Philip E Castle

Increasing power in screening trials by testing control-arm specimens: application to multicancer detection screening

Abstract Background Cancer screening trials have required large sample sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the “intended effect” (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control arm, such as stored blood for multicancer detection (MCD) tests. Methods We simulated hypothetical MCD screening trials to compare power and sample size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial [NLST], Minnesota Colon Cancer Control Study [MINN-FOBT-A], and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial—colorectal component [PLCO-CRC]). Results Compared with the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality P values 6-fold (NLST), 33-fold (MINN-FOBT-A), or 260 000-fold (PLCO-CRC) or, alternately, reduced sample size (90% power) by 25% (NLST), 47% (MINN-FOBT-A), or 63% (PLCO-CRC). For potential MCD trial designs requiring 100 000 subjects per arm to achieve 90% power for multicancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37 500-50 000 per arm, depending on assumptions concerning control-arm test-positives. Conclusions Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample size or accelerate trials and could provide particularly strong power gains for MCD tests.

Retracted and Replaced: Increasing power in screening trials by testing control-arm specimens: application to multicancer detection screening

Abstract Background Cancer screening trials have required large sample sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the “intended effect” (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control arm, such as stored blood for multicancer detection (MCD) tests. Methods We simulated hypothetical MCD screening trials to compare power and sample size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial [NLST], Minnesota Colon Cancer Control Study [MINN-FOBT-A], and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial—colorectal component [PLCO-CRC]). Results Compared with the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality P values 5-fold (NLST), 33-fold (MINN-FOBT-A), or 14 160-fold (PLCO-CRC) or, alternately, reduced sample size (90% power) by 26% (NLST), 48% (MINN-FOBT-A), or 59% (PLCO-CRC). For potential MCD trial designs requiring 100 000 subjects per arm to achieve 90% power for multicancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37 500-50 000 per arm, depending on assumptions concerning control-arm test-positives. Conclusions Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample size or accelerate trials and could provide particularly strong power gains for MCD tests.

Impact of repeatedly screening negative on cervical cancer risk

Abstract Background We demonstrated that cervical cancer risk following any screening result is lower if there is a known prior negative screening history vs an unknown screening history. We extended these findings to look at how screening performs following repeatedly negative screening results. Methods Approximately 1.7 million women aged 30-64 years underwent triennial human papillomavirus (HPV) and cytology co-testing from 2003 to 2021. We modeled 5-year risks of cervical intraepithelial neoplasia grade 3 or more severe diagnoses (CIN3+) and invasive cervical cancer for the initial co-test, and then successive rounds following negative co-testing. A logistic-Weibull prevalence-incidence model was used to model risks. Results HPV test positivity was greater than cytology positivity for only the first co-test, and both positivity rates decreased with each screening round. Diagnostic yields of CIN3+ and cancer declined with each round of screening so the first screen yielded 8-fold more CIN3+ and invasive cancer than the fifth screen following 4 consecutive negative co-tests. Five-year risks of CIN3+ for positive and negative HPV and cytology results, individually or combined, decreased considerably after the first screen, with smaller decreases in each subsequent round. For cancer, we noticed a considerable decrease with the first screen only. Five-year CIN3+ risks were greater for positive HPV or cytology results, with a longer antecedent screening interval and younger age at screening (Ptrend < .001). Conclusions Triennial screening that includes HPV testing becomes inefficient after a single and more so after multiple negative screens. These data support the use of longer screening intervals, especially following negative screen(s).

Challenges and Opportunities for Global Cervical Cancer Elimination: How Can We Build a Model for Other Cancers?

Cervical cancer remains a leading cause of cancer-related death among women globally, despite the availability of effective prevention through human papillomavirus (HPV) vaccination and HPV-based screening. This review explores the state-of-the-art technologies for cervical cancer prevention, examining their efficacy, implementation challenges, and global disparities in access. Prophylactic HPV vaccination and HPV DNA testing have demonstrated high efficacy in reducing cervical cancer incidence, yet their uptake remains uneven—especially in low- and middle-income countries (LMICs), where the disease burden is greatest. Barriers include infrastructure limitations, workforce shortages, sociocultural obstacles, and competing health priorities. Strategies such as single-dose vaccination, early childhood immunization, self-sampling, and screen-and-treat approaches offer promising pathways to expand access. In high-income countries (HICs), where HPV vaccine uptake is higher and screening systems are more established, the reduced risk of infection and high negative predictive value of HPV testing support a shift toward screening deintensification. Precision prevention frameworks—leveraging biomarkers, genotyping, and artificial intelligence—offer further opportunities to enhance accuracy and efficiency. The review also underscores the importance of health system strengthening, international collaboration, and policy support to achieve the WHO's 90-70-90 targets for cervical cancer elimination. Moreover, innovations developed for cervical cancer prevention—such as decentralized screening, mobile health platforms, and task-shifting—offer a valuable model for improving strategies for primary and secondary prevention of other cancers.

