Reporting and Assessing the Quality of Diagnostic Accuracy Studies for Cervical Cancer Screening and Management.

ObjectiveWe adapted the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for studies of cervical cancer screening and management and used the adapted tool to evaluate the quality of studies included in a systematic review supporting the 2019 Risk-Based Management Consensus Guidelines.MethodsWe evaluated the quality of all studies included in our systematic review for postcolposcopy (n = 5) and posttreatment (n = 23) surveillance using QUADAS-2 criteria. Subsequently, we adapted signaling questions to indications of cervical cancer screening and management. An iterative process was carried out to evaluate interrater agreement between 2 study authors (M.A.C. and N.W.). Discrepant ratings were discussed, and criteria were adapted accordingly. We also evaluated the influence of study quality on risk estimates and between study variation using stratified subgroup meta-analyses.ResultsTwelve signaling questions for bias assessment that were adapted to or newly developed for cervical cancer screening and management are described here. Interrater agreement on bias assessment increased from 70% to 83% during the adaptation process. Detailed assessment of bias and applicability showed that all studies on postcolposcopy management and 90% of studies on posttreatment management had high risk of bias in at least 1 domain. Most commonly, high risk of bias was observed for the patient selection domain, indicating the heterogeneity of study designs and clinical practice in reported studies.ConclusionsThe adapted QUADAS-2 will have broad application for researchers, evidence evaluators, and journals who are interested in designing, conducting, evaluating, and publishing studies for cervical cancer screening and management

Implementation of and Early Outcomes From Anal Cancer Screening at a Community-Engaged Health Care Facility Providing Care to Nigerian Men Who Have Sex With Men.

PurposeAnal cancer risk is substantially higher among HIV-infected men who have sex with men (MSM) as compared with other reproductive-age adults, but screening is rare across sub-Saharan Africa. We report the use of high-resolution anoscopy (HRA) as a first-line screening tool and the resulting early outcomes among MSM in Abuja, Nigeria.MethodsFrom August 2016 to August 2017, 424 MSM enrolled in an anal cancer screening substudy of TRUST/RV368, a combined HIV prevention and treatment cohort. HRA-directed biopsies were diagnosed by histology, and ablative treatment was offered for high-grade squamous intraepithelial lesions (HSIL). HRA proficiency was assessed by evaluating the detection of squamous intraepithelial lesions (SIL) over time and the proportion biopsied. Prevalence estimates of low-grade squamous intraepithelial lesions and HSIL with 95% CIs were calculated. Multinomial logistic regression was used to identify those at the highest risk of SIL.ResultsMedian age was 25 years (interquartile range [IQR], 22-29), median time since sexual debut was 8 years (IQR, 4-12), and 59% (95% CI, 54.2% to 63.6%) were HIV infected. Rate of detection of any SIL stabilized after 200 screenings, and less than 20% had two or more biopsies. Preliminary prevalence estimates of low-grade squamous intraepithelial lesions and HSIL were 50.0% (95% CI, 44.7% to 55.3%) and 6.3% (95% CI, 4.0% to 9.3%). HIV infection, at least 8 years since anal coital debut, concurrency, and external warts were independently statistically associated with SIL.ConclusionProficiency with HRA increased with experience over time. However, HSIL detection rates were low, potentially affected by obstructed views from internal warts and low biopsy rates, highlighting the need for ongoing evaluation and mentoring to validate this finding. HRA is a feasible first-line screening tool at an MSM-friendly health care facility. Years since anal coital debut and external warts could prioritize screening

Prevalence, incidence, and clearance of human papillomavirus types covered by current vaccines in men with human immunodeficiency virus in the SUN Study

