16/18 genotyping in triage of persistent human papillomavirus infections with negative cytology in the English cervical screening pilot.
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ABSTRACT: Background
In the English pilot of primary cervical screening with high-risk human papillomavirus (HR-HPV), we exploited natural viral clearance over 24 months to minimise unnecessary referral of HR-HPV+ women with negative cytology. Three laboratories were permitted to use 16/18 genotyping to select women for referral at 12-month recall. We estimated the clinical impact of this early genotyping referral.Methods
The observed numbers of women referred to colposcopy and with detected high-grade cervical intraepithelial neoplasia (CIN2+), and of women who did not attend early recall in the three laboratories were compared with those estimated to represent a situation without an early genotyping referral. The 95% confidence intervals (CI) for the differences between the protocols were calculated by using a parametric bootstrap.Results
Amongst 127,238 screened women, 16,097 (13%) had HR-HPV infections. The genotyping protocol required 5.9% (95% CI: 4.4-7.7) additional colposcopies and led to a detection of 1.2% additional CIN2+ (95% CI: 0.6-2.0), while 2.3% (95% CI: 2.1-2.5) fewer HR-HPV+/cytology- women did not attend the early recall compared with the non-genotyping protocol.Conclusions
In a screening programme with high quality of triage cytology and high adherence to early recall,16/18 genotyping of persistent HPV infections does not substantially increase CIN2+ detection.
SUBMITTER: Rebolj M
PROVIDER: S-EPMC6738108 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTesting for human papillomavirus (HPV) 16 and 18 genotypes, which are known to cause approximately 65-70% of invasive cervical cancer cases, may allow clinicians to identify women at highest risk for underlying cervical intraepithelial neoplasia missed by Pap cytology. Our objective was to determine the cost-effectiveness of adding HPV-16 and 18 genotype triage to current cervical cancer screening strategies in the United States.MethodsWe developed a lifetime Markov model to assess the cost-effectiveness of the following cervical cancer screening algorithms: (1) liquid-based cytology (LBC), (2) LBC+HPV triage, (3) HPV+LBC triage, (4) co-screening, (5) co-screening+HPV genotyping, and (6) HPV only+HPV genotyping. Costs were estimated from a payer perspective in 2007 U.S. dollars. Outcome measures included lifetime risk of cervical cancer, quality-adjusted life years saved (QALYs), and incremental cost-effectiveness ratios (ICERs).ResultsIn our model, the use of HPV genotyping strategies prevented 51-73 deaths per 100,000 women screened compared to screening using LBC followed by HPV triage and 4-26 deaths compared to co-screening with LBC and high-risk HPV. Use of HPV genotyping to triage all high-risk HPV-positive women every three years had an ICER of $34,074 per QALY compared to HPV and LBC co-screening. HPV genotyping with co-screening was the most effective strategy and had an ICER of $33,807 per QALY compared to HPV genotyping for all high-risk HPV-positive women.ConclusionThe addition of HPV-16 and -18 genotype triage to HPV and LBC co-screening was a cost-effective screening strategy in the United States.
| S-EPMC4568837 | biostudies-literature
Project description:BackgroundHigh-risk human papillomavirus (HPV)-positive women require triage to identify those at higher risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). We aimed to compare visual assessment of the cervix, manual cytology and automated cytology as triage tests to screen HPV-positive women, and to assess over-treatment rates after visual assessment and over-referral rates to colposcopy after cytology.MethodsThe present cross-sectional study is nested in a large prospective screening trial in Cameroon. Evaluations of the tests have been conducted individually and in combination with HPV-16/HPV-18/45 genotyping. For the evaluation of over-treatment and colposcopic over-referral, we simulated two screening scenarios: (1) one-visit scenario (test-triage-and-treatment); and (2) two-visit scenario (test-triage-and-colposcopy).Results1582 women with a median age of 40 years (IQR 35-45) performed self-sampling for HPV testing, of which 294 (18.6%) were HPV-positive, and 12.2% had CIN2+. Sensitivities for CIN2+ detection were 77.1% for visual assessment, 80.0% for manual cytology, and 84.8% for automated cytology. Sensitivity of combined tests was higher compared with single tests. The highest sensitivity was obtained by the combination of genotyping and automated cytology (91.2%). In the one-visit scenario, the over-treatment rate was 83.9% in referred women, with a ratio of 6.2 treated women per CIN2+. In the two-visit scenario, the lowest over-referral rate would have been under manual cytology (45.0%), with a ratio of 1.8 referred women per CIN2+. Single and combined triage strategies by automated cytology gave rise to over-referral rates of 69.2% and 76.7%, respectively, and a ratio of 3.2 and 4.3 referred women per CIN2+, respectively.DiscussionTriage of HPV-positive women using a combination of genotyping and automated cytology for CIN2+ detection may provide public benefits in low- and middle-income countries.
