Search

Human papillomavirus (HPV) is the well‐established etiologic factor for cervical neoplasia. Cervical conization constitutes an effective treatment for high‐grade cervical intraepithelial neoplasia (HG‐CIN). We conducted an observational study for long‐term outcomes and HPV genotype changes after conization for HG‐CIN. Between 2008 and 2014, patients with newly diagnosed HG‐CIN before conization (surveillance new [SN] group) and those who had undergone conization without hysterectomy (surveillance previous [SP] group) were enrolled. HPV testing and Pap smear were performed periodically for the SN and SP (collectively S) groups. All other patients receiving conization for HG‐CIN during the study period were identified from our hospital database. Those eligible but not enrolled into our study were assigned to the non‐surveillance (non‐S) group. For the S group (n = 493), the median follow‐up period was 74.3 months. Eighty‐four cases had recurrent CIN Grade 2 or worse (CIN2+) (5‐year cumulative rate: 14.8%), of which six had invasive cancer. Among the 84 patients, 65 (77.4%) exhibited type‐specific persistence in the paired HPV results, whereas only 7 (8.3%) harbored new HPV types that belonged to the 9‐valent vaccine types. Among the 7397 non‐S patients, 789 demonstrated recurrent CIN2+, of which 57 had invasive cancer. The stages distribution of those progressed to invasive cancer in the non‐S group were more advanced than the S group (P = .033). Active surveillance might reduce the severity of those progressed to cancer. Because a majority of the patients with recurrent CIN2+ had persistent type‐specific HPV infections, effective therapeutic vaccines are an unmet medical need., What's new? High‐grade cervical intraepithelial neoplasia (HG‐CIN), a cervical carcinoma precursor, frequently is caused by high‐risk human papillomavirus (hr‐HPV) infection. HG‐CIN can be treated by cervical conization, though the procedure does not eradicate hr‐HPV, potentially enabling CIN recurrence. Here, in Taiwanese patients, investigation of HPV genotype changes in relation to HG‐CIN status after conization shows that 77.4 percent of patients with recurrent CIN 2 grade or worse (CIN2+) after conization had persistent type‐specific HPV infections. Vaccination against the remaining high‐risk HPVs prevented recurrent CIN2+ in only 8.3 percent of patients, revealing an unmet need for effective therapeutic vaccines.

Objective To evaluate the efficacy and toxicity of topical imiquimod for the treatment of persistent human papillomavirus (HPV) infection in patients with or without cervical/vaginal intraepithelial neoplasia (CIN/VAIN). Methods Patients with persistent HPV infection (≥1 year) after a history of treatment for cervical or vaginal neoplasm but normal histology and cytology, abnormal Papanicolaou (Pap) smears without abnormal histology, and untreated histology-documented CIN/VAIN Grade 1/2/3 with HPV-positive testing were recruited. Patients were instructed to apply 250 mg of 5% imiquimod cream intravaginally on consecutive days or at least twice weekly on an outpatient basis for a minimum of 12 doses. A group of age- and previous diagnosis-matched, imiquimod-untreated historical controls ( n = 20) were selected. The main outcome measures included HPV DNA detection, cytology, and colposcopy/histology at 6 months after treatment. Results A total of 72 patients were eligible for analysis. At a median follow-up of 33.6 months, 37 patients (51.4%) had cytological/histological regression and tested HPV-negative. Six patients (8.3%) had progressive cytology/histology with persistent HPV infections. Of the 72 treated patients, 26 patients who had a normal Pap test but were persistently HPV-positive for at least 1 year had a complete regression rate of 65.4%, which was significantly different from the rate (30%) observed in the untreated historical control ( p = 0.036). Six patients with histologically proven CIN2/3 or VAIN2/3 had a complete regression rate of 66.6% (4/6). Conclusions The tolerability of intravaginal self-administered imiquimod is confirmed. Its efficacy in the treatment of women with persistent HPV infection and normal cytology warrants further randomized, controlled trials to determine appropriate dosages and scheduling.

We aimed to assess the distribution of human papillomavirus (HPV) genotypes in high-grade cervical lesions in Taiwan. The study included 1,086 paraffin-embedded, formaldehyde-fixed cervical intraepithelial neoplasia (CIN) 2/3 specimens. HPV genotyping was performed using polymerase chain reaction (PCR)-based methods. Multiple HPV types were validated by E6 type-specific PCR, direct sequencing and/or real-time PCR. HPV DNA was detected in 995 (91.6%) specimens, and multiple HPV types were identified in 192 (19.3%) samples. The leading HPV types were HPV16 (24%), HPV52 (20%), HPV58 (20%), HPV33 (13%), HPV31 (8%) and HPV18 (4.6%). Although the leading six types consisted of 87.6%, HPV16 or 18 comprised only 30.9%. The prevalence of different HPV types showed a significant association with age. In women older than 50 yr, HPV16 and 18 comprised 21.3% (83/389), while HPV52, 58 and 33 represented 55.5% (216/389). In women aged less than 50 yr, HPV16 and 18 comprised 32.1% (224/697, p < 0.0001), while HPV 52, 58 and 33 represented 47.9% (334/697, p = 0.02). The distribution of HPV genotypes was compared with previously reported findings for Taiwanese women with cervical cancer (CC). The overall HPV16 positivity rate was significantly higher in CC than in CIN 2/3 (odds ratio: 2.14, 95% CI: 1.91-2.40). In addition, HPV18, 39 and 45 were significantly overrepresented in CC, whereas HPV52, 58, 33, 31, 35, 51 and 53 were underrepresented. We concluded that an effective vaccine against the most common HPV types could prevent a significant proportion of cervical cancer cases that occur in Taiwan.