BACKGROUND: High-risk anal human papillomavirus (HPV) infection is prevalent among men living with human immunodeficiency virus (HIV); the association between 9-valent (9v) high-risk HPV (HR-HPV) vaccine types and abnormal cytology has not been well characterized. METHODS: We followed a prospective cohort study of persons with HIV at 7 HIV clinics in 4 US cities from March 2004 through June 2012. Annually, providers collected separate anal swabs for HPV detection and cytopathologic examination. Among men, we examined prevalence, incidence, and clearance of 9v HR-HPV vaccine types, compared with other HR types, and associations with abnormal cytology to assess potential vaccine impact. RESULTS: Baseline prevalence of any anal 9v HR-HPV type among men who have sex with men (MSM) and men who have sex with women (MSW) was 74% and 25% (P \u3c .001), respectively. Among 299 MSM, abnormal cytology was detected in 161 (54%) MSM and was associated with the presence of any 9v HR-HPV (relative risk [RR], 1.8 [95% confidence interval {CI}, 1.3-2.6]; P \u3c .001). Among 61 MSW, abnormal anal cytology was detected in 12 (20%) and was associated with the presence of any 9v HR-HPV (RR, 4.3 [95% CI, 1.6-11.5]; P \u3c .001). CONCLUSIONS: Among men with HIV, the prevalence of the 7 HR-HPV types in the 9v vaccine was high and was associated with abnormal cytology. These findings indicate that men with HIV could benefit from prophylactic administration of the 9v HPV vaccine

Prevalence, incidence, and clearance of anal high-risk human papillomavirus infection among HIV-infected men in the SUN study

BACKGROUND: The natural history of anal human papilloma virus (HPV) infection among human immunodeficiency virus (HIV)-infected men is unknown. METHODS: Annually, from 2004 to 2012, we examined baseline prevalence, incidence, and clearance of anal HPV infection at 48 months, and associated factors among HIV-infected men. RESULTS: We examined 403 men who have sex with men (MSM) and 96 men who have sex with women (MSW) (median age 42 years for both, 78% versus 81% prescribed cART, median CD4+ T-lymphocyte cell count 454 versus 379 cells/mm3, and 74% versus 75% had undetectable viral load, respectively). Type 16 prevalence among MSM and MSW was 38% versus 14% (P \u3c .001), and incidence 24% versus 7% (P = .001). Type 18 prevalence was 24% versus 8% (P \u3c .001), and incidence 13% versus 4% (P = .027). Among MSM and MSW, clearance of prevalent HPV 16 and HPV 18 was 31% and 60% (P = .392), and 47% and 25% (P = .297), respectively. Among MSM, receptive anal sex (with or without a condom) was associated with persistent HPV 16 (OR 2.24, P \u3c .001). CONCLUSIONS: MSM had higher prevalence and incidence of HPV than MSW, but similar clearance. Receptive anal sex may predict cancer risk among HIV-infected MSM

Investigating Potential Associations between Cervical Procedures and HIV Acquisition

Objective. Cervical human papillomavirus (HPV) infection has been associated with human immunodeficiency virus (HIV) acquisition in populations with a high prevalence of both infections. Procedures performed in the management of cervical dysplasia may facilitate HIV entry via mechanical injury. We sought to investigate the association between cervical procedures and incident HIV. Methods. Data on cervical cancer screening and procedures were collected in a cohort study evaluating the diaphragm for HIV prevention in 2040 women. In this secondary analysis, we investigated the association between cervical procedures and HIV acquisition. Results. Out of 2027 HIV-negative women at baseline, 199 underwent cervical procedures. Cumulative risk of HIV was 4.3% over 21 months of median followup (n = 88). Compared with women without cervical procedures, we observed no difference in HIV incidence after a cervical biopsy (RR 0.92, 95% CI 0.39–2.16), endocervical curettage (RR 0.29, 95% CI 0.07–1.22), or loop electrosurgical excision procedure (RR 1.00, 95% CI 0.30–3.30). Conclusions. In this cohort, cervical procedures were not associated with HIV incidence. This lack of association could be due to the small number of events

