regional, and national cervical screening coverage estimates against the backdrop of the 70% coverage target set by WHO. In this review and synthetic analysis, we searched scientific literature, government websites, and official documentation to identify official national recommendations and coverage data for cervical cancer screening for the 194 WHO member states and eight associated countries and territories published from database inception until Oct 30, 2020, supplemented with a formal WHO country consultation from Nov 27, 2020, to Feb 12, 2021. We extracted data on the year of introduction of recommendations, the existence of individual invitation to participate, financing of screening tests, primary screening and triage tests used, recommended ages and screening intervals, use of self-sampling, and use of screen-and-treat approaches. We also collected coverage data, either administrative or survey-based, as disaggregated as possible by age and for any available screening interval. According to data completeness and representativeness, different statistical models were developed to produce national age-specific coverages by screening interval, which were transformed into single-age datapoints. Missing data were imputed. Estimates were applied to the 2019 population and aggregated by region and income level. We identified recommendations for cervical screening in 139 (69%) of 202 countries and territories. Cytology was the primary screening test in 109 (78%) of 139 countries. 48 (35%) of 139 countries recommended primary HPV-based screening. Visual inspection with acetic acid was the most recommended test in resource-limited settings. Estimated worldwide coverage in women aged 30-49 years in 2019 was 15% in the previous year, 28% in the previous 3 years, and 32% in the previous 5 years, and 36% ever in lifetime. An estimated 1·6 billion (67%) of 2·3 billion women aged 20-70 years, including 662 million (64%) of 1·0 billion women aged 30-49 years, had never been screened for cervical cancer. 133 million (84%) of 158 million women aged 30-49 years living in high-income countries had been screened ever in lifetime, compared with 194 million (48%) of 404 million women in upper-middle-income countries, 34 million (9%) of 397 million women in lower-middle-income countries, and 8 million (11%) of 74 million in low-income countries. Two in three women aged 30-49 years have never been screened for cervical cancer. Roll-out of screening is very low in low-income and middle-income countries, where the burden of disease is highest. The priority of the WHO elimination campaign should be to increase both screening coverage and treatment of detected lesions; however, expanding the efforts of surveillance systems in both coverage and quality control are major challenges to achieving the WHO elimination target. Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020. For the French, Spanish translations of the abstract see Supplementary Materials section.

Same-day test and treat for early detection and treatment of cervical cancer in LMICs

Estimates of the global burden of cervical cancer associated with HIV

HIV enhances human papillomavirus (HPV)-induced carcinogenesis. However, the contribution of HIV to cervical cancer burden at a population level has not been quantified. We aimed to investigate cervical cancer risk among women living with HIV and to estimate the global cervical cancer burden associated with HIV. We did a systematic literature search and meta-analysis of five databases (PubMed, Embase, Global Health [CABI.org], Web of Science, and Global Index Medicus) to identify studies analysing the association between HIV infection and cervical cancer. We estimated the pooled risk of cervical cancer among women living with HIV across four continents (Africa, Asia, Europe, and North America). The risk ratio (RR) was combined with country-specific UNAIDS estimates of HIV prevalence and GLOBOCAN 2018 estimates of cervical cancer to calculate the proportion of women living with HIV among women with cervical cancer and population attributable fractions and age-standardised incidence rates (ASIRs) of HIV-attributable cervical cancer. 24 studies met our inclusion criteria, which included 236 127 women living with HIV. The pooled risk of cervical cancer was increased in women living with HIV (RR 6·07, 95% CI 4·40-8·37). Globally, 5·8% (95% CI 4·6-7·3) of new cervical cancer cases in 2018 (33 000 new cases, 95% CI 26 000-42 000) were diagnosed in women living with HIV and 4·9% (95% CI 3·6-6·4) were attributable to HIV infection (28 000 new cases, 20 000-36 000). The most affected regions were southern Africa and eastern Africa. In southern Africa, 63·8% (95% CI 58·9-68·1) of women with cervical cancer (9200 new cases, 95% CI 8500-9800) were living with HIV, as were 27·4% (23·7-31·7) of women in eastern Africa (14 000 new cases, 12 000-17 000). ASIRs of HIV-attributable cervical cancer were more than 20 per 100 000 in six countries, all in southern Africa and eastern Africa. Women living with HIV have a significantly increased risk of cervical cancer. HPV vaccination and cervical cancer screening for women living with HIV are especially important for countries in southern Africa and eastern Africa, where a substantial HIV-attributable cervical cancer burden has added to the existing cervical cancer burden. WHO, US Agency for International Development, and US President's Emergency Plan for AIDS Relief.

Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis

The knowledge that persistent human papillomavirus (HPV) infection is the main cause of cervical cancer has resulted in the development of prophylactic vaccines to prevent HPV infection and HPV assays that detect nucleic acids of the virus. WHO has launched a Global Initiative to scale up preventive, screening, and treatment interventions to eliminate cervical cancer as a public health problem during the 21st century. Therefore, our study aimed to assess the existing burden of cervical cancer as a baseline from which to assess the effect of this initiative. For this worldwide analysis, we used data of cancer estimates from 185 countries from the Global Cancer Observatory 2018 database. We used a hierarchy of methods dependent on the availability and quality of the source information from population-based cancer registries to estimate incidence of cervical cancer. For estimation of cervical cancer mortality, we used the WHO mortality database. Countries were grouped in 21 subcontinents and were also categorised as high-resource or lower-resource countries, on the basis of their Human Development Index. We calculated the number of cervical cancer cases and deaths in a given country, directly age-standardised incidence and mortality rate of cervical cancer, indirectly standardised incidence ratio and mortality ratio, cumulative incidence and mortality rate, and average age at diagnosis. Approximately 570 000 cases of cervical cancer and 311 000 deaths from the disease occurred in 2018. Cervical cancer was the fourth most common cancer in women, ranking after breast cancer (2·1 million cases), colorectal cancer (0·8 million) and lung cancer (0·7 million). The estimated age-standardised incidence of cervical cancer was 13·1 per 100 000 women globally and varied widely among countries, with rates ranging from less than 2 to 75 per 100 000 women. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa. The highest incidence was estimated in Eswatini, with approximately 6·5% of women developing cervical cancer before age 75 years. China and India together contributed more than a third of the global cervical burden, with 106 000 cases in China and 97 000 cases in India, and 48 000 deaths in China and 60 000 deaths in India. Globally, the average age at diagnosis of cervical cancer was 53 years, ranging from 44 years (Vanuatu) to 68 years (Singapore). The global average age at death from cervical cancer was 59 years, ranging from 45 years (Vanuatu) to 76 years (Martinique). Cervical cancer ranked in the top three cancers affecting women younger than 45 years in 146 (79%) of 185 countries assessed. Cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in less-resourced countries. The global scale-up of HPV vaccination and HPV-based screening-including self-sampling-has potential to make cervical cancer a rare disease in the decades to come. Our study could help shape and monitor the initiative to eliminate cervical cancer as a major public health problem. Belgian Foundation Against Cancer, DG Research and Innovation of the European Commission, and The Bill & Melinda Gates Foundation.

Participatory innovation for human papillomavirus screening to accelerate the elimination of cervical cancer