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1.  Prevalence of and Risk Factors for Oral Human Papillomavirus Among Young Women in Costa Rica 
The Journal of Infectious Diseases  2013;208(10):1643-1652.
Background. Little is known about the epidemiology of oral human papillomavirus (HPV) in Latin America.
Methods. Women (N = 5838) aged 22–29 in the control and vaccine arms of an HPV-16/18 vaccine trial in Costa Rica had oral, cervical, and anal specimens collected. Samples were tested for alpha mucosal HPV types (SPF10/LiPA25 version 1); a subset of oral samples (n = 500) was tested for cutaneous HPV types in the genera alpha, beta, gamma, mu, and nu.
Results. In the control arm (n = 2926), 1.9% of women had an oral alpha mucosal HPV detected, 1.3% had carcinogenic HPV, and 0.4% had HPV-16; similar patterns for non-16/18 HPV types were observed in the vaccine arm. Independent risk factors for any oral alpha mucosal HPV among women in the control arm included marital status (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.8–5.7 for single compared to married/living as married), number of sexual partners (AOR, 2.4; 95% CI, 1.0–6.1 for ≥4 partners compared to 0–1 partners), chronic sinusitis (AOR, 3.1; 95% CI, 1.5–6.7), and cervical HPV infection (AOR, 2.6; 95% CI, 1.4–4.6). Detection of beta HPV was common (18.6%) and not associated with sexual activity.
Conclusions. Unlike cutaneous HPV types, alpha mucosal HPV types were uncommon in the oral region and were predominately associated with sexual behavior.
Clinical Trials Registration. NCT00128661.
PMCID: PMC3805238  PMID: 24014882
human papillomavirus vaccine; HPV; oropharynx cancer; Costa Rica; Guanacaste; oral HPV DNA
2.  Evaluation of a multiplex panel of immune-related markers in cervical secretions: a methodologic study 
While persistent carcinogenic human papillomvirus (HPV) infection is necessary for cervical carcinogenesis, the co-factors involved in HPV persistence and disease progression are poorly understood. Chronic cervical inflammation may increase risk, but few studies have measured immune markers (cytokines/chemokines/soluble receptors) in cervical secretions. We evaluated the performance of 74 multiplexed, bead-based immune markers in cervical secretions from three groups of women with biopsy evaluation of cervical intraepithelial neoplasia (CIN): 1) 25% detectability and >80% interclass correlation coefficients (ICC) acceptable for epidemiologic studies. Within-batch coefficients of variation (CV) of ≥25% indicated room for assay improvement. Secondarily, we explored associations between marker levels and CIN/HPV status adjusted for matching variables, assay batch, age, and number of sexual partners. Sixty-two markers (84%) had >25% detectability and ICCs>80%. Of those, 53 (85%) had CVs<25%. Using these preliminary data, we found that HPV-positivity was associated with increased eotaxin-1 (OR: 15.63, 95% CI: 1.26–200.00) and G-CSF (OR: 12.99, 95% CI: 1.10–142.86) among CIN-negative women. There was suggestive evidence that higher chemoattractant marker levels were associated with CIN2/3 (e.g., MIP-1delta, OR: 4.48, 95% CI: 0.87–23.04 versus
PMCID: PMC3872247  PMID: 23824624
Vaccine  2013;31(0 8):I1-31.
Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread—optimally universal—implementation of HPV prevention strategies in both developed and developing countries.
This article summarizes information from the chapters presented in a special ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.
PMCID: PMC4062073  PMID: 24229716
HPV; Cervical cancer; Anal cancer; Penile cancer; Vaginal cancer; Vulvar cancer; Oropharyngeal cancer; Screening; HPV vaccination; HPV testing; Prevention
Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well-understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study (ALTS) provided blood samples at trial enrollment for serological testing. A Luminex assay based on GST-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52, 58). We analyzed the relationship between seroprevalence in women free of precancer (N=2464) and HPV DNA status, age, sexual behavior, and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and ~ 20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR= 1.36, 95%CI: 1.04–1.79) and HPV18 (OR= 2.31, 95%CI: 1.61–3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants’ HPV serostatus.