Whole‐genome sequencing of 1,083 HPV45 cases and controls identifies genetic variants associated with glandular cervical lesions

AbstractHuman papillomavirus type 45 (HPV45) causes ~6% of all cervical cancers and an even greater proportion of adenocarcinomas, the latter of which are challenging to detect using current cervical cancer screening. Little is known about how HPV45 genetic variation is related to the risk of cervical precancer/cancer. To investigate this, we whole‐genome sequenced a total of 1,083 HPV45‐positive samples from two large studies. We evaluated associations of HPV45 genetic variation (sublineages, subclades, and SNPs) with histology‐specific precancer/cancer risk using logistic regression and evaluated risk modification by self‐reported race/ethnicity. Compared to the common A1 sublineage, A2 and B1 were associated with increased precancer/cancer (A2, OR = 3.9, 95% CI = 1.9–8.5; B1, OR = 2.7, 95% CI = 1.3–5.8; B2, OR = 3.3, 95% CI = 1.6–7.3), and most strongly with the glandular precancers/cancers (AIS/ADC; A2, OR = 6.9, 95% CI = 1.0–184; B1, OR = 6.2, 95% CI = 1.1–159). The A2 sublineage was most prevalent in women in East Asia and women who self‐reported as Asian/Pacific Islander (PI) in the U.S.; East Asian and Asian/PI women had the greatest precancer/cancer risk associated with A2 infections (OR = 5.8, 95% CI = 1.3–37.4) compared to all other sublineages among these women. We further evaluated precancer/cancer risk associations for 262 individual HPV45 SNPs and identified four SNPs significantly associated with only glandular precancers/cancers after correction for multiple tests (ORs ranged 7.8–20.7). One of these SNPs was a nonsynonymous variant in both overlapping viral E2/E4 ORFs. In summary, we show that HPV45 genetic variation influences the risk of precancer/cancer, specifically glandular precancer/cancer. Further studies of these genetic variants may improve our understanding of glandular lesions.

Looking Back, Moving Forward: Challenges and Opportunities for Global Cervical Cancer Prevention and Control

Despite the introduction of Pap testing for screening to prevent cervical cancer in the mid-20th century, cervical cancer remains a common cause of cancer-related mortality and morbidity globally. This is primarily due to differences in access to screening and care between low-income and high-income resource settings, resulting in cervical cancer being one of the cancers with the greatest health disparity. The discovery of human papillomavirus (HPV) as the near-obligate viral cause of cervical cancer can revolutionize how it can be prevented: HPV vaccination against infection for prophylaxis and HPV testing-based screening for the detection and treatment of cervical pre-cancers for interception. As a result of this progress, the World Health Organization has championed the elimination of cervical cancer as a global health problem. However, unless research, investments, and actions are taken to ensure equitable global access to these highly effective preventive interventions, there is a real threat to exacerbating the current health inequities in cervical cancer. In this review, the progress to date and the challenges and opportunities for fulfilling the potential of HPV-targeted prevention for global cervical cancer control are discussed.