Objective Previous studies have shown that SPF1/GP6+ PCR followed by HPV Blot has high sensitivity and high reproducibility for the detection of human papillomavirus (HPV). However, there have been reports of false-negative results. In the present study we endeavoured to improve the diagnostic performance of HPV DNA testing in cervical swab specimens. We also aimed to identify viral load thresholds. Methods We examined DNA from cervical swabs of 7 women with a cervical intraepithelial neoplasia grade 2 or worse (CIN2+) who were negative by HPV DNA testing. For control purposes, 106 cytology negative/HPV-negative samples were included. PCR was performed with either 1μL of DNA solution or different amounts of input DNA (25, 50, and 100ng). We tested two different commercial alkaline phosphatases (ALPs) at two distinct reaction times. The overall conclusions were based on HPV Blot, type-specific PCR, direct sequencing, and real-time quantitative PCR (qPCR). Results All seven patients with CIN2+ disease turned HPV-positive when 100ng of input DNA and E6 type-specific PCR were used. Discrepant and false-negative results were obtained using different amounts of input DNA. Different commercial ALPs showed a significant impact on detection performance. Analysis of viral load indicated that the detection threshold for HPV infection using SPF1/GP6+ PCR plus HPV Blot was approximately 10 2 –10 3 copies. Conclusions Reliable determination of HPV status is crucially dependent on the amount of input genomic DNA.

Little is known about acquisition of human papillomavirus (HPV) and its outcome among older women with negative HPV testing and normal cytology. A longitudinal 3-yr follow-up of nested-cohort subjects (n = 8825) from a population-based cervical cancer screening study whose Pap and HPV tests were negative at baseline were conducted. Every active HPV-negative (n = 413) participant had 12-mo follow-ups of Pap smear and HPV testing. Colposcopy was performed if either HPV-positive or cytology was abnormal. The cytology and histology information of the remaining subjects (passive HPV-negative, n = 8412) was obtained from national registry database. Median age of participants was 45 yr (range, 30-73 yr). The incidence of new acquisition was 4.2/100 woman-years. The 3-yr cumulative total HPV acquisition rate was 11.1% (95% confidence interval [CI]: 8.1-14.1). Increased number of sexual partners (> or =2 vs. 1) of the participant was associated with risk of acquisition (odds ratio [OR]: 5.0, 95% CI: 2.0-12.6) by multivariate analysis. Three cases of > or = cervical intraepithelial neoplasia (CIN) 2 were identified in 3-yr follow-up in active HPV-negative subjects. HPV genotypes in the dysplastic tissue were actually present at baseline samples after reanalysis. From the passive HPV-negative group, only 1 case progressed to CIN2 probably after HPV acquisition. Negative Pap and HPV tests assured a very low risk of developing > or = CIN2 within 3 yr despite incident HPV infection.

Objective: To evaluate whether human papillomavirus (HPV) activity in symptomatic patients with abnormal Papanicolaou smears (minimal abnormal cytology) was affected by a complete vaginal douche, applied to the cervix prior to colposcopic examination. Materials and Methods: A total of 132 women with abnormal Papanicolaou smears were prospectively registered in this study from 1999 to 2004. Two specimens were collected from each patient; one before and one after the cervix was swabbed with a complete vaginal douche during a colposcopic examination. We compared the HPV detection results before and after douching in the same patients. The samples were analyzed using the Hybrid Capture II assay. Results: Before douching, 57.6% (76/132) of the samples were HPV-positive, compared with 58.3% (77/132) of the samples after douching. There was a strong correlation between the cervical HPV detection rates between the before and after douche samples (p < 0.001). The kappa statistic was 0.891 for the correlation (positive– positive, negative–negative) and the discrepancy (positive–negative) between the inter-douche rates of HPV activity. A comparison of the HPV assay before and after vaginal douching demonstrated a statistically significant relationship (p < 0.001). The sensitivity of the HPV test after douching was higher (97.8%) than that before douching (95.6%). The false-negative rate before douching in women with inflammatory smears was 3% (4/132) and the false-positive rate before douching in women with atypical squamous cells of undetermined significance was 2.1% (3/132). Conclusion: Our results indicate that self-administration of a vaginal douche is not a reliable method of eradicating HPV infection.