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Project description:The detection of HPV viral DNA is regularly conducted with cervical screening. However, using a molecular marker such as the viral load may serve as a predictor associated with disease detection and progression. The present study aimed to screen for and genotype HPV among women in Saudi Arabia, develop and validate sensitive quantitative polymerase chain reaction (qPCR) assays to detect viral load for the two most common HPV types, namely 16 and 18, and assess whether HPV viral load could be used as a marker for cervical abnormality and disease progression. This study examined 733 specimens (both formalin-fixed paraffin embedded specimens and PAP smear samples) from women who underwent cervical screening. The specimens and samples were processed for DNA extraction and then tested for HPV DNA using nested PCR. Approximately 165 specimens (18%) were positive for HPV. Those specimens were genotyped using a reverse line blotting hybridization assay. The results indicated that the most common HPV types detected were a single infection with HPV 16 (51%) or with HPV 18 (28%) followed by infections with multiple HPV types (~7%). A qPCR TaqMan assay developed and validated in-house was used to determine viral load for HPV genotypes 16 (n = 80) and 18 (n = 45). Viral loads for both HPV types were significantly associated with cervical cytology grade (P < 0.05). The odds ratio (OR) for the HPV 16 viral load was high for specimens with cervical cancer (OR, 18.8; 95% CI, 4.3-82.9) or for those with high-grade squamous intraepithelial lesions (OR, 14.7; 95% Cl, 2.43-88.49). For the HPV 18 viral load, the OR was significant only for specimens with cervical cancer (OR, 11.1; 95% Cl, 2.2-54.9). Logistic regression models for HPV 16 and for HPV 18 viral load levels were significant, with higher viral load associated with cervical abnormalities. These findings indicate that viral load is a predictor significantly associated with cytology abnormality in women who are positive for high-risk HPVs and suggest that integrating a viral load test into current clinical screening practices for HPV-positive women is warranted in Saudi Arabia.
| S-EPMC7047185 | biostudies-literature
Project description:ImportanceTriage tests enhance the efficiency cervical cancer screening based on human papillomavirus (HPV), but the best approach for maximizing programmatic effectiveness is still uncertain, particularly in a real-world scenario.ObjectiveTo compare the clinical performance of 6 triage strategies based on liquid-based cytology (LBC) and HPV-16 and HPV-18 genotyping individually or in combination as sequential triage tests to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher among women with high-risk HPV.Design, setting, and participantsThis diagnostic study of routine cervical cancer screening was conducted at 100 primary health centers in Tlaxcala, Mexico. Women aged 30 to 64 years were recruited from August 1, 2013, to February 24, 2016, as part of the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage study. Six triage scenarios for referral to colposcopy were examined: (1) LBC testing that found atypical squamous cells of undetermined significance (ASC-US) or worse, (2) positive results in HPV-16 genotyping, (3) positive results in HPV-18 genotyping, (4) positive results in HPV-16/HPV-18 genotyping, (5) positive results in HPV-16 genotyping or, if genotyping results were negative, reflex LBC testing that found ASC-US or worse, and (6) positive results in HPV-16/HPV-18 genotyping or, if genotyping results were negative, reflex LBC testing that found ASC-US or worse. Data were analyzed from October 2017 to August 2018.ExposuresLiquid-based cytological testing with simultaneous HPV-16 and HPV-18 genotyping. Women whose HPV genotyping results were positive for HPV-16 or HPV-18 or whose LBC results found ASC-US or worse and a random set of negative and normal results were referred to colposcopy with histologic analysis used for disease confirmation.Main outcomes and measuresClinical performance of each test strategy for detection of CIN grade 2 or higher. Secondary outcomes included resource utilization of each triage scenario, measured by the number of tests performed, the referral rate for colposcopy, and the numbers of colposcopies per CIN grade 2 or higher detected.ResultsA total of 36 212 women (median [interquartile range] age, 40 [35-47] years) were screened, and 4051 women (11.2%) had high-risk HPV. Of these women, 1109 (24.6%) were found to have HPV-16, HPV-18, or ASC-US or worse. Further histologic testing detected CIN grade 2 or higher in 110 of 788 women (14.0%) who underwent follow-up colposcopy. Sensitivity and specificity for 3 main triage strategies were 42.9% and 74.0% for LBC; 58.3% and 54.4% for HPV-16/HPV-18 genotyping; and 86.6% and 34.0% for HPV-16/HPV-18 genotyping with reflex LBC. The referral rate to colposcopy was 29% for HPV-16/HPV-18 with reflex LBC, which was 2-fold higher than the referral rate of 12% for LBC.Conclusions and relevanceTriage of women with high-risk HPV with HPV-16/HPV-18 genotyping with reflex LBC was significantly associated with improvement in detection of CIN grade 2 or higher compared with LBC alone. The benefit of disease prevented may outweigh the cost of increasing requirements for colposcopy services in settings with limited adherence to follow-up after a positive screening result.