Cervical cancer screening intervals and management for women living with HIV

ObjectiveWe suggested cervical cancer screening strategies for women living with HIV (WLHIV) by comparing their precancer risks to general population women, and then compared our suggestions with current Centers for Disease Control and Prevention (CDC) guidelines.DesignWe compared risks of biopsy-confirmed cervical high-grade squamous intraepithelial neoplasia or worse (bHSIL+), calculated among WLHIV in the Women's Interagency HIV Study, to 'risk benchmarks' for specific management strategies in the general population.MethodsWe applied parametric survival models among 2423 WLHIV with negative or atypical squamous cell of undetermined significance (ASC-US) cytology during 2000-2015. Separately, we synthesized published general population bHSIL+ risks to generate 3-year risk benchmarks for a 3-year return (after negative cytology, i.e. 'rescreening threshold'), a 6-12-month return (after ASC-US), and immediate colposcopy [after low-grade squamous intraepithelial lesion (LSIL)].ResultsAverage 3-year bHSIL+ risks among general population women ('risk benchmarks') were 0.69% for a 3-year return (after negative cytology), 8.8% for a 6-12-month return (after ASC-US), and 14.4% for colposcopy (after LSIL). Most CDC guidelines for WLHIV were supported by comparing risks in WLHIV to these benchmarks, including a 3-year return with CD4 greater than 500 cells/μl and after either three negative cytology tests or a negative cytology/oncogenic human papillomavirus cotest (all 3-year risks≤1.3%); a 1-year return after negative cytology with either positive oncogenic human papillomavirus cotest (1-year risk = 1.0%) or CD4 cell count less than 500 cells/μl (1-year risk = 1.1%); and a 6-12-month return after ASC-US (3-year risk = 8.2% if CD4 cell count at least 500 cells/μl; 10.4% if CD4 cell count = 350-499 cells/μl). Other suggestions differed modestly from current guidelines, including colposcopy (vs. 6-12 month return) for WLHIV with ASC-US and CD4 cell count less than 350 cells/μl (3-year risk = 16.4%) and a lengthened 2-year (vs. 1-year) interval after negative cytology with CD4 cell count at least 500 cells/μl (2-year risk = 0.98%).ConclusionsCurrent cervical cancer screening guidelines for WLHIV are largely appropriate. CD4 cell count may inform risk-tailored strategies

Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections

BackgroundResults from the Costa Rica Vaccine Trial (CVT) demonstrated partial cross-protection by the bivalent human papillomavirus (HPV) vaccine, which targets HPV-16 and HPV-18, against HPV-31, -33, and -45 infection and an increased incidence of HPV-51 infection.MethodsA study nested within the CVT intention-to-treat cohort was designed to assess high-risk HPV variant lineage-specific vaccine efficacy (VE). The 2 main end points were (1) long-term incident infections persisting for ≥2 years and/or progression to high-grade squamous intraepithelial lesions (ie, cervical intraepithelial neoplasia grade 2/3 [CIN 2/3]) and (2) incident transient infections lasting for <2 years. For efficiency, incident infections due to HPV-16, -18, -31, -33, -35, -45, and -51 resulting in persistent infection and/or CIN 2/3 were matched (ratio, 1:2) to the more-frequent transient viral infections, by HPV type. Variant lineages were determined by sequencing the upstream regulatory region and/or E6 region.ResultsVEs against persistent or transient infections with HPV-16, -18, -33, -35, -45, and -51 did not differ significantly by variant lineage. As the possible exception, VEs against persistent infection and/or CIN 2/3 due to HPV-31 A/B and HPV-31C variants were -7.1% (95% confidence interval [CI], -33.9% to 0%) and 86.4% (95% CI, 65.1%-97.1%), respectively (P = .02 for test of equal VE). No difference in VE was observed by variant among transient HPV-31 infections (P = .68).ConclusionsOverall, sequence variation at the variant level does not appear to explain partial cross-protection by the bivalent HPV vaccine

Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment

BackgroundHuman papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood.ObjectivesTo determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions.Study DesignWe included 1711 women (18−25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated.ResultsMedian follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were −5.4% (95% confidence interval −19,10) and 0.3% (95% confidence interval −69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval −131, 82) and −211% (95% confidence interval −2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval −43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively.ConclusionWe find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies

Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America : an analysis within the ESTAMPA study

Corresponding author. E-mail address: [email protected] (A.T. Ramírez).Background. Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30–64 years participating in the ESTAMPA study. Methods. Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings. 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0–53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3–96.7). Specificity was 96.5% (95% CI: 96.3–96.7) using cytology and 88.7% (95% CI: 88.3–89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%–100% and 83.6–90.8%, respectively). Interpretation. The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America.Consejo Nacional de Ciencia y TecnologíaPrograma Paraguayo para el Desarrollo de la Ciencia y Tecnología. Proyectos de investigación y desarroll