Human papillomavirus genotype-specific prevalence and infection risks: a 10-year population-based study from the United States

Abstract Background Various studies have reported on the impact of human papillomavirus (HPV) vaccines. Here we present the largest population-based investigation of genotype-specific distributions over the decade following implementation of the quadrivalent HPV vaccine (HPV-6/11/16/18) in the United States. Methods Liquid-based cervical cytology samples from individuals aged 15-30 years undergoing cervical screening throughout New Mexico were tested by broad-spectrum HPV genotyping. Weighted relative differences in HPV type-specific prevalence and 95% confidence intervals (CIs) were calculated by comparing individuals screened between 2007 and 2009 (n = 95 915) with individuals screened between 2013 and 2016 (n = 103 371). Weighted logistic regression was used to estimate relative risk of type-specific HPV infections. Tests of significance were 2-sided. Results Genotype-specific prevalence fell with statistical signficance for HPV-16 (relative difference = ‒52.6%, 95% CI = ‒56.9 to ‒48.3), HPV-18 (relative difference = ‒62.1%, 95% CI = ‒68.5 to ‒55.8), HPV-31 (relative difference = ‒34.2%, 95% CI = ‒42.1 to ‒26.3), and HPV-33 (relative difference = ‒31.8%, 95% CI = ‒48.4 to ‒15.1). The relative difference increased for other carcinogenic HPV types by 19.5% (95% CI = 14.3 to 24.6) when excluding HPV-16/18. Large reductions in HPV-6/11 relative differences were observed, but overall, noncarcinogenic, nonvaccine types increased. Comparing female individuals born in 1996 with female individuals born in 1989, risk of infection with HPV-6, 11, 16, and 18 decreased by 80.0% among individuals aged 21-25 years. High-grade squamous intraepithelial lesions or worse decreased by 49.4% when extending the evaluation from 2007 to 2018. Conclusion The incidence of high-grade squamous intraepithelial lesions or worse is decreasing, with large reductions in the prevalence of quadrivalent HPV vaccine types and nonvaccine types HPV-31 and HPV-33, reflecting vaccine cross-protection. Increases in nonvaccine HPV genotypes may attenuate anticipated reductions in HPV-related abnormalities, including cancers, but the benefits of HPV vaccination remain substantial.

Letter to the Editor Re: A population study of screening history and diagnostic outcomes of women with invasive cervical cancer

Outcomes for Step-Wise Implementation of a Human Papillomavirus Testing–Based Cervical Screen-and-Treat Program in El Salvador

PURPOSE The Cervical Cancer Prevention in El Salvador (CAPE) project is a public-sector intervention introducing lower-cost human papillomavirus (HPV) testing in all four departments of the Paracentral region that screened a total of 28,015 women. After demonstrating success of an HPV screen-and-treat (S&T) algorithm over colposcopy management in the first two phases, the third phase scaled up the S&T strategy. We present results from phase III and evaluate S&T components across the entire project. METHODS During phase III, 17,965 women age 30-59 years underwent HPV testing. HPV-positive women were asked to return and, if eligible, received gas-based cryotherapy. We compare loss to follow-up and time intervals between S&T steps across the three phases. RESULTS There were no differences in HPV positivity across phases (phase I, 11.9%; phase II, 11.4%; phase III, 12.3%; P = .173). Although most HPV-positive women completed indicated follow-up procedures within 6 months in phases I (93.3%, 111 of 119) and II (92.3%, 429 of 465), this proportion declined to 74.9% (1,659 of 2,214; P < .001) in phase III. Mean days between testing and delivery of results to patients increased over program phases (phase I, 23.2 days; phase II, 46.7 days; phase III, 99.8 days; P < .001). CONCLUSION A public-sector implementation of an HPV-based S&T algorithm was successfully scaled up in El Salvador, albeit with losses in efficiency. After CAPE, the Ministry of Health changed its screening guidelines and procured additional tests to expand the program.

A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus–positive and -Negative Cervical Precancers

Abstract Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Epidemiological evidence that common HPV types may be common because of their ability to evade immune surveillance: Results from the Women's Interagency HIV study

Infection by human papillomavirus (HPV) type 16, the most oncogenic HPV type, was found to be the least affected by HIV‐status and CD4 count of any of the approximately 13 oncogenic HPV types. This relative independence from host immune status has been interpreted as evidence that HPV16 may have an innate ability to avoid the effects of immunosurveillance. However, the impact of immune status on other individual HPV types has not been carefully assessed. We studied type‐specific HPV infection in a cohort of 2,470 HIV‐positive (HIV[+]) and 895 HIV‐negative (HIV[−]) women. Semi‐annually collected cervicovaginal lavages were tested for >40 HPV types. HPV type‐specific prevalence ratios (PRs), incidence and clearance hazard ratios (HRs), were calculated by contrasting HPV types detected in HIV[+] women with CD4 < 200 to HIV[−] women. HPV71 and HPV16 prevalence had the weakest associations with HIV‐status/CD4 count of any HPV, according to PRs. No correlations between PRs and HPV phylogeny or oncogenicity were observed. Instead, higher HPV type‐specific prevalence in HIV[−] women correlated with lower PRs (ρ = −0.59; p = 0.0001). An alternative (quadratic model) statistical approach (PHIV+ = a*PHIV− + b*PHIV−2; R2 = 0.894) found similar associations (p = 0.0005). In summary, the most prevalent HPV types in HIV[−] women were the types most independent from host immune status. These results suggest that common HPV types in HIV[−] women may have a greater ability to avoid immune surveillance than other types, which may help explain why they are common.

