HPV-based cervical screening: Rationale, expectations and future perspectives of the new Dutch screening programme.

Based on scientific data showing that HPV testing provides better protection against cervical precancer and cancer than cytology, in 2011 the Dutch Health Council advised the Minister of Welfare, Health and Sports to replace cytology by HPV testing in the Dutch population-based screening programme. After a successful evaluation of the feasibility of HPV-based screening in 2014, primary HPV testing for cervical screening was implemented in 2017. The Netherlands has been one of the first countries worldwide to implement nationwide HPV-based screening and its experience with the new programme is therefore followed with great interest. In this manuscript, we present an overview of the studies that were instrumental in the choice of HPV assay and triage strategy, the adjustment of screening starting and exit ages and intervals, and the implementation of HPV self-sampling. Finally, we review the cost-effectiveness of the proposed new screening algorithm and we explore future perspectives. The rationale behind the new Dutch HPV-based screening programme, which is based on risk management, could serve as a guidance to other countries that are planning to implement HPV-based screening in the near future.

Evaluation of the Clinical Performance of the HPV-Risk Assay Using the VALGENT-3 Panel.

Human papillomavirus (HPV) testing is increasingly being incorporated into cervical cancer screening. The Validation of HPV Genotyping Tests (VALGENT) is a framework designed to evaluate the clinical performance of various HPV tests relative to that of the validated and accepted comparator test in a formalized and uniform manner. The aim of this study was to evaluate the clinical performance of the HPV-Risk assay with samples from the VALGENT-3 panel and to compare its performance to that of the clinically validated Hybrid Capture 2 assay (HC2). The VALGENT-3 panel comprises 1,300 consecutive samples from women participating in routine cervical cancer screening and is enriched with 300 samples from women with abnormal cytology. DNA was extracted from original ThinPrep PreservCyt medium aliquots, and HPV testing was performed using the HPV-Risk assay by investigators blind to the clinical data. HPV prevalence was analyzed, and the clinical performance of the HPV-Risk assay for the detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) and CIN2 or worse (CIN2+) relative to the performance of HC2 was assessed. The sensitivity of the HPV-Risk assay for the detection of CIN3+ was similar to that of HC2 (relative sensitivity, 1.00; 95% confidence interval [CI], 0.95 to 1.05; P = 1.000), but the specificity of the HPV-Risk assay was significantly higher than that of HC2 (relative specificity, 1.02; 95% CI, 1.01 to 1.04; P < 0.001). For the detection of CIN2+, similar results were obtained, with the relative sensitivity being 0.98 (95% CI, 0.93 to 1.02; P = 0.257) and the relative specificity being 1.02 (95% CI, 1.01 to 1.03; P < 0.001). The performance of the HPV-Risk assay for the detection of CIN3+ and CIN2+ was noninferior to that of HC2, with all P values being ≤0.006. In conclusion, the HPV-Risk assay demonstrated noninferiority to the clinically validated HC2 by the use of samples from the VALGENT-3 panel for test validation and comparison.

Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment.

BACKGROUND: Data on non-small-cell lung cancer (NSCLC) patients with non-classic epidermal growth factor receptor (EGFR) mutations are scarce, especially in non-Asian populations. The purpose of this study was to evaluate prevalence, clinical characteristics and outcome on EGFR-TKI treatment according to type of EGFR mutation in a Dutch cohort of NSCLC patients. METHODS: We retrospectively evaluated a cohort of 240 EGFR-mutated NSCLC patients. Data on demographics, clinical and tumour-related features, EGFR-TKI treatment and clinical outcome were collected and compared between patients with classic EGFR mutations, EGFR exon 20 insertions and other uncommon EGFR mutations. RESULTS: Classic EGFR mutations were detected in 186 patients (77.5%) and non-classic EGFR mutations in 54 patients (22.5%); 23 patients with an exon 20 insertion (9.6%) and 31 patients with an uncommon EGFR mutation (12.9%). Median progression-free survival (PFS) and overall survival (OS) on EGFR-TKI treatment were 2.9 and 9.7 months, respectively, for patients with an EGFR exon 20 insertion, and 6.4 and 20.2 months, respectively, for patients with an uncommon EGFR mutation. Patients with a double uncommon EGFR mutation that included G719X/L861Q/S768I had longer PFS and OS on EGFR-TKI treatment compared with patients with a single G719X/L861Q/S768I EGFR mutation (both P=0.02). CONCLUSIONS: In our Dutch cohort, prevalence and genotype distribution of non-classic EGFR mutations were in accordance with previously reported data. The PFS and OS on EGFR-TKI treatment in patients with an uncommon EGFR mutation were shorter compared with patients with classic EGFR mutations, but varied among different uncommon EGFR mutations.

