Different human papillomavirus types share early natural history transitions in immunocompetent women.

Necessary stages of cervical carcinogenesis include acquisition of a carcinogenic human papillomavirus (HPV) type, persistence associated with the development of precancerous lesions, and invasion. Using prospective data from immunocompetent women in the Guanacaste HPV Natural History Study (NHS), the ASCUS-LSIL Triage Study (ALTS) and the Costa Rica HPV Vaccine Trial (CVT), we compared the early natural history of HPV types to inform transition probabilities for health decision models. We excluded women with evidence of high-grade cervical abnormalities at any point during follow-up and restricted the analysis to incident infections in all women and prevalent infections in young women (aged <30 years). We used survival approaches accounting for interval-censoring to estimate the time to clearance distribution for 20 529 HPV infections (64% were incident and 51% were carcinogenic). Time to clearance was similar across HPV types and risk classes (HPV16, HPV18/45, HPV31/33/35/52/58, HPV 39/51/56/59 and noncarcinogenic HPV types); and by age group (18-29, 30-44 and 45-54 years), among carcinogenic and noncarcinogenic infections. Similar time to clearance across HPV types suggests that relative prevalence can predict relative incidence. We confirmed that there was a uniform linear association between incident and prevalent infections for all HPV types within each study cohort. In the absence of progression to precancer, we observed similar time to clearance for incident infections across HPV types and risk classes. A singular clearance function for incident HPV infections has important implications for the refinement of microsimulation models used to evaluate the cost-effectiveness of novel prevention technologies.

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

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.

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 adenocarcinoma in 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 harms versus benefits of continued screening. Ideally, this guideline should be informed by longer-term follow-up given that exiting is a long-term decision.

Proof-of-principle study of a novel cervical screening and triage strategy: Computer-analyzed cytology to decide which HPV-positive women are likely to have ≥CIN2.

A challenge in implementation of sensitive HPV-based screening is limiting unnecessary referrals to colposcopic biopsy. We combined two commonly recommended triage methods: partial HPV typing and "reflex" cytology, evaluating the possibility of automated cytology. This investigation was based on 1,178 exfoliated cervical specimens collected during the enrollment phase of The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED, Oklahoma City, OK). We chose a colposcopy clinic population to maximize number of outcomes, for this proof-of-principle cross-sectional study. Residual aliquots of PreservCyt were HPV-typed using Linear Array (LA, Roche Molecular Systems, Pleasanton, CA). High-risk HPV typing data and cytologic results (conventional and automated) were used jointly to predict risk of histologically defined ≥CIN2. We developed a novel computer algorithm that uses the same optical scanning features that are generated by the FocalPoint Slide Profiler (BD, Burlington, NC). We used the Least Absolute Shrinkage and Selection Operator (LASSO) method to build the prediction model based on a training dataset (n = 600). In the validation set (n = 578), for triage of all HPV-positive women, a cytologic threshold of ≥ASC-US had a sensitivity of 0.94, and specificity of 0.30, in this colposcopy clinic setting. When we chose a threshold for the severity score (generated by the computer algorithm) that had an equal specificity of 0.30, the sensitivity was 0.91. Automated cytology also matched ≥ASC-US when partial HPV typing was added to the triage strategy, and when we re-defined cases as ≥CIN3. If this strategy works in a prospective screening setting, a totally automated screening and triage technology might be possible.

Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up.

PURPOSE: To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction. METHODS: Cervicovaginal lavages collected from 19,512 women attending a health maintenance program were retrospectively tested for HPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a research test. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance (ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively with routine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervical intraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated. RESULTS: A baseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up than a normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who would develop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+ 10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevated risk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk of CIN3+ compared with women with a low-grade squamous intraepithelial Pap. CONCLUSION: HPV testing to rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16 and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficient algorithm for cervical cancer screening, especially in women age 30 years or older.

A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study.

BACKGROUND: Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 3 and cancer (≥CIN3). Adding HPV testing to cytology is recommended for women ≥30 but long-term prospective studies of HPV testing are rare. METHODS: Beginning in 1989-1990, ~20,000 women in a prepaid health maintenance organization (median age = 34) were followed passively by recommended annual cytology. We tested archived cervicovaginal lavage specimens collected at enrollment, primarily by MY09-MY11 PCR-based methods, for carcinogenic HPV types. We calculated positive and negative predictive values for the entire study period, and Kaplan-Meier estimates of cumulative probability for ≥CIN3, up to 18 years of follow-up. RESULTS: We observed 47 cases of invasive cervical cancer during the study period, and 156 cases of CIN3. Predictive values and Kaplan-Meier analyses yielded the same conclusions. In women 30 and older, the reassurance against ≥CIN3 following a single negative HPV test was long-lasting (cumulative probability = 0.7% during follow-up). In this age group, a single HPV test (positive vs. negative, hazard ratio of 8.5, 95% CI = 4.8-15.1) provided greater long-term risk stratification than a single cytologic result (abnormal vs. normal, HR = 2.9, 95% CI = 1.2-6.6). The risk for ≥CIN3 was higher for HPV16 than for the average of the other carcinogenic types (hazard ratio = 2.7). CONCLUSION AND IMPACT: The data from this cohort study show the long-term predictive value of HPV testing, particularly in women ≥30, and a possible role for distinguishing particularly carcinogenic types like HPV16.

