Colposcopic performance in a birth cohort previously eligible for human papillomavirus vaccination.

BACKGROUND: Sweden started subsidized quadrivalent human papillomavirus vaccination for girls aged 13 to 17 in 2007. Since 2012, vaccination has been offered to all girls aged 10 to 12 within a school-based vaccination program, with a coverage of 80% or more. In addition, the vaccine has been offered on-demand as catch-up vaccination for girls aged 13 to 18, with a cumulative coverage of 55% to 60%. Since the first women in Sweden eligible for human papillomavirus vaccination entered the cervical screening program, questions on how to evaluate colposcopic findings among vaccinated women have arisen. Evidence is inconsistent on whether colposcopic features for the detection of cervical lesions are influenced by specific human papillomavirus genotypes and what role they can play in the prevention of invasive cervical cancer in vaccinated women. OBJECTIVE: The primary objective of the study was to compare colposcopic evaluation in vaccinated and unvaccinated women entering the organized cervical screening program. STUDY DESIGN: Women in the 1994 and 1995 birth cohorts who entered the cervical screening program at age 23 in 1 region in Sweden were identified. Colposcopy was performed within 2 to 4 months after a positive screening result in accordance with national guidelines. Colposcopic performance was evaluated according to national guidelines with the Swede score and colposcopic impression. Punch biopsies were taken from colposcopic lesions and as "random biopsies" in the absence of lesions. These biopsies were used as the gold standard for the analysis. An endocervical sample was analyzed for cytologic findings and detection of 14 high-risk human papillomavirus genotypes. All colposcopic imaging was saved digitally for re-review. Vaccination status was obtained through linkage to national vaccination registries. Results were compared between vaccinated and unvaccinated women. RESULTS: In 2018 and 2019, 160 out of 165 (98%) women with a positive screening result attended colposcopy, of which 90 (56%) were vaccinated and 70 (44%) were unvaccinated. Only 7 out of 90 (5%) women in the vaccinated group were human papillomavirus 16/18-positive, compared with 23 out of 70 (33%) in the unvaccinated group (P<.001). There was a total of 61 out of 160 (38%) women with high-grade lesions-33 out of 90 (37%) in the vaccinated group and 28 out of 70 (40%) in the unvaccinated group (P=.697). There was 64% (21/33) of vaccinated women and 75% (21/28) of unvaccinated women with high-grade squamous intraepithelial lesions who had a Swede score of 6 to 10 (indicating high-grade squamous intraepithelial lesions) (P=.124). The sensitivity was slightly higher for the detection of high-grade squamous intraepithelial lesions in unvaccinated women using both colposcopic tests (Swede score, 0.67 vs 0.75; colposcopic impression, 0.67 vs 0.68), but the difference was not statistically significant. CONCLUSION: We found no statistically significant difference between the colposcopic evaluation of vaccinated and unvaccinated women, although human papillomavirus vaccination reduced the prevalence of human papillomavirus 16/18 infection in human papillomavirus-vaccinated women. Our results indicate that colposcopic examination is still a useful tool in vaccinated women entering the organized cervical screening program.

Organized primary human papillomavirus-based cervical screening: A randomized healthcare policy trial.

BACKGROUND: Clinical trials in the research setting have demonstrated that primary human papillomavirus (HPV)-based screening results in greater protection against cervical cancer compared with cytology, but evidence from real-life implementation was missing. To evaluate the effectiveness of HPV-based cervical screening within a real-life screening program, the organized, population-based cervical screening program in the capital region of Sweden offered either HPV- or cytology-based screening in a randomized manner through a randomized healthcare policy (RHP). METHODS AND FINDINGS: A total of 395,725 women aged 30 to 64 years that were invited for their routine cervical screening visit were randomized without blinding to either cytology-based screening with HPV triage (n = 183,309) or HPV-based screening, with cytology triage (n = 212,416 women) between September 1, 2014 and September 30, 2016 and follow-up through June 30, 2017. The main outcome was non-inferior detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Secondary outcomes included superiority in CIN2+ detection, screening attendance, and referral to histology. In total, 120,240 had a cervical screening sample on record in the study period in the HPV arm and 99,340 in the cytology arm and were followed for the outcomes of interest. In per-protocol (PP) analyses, the detection rate of CIN2+ was 1.03% (95% confidence interval (CI) 0.98 to 1.10) in the HPV arm and 0.93% (0.87 to 0.99) in the cytology arm (p for non-inferiority <0.0001; odds ratio (OR) 1.11 (95% CI 1.02 to 1.22)). There were 46 cervical cancers detected in the HPV arm (0.04% (0.03 to 0.06)) and 48 cancers detected in the cytology arm (0.05% (0.04 to 0.07)) (p for non-inferiority <0.0001; OR 0.79 (0.53 to 1.18)). Intention-to-screen (ITS) analyses found few differences. In the HPV arm, there was a modestly increased attendance after new invitations (68.56% (68.31 to 68.80) vs. 67.71% (67.43 to 67.98); OR 1.02 (1.00 to 1.03)) and increased rate of referral with completed biopsy (3.89% (3.79 to 4.00) vs. 3.53% (3.42 to 3.65); OR 1.10 (1.05 to 1.15)). The main limitations of this analysis are that only the baseline results are presented, and there was an imbalance in invitations between the study arms. CONCLUSIONS: In this study, we observed that a real-life RHP of primary HPV-based screening was acceptable and effective when evaluated against cytology-based screening, as indicated by comparable participation, referral, and detection rates. TRIAL REGISTRATION: ClinicalTrials.gov NCT01511328.