PMCID: PMC4238230  PMID: 23588935
Human papillomavirus; seroepidemiology; antibodies
Sexually transmitted diseases  2009;36(11):675-679.
PMCID: PMC4237610  PMID: 19773679
Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. HPV DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches.
Experimental Design
Liquid based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were performed from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with an LSIL Pap.
p16/Ki-67-positivity increased with histological severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2, to 92.8% in CIN3. Among women with CIN3, p16/Ki-67-positivity increased from 77.8% for women <30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with HR-HPV-positive ASC-US and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively.
p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared to HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies.
PMCID: PMC4237612  PMID: 22675168
cervical cancer screening; p16; p16/Ki67; HPV; colposcopy
Human pathology  2013;44(11):10.1016/j.humpath.2013.06.015.
Whole slide imaging (WSI) is increasingly used for primary and consultative diagnoses, teaching, telepathology, slide sharing and archiving. We compared pathologist evaluations of glass slides and corresponding digitized images within the context of a statewide surveillance effort. Cervical specimens collected by the New Mexico HPV Pap Registry (NMHPVPR) research program targeted cases diagnosed between 2006–2010. Two samples of 250 slides each were digitized with the ScanScope XT (Aperio, Vista, California) microscope and reviewed with Aperio ImageScope reader. (1) A “random set” had a distribution of community diagnoses: 70% from cases of cervical intraepithelial neoplasia grade 2 (CIN2) or higher, 20% from cases of CIN grade 1 (CIN1) and 10% from negative cases. (2) A “discrepant set” was represented by difficult cases where two study pathologists initially disagreed. Within the regular workflow of the NMHPVPR, 3 pathologists read the slides 2–3 times each without knowledge of clinical history, previous readings or sampling scheme. Pathologists also read each corresponding image twice. For within- and between-reader comparisons we calculated unweighted Kappa statistics and asymmetry Chi-square tests. Across all comparisons, slides and images yielded similar results. For the random set, almost all within-reader and between-reader Kappa values ranged between 0.7–0.8 and 0.6–0.7, respectively. For the discrepant set, most within- and between-reader Kappa values were 0.4–0.6. As CIN diagnostic terminology changes, pathologists may need to re-read histopathology slides to compare disease trends over time, e.g., before/after introduction of human papillomavirus (HPV) vaccination. Diagnosis of CIN differed little between slides and corresponding digitized images.
PMCID: PMC3852412  PMID: 24075599
Cervical intraepithelial neoplasia; whole slide imaging; clinical pathology; reliability; registries
Patients with Fanconi anemia (FA) and dyskeratosis congenita (DC) are at high risk of head and neck and anogenital squamous cell carcinomas (SCC). In the general population, these sites (particularly oropharyngeal SCC) may be associated with infection with human papillomavirus (HPV). In FA and DC, however, the majority of HNSCC occur in the oral cavity. We investigated the HPV status of HNSCC and vulvar SCC from 9 patients with FA and 4 with DC using a very sensitive PCR assay, and found HPV16 DNA in only a single vulvar tumor from one FA patient, and in none of the HNSCC. These results suggest that HPV may not be the cause of SCC in patients with FA or DC, and that vaccination may not reduce the incidence of HNSCC in these patients.
PMCID: PMC3707947  PMID: 23558727
Fanconi anemia; dyskeratosis congenita; squamous cell carcinoma; human papillomavirus
Gynecologic oncology  2013;130(3):10.1016/j.ygyno.2013.06.005.
Chromosomal gains at 3q26, 5p15 and 20q13 have been described in cervical precancer and cancer. We evaluated a novel fluorescence in situ hybridization (FISH) assay that detects gains at these three loci simultaneously as a possible biomarker for detecting cervical precancer.
Chromosomal copy numbers at 3q26 (3q), 5p15 (5p), 20q13 (20q) and the centromere of chromosome7 (cen7) in liquid-based cytology specimens from 168 women enrolled in the Biopsy Study were determined by FISH. The number of cells with ≥3 or ≥4 signals for a genomic locus was enumerated and diagnostic test performance measures were calculated using receiver operating characteristic (ROC) analyses. Sensitivity and specificity values were determined for the detection of CIN2+ and/or HSIL.