Performance of CADM1/MAL-methylation analysis for monitoring of women treated for high-grade CIN.

INTRODUCTION: Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3). METHODS AND MATERIALS: A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done. RESULTS: We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 (64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of ≥rCIN3 (from 0.7% to 18.4%), and ≥rCIN2 (from 8.2% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value: <0.001). CONCLUSION: Post-treatment monitoring by CADM1/MAL-methylation analysis identifies women with an increased risk of rCIN2/3. Our results confirm previous data indicating that CADM1/MAL-methylation analysis provides a high reassurance against cancer.

Different prognostic models for different patient populations: validation of a new prognostic model for patients with oropharyngeal cancer in Western Europe.

OBJECTIVE: The presence of human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modelling. Recently, a prognostic model was proposed in which HPV status, comorbidity and nodal stage were the most important prognostic factors to determine high-, intermediate- and low-risk survival groups. Here, we report on the validation of this model using an independent single-institutional cohort. METHODS: A total number of 235 patients curatively treated for OPSCC in the period 2000-2011 at the MUMC (Maastricht University Medical Center, The Netherlands) were included. The presence of an oncogenic HPV infection was determined by p16 immunostaining, followed by a high-risk HPV DNA PCR on the p16-positive cases. The model variables included were HPV status, comorbidity and nodal stage. As a measure of model performance, the Harrell's Concordance index (Harrell's C-index) was used. RESULTS: The 5-year overall survival (OS) estimates were 84.6%, 54.5% and 28.7% in the low-, intermediate- and high-risk group, respectively. The difference between the survival curves was highly significant (P<0.001). The Harrell's C-index was 0.69 (95% confidence interval (CI): 0.63-0.75). CONCLUSION: In this study a previously developed prognostic risk model was validated. This model will help to personalise treatment in OPSCC patients. This model is publicly available at www.predictcancer.org.

DNA hypermethylation analysis in sputum for the diagnosis of lung cancer: training validation set approach.

BACKGROUND: Lung cancer has the highest mortality of all cancers. The aim of this study was to examine DNA hypermethylation in sputum and validate its diagnostic accuracy for lung cancer. METHODS: DNA hypermethylation of RASSF1A, APC, cytoglobin, 3OST2, PRDM14, FAM19A4 and PHACTR3 was analysed in sputum samples from symptomatic lung cancer patients and controls (learning set: 73 cases, 86 controls; validation set: 159 cases, 154 controls) by quantitative methylation-specific PCR. Three statistical models were used: (i) cutoff based on Youden's J index, (ii) cutoff based on fixed specificity per marker of 96% and (iii) risk classification of post-test probabilities. RESULTS: In the learning set, approach (i) showed that RASSF1A was best able to distinguish cases from controls (sensitivity 42.5%, specificity 96.5%). RASSF1A, 3OST2 and PRDM14 combined demonstrated a sensitivity of 82.2% with a specificity of 66.3%. Approach (ii) yielded a combination rule of RASSF1A, 3OST2 and PHACTR3 (sensitivity 67.1%, specificity 89.5%). The risk model (approach iii) distributed the cases over all risk categories. All methods displayed similar and consistent results in the validation set. CONCLUSIONS: Our findings underscore the impact of DNA methylation markers in symptomatic lung cancer diagnosis. RASSF1A is validated as diagnostic marker in lung cancer.

The performance of Dynamic Spectral Imaging colposcopy depends on indication for referrals.