Colposcopic and histopathologic evaluation of women with HPV persistence exiting an organized screening program.

BACKGROUND: Human papillomavirus-based screening has a higher sensitivity for precursors of cervical cancer compared with cytology-based screening. However, more evidence is needed on optimal management of human papillomavirus-positive women. OBJECTIVE: The objective of the study was to compare the risk of histopathologically confirmed cervical intraepithelial lesions grade 2 or worse after 1 and 3 years of human papillomavirus persistence, respectively, and evaluate the clinical management of human papillomavirus-positive women in the 56-60 year age group. STUDY DESIGN: This was a randomized health care policy offering human papillomavirus screening to 50% of resident women aged 56-60 years in the Stockholm/Gotland region of Sweden during January 2012 through May 2014. Women who were human papillomavirus positive/cytology negative at baseline were referred for a repeat test after 1 or 3 years. In case of human papillomavirus persistence, women were referred for colposcopy, including biopsies and endocervical sampling. RESULTS: The human papillomavirus prevalence was 5.5% (405 women of 7325 attending). Among the 405 human papillomavirus-positive women, 313 were reflex test cytology negative at baseline and were referred for a repeat human papillomavirus test, 176 women after 1 year and 137 women after 3 years. After 1 year, 91 of 176 (52%) were persistently human papillomavirus positive and after 3 years 55 of 137 (40%) (P = .042). In repeat cytology, 10 of the 91 (12%) were positive after 1 year and 15 of 55 (33%) after 3 years (P = .005). The attendance rates for colposcopy were similar: 82 of 91 (90%) in the 1 year group and 45 of 55 (82%) in the 3 year group. All women attending colposcopy were postmenopausal, and endocervical sampling and punch biopsies were performed to facilitate colposcopic management, with a positive predictive value of 43-50% and 28-31%, respectively. Histopathologically confirmed cervical intraepithelial lesions grade 2 or worse was found in 19 of 82 women (23%) and 9 of 45 women (20%) in the 1 year and 3 year groups, respectively, and registry linkage follow-up found no cancers in either group. Human papillomavirus genotyping was predictive of cervical intraepithelial lesions grade 2 or worse, and human papillomavirus 16 was the most common genotype at human papillomavirus persistence, occurring in 18% of the cases in the 1 year group and 20% in the 3 year group. CONCLUSION: It was safe to postpone repeat human papillomavirus tests for 3 years in postmenopausal women attending the organized cervical screening program. There was a high risk for cervical intraepithelial lesions grade 2 or worse at follow-up and noteworthy yields from human papillomavirus genotyping as well as endocervical sampling and random biopsies in the absence of visible colposcopic lesions.

Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial.