The median number of cells with ≥3 signals increased with the severity of cervical lesion for each genomic locus (p-trend<0.02 for each locus). ROC analysis for the number of cells with ≥3 signals resulted in area under the curve values of 0.70 (95% CI: 0.54-0.86), 0.67 (0.52-0.83), 0.67 (0.51-0.83) and 0.78 (0.64-0.92) for 3q, 5p, 20q and cen7, respectively, for the detection of CIN2+ and/or HSIL. Positivity for gains at multiple loci resulted in only slightly better test performance measures than those for the individual probes for four distinct combinations of probes.
Chromosomal gains at 3q, 5p, 20q and cen7 are associated with severity of cervical lesions. Further studies are required to quantify risk stratification of FISH assays for cervical cancer screening.
PMCID: PMC3833871  PMID: 23769811
cervical cancer; genomic gains; 3q; FISH; HPV
American Journal of Epidemiology  2013;178(5):752-760.
The impact of human papillomavirus (HPV) vaccination on cervical screening, colposcopy, and treatment is incompletely understood. In 2004–2005, investigators in the Costa Rica Vaccine Trial randomized 7,466 women aged 18–25 years, 1:1, to receive HPV vaccination or hepatitis A vaccination. The worst-ever cytology diagnosis and the 4-year cumulative proportions of colposcopy referral and treatment by vaccination arm were compared for 2 cohorts. The total vaccinated cohort included 6,844 women who provided cervical samples. The naive cohort included 2,284 women with no evidence of previous HPV exposure. In the total vaccinated cohort, HPV-vaccinated women had a significant (P = 0.01) reduction in cytological abnormalities: 12.4% for high-grade lesions and 5.9% for minor lesions. Colposcopy referral was reduced by 7.9% (P = 0.03) and treatment by 11.3% (P = 0.24). Greater relative reductions in abnormal cytology (P < 0.001) were observed for HPV-vaccinated women in the naive cohort: 49.2% for high-grade lesions and 18.1% for minor lesions. Colposcopy referral and treatment were reduced by 21.3% (P = 0.01) and 45.6% (P = 0.08), respectively, in the naive cohort. The overall impact on health services will be modest in the first years after vaccine introduction among young adult women, even in regions with high coverage.
PMCID: PMC3755646  PMID: 23843026
cervical cancer; HPV; HPV vaccination; human papillomavirus; screening
To inform the proposed systematic adjudicative staining of cervical intraepithelial neoplasia grade 2 (CIN2) and equivocal diagnoses, we characterized diagnostic heterogeneity across 15 laboratories. Laboratory-specific distributions of 37,486 biopsy specimen diagnoses were compared after adjusting for preceding cytology. In a subset of preceding cytology specimens, HPV16 genotyping was considered an indicator of lesion severity. Distributions of normal and CIN1 diagnoses varied widely, with laboratories favoring either normal (5.5%–57.7%) or CIN1 diagnoses (23.3%–86.7%; P < .001 for normal:CIN1 variability). Excluding extreme values, 6.2% to 14.4% of diagnoses were CIN2 (P < .001). For CIN2 diagnoses, HPV16 positivity in the preceding cytology varied between 39.0% in the largest laboratory and 57.4% in others (P < .001), suggesting differential interpretation, not population differences, as a cause of variability. In conclusion, the frequency of diagnoses requiring special staining (p16INK4a immunostaining) to adjudicate equivocal CIN2 will be sizable and vary between laboratories, especially if extended to a fraction of CIN1 lesions.
PMCID: PMC4125616  PMID: 23429369
Cervical intraepithelial neoplasia; Histopathology; Reproducibility
Journal of Clinical Microbiology  2014;52(1):187-192.
While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance.
PMCID: PMC3911475  PMID: 24197879
Human Vaccines & Immunotherapeutics  2013;9(7):1399-1406.