Long-term persistence of prevalently detected human papillomavirus infections in the absence of detectable cervical precancer and cancer.

BACKGROUND: Detailed descriptions of long-term persistence of human papillomavirus (HPV) in the absence of cervical precancer are lacking. METHODS: In a large, population-based natural study conducted in Guanacaste, Costa Rica, we studied a subset of 810 initially HPV-positive women with ≥ 3 years of active follow-up with ≥ 3 screening visits who had no future evidence of cervical precancer. Cervical specimens were tested for >40 HPV genotypes using a MY09/11 L1-targeted polymerase chain reaction method. RESULTS: Seventy-two prevalently-detected HPV infections (5%) in 58 women (7%) persisted until the end of the follow-up period (median duration of follow-up, 7 years) without evidence of cervical precancer. At enrollment, women with long-term persistence were more likely to have multiple prevalently-detected HPV infections (P < .001) than were women who cleared their baseline HPV infections during follow-up. In a logistic regression model, women with long-term persistence were more likely than women who cleared infections to have another newly-detected HPV infection detectable at ≥ 3 visits (odds ratio, 2.6; 95% confidence interval, 1.2-5.6). CONCLUSIONS: Women with long-term persistence of HPV infection appear to be generally more susceptible to other HPV infections, especially longer-lasting infections, than are women who cleared their HPV infections.

Influence of loop electrosurgical excision procedure on subsequent acquisition of new human papillomavirus infections.

BACKGROUND: The impact of loop electrosurgical excision procedure (LEEP) treatment for cervical precancerous lesions on subsequent acquisition of new human papillomavirus (HPV) infections is not well described. METHODS: The acquisition of new HPV infections was compared in HPV-positive women who underwent colposcopy and were treated by LEEP (n = 195) and those who were untreated (n = 1625) at entry into a 2-year study. Cumulative incidence rate ratios (IRRs) for treated versus untreated women at 6- and 24-months of follow-up, with 95% confidence intervals (CIs), were calculated for infection by individual HPV genotypes, any HPV genotypes, any carcinogenic HPV genotypes, any noncarcinogenic HPV genotypes, and phylogenetic groups of HPV genotypes. RESULTS: Treated women were 29% less likely than untreated women to have carcinogenic HPV genotypes detected at 6-month follow-up visits (IRR, 0.71; 95% CI, 0.50-1.00) and were 18% less likely to have these genotypes detected at 24-month follow-up visits (IRR, 0.82; 95% CI, 0.68-1.01). Treated women were 56% less likely to have HPV genotypes of the alpha9 phylogenetic species (which includes HPV-16) detected at 6-month follow-up visits (IRR, 0.44; 95% CI, 0.23-0.85) and were 40% less likely to have these genotype detected at 24-month follow-up visits (IRR, 0.60; 95% CI, 0.42-0.85). CONCLUSION: LEEP may reduce the acquisition of certain carcinogenic HPV genotypes related to HPV-16.

Effect of the number of biopsies on the subsequent acquisition of new human papillomavirus infections.

OBJECTIVE: To analyze the effect of number of biopsies taken at enrollment with incident human papillomavirus (HPV) infections detected at the next 6-month visit. METHODS: Using data from the Atypical Squamous Cells of Undetermined Significance (ASCUS) and Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study (ALTS), we compared the 6-month acquisition of new HPV infections among 988 women who underwent colposcopy, were not diagnosed and treated for cervical intraepithelial neoplasia grade 2 or more severe lesions, and had polymerase chain reaction results for 38 HPV genotypes at enrollment and follow-up. Our analysis considered each woman's possible acquisition of each of these HPV genotypes. RESULTS: The average 6-month acquisition of any HPV genotype for women with zero, one, and two or more biopsies was 1.82%, 1.74%, and 1.97%, respectively (Ptrend=.7). In a logistic regression model that controlled for age, baseline HPV status, and having a new sexual partner during the 6-month follow-up, two or more biopsies (compared with one biopsy) was not associated with acquiring HPV (odds ratio 1.0, 95% confidence interval 0.75-1.3). CONCLUSION: Multiple biopsies compared with a single biopsy did not increase the likelihood of acquiring new HPV infections. LEVEL OF EVIDENCE: II.