BACKGROUND: Introduction of human papillomavirus-based screening is ongoing in many countries, given its higher sensitivity and longer-lasting protection compared with cytology-based screening. However, optimal clinical management of human papillomavirus-positive but cytology-negative women is unclear, and additional studies with clinical follow-up are warranted. OBJECTIVE: The aim of the current study was to investigate the long-term outcomes of the clinical management used in a double-blind, randomized clinical trial of human papillomavirus screening conducted in the context of the routine, organized screening program in Sweden. STUDY DESIGN: Among 12,527 women aged 32-38 years enrolled in the trial, we followed up the 195 women who attended the colposcopy screening who were cytologically normal but persistently human papillomavirus positive (at least 12 months later; median, 19 months) in the human papillomavirus testing arm (n = 100) or were randomly selected from the control arm (n = 95). Women in the human papillomavirus testing arm were followed up with repeated human papillomavirus testing, cytologies, and colposcopies if persistently human papillomavirus-positive without cervical intraepithelial neoplasia grade 2 or worse. A similar number of random colposcopies and tests were carried out in the control arm. Women were followed up over 13 years for the main outcome measures: cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse and cervical intraepithelial neoplasia grade 3 or worse. RESULTS: Among women who continued to attend and had continuous human papillomavirus persistence, all (40 of 40, 100% [95% confidence interval, 91-100%]) developed cervical intraepithelial neoplasia grade 2 or worse. There were no cases among women who cleared their human papillomavirus persistence (0 of 35, 0% (95% confidence interval, 0-10%) (P < .001). Among women who had had human papillomavirus persistence but did not continue with repeated human papillomavirus tests (unknown persistence status), 56% (15 of 27 women) developed cervical intraepithelial neoplasia grade 2 or worse. Almost all cases occurred within 6 years. The intensive clinical management in the trial appeared to result in diagnoses of earlier cervical intraepithelial neoplasia grade 2 or worse but apparently did not prevent cervical intraepithelial neoplasia grade 2 or worse. CONCLUSION: Women with human papillomavirus persistence will, in general, either become human papillomavirus negative or develop cervical intraepithelial neoplasia grade 2 or worse within 6 years, even with intensive clinical follow-up.

Impact of immunosuppression and region of birth on risk of cervical intraepithelial neoplasia among migrants living with HIV in Sweden.

Little is known about the incidence and risk of cervical intraepithelial neoplasia (CIN) grade 3, adenocarcinoma in situ and invasive cervical cancer (CIN3+) among migrants living with HIV in a European setting. We assessed the cumulative incidence (CuI) and hazard ratio (HR) of CIN2+ and CIN3+ in a cohort of women living with HIV (WLWH) (n = 893) identified from the Swedish national HIV register and HIV-negative women (n = 205,842) identified from the Swedish Population Register, matched on region of birth and age. Data was collected between 1993 and 2011 by linking our cohort with the Swedish National Cervical Screening Registry, collecting all cytological and histological results since 1993. The CuI of CIN3+ was 13.1% [95% confidence interval (CI) 8.9-17.2] for WLWH and 2.1% (95% CI 2.0-2.2) for HIV-negative after 18 years of follow-up. WLWH had more than eight times higher, age and region of birth matched, risk of CIN3+ than HIV-negative (HR 8.8: 95% CI 6.9-11.3). WLWH born in the East region, dominated by Thai women, had a two times higher risk of CIN3+ compared with WLWH born in Sweden (HR 2.47: 95% CI 1.2-5.0), which remained after adjusting for immunosuppression. Our results showed a substantially increased risk of CIN3+ among WLWH, which differed depending on birth region. Early HIV diagnosis and attendance to cervical cancer screening, with focus on migrants, is of crucial importance to minimize the incidence of cervical intraepithelial neoplasia.

Feasibility of sending a direct send HPV self-sampling kit to long-term non-attenders in an organized cervical screening program.

INTRODUCTION: Non-participation in screening is a main risk factor for cervical cancer. Human-papillomavirus (HPV) self-sampling may be an alternative to repeated invitations for non-attenders. Several studies have concluded that participation among non-attenders increases significantly when offering self-sampling kits for HPV. However, participation rates are highly variable between settings, and therefore pilots to determine optimal implementation strategy have been recommended before routine roll out. MATERIALS AND METHODS: All women who had not participated in the organized screening program for at least 10 years aged 33-62 in one Swedish county were identified through screening registers. HPV self-sampling kits were sent to all eligible women. Participation was defined as returning a self-sample kit or attending routine screening within 6 months. Women who did not submit the kit within 8 weeks were randomized to receive a written reminder. HPV-positive women were referred directly to colposcopy without prior triage. Biopsies for histopathologic confirmation were used as gold standard. RESULTS: Among eligible women, 150/741 (20.2%) returned the self-sample kit or attended routine screening. A randomized written reminder was sent out to 319/591 non-responders and another 11 women returned the kit. In total, 23/147 (16.3%) of returned kits were HPV positive. Out of the 23 HPV-positive women, 17 (74%) attended colposcopy; 10/17 (59%) had a histopathological high-grade squamous intraepithelial lesions (HSIL) or cervical cancer. The most common HPV type was HPV 52, and 2 out of 3 women with HPV 16 had a histopathologically confirmed cancer. CONCLUSION: The direct send kit strategy and referral of all HPV-positive women to colposcopy without prior triage appears to be feasible if resources are available and should be prioritized given the high prevalence of HSIL lesions and cancer among non-attenders. A written reminder might further increase attendance.