| S-EPMC6902808 | biostudies-literature
Project description:At present, human papillomavirus (HPV) testing is replacing morphology-based cytology as the primary tool for cervical cancer screening in several countries. However, the HPV assays approved for screening lack detection for all but one of the possibly carcinogenic HPV types and do not genotype all included HPV types. This study demonstrates the use of a targeted HPV next generation sequencing (NGS) panel to detect and genotype all 25 carcinogenic, probably carcinogenic, and possibly carcinogenic HPV types as well as the low-risk types HPV6 and HPV11. The panel was validated using a cohort of 93 paired liquid-based cytology samples (general practitioner (GP)-collected cervical samples and cervico-vaginal self-samples (SS)). Overall, the targeted panel had a sensitivity (GP = 97.7%, SS = 92.1%) and specificity (GP = 98.0%, SS = 96.4%) similar to the commercial HPV assays, Cobas® 4800 HPV DNA test (Roche) and CLART® HPV4S assay (GENOMICA). Interestingly, of the samples that tested positive with the NGS panel, three (6.4%) of the GP-collected samples and four (9.1%) of the self-samples tested positive exclusively for HPV types only included in the NGS panel. Thus, targeted HPV sequencing has great potential to improve the HPV screening programs since, as shown here, it can identify additional HPV positive cases, cases with HPV integration, variants in the HPV genome, and which HPV type is dominant in multi-infected cases.
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Project description:BackgroundHow vaginal infections such as bacterial vaginosis, Candida spp, and Trichomonas vaginalis affect persistence of human papillomavirus (HPV) infection is not well established. Our study aimed to evaluate the association between common vaginal infections and cervical non-HPV16/18 infection, as risk factors associated with persistence of nonvaccine HPV types will become increasingly relevant in the setting of HPV vaccination.MethodsWe performed an analysis in 2039 AS04-HPV16/18-vaccinated women enrolled in a phase II/III trial in China, who were HPV DNA negative at month 0 and 6 and had at least 1 subsequent follow-up visit. Vaginal infections were detected in liquid-based cytology according to the diagnostic criteria of the Bethesda System. Associations between vaginal infections and incident and 6-month persistent non-HPV16/18 infections in the cervix were evaluated using generalized estimating equations, adjusting for the age at initial vaccination, as well as HPV types in the persistence analysis.ResultsStudy visits with any vaginal infection had a statistically significant increased risk of incident non-HPV16/18 infection compared to those without vaginal infections (odds ratio [OR], 1.44 [95% confidence interval {CI}, 1.09-1.92]). However, vaginal infections were not associated with 6-month persistent non-HPV16/18 infection (OR, 1.02 [95% CI, .62-1.69]).ConclusionsOur study suggests that common vaginal infections are not associated with persistence of non-HPV16/18 infection among HPV16/18-vaccinated women.