Human papillomavirus (HPV) persistence is essential for cervical cancer development. We accrued nested-cohort subjects from a population-based study to investigate the host and viral factors related to outcome of HPV infection. Women (age ≥ 30 years old) with HPV-positive but normal cytology and negative colposcopy were invited to participate. After signing informed consent, every participant completed a structured questionnaire and had 6monthly follow-ups of Pap smear, HPV testing and colposcopy. Total and type-specific HPV clearance rates as well as host and viral factors associated with clearance in 3-year longitudinal followup were analyzed. Adjusted hazard ratios (HRs) of progression to ≥ cervical intraepithelial neoplasia (CIN) 2 according to baseline HPV of the women with normal cytology were calculated from national registry database. Among the 626 eligible women, 526 (median age 47, 29–75) were enrolled and 412 returned for followup at least once. The median follow-up of enrolled subjects was 23 months (range 6.8–39). The 3-year cumulative total HPV clearance rate was 49.0% (95% confidence interval [CI]: 43.3–54.7%). The median 3-year cumulative type-specific HPV clearance rate was 50.0% (range 0–100.0%) with a median time to clearance of 12.4 months (6.4–24.5). Older age was associated with significantly decreased total HPV clearance and decreased type-specific clearance in HPV-18 and -53, while high viral load was associated with decreased total and type-specific clearance. After adjusting confounding variables, the HR of developing CIN2 in baseline HPVpositive women was 34.0-fold (95% CI: 15.5–74.7) as compared to HPV-negative women. ' 2008 Wiley-Liss, Inc.

We aimed to define the adjunctive role of human papillomavirus (HPV) DNA testing in the follow-up of high-grade cervical intraepithelial neoplasia (CIN) after conization.We analyzed a consecutive series of 2,154 patients who received conization. Patients who had cone diagnosis of cervical cancer or CIN 1, a hysterectomy within 12 weeks after conization, and no follow-up data were excluded. The remaining 765 patients (monitored by Pap smears, colposcopy with or without high-risk HPV DNA testing) were analyzed.Of the 765 patients, 279 had CIN at cone margin or endocervix (group A) while 486 were both margin- and endocervix-free (group B). The 3-year cumulative rate of residual/recurrent high-grade CIN was 10.3% (95% CI, 6.9-13.7). HPV follow-up status (P=.015), margin status (P=.001), and follow-up cervical cytology (P.0001) were significant predictors for residual/recurrent high-grade CIN by multivariate analysis. Four high-grade CINs and 1 microinvasive carcinoma of group A were detected initially by HPV testing, while 48.3% (199/410) of those without recurrent/persistent high-grade CIN still had persistent HPV infection.HPV DNA testing is useful in the follow-up and understanding of the natural history after conization for high-grade CIN.

Objective: Our aim was to evaluate human papillomavirus deoxyribonucleic acid testing after conization in predicting residual disease in the subsequent hysterectomy specimen. Study Design: A prospective study was conducted on 75 patients with grade 3 cervical intraepithelial neoplasia who had cone margins or endocervical curettage specimens showing disease and who elected to undergo hysterectomy after conization. All patients underwent high-risk human papillomavirus deoxyribonucleic acid testing by the Hybrid Capture II (Digene Corporation, Gaithersburg, MD) system before conization and at the time of hysterectomy (within 2-7 weeks after conization). The presence of human papillomavirus deoxyribonucleic acid in cells obtained by endocervical brush before hysterectomy was correlated with residual disease in the hysterectomy specimens. Results: Of the 92 patients enrolled, 75 were eligible. Of these 75 patients, 52 (69.3%) had persistent human papillomavirus deoxyribonucleic acid after conization, and 27 (36.0%) of the 75 patients had residual cervical neoplasia in the hysterectomy specimens. Those with negative results for human papillomavirus deoxyribonucleic acid after conization were all (23/23) without residual disease in the uterus (100% negative predictive value). All those who had residual disease (27/27) had positive results for human papillomavirus deoxyribonucleic acid at the time of hysterectomy (100% sensitivity). Postconization human papillomavirus deoxyribonucleic acid status (odds ratio, 4.000; 95% confidence interval, 1.531-10.449; P =.005) and grade of dysplasia after endocervical curettage (classified as grade 2 cervical intraepithelial neoplasia or less severe disease vs grade 3 cervical intraepithelial neoplasia: odds ratio, 6.612; 95% confidence interval, 2.837-15.409; P =.0002) were significantly associated with residual tumor in the uterus. Conclusions: This prospective study confirms an excellent sensitivity and negative predictive value of human papillomavirus deoxyribonucleic acid testing after conization in predicting residual cervical neoplasia. A strategy of managing patients with grade 3 cervical intraepithelial neoplasia, based on postconization human papillomavirus deoxyribonucleic acid findings and endocervical curettage results, is proposed. (Am J Obstet Gynecol 2001;184:940-5.)