Randomized healthservices study of human papillomavirus-based management of low-grade cytological abnormalities.

Human papillomavirus (HPV)-based management of women with borderline atypical squamous cells of undetermined significance (ASCUS) or mildly abnormal cervical intraepithelial neoplasia (CINI) cervical cytology has been extensively studied in the research setting. We wished to assess safety and health care resource use of a real-life health care policy using HPV triaging. All 15 outpatient clinics involved in the organized population-based screening program in Stockholm, Sweden screening program were randomized to either continue with prior policy (colposcopy of all women with ASCUS/CINI) or to implement a policy with HPV triaging and colposcopy only of HPV-positive women. The trial enrolled the 3,319 women who were diagnosed with ASCUS (n = 1,335) or CINI (n = 1,984) in Stockholm during 17th March 2003 to 16th January 2006. Detection of high-grade cervical lesions (CINII+) and health care cost consumption was studied by registry linkages. The proportion of histopathology-verified CINII+ was similar for the two policies (395 of 1,752 women (22.5%; 95% Confidence interval [CI]: 20.6-24.6%) had CINII+ diagnosed with HPV triaging policy, 318 of 1,567 women (20.3%; 95%CI: 18.3-22.4%) had CINII+ with colposcopy policy). Sixty-four percent of women with ASCUS and 77% of women with CINI were HPV positive. HPV-positivity was age-dependent, with 81% of women below 35 years of age and 44% of women above 45 years of age testing HPV-positive. HPV triaging was cost-effective only above 35 years of age. In conclusion, a real-life randomized healthservices study of HPV triaging of women with ASCUS/CINI demonstrated similar detection of CINII+ as colposcopy of all women.

[HPV vaccines effective and safe]. / HPV-vacciner effektiva och säkra.

In this review we summarize the current knowledge about the HPV vaccines developed in the beginning of the 21st century. The vaccines are very effective and safe, with no serious side effects. In Sweden we have a school-based prophylactic vaccination programme for both girls and boys. To this age group, we offer two doses of the nonavalent vaccine. The main purpose of the vaccination is to decrease the rate of genital cancer and its precursor lesions. This has mainly been studied for the cervix, which is the locus for the most important HPV-related cancer. Among other HPV 16-related malignancies that can be prevented by the vaccine is anal cancer. Genital warts are a challenging benign condition difficult to treat, often associated with psychosexual consequences. In Sweden we already have seen a decrease of HPV infection, genital warts, precancerous cervical lesions and cervical cancer.

Human papillomavirus and Papanicolaou tests to screen for cervical cancer.

BACKGROUND: Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS: In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS: At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS: The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).

HPV Types in Cervical Precancer by HIV Status and Birth Region: A Population-Based Register Study.

BACKGROUND: Data are lacking regarding which human papillomavirus (HPV) types cause high-grade cervical neoplasia (CIN2+) in people with HIV in Europe. We assessed which HPV types are associated with CIN2+ in women living in Sweden by HIV status. METHODS: The Swedish National HIV Registry, the Swedish Population Registry, and the Swedish National Cervical Screening Registry were linked. CIN2+ tissue blocks of 130 women living with HIV (WLWH) and 234 HIV-negative women, matched for country of birth (1:2), were retrieved from bio-banks and HPV genotyped. Adjusted ORs (adjOR), stratified by country of birth, were calculated using conditional logistic regression. Matching was broken for cross-group comparisons. RESULTS: WLWH with CIN2 were less likely to have HPV16 [14% vs. 40%; adjOR 0.1; 95% confidence interval (CI), 0.04-0.56] than HIV-negative women, but among women with CIN3, there was no difference in HPV16 prevalence by HIV status (adjOR 0.9; 95% CI, 0.51-1.70). WLWH were six times more likely to have HPV35 in CIN3 than HIV-negative women (adjOR 6.2; 95% CI, 1.3-30.4). WLWH from sub-Saharan Africa (SSA) had less 9-valent vaccine types, compared with both HIV-negative women born in Sweden (adjOR 0.1; 95% CI, 0.02-0.44) and WLWH born in Sweden (adjOR 0.1; 95% CI, 0.01-0.73), mostly because of decreased HPV16 and increased HPV35. CONCLUSIONS: WLWH from SSA were less likely to be covered by the 9-valent vaccine, mostly due to less HPV16 and more HPV35. IMPACT: This could have implications for HPV vaccines, currently not including HPV35, and for HPV-screening algorithms in women with origin from SSA.