Absolute risks of cervical precancer among women who fulfill exiting guidelines based on HPV and cytology cotesting

US guidelines recommend that most women older than 65 years cease cervical screening after two consecutive negative cotests (concurrent HPV and cytology tests) in the previous 10 years, with one in the last 5 years. However, this recommendation was based on expert opinion and modeling rather than empirical data on cancer risk. We therefore estimated the 5‐year risks of cervical precancer (cervical intraepithelial neoplasia grade 3 or adenocarcinomain situ[CIN3]) after one, two and three negative cotests among 346,760 women aged 55–64 years undergoing routine cotesting at Kaiser Permanente Northern California (2003–2015). Women with a history of excisional treatment or CIN2+ were excluded. No woman with one or more negative cotests was diagnosed with cancer during follow‐up. Five‐year risks of CIN3 after one, two, and three consecutive negative cotests were 0.034% (95% CI: 0.023%–0.046%), 0.041% (95% CI: 0.007%–0.076%) and 0.016% (95% CI: 0.000%–0.052%), respectively (ptrend< 0.001). These risks did not appreciably differ by a positive cotest result prior to the one, two or three negative cotest(s). Since CIN3 risks after one or more negative cotests were significantly below a proposed 0.12% CIN3+ risk threshold for a 5‐year screening interval, a longer screening interval in these women is justified. However, the choice of how many negative cotests provide sufficient safety against invasive cancer over a woman's remaining life represents a value judgment based on the harmsversusbenefits of continued screening. Ideally, this guideline should be informed by longer‐term follow‐up given that exiting is a long‐term decision.

The Improving Risk Informed HPV Screening (IRIS) Study: Design and Baseline Characteristics

Abstract Background: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed. Endometrial and ovarian cancers could be amenable to similar testing. Methods: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. Results: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. Conclusions: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. Impact: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

Primary HPV and Molecular Cervical Cancer Screening in US Women Living With Human Immunodeficiency Virus

Abstract Background Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH). Methods We enrolled n = 865 WLWH (323 from the Women’s Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[−]/Pap[−] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry. Results Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). “PHS with reflex HPV16/18-genotyping and Pap testing” had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. “Concurrent oncHPV and Pap Testing” (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy. Conclusions PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.

Long-term human papillomavirus vaccination effectiveness and immunity in Rwandan women living with and without HIV: a study protocol

Introduction Prophylactic human papillomavirus (HPV) vaccines have been shown to be highly effective in protecting women against cervical infections, high-grade abnormalities and cancer caused by the targeted HPV types. However, the evidence for their effectiveness in women living with HIV (WLWH) is less clear. Methods WLWH and HIV-negative women who likely did (birth cohorts 1996 and later) and WLWH and HIV(−) negative who likely did not (birth cohorts before 1996) receive HPV vaccination (n=3028; 757 participants for each of the four groups). Between groups, we will compare cervicovaginal, anal and oral prevalent and 6–12 month persistent HPV6/11/16/18 infections as measured using a modified AmpFire HPV genotyping assay that tests for 15 high-risk or intermediate-risk HPV genotypes, HPV6 and HPV11. We will also compare the HPV immune response in HPV-vaccinated WLWH to HPV-vaccinated HIV-negative women using an anti-HPV16 and anti-HPV18 ELISA. Vaccination status will be confirmed through national vaccination records. Analysis We will calculate point prevalence and prevalence of 6–12 month persisting infections by individual HPV-type specific infections and groups of infections for each anatomic site and for each group of women. Results will be stratified by age at vaccination, age at enrolment and the number of doses (3 vs 2) as well as other factors possibly associated with HPV prevalence. Differences in endpoints between groups, overall and between subgroups, will be tested for statistical significance (p<0.05) using Fisher’s exact or Pearson χ2 test. Differences in geometric mean titres and seropositivity will be tested for statistical significance using the Mann-Whitney and Fisher’s exact tests, respectively. Ethics and dissemination The study was approved by the Albert Einstein College of Medicine Institutional Review Board and the Rwanda National Ethics Committee. Results will be disseminated through publication in peer-reviewed journals.