OBJECTIVE. A previous study has shown that Dynamic Spectral Imaging (DSI) colposcopy increases the sensitivity of the colposcopic examination in women referred with abnormal cytology. In this study we have reanalyzed the performance of DSI and conventional colposcopy for new referral conditions and for low-grade cytology referrals versus high-grade cytology referrals. METHOD. Data from a previous validation trial was used to assess the performance of DSI in different cytology groups:Women referred with BMD (borderline and mild dyskaryosis) cytology and women referred with NBMD cytology either hrHPV positive or negative were separately analyzed. Furthermore, we tried to assess the clinical performance by appropriate filtering of patients to replicate two different referral strategies. RESULTS. The sensitivity of DSI and conventional colposcopy to detect CIN2+ lesions in women referred with BMD cytology is 82% and 44% respectively (p= 0.001) and in the NBMD group 77% and 64% respectively (p= 0.24). If the two techniques are combined the sensitivity is 85%.When the conditions of new screening strategies are applied DSI colposcopy has a higher sensitivity to detect CIN2+ than conventional colposcopy. Findings are similar when CIN3+ is used as a threshold. CONCLUSION. We found that in most cases DSI colposcopy has a higher sensitivity than conventional colposcopy, even when referral criteria are changed. Unlike conventional colposcopy, the sensitivity of colposcopy with DSI in low-grade cytology referrals was found similar to the sensitivity in high-grade cytology referrals. This suggests that a baseline colposcopy sensitivity may be possible with the adjunctive use of the DSI map, irrespective of referral cytology.

Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy.

Methylation markers were studied for their suitability to triage human papillomavirus (HPV)-positive women by testing self-collected cervico-vaginal lavage specimens. For this purpose, we analyzed 355 hrHPV-positive self-collected specimens with three methylation markers, that is, CADM1-m18, MAL-m1 and miR-124-2 by quantitative methylation-specific PCR. The areas under the receiver-operating characteristic (ROC) curve for end-point cervical intraepithelial neoplasia grade 3 or worse (CIN3+) were 0.637 for CADM1-m18, 0.767 for MAL-m1 and 0.762 for miR-124-2. This indicates that CADM1-m18 is not suitable as single marker. By varying the thresholds of both markers in the bi-marker panels CADM1-m18/MAL-m1, CADM1-m18/miR-124-2 and MAL-m1/miR-124-2 upper and lower ROC curves were obtained, depicting the maximum and minimum CIN3+ sensitivity, respectively, at given specificity. For all these bi-marker combinations, the upper curves were similar. However, for the MAL-m1/miR-124-2 panel, the distance between upper and lower ROC curves was closest and this panel displayed the highest assay thresholds, indicating that this combination was most robust. At clinical specificities of 50 and 70%, the MAL-m1/miR-124-2 sensitivity for detection of CIN3+ ranged from 77.0 to 87.8% and from 64.9 to 71.6%, respectively. At 70% specificity thresholds no carcinomas were missed. By comparison, the CIN3+ sensitivity of HPV16/18 genotyping on the self-sampled lavage specimens was 58.1% (95%CI: 46.6-68.8) at a specificity of 87.7% (95%CI: 83.2-91.2). In conclusion, methylation analysis is a promising triage tool that in combination with HPV-DNA testing offers feasible, full molecular screening on self-collected cervico-vaginal lavage specimens.

Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: cross-sectional and longitudinal outcome study.

BACKGROUND: Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing. METHODS: Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results. RESULTS: p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6%; P=0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1%; P=0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women. CONCLUSIONS: Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD.

Cervical cancer screening: on the way to a shift from cytology to full molecular screening.

Cytology-based nation-wide cervical screening has led to a substantial reduction of the incidence of cervical cancer in western countries. However, the sensitivity of cytology for the detection of high-grade precursor lesions or cervical cancer is limited; therefore, repeated testing is necessary to achieve program effectiveness. Additionally, adenocarcinomas and its precursors are often missed by cytology. Consequently, there is a need for a better screening test. The insight that infection with high-risk human papillomavirus (hrHPV) is the causal agent of cervical cancer and its precursors has led to the development of molecular tests for the detection of hrHPV. Strong evidence now supports the use of hrHPV testing in the prevention of cervical cancer. In this review, we will discuss the arguments in favor of, and concerns on aspects of implementation of hrHPV testing in primary cervical cancer screening, such as the age to start hrHPV-based screening, ways to increase screening attendance, requirements for candidate hrHPV tests to be used, and triage algorithms for screen-positive women.

Clinical evaluation of a GP5+/6+-based luminex assay having full high-risk human papillomavirus genotyping capability and an internal control.