Background: We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies (VE) observed from randomized clinical trials of the HPV16/18 bivalent vaccine.
Results: HPV31 cases had lower HPV16 antibody levels than controls (OR4th quartile compared with 1st quartile = 0.63; 95%CI: 0.36–1.08; p-trend = 0.03). HPV31 cases were also less likely to have detectable HPV31 neutralization, and HPV16 avidity than controls. No statistically significant differences by HPV18 antibody or HPV45 neutralization were observed among HPV45 cases and controls. Protection against HPV58 was not associated with any of the markers, confirming the specificity of our findings.
Methods: Samples are from three-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial. Women with a new HPV31, HPV45, or HPV58 infections over four years of follow-up were compared with randomly selected control women—with no new infection with HPV31/45/58—with respect to HPV16 and HPV18 antibody, HPV31, HPV45, and HPV58 neutralization, and HPV16 avidity.
Conclusions: High HPV16 levels and avidity, and the ability to neutralize HPV31 were associated with protection against newly detected HPV31 infections, suggesting that the partial VE demonstrated for HPV31 is likely to be mediated at least in part through antibodies induced by HPV16/18 vaccination.
PMCID: PMC3974884  PMID: 23571174
HPV vaccine; humoral; immune response; cross-protection; mechanisms for protection
Studies suggest that testing for individual HPV genotypes can improve risk stratification in women with minor cytological abnormalities. We evaluated genotyping for HPV16, HPV16/18, and HPV16/18/45 in carcinogenic HPV-positive women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology.
For women enrolled in the ASCUS-LSIL Triage Study (ALTS), we calculated the age-stratified (<30 and 30+ years) positivity, and cumulative risk over two years of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) when testing positive or negative for three genotype combinations: HPV16, HPV16/18, and HPV16/18/45.
Among women with ASCUS cytology, HPV16 positivity was 17.1% and increased to 22.0% (P<.001) for HPV16/18 and 25.6% (P<.001) for HPV16/18/45. Among women with LSIL cytology, HPV16 positivity was 21.1% and increased to 30.0% (P<.001) for HPV16/18 and 34.0% (P=.017) for HPV16/18/45. Regardless of cytology and age group, the greatest risk difference between test-positives and test-negatives was observed for HPV16 with decreasing risk stratification for HPV16/18 and HPV16/18/45. However, testing negative for any of the three combinations while being positive for another carcinogenic type still implied a 2-year risk of CIN3+ of 7.8% or greater.
Although genotyping for HPV16, 18, and 45 provided additional risk stratification in carcinogenic HPV-positive women with minor cytological abnormalities, the risk among genotype-negative women was still high enough to warrant immediate colposcopy referral.
HPV genotyping in HPV-positive women with minor cytological abnormalities will likely not alter clinical management. Adding HPV45 to genotyping assays is not warranted.
PMCID: PMC3687215  PMID: 23603204
HPV testing; cervical intraepithelial neoplasia; cervical cytology; risk stratification
Journal of lower genital tract disease  2013;17(5 0 1):S78-S84.
After excisional treatment, CIN2+ can recur. It is not clear how many negative post-treatment Pap or cotest results are needed to assure adequate safety against CIN2+, prior to return to extended retesting intervals.
We observed 5-year risks of CIN2+, and outcomes for 3 follow-up management strategies after treatment (Pap alone, HPV alone, and cotesting) for 3273 women aged 25 and older who were treated for CIN2, CIN3, or AIS between 2003–2010 at Kaiser Permanente Northern California.
Five-year risks of recurrent CIN2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN2 preceded by HPV-positive/ASC-US or LSIL to 16% for CIN3/AIS preceded by AGC/ASC-H/HSIL+ (p<0.0001). However, after post-treatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN2+ risk associated with a negative post-treatment cotest (2.4%) was lower than that of an HPV-negative test alone (3.7%, p=0.3) or Pap-negative result alone (4.2%, p=0.1). Two negative post-treatment tests of each kind conferred slightly lower 5-year CIN2+ risk than one (Pap-negative: 2.7% vs. 4.2%, p=0.2; HPV-negative: 2.7% vs. 3.7%, p=0.7; HPV-negative/Pap-negative: 1.5% vs. 2.4%, p=0.8). The 5-year CIN2+ risk associated with 2 negative cotests of 1.5% (95%CI 0.3% to 7.2%) approached the 0.68% risk associated with a negative Pap test during routine screening.