| S-EPMC7982446 | biostudies-literature
Project description:OBJECTIVE:To calculate pooled risk estimates for combinations of cytology result, human papillomavirus (HPV) 16/18 genotype and colposcopy impression to provide a basis for risk-stratified colposcopy and biopsy practice. DATA SOURCE:A PubMed search was conducted on June 1, 2016, and a ClinicalTrials.gov search was conducted on June 9, 2018, using key words such as "uterine cervical neoplasms," "cervical cancer," "mass screening," "early detection of cancer," and "colposcopy." METHODS OF STUDY SELECTION:Eligible studies must have included colposcopic impression and either cytology results or HPV 16/18 partial genotype results as well as a histologic biopsy diagnosis from adult women. Manuscripts were reviewed for the following: cytology, HPV status, and colposcopy impression as well as age, number of women, and number of cervical intraepithelial neoplasia (CIN) 2, CIN 3, and cancer cases. Strata were defined by the various combinations of cytology, genotype, and colposcopic impression. TABULATION, INTEGRATION, AND RESULTS:Of 340 abstracts identified, nine were eligible for inclusion. Data were also obtained from three unpublished studies, two of which have since been published. We calculated the risk of CIN 2 or worse and CIN 3 or worse based on cytology, colposcopy, and HPV 16/18 test results. We found similar risk patterns across studies in the lowest risk groups such that risk estimates were similar despite different referral populations and study designs. Women with a normal colposcopy impression (no acetowhitening), less than high-grade squamous intraepithelial lesion cytology, and HPV 16/18-negative were at low risk of prevalent precancer. Women with at least two of the following: high-grade squamous intraepithelial lesion cytology, HPV16- or HPV18-positive, and high-grade colposcopic impression were at highest risk of prevalent precancer. CONCLUSION:Our results support a risk-based approach to colposcopy and biopsy with modifications of practice at the lowest and highest risk levels.
| S-EPMC6105396 | biostudies-literature
Project description: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.
| S-EPMC4967374 | biostudies-literature
Project description:BackgroundFactors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood. We evaluated co-factors for acquisition, persistence, and progression of non-HPV-16/18 infections among HPV-vaccinated women.MethodsWe analyzed 2153 women aged 18-25 years randomized to the HPV-vaccine arm of the Costa Rica HPV Vaccine Trial. Women were HPV DNA negative for all types at baseline and followed for approximately 11 years. Generalized estimating equation methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonally related factors, number of full-term pregnancies (FTPs), smoking behavior, and baseline body mass index.ResultsA total of 1777 incident oncogenic non-HPV-16/18 infections were detected in 12 292 visits (average, 0.14 infections/visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV-16/18 acquisition. Twenty-six percent of incident infections persisted for ≥1 year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV-16/18 infections. Risk of progression to Cervical Intraepithelial Neoplasia grade 2 or worst (CIN2+) increased with increasing age (P for trend = .001), injectable contraceptive use (relative risk, 2.61 [95% confidence interval, 1.19-5.73] ever vs never), and increasing FTPs (P for trend = .034).ConclusionsIn a cohort of HPV-16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV-16/18 infections; no notable factors are associated with persistence of acquired infections; and age, parity, and hormonally related exposures are associated with progression to CIN2+.
| S-EPMC8496490 | biostudies-literature
Project description:ObjectiveInfection with high-risk genotypes of human papillomavirus (HR-HPV) is the major cause of invasive cervical cancers. HPV-16 and HPV-18 are known to be responsible for two-thirds of all invasive cervical carcinomas, followed by HPV-45, -31, and -33. Current guidelines only differentiate HPV-16/18 (+) by recommending direct colposcopy for treatment. We tried to evaluate whether there are differences in risk among 12 non-16/18 HR-HPV genotypes in this study.MethodsThe pathology archive database records of 1,102 consecutive gynecologic patients, who had results for cervical cytology and histology and for HPV testing, as determined by HPV 9G DNA chip, were reviewed.ResultsAmong the 1,102 patients, 346 were non-16/18 HR-HPV (+) and 231 were HPV-16/18 (+). We calculated the odds ratios for ≥cervical intraepithelial neoplasia 2 (CIN 2) of 14 groups of each HR-HPV genotype compared with a group of HR-HPV (-) patients. Based on the odds ratio of each genotype, we divided patients with non-16/18 HR-HPV genotypes (+) into two groups: HPV-31/33/35/45/52/58 (+) and HPV-39/51/56/59/66/68 (+). The age-adjusted odds ratios for ≥CIN 2 of the HPV-31/33/35/45/52/58 (+) and HPV-39/51/56/59/66/68 (+) groups compared with a HR-HPV (-) group were 11.9 (95% CI, 7.6 to 18.8; p<0.001) and 2.4 (95% CI, 1.4 to 4.3; p<0.001), respectively, while that of the HPV-16/18 (+) group was 18.1 (95% CI, 11.6 to 28.3; p=0.003).ConclusionThe 12 non-16/18 HR-HPV genotypes can be further categorized (HPV-31/33/35/45/52/58 vs. HPV-39/51/56/59/66/68) by risk stratification. The HPV-31/33/35/45/52/58 genotypes might need more aggressive action. Large scale clinical trials or cohort studies are necessary to confirm our suggestion.
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