The LMNX genotyping kit HPV GP (LMNX) is based on the clinically validated GP5+/6+ PCR, with a genotyping readout as an alternative for the more established enzyme immunoassay (EIA) detection of 14 targeted high-risk human papillomavirus (HPV) types. LMNX is additionally provided with an internal control probe. Here, we present an analysis of the clinical performance of the LMNX using a sample panel and infrastructure provided by the international VALGENT (Validation of Genotyping Tests) project. This panel consisted of cervical specimens from approximately 1,000 women attending routine screening, "enriched" with 300 women with abnormal cytology. Cases were defined as women classified with cervical intraepithelial neoplasia (CIN) grade 2+ (CIN2+) (n = 102) or CIN3+ (n = 55) within the previous 18 months. Controls were women who had normal cytology results over two subsequent screening rounds at a 3-year interval (n = 746). The GP5+/6+-PCR EIA (EIA) was used as a comparator assay and showed sensitivities of 94.1% and 98.2% for CIN2+ and CIN3+, respectively, with a clinical specificity of 92.4% among women aged ≥ 30 years. The LMNX demonstrated clinical sensitivities of 96.1% for CIN2+ and of 98.2% for CIN3+ and a clinical specificity of 92.6% for women aged ≥ 30 years. The LMNX and EIA were in high agreement (Cohen's kappa = 0.969) for the detection of 14 hrHPVs in aggregate, and no significant difference was observed (McNemar's P = 0.629). The LMNX internal control detected 0.6% inadequate specimens. Based on our study results, we consider the LMNX, similarly to the EIA, useful for HPV-based cervical cancer screening.

TP53 mutation and human papilloma virus status of oral squamous cell carcinomas in young adult patients.

OBJECTIVE: Little is known about the molecular carcinogenesis of oral squamous cell carcinoma (OSCC) in young adult patients. The aim of this study was to investigate the detailed TP53 mutation and human papilloma virus (HPV) status of OSCC in patients, younger than 45 years. METHODS: TP53 mutations were determined with direct sequencing on paraffin-embedded carcinoma tissue from 31 young patients and compared with two older age OSCC reference groups: one from the same institute (N = 87) and an independent one (N = 675). Biologically active tumour HPV was detected by p16-immunohistochemistry followed by a HPV-DNA GP5 + /6 + -PCR. RESULTS: HPV16 was present in one OSCC (3%). TP53 mutations were found in 14 (45%) OSCC: five were missense and nine resulted in a truncated protein. Six of these latter were insertions or deletions of one or more nucleotides leading to frameshift, one was at a splice site and two resulted in a stop codon. The percentage of truncating mutations (64% of all mutations) was higher than that observed in the institute's reference group (44%, P = 0.23) and in the independent reference group (24%, P = 0.002). CONCLUSIONS: This study shows that TP53 mutations are common in OSCC of young adult patients; infection with biologically active HPV is rare.

Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials.

BACKGROUND: The presence of human papillomavirus (HPV)-infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modeling. However, most risk models are based on clinical trials which only include a selected patient population. The clinical significance of HPV and other prognostic factors in patients with OPSCC remains to be evaluated in a large, unselected cohort, which also includes patients with stage I/II disease and patients with severe comorbidity. PATIENTS AND METHODS: All patients diagnosed with OPSCC in 2000-2006 in two Dutch university hospitals were included. The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-positive cases. Cox regression analysis was carried out to compare survival rates between HPV-positive and HPV-negative patients and a prognostic model was generated by recursive partitioning. RESULTS: In total, 163 of 841 (19.4%) tumors were HPV-positive. Patients with HPV-positive OPSCC had a more favorable overall survival [73.5% versus 40.9% after 5 years; P < 0.001; hazard ratio = 0.34, 95% confidence interval (CI) 0.25-0.48] compared with patients with HPV-negative OPSCC. Patients with p16-positive but HPV DNA-negative tumors showed a significantly less favorable survival than patients with p16-positive and HPV DNA-positive tumors (P < 0.001). A prognostic model was developed in which patients were classified into three risk groups according to HPV status, nodal stage and comorbidity. [Harrell's concordance index of 0.68 (95% CI 0.65-0.71)]. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with OPSCC. A prognostic risk model was proposed, based on our large, unselected cohort of patients with HPV status, comorbidity and nodal stage being the important prognostic factors. In addition, this study emphasizes the importance of performing an HPV DNA-specific test besides p16-immunostaining.