Women with antecedent AGC/ASC-H/HSIL+ Pap results or those treated with CIN3/AIS had a substantial risk of developing CIN2+ after treatment. Based on the principle of “benchmarking to implicit risk thresholds”, after negative test results following treatment, no subgroup of women achieved risk sufficiently low risk to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN2+ than either negative Pap tests or HPV tests alone.
PMCID: PMC3616418  PMID: 23519309
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelialneoplasia (CIN); Hybrid Capture 2 (HC2); post-treatment; test of cure
Journal of lower genital tract disease  2013;17(5 0 1):S28-S35.
In 2012, the United States Preventive Services Task Force (USPSTF) and a consensus of 25 organizations endorsed concurrent cytology and HPV testing (“cotesting”) for cervical cancer screening. Past screening and management guidelines were implicitly based on risks defined by Pap-alone, without consideration of HPV test results. To promote management that is consistent with accepted practice, new guidelines incorporating cotesting should aim to achieve equal management of women at equal risk of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+).
We estimated cumulative 5-year risks of CIN3+ for 965,360 women aged 30–64 undergoing cotesting at Kaiser Permanente Northern California 2003–2010. We calculated the implicit risk thresholds for Pap-alone and applied them for new management guidance on HPV and Pap cotesting, citing 2 examples: HPV-positive/ASC-US and HPV-negative/Pap-negative. We call this guidance process “benchmarking”.
LSIL, for which immediate colposcopy is prescribed, carries 5-year CIN3+ risk of 5.2%, suggesting that test results with similar risks should be managed with colposcopy. Similarly, ASC-US (2.6% risk) is managed with 6–12 month follow-up and Pap-negative (0.26% risk) is managed with 3-year follow-up. The 5-year CIN3+ risk for women with HPV-positive/ASC-US was 6.8% (95%CI 6.2% to 7.6%). This is greater than the 5.2% risk implicitly leading to referral to colposcopy, consistent with current management recommendations that HPV-positive/ASC-US should be referred for immediate colposcopy. The 5-year CIN3+ risk for women with HPV-negative/Pap-negative was 0.08% (95%CI 0.07% to 0.09%), far below the 0.26% implicitly required for a 3-year return and justifying a longer (e.g., 5-year) return.
Using the principle of “equal management of equal risks,” benchmarking to implicit risk thresholds based on Pap-alone can be used to achieve safe and consistent incorporation of cotesting.
PMCID: PMC3616419  PMID: 23519302
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2)
Journal of lower genital tract disease  2013;17(5 0 1):S56-S63.
Current US guidelines for cotesting recommend that the large numbers of women who test Pap-negative, but HPV-positive, return in 1 year, and those who remain HPV-positive or have LSIL (or worse) Pap be referred for colposcopy. However, the performance of these guidelines in routine clinical practice has not been evaluated.
We estimated cumulative 5-year risks of CIN3+ for 32,374 women aged 30–64 with HPV-positive/Pap-negative cotest results at Kaiser Permanente Northern California during 2003–2010.
The 5-year CIN3+ risk following an HPV-positive/Pap-negative cotest result, which was found in 3.6% of women, was 4.5% (95%CI 4.2%–4.8%). The 5-year cancer risk was 0.34% (95%CI 0.26% to 0.45%) and half of the cases were adenocarcinoma. Overall, 47% of the women remained HPV-positive upon return (median 415 days after baseline), a percentage that varied little over ages 30–64. At the return following a baseline HPV-positive/Pap-negative result, almost every repeat cotest result predicted greater subsequent 5-year CIN3+ risk than the same cotest result had at baseline (HPV-positive/LSIL: 9.2% vs. 6.1%, p=0.01; HPV-positive/ASC-US: 7.9% vs. 6.8%, p=0.2; HPV-positive/Pap-negative: 7.4% vs. 4.5%, p<0.0001; HPV-negative/LSIL: 1.7% vs. 2.0%, p=0.8; HPV-negative/ASC-US: 2.9% vs. 0.43%, p=0.0005; HPV-negative/Pap-negative: 0.93% vs. 0.08%, p<0.0001).