Randomized Implementation of a Primary Human Papillomavirus Testing–based Cervical Cancer Screening Protocol for Women 34 to 69 Years in Norway

Abstract Background: Cervical cancer screening programs are facing a programmatic shift where screening protocol based on human papillomavirus testing (HPV-Screening protocol) is replacing the liquid-based cytology (LBC-Screening protocol). For safe technology transfer within the nationwide screening programme in Norway, HPV-Screening protocol was implemented randomized to compare the real-world effectiveness of HPV-Screening protocol and LBC-Screening protocol at the first screening round. Methods: Among 302,295 women ages 34 to 69 years scheduled to attend screening from February 2015 to June 2017, 157,447 attended. A total of 77,207 were randomly allocated to the HPV-Screening protocol and 80,240 were allocated to the LBC-Screening protocol. All women were followed up for 18 months. Results: The HPV-Screening protocol resulted in a relative increase of 60% in the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse [risk ratio (RR) = 1.6, 95% confidence interval (CI) = 1.5–1.7], 40% in CIN grade 3 or worse (RR = 1.4, 95% CI = 1.3–1.6), 40% in cancer (RR = 1.4, 95% CI = 1.0–2.1), and 60% in colposcopy referrals (RR = 1.6, 95% CI = 1.5–1.6) compared with LBC-Screening. The performance of both protocols was age dependent, being more effective in women ages under 50 years. Conclusions: The HPV-Screening protocol was well accepted by women in Norway and detected more CIN2, CIN3, and cancers compared with the LBC-Screening protocol. Impact: A randomized implementation of the HPV-Screening protocol with real-world assessment enabled a gradual, quality assured, and safe technology transition. HPV-based screening protocol may further be improved by using HPV genotyping and age-specific referral algorithms.

Cervical Precancers and Cancers Attributed to HPV Types by Race and Ethnicity: Implications for Vaccination, Screening, and Management

AbstractBackgroundRacial and ethnic variations in attribution of cervical precancer and cancer to human papillomavirus (HPV) types may result in different HPV vaccine protection, screening test coverage, and clinical management.MethodsPooling data from 7 US studies, we calculated the proportional attribution of precancers and cancers to HPV types using HPV DNA typing from diagnosis. All statistical tests were 2-sided.ResultsFor all racial and ethnic groups, most cases of cervical intraepithelial neoplasia grade 3 (CIN3) (84.2%-90.8% of 5526) and squamous cell carcinoma (SCC) (90.4%-93.8% of 1138) were attributed to types targeted by the 9-valent vaccine. A higher proportion of CIN3s were attributed to nonvaccine HPV types among non-Hispanic Black women (15.8%) compared with non-Hispanic Asian or Pacific Islander (9.7%; P = .002), non-Hispanic White (9.2%; P < .001), and Hispanic (11.3%; P = .004) women. The proportion of SCCs attributed to 9-valent types was similar by race and ethnicity (P = .80). A higher proportion of CIN3s were attributed to nonvaccine HPV35 among non-Hispanic Black (9.0%) compared with non-Hispanic Asian or Pacific Islander (2.2%), non-Hispanic White (2.5%), and Hispanic (3.0%; all P < .001) women. Compared with CIN3, the proportion of SCCs attributed to HPV35 among non-Hispanic Black women (3.2%) was lower and closer to other groups (0.3%-2.1%; P = .70).ConclusionThe 9-valent HPV vaccine will prevent nearly all cervical precancers and invasive cancers among major racial and ethnic groups in the United States. Adding HPV35 to vaccines could prevent a small percentage of CIN3s and SCCs, with greater potential impact for CIN3s among Black women. HPV screening tests target high-risk HPV types, including HPV35. Future genotyping triage strategies could consider the importance of HPV35- and other HPV16-related types.