Suppressive antiretroviral therapy associates with effective treatment of high-grade cervical intraepithelial neoplasia.

OBJECTIVES: To assess if women living with HIV (WLWH) have poorer outcome after treatment of cervical intraepithelial neoplasia grade 2, grade 3, adenocarcinoma in situ or cervical cancer (CIN2+) than HIV-negative women (HNW) and to identify predictors of CIN2+ treatment failure and recurrence in WLWH. DESIGN: Population-based cohort study with follow-up between 1983 and 2015. METHODS: The Swedish National HIV Registry, the Swedish Population Registry and the Swedish National Cervical Screening Registry were linked to identify all women in Stockholm and Gothenburg counties (Sweden) living with HIV and diagnosed with CIN2+ (n = 179) sometime between 1983 and 2014. For each WLWH, two HNW resident in the same counties and matched for country of birth, diagnosed with CIN2+, were chosen as controls. Treatment failure was defined as the presence of CIN2+ at initial follow-up. Recurrence was defined as the presence of CIN1+ subsequent to an initial normal follow-up. RESULTS: WLWH were three times more likely to have treatment failure (odds ratio (OR) 3.7 [95% confidence interval (CI) 2.0-6.8]) and five times more likely to recur (hazard ratio 5.0 [95% CI 2.1-11.6]) than HNW. Suppressive antiretroviral therapy (ART) at time of treatment of CIN2+ was associated with reduced OR of treatment failure (OR 0.3 [95% CI 0.1-0.8]). Immunosuppression (CD4 cell count <200 cells/µl) associated strongly with treatment failure (OR compared with CD4 cell count ≥500: 8.5 [95% CI 2.3-30.7]). CONCLUSION: Suppressive ART is associated with effective treatment of CIN2+. Early HIV diagnosis and ART are essential for successful CIN2+ treatment.

A comparison of liquid-based cytology and Pap smear as a screening method for cervical cancer.

The implementation of population-based screening for cervical cancer with Pap smear in the early sixties was set to detect and treat precancerous lesions, hopefully preventing a subsequent invasive cervical cancer. Epidemiological data indicate that organized screening has a major impact on morbidity and mortality from cervical cancer. The limited sensitivity of a single smear necessitates repeated smears in organized program. It is suggested that liquid-based cytology improves the sensitivity. The aim of this split-sample study was to compare ThinPrep liquid-based cytology with conventional Pap smear, relying on a laboratory with long-term experience of the latter. In total, 137 women with atypical Pap smear in population-based cervical screening were enrolled for the split-sample study. The performance of both techniques (ThinPrep liquid-based cytology and conventional Pap smear) were compared and validated by a histological follow-up. Women without representative histological biopsy were excluded from the study. Pap smear had sensitivity for detection of CIN2-3 of 47% compared to 66% for liquid-based material. The concordance of the two sampling techniques with the histological diagnosis was 37% and 53%, respectively, this difference being statistically significant. The proportion of reports on atypical squamous cells of undetermined significance (ASCUS) was significantly less in the liquid-based material, 4.3% compared to 8% of the conventional smears. This improved sensitivity in combination with the possibility to perform reflex testing such as HPV DNA or p16 immunocytochemistry without renewed sampling gives ThinPrep a substantial advantage and makes the liquid-based technique interesting.

Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56-60.

OBJECTIVE: The aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme. PARTICIPANTS: Resident women in the Stockholm/Gotland region of Sweden, aged 56-60 years were randomised to either (1) screening with cervical cytology, with HPV test in triage of low-grade cytological abnormalities (old policy) or (2) screening with HPV testing, with cytology in triage of HPV positives (new policy). OUTCOME: The primary evaluation was the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: During January 2012-May 2014, the organised screening programme sent 42 752 blinded invitations with a prebooked appointment time to the women in the target age group. 7325 women attended in the HPV policy arm and 7438 women attended in the cytology arm. In the new policy, the population HPV prevalence was 5.5%, using an accredited HPV test (Cobas 4800). HPV16 prevalence was 1.0% (73/7325) and HPV18 prevalence was 0.3% (22/7325). In the HPV policy arm, 78/405 (19%) HPV-positive women were also cytology positive. There were 19 cases of CIN2+ in histopathology, all among women who were both HPV positive and cytology positive. The positive predictive value for CIN2+ in this group was 33.3% (19/57). In the cytology policy, 153 women were cytology positive and there were 18 cases of CIN2+ in histopathology. Both the total number of cervical biopsies and the number of cervical biopsies with benign histopathology were much lower in thepositive predictive value policy (49 benign, 87 total vs 105 benign, 132 total). CONCLUSION: Primary HPV screening had a similar detection rate for CIN2+ as cytology-based screening, already before follow-up of HPV-positive, cytology-negative women with new HPV test and referral of women with persistence. TRIAL REGISTRATION NUMBER: NCT01511328.