Clinical validation of the Abbott RealTime High Risk HPV assay according to the guidelines for human papillomavirus DNA test requirements for cervical screening.

This study showed that the Abbott RealTime High Risk HPV assay fulfilled cross-sectional clinical equivalence and reproducibility criteria of international consensus guidelines, which indicates that this assay can be considered clinically validated for cervical cancer screening purposes.

The Aptima HPV assay fulfills the cross-sectional clinical and reproducibility criteria of international guidelines for human papillomavirus test requirements for cervical screening.

The Aptima HPV assay (Hologic Gen-Probe, San Diego, CA) is an FDA-approved assay for detecting human papillomavirus (HPV) E6/E7 mRNA from 14 high-risk HPV types. This study evaluated the clinical performance of the Aptima HPV assay for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+), relative to the high-risk HPV GP5+/GP6+ PCR, in a cross-sectional clinical equivalence analysis using the noninferiority score test with cervical samples from population-based screening, i.e., 69 cervical scraping samples from women with CIN2+ and 843 from women without evidence of CIN2+. In addition, intralaboratory reproducibility over time and interlaboratory agreement of the Aptima HPV assay results were assessed with another set of 548 cervical samples. The Aptima HPV assay showed a clinical sensitivity for CIN2+ of 94.2% (95% confidence interval [CI], 85.5 to 97.8%) and a clinical specificity for CIN2+ of 94.5% (95% CI, 92.8 to 95.9%); by comparison, these figures were 97.1% (95% CI, 89.1 to 99.3%) (67/69 samples) and 93.6% (95% CI, 91.7 to 95.0%) (785/839 samples), respectively, for GP5+/GP6+ PCR. The clinical sensitivity and specificity of the Aptima HPV assay were noninferior to those of GP5+/GP6+ PCR (P = 0.039 and 0.00016, respectively). In addition, high reproducibility of the Aptima HPV assay, as reflected by the intralaboratory reproducibility over time of 96.0% (95% CI, 94.4 to 97.3%) (526/548 samples; kappa = 0.89) and interlaboratory agreement of 96.7% (95% CI, 95.4 to 98.1%) (531/548 samples; kappa = 0.91), was found. Altogether, these data show that the Aptima HPV assay meets the cross-sectional clinical and reproducibility criteria of the international guidelines for HPV test requirements for cervical screening. Longitudinal data are needed to ensure that the long-term negative predictive value of this mRNA assay is similar to those of validated HPV DNA tests.

The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q.

Triphalangeal thumb is a developmental anomaly, sometimes dominantly transmitted, characterized by a long, finger-like thumb with three phalanges instead of two. The underlying genetic defect is unknown, but presumably involves genes that regulate the differentiation of the developing forelimb. In two large kindreds with triphalangeal thumb, evidence for linkage to the long arm of chromosome 7 was obtained with a maximum lod score of 12.61. Multipoint linkage and haplotype analysis placed the gene close to the telomere of the long arm. To our knowledge this is the first time that a human gene involved solely in the pathologic morphogenesis of the hand and feet has been localized.

A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis.

Hereditary hemochromatosis (HH) is a very common disorder characterized by iron overload and multi-organ damage. Several genes involved in iron metabolism have been implicated in the pathology of HH (refs. 1-4). We report that a mutation in the gene encoding Solute Carrier family 11, member A3 (SLC11A3), also known as ferroportin, is associated with autosomal dominant hemochromatosis.

Long-term CIN3+ risk in women with abnormal cytology; role of hrHPV testing.

BACKGROUND: Many studies have examined the short-term value of high-risk human papillomavirus (hrHPV) testing in predicting cumulative risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). This study focuses on long-term CIN3+ risk after initial wait and see policy. METHODS: A total of 342 women with abnormal cytology of borderline/mild dyskaryosis (BMD) or worse (>BMD), included between 1990 and 1992, were followed-up by cytology and hrHPV testing until 1996 and monitored by cytology thereafter. Primary endpoint was cumulative CIN3+ risk by December 2009. RESULTS: Women with BMD had a 5-year CIN3+ risk of 22.5% (95% confidence interval (CI) 17.0-29.1) and of 0.7% (0.1-4.5) in the subsequent 5 years. High-risk human papillomavirus-negative women with BMD had a 5-year risk of <0.01% (95% CI 0.0-5.1) and of <0.01% (0.0-5.7) in the following 5 years, while for hrHPV-positive women these risks were 37.5% (29.0-46.9) and 1.6% (0.2-9.5), respectively. Women with >BMD had a 5-year risk of 45.1% (36.4-54.1) and of 3.5% (0.9-12.2) in the subsequent 5 years. High-risk human papillomavirus-negative women with >BMD had a 5-year risk of 7.3% (2.0-23.6) and hrHPV-positive women of 56.6% (46.4-66.3). CONCLUSION: Women with BMD have an elevated CIN3+ risk for 5 years only; afterwards their risk is similar to the general population. High-risk human papillomavirus-negative women with BMD may return to regular screening directly. All other women with BMD should be referred for additional testing and/or colposcopy.