An integrated isothermal nucleic acid amplification test to detect HPV16 and HPV18 DNA in resource-limited settings

High-risk human papillomavirus (HPV) DNA testing is widely acknowledged as the most sensitive cervical cancer screening method but has limited availability in resource-limited settings, where the burden of cervical cancer is highest. Recently, HPV DNA tests have been developed for use in resource-limited settings, but they remain too costly for widespread use and require instruments that are often limited to centralized laboratories. To help meet the global need for low-cost cervical cancer screening, we developed a prototype, sample-to-answer, point-of-care test for HPV16 and HPV18 DNA. Our test relies on isothermal DNA amplification and lateral flow detection, two technologies that reduce the need for complex instrumentation. We integrated all test components into a low-cost, manufacturable platform, and performance of the integrated test was evaluated with synthetic samples, provider-collected clinical samples in a high-resource setting in the United States, and self-collected clinical samples in a low-resource setting in Mozambique. We demonstrated a clinically relevant limit of detection of 1000 HPV16 or HPV18 DNA copies per test. The test requires six user steps, yields results in 45 min, and can be performed using a benchtop instrument and minicentrifuge by minimally trained personnel. The projected per-test cost is <$5, and the projected instrumentation cost is <$1000. These results show the feasibility of a sample-to-answer, point-of-care HPV DNA test. With the inclusion of other HPV types, this test has the potential to fill a critical gap for decentralized and globally accessible cervical cancer screening.

A randomized clinical trial to assess the effectiveness of thermal ablation versus loop electrosurgical excision procedure for cervical cancer risk reduction in women living with HIV in Mozambique.

Cervical cancer remains a leading cause of death in low- and middle-income countries. Women living with human immunodeficiency virus (HIV) carry a 6-fold higher risk of cervical cancer than the general population. The effectiveness of thermal ablation versus loop electrosurgical excision procedure (LEEP) in women living with HIV is uncertain, prompting this study. To compare the effectiveness of thermal ablation versus LEEP for the management of abnormal cervical cancer screening results in women living with HIV. Thermal ablation is non-inferior to LEEP for treatment of cervical intra-epithelial neoplasia (CIN) 2/3 and high-risk human papillomavirus (hrHPV) infection in women living with HIV. This is a prospective randomized clinical trial. Participants undergo screening with primary hrHPV testing. Those with positive hrHPV results undergo visual inspection with acetic acid and a review of genotyping results to determine eligibility for treatment. Those who are hrHPV-positive and positive by visual assessment with acetic acid, or human papillomavirus16/18 positive regardless of visual assessment with acetic acid result, are randomized to thermal ablation or LEEP. Participants undergo follow-up at 4 to 8 weeks, 6 months, and 12 months post-procedure. Participants include 25 to 49-year-old women living with HIV in Mozambique. Exclusion criteria include pregnancy, previous total hysterectomy, history of cervical cancer or prior treatment for CIN, or any condition that would preclude adherence to the study protocol. Persistent or recurrent CIN 2/3 (or worse diagnosis) and hrHPV infection at 12 months after initial treatment. To meet our primary objectives and to achieve a power of 0.8 (α = 0.025), we will need to randomize 126 participants with CIN 2/3, 63 to thermal ablation, and 63 to LEEP. We estimate that this will require screening a total of 4844 women living with HIV. We anticipate that study accrual will be completed in 3 years (2027), with an additional 18 months to complete all follow-up visits and data analysis. We anticipate presenting results in 2029. ClinicalTrials.gov #NCT06326294.

HPV Vaccine Effectiveness Study in Rwandan Women Living With HIV

Our study will assess and measure population effectiveness of prophylactic HPV vaccine in reducing cervical, anal, and/or oral prevalent and 6-month persistent infections among HPV-vaccinated and 757 HPV-unvaccinated Rwandan WLWH aged 18-26 years. Additional objectives include the quantification \& examination of long-term antibody (into young adulthood) responses to HPV vaccination and to validate the performance (e.g., sensitivity and specificity) of a low-cost, POC (point-of-care) anti-HPV16 antibody test to determine/confirm HPV vaccination status. The findings for this study will provide necessary evidence regarding the long-term protection afforded by HPV vaccination in WLWH living in SSA, who are at the greatest risk of HPV-related cancers.