Rate of human papillomavirus clearance after treatment of cervical intraepithelial neoplasia.

OBJECTIVE: To investigate the rate of clearance of human papillomavirus (HPV) infection after surgical treatment for cervical intraepithelial neoplasia (CIN). METHODS: One hundred nine women with CIN I-III, treated with cryosurgery or conization at a university hospital, were observed with cervical HPV deoxyribonucleic acid (DNA) testing by general primer polymerase chain reaction and HPV typing at 0, 3, 6, 9, 12, and 24 months after treatment. Penile HPV DNA was analyzed from current sexual partners. RESULTS: Eighty-one percent of evaluable women were HPV DNA positive at treatment or enrollment. One year later, seven women (9%) remained positive for the same HPV type. Most women had cleared the HPV infection diagnosed at treatment within 3 months. The cryotherapy group had lower CIN grades, was younger, and had a slower HPV clearance rate (P <.002). Only four couples had HPV DNA of the same type detected. CONCLUSION: Surgical treatment of CIN usually results in clearance of HPV infection within 3 months. Human papillomavirus DNA testing may be useful as a rapid intermediate end point for monitoring the efficacy of treatments.

Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening.

BACKGROUND: Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS: We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS: Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS: Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine.

BACKGROUND: The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions. Some vaccines induce long-term immunity, while others require booster doses. Vaccines that induce long-term protection are usually characterized by the generation of immune memory. Recent trials of a quadrivalent (types 6, 11, 16, 18) human papillomavirus (HPV) vaccine have demonstrated high efficacy through 5 years of follow-up. We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory. METHODS: A total of 552, 16-23-year-old women were enrolled in a double-blind, placebo-controlled study. At enrollment, subjects were randomized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years' follow-up. A subset of 241 subjects (n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group) underwent 2 further years of follow-up. All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series. RESULTS: Serum anti-HPV levels declined post-vaccination, but reached a plateau at month 24 that remained stable through month 60. Administration of a challenge dose of vaccine induced a classic anamnestic response, with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series. At 1 month post-challenge, anti-HPV responses were higher than those observed 1-month post-dose 3. DISCUSSION: A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years. Vaccination also induces robust immune memory. These findings suggest that the efficacy of this vaccine will be long lasting.

A comparison of the human papillomavirus test and Papanicolaou smear as a second screening method for women with minor cytological abnormalities.

BACKGROUND: Of the estimated one million Papanicolaou (pap) smears performed annually in Sweden, about 4% show any degree of abnormality. Approximately, 1% of these cases contain moderate or severe atypia (high-grade squamous intraepithelial lesions) and the rest contain low-grade atypia. Recommendations for the management of minor abnormalities vary in various parts of Sweden. Generally, a second Pap smear is obtained 4-6 months after the first one showing low-grade atypia. The aim of this study is to compare the sensitivity of human papilloma virus (HPV)-DNA testing for the detection of cervical intraepithelial neoplasia (CIN) 2-3 with that of a second Pap smear in women, who had low-grade atypia in their first Pap smear. METHODS: Women with low-grade atypia in the Stockholm area, detected at a population-based cytology screening, were enrolled. A repeat Pap smear, HPV test, and colposcopically directed biopsies were obtained. For the detection of HPV, Hybrid Capture II (HC II) was used. RESULTS: The HPV-DNA test was positive in 66% of the 177 participating women. The sensitivity of the second Pap smear and HPV-DNA test to detect CIN 2-3 was 61 (95% CI = 45-74) and 82% (95% CI = 67-91), respectively. The positive and negative predictive values of HPV testing were 27 (95% CI = 18-35) and 89% (95% CI = 80-97), respectively. CONCLUSIONS: In Sweden, a second Pap smear is often obtained for the follow-up of women with low-grade atypia. The results of our study show that compared to the second Pap smear, HPV testing with HC II is a more sensitive method for detecting high-grade lesions.