Prevalence and determinants of human papillomavirus infection and cervical lesions in HIV-positive women in Kenya.

BACKGROUND: We assessed the association of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) with various characteristics, CD4 count and use of combination antiretroviral therapy (cART) among HIV-positive women. METHODS: Cross-sectional study of 498 HIV-positive women who underwent HPV PCR-based testing, cytology, and systematic cervical biopsy. RESULTS: In all, 68.7% of women were HPV-positive, 52.6% had high-risk (hr) HPV, and 40.2% multiple type infections. High-risk human papillomavirus-positivity did not vary significantly by age but it was negatively associated with education level. The most frequent types in 113 CIN2/3 were HPV16 (26.5%), HPV35 (19.5%), and HPV58 (12.4%). CD4 count was negatively associated with prevalence of hrHPV (P<0.001) and CIN2/3 among non-users of cART (P=0.013). Combination antiretroviral therapies users (≥2 year) had lower hrHPV prevalence (prevalence ratio (PR) vs non-users=0.77, 95% confidence interval (CI): 0.61-0.96) and multiple infections (PR=0.68, 95% CI: 0.53-0.88), but not fewer CIN2/3. The positive predictive value of hrHPV-positivity for CIN2/3 increased from 28.9% at age <35 years to 53.3% in ≥45 years. CONCLUSION: The burden of hrHPV and CIN2/3 was high and it was related to immunosuppression level. Combination antiretroviral therapies ( ≥2 year) use had a favourable effect on hrHPV prevalence but cART in our population may have been started too late to prevent CIN2/3.

HPV DNA testing in population-based cervical screening (VUSA-Screen study): results and implications.

BACKGROUND: Human papillomavirus (HPV) testing is more sensitive than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We evaluated the performance of high-risk HPV (hrHPV) testing in routine screening. METHODS: In all, 25,871 women (29-61) enrolled in our population-based cohort study were offered both cytology and hrHPV testing. High-risk HPV-positive women with normal cytology and an age-matched subcohort of hrHPV-negative women with normal cytology were invited for repeat testing after 1 and/or 2 years and were referred for colposcopy if they presented with abnormal cytology and/or a positive hrHPV test. The hrHPV-positive women with borderline or mild dyskaryosis (BMD) and all women with moderate dyskaryosis or worse (>BMD) were directly referred for colposcopy. Women with BMD and an hrHPV-negative test were advised to repeat cytology at 6 and 18 months and were referred for colposcopy if the repeat cytology test was abnormal. The main outcome measure was CIN grade 3 or worse (CIN3+). Results were adjusted for non-attendance at repeat testing. RESULTS: The hrHPV-positive women with abnormal cytology had a CIN3+ risk of 42.2% (95% confidence interval (CI): 36.4-48.2), whereas the hrHPV-positive women with normal cytology had a much lower risk of 5.22% (95% CI: 3.72-7.91). In hrHPV-positive women with normal cytology, an additional cytology step after 1 year reduced the CIN3+ risk to only 1.6% (95% CI: 0.6-4.9) if the repeat test was normal. The CIN3+ risk in women with hrHPV-positive normal cytology was higher among women invited for the first time (29-33 years of age) (9.1%; 95% CI: 5.6-14.3) than among older women (3.0%; 95% CI: 1.5-5.5). CONCLUSION: Primary hrHPV screening with cytology triage in women aged 30 years is an effective way to stratify women on CIN3+ risk and seems a feasible alternative to cytological screening. Repeat cytology after 1 year for hrHPV-positive women with normal cytology is however necessary before returning women to routine screening.