Using the principle of “equal management of equal risks”, HPV-positive/Pap-negative women had subsequent CIN3+ risk consistent with risk thresholds for a 1-year return. However, upon returning in approximately 1 year, about one-half of women will be referred for colposcopy due to continued HPV positivity or Pap abnormality. Clinicians should keep in mind that cotest results at the return following a baseline HPV-positive/Pap-negative finding are riskier than the same baseline cotest results in the general population, supporting intensified clinical management of return cotests.
PMCID: PMC3616446  PMID: 23519306
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); prospective cohort
Journal of lower genital tract disease  2013;17(5 0 1):S50-S55.
High-grade Pap results (e.g., AGC, ASC-H, and HSIL) predict high cancer risks, resulting in referral to colposcopy without HPV triage. However, new guidelines recommending cotesting for women 30 and older imply that clinicians will often receive the HPV test result concurrently for high-grade Pap results. We examined whether HPV testing provides useful risk stratification in this context.
From a cohort of 965,360 women age 30–64 undergoing cotesting at Kaiser Permanente Northern California, we estimated 5-year risks of cervical cancer and CIN3+ for AGC (2,074 women), ASC-H (1,647 women), and HSIL (2,019 women) according to HPV test results.
HPV positivity of AGC Pap results was 25% and decreased with age (30–34: 44% vs. 60–64: 17%, p<0.0001), while HPV-positivity of ASC-H and HSIL were much higher (71% and 94% respectively) and decreased less with age. Even for these high-grade Pap results, 5-year CIN3+ risks differed substantially between HPV-positive and HPV-negative women (AGC: 33% vs. 0.93%, p<0.0001; ASC-H: 25% vs. 3.5%, p<0.0001; HSIL: 49% vs. 30%, p=0.006). However, except for AGC, cervical cancer risks differed less between HPV-positive and HPV-negative women (AGC: 9.0% vs. 0.37%, p<0.0001; ASC-H: 2.5% vs. 2.1%, p=0.8; HSIL: 6.6% vs. 6.8%, p=0.7).
The risks of CIN3+ for HPV-negative high-grade Pap results were lower than for HPV-positive high-grade Pap results, especially for AGC. However, by the principle of “equal management of equal risks”, all HPV-negative high-grade Pap results had cancer risks high enough to warrant colposcopy, confirming that there is no current role for HPV triage of high-grade Pap results.
PMCID: PMC3616447  PMID: 23519305
Human Papillomavirus (HPV); cancer prevention; baseline; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); screening guidelines; HSIL; AGC; ASC-H
Journal of lower genital tract disease  2013;17(5 0 1):S64-S68.
Current US national guidelines recommend beginning screening at age 21 using Pap tests only, with cotesting starting at age 30. To inform the management of Pap test abnormalities among women aged 21–24, who have extremely low cancer risks, we compared risks of CIN3+ for women aged 21–24 versus 25–29 or 30–64.
We estimated 5-year risks of CIN3+ for Pap test results, with HPV triage of ASC-US, for 133,947 women aged 21–24, compared with 135,382 women age 25–29 and 965,360 women age 30–64, between 2003–2010 at Kaiser Permanente Northern California.
There were 3 cancers diagnosed during follow-up in women aged 21–24. Following high-grade Pap results (0.6% of Pap results), 5-year CIN3+ risks for women aged 21–24 were comparable to those aged 25–29 and 30–64 (AGC: 6.9% vs. 14% vs. 8.5%, p=0.8; ASC-H: 16% vs. 24% vs. 18%, p=0.8; HSIL: 28% vs. 28% vs. 47%, p=0.4). Following LSIL, 5-year CIN3+ risk was lower for ages 21–24 (3.0%) than ages 25–29 (5.0%, p=0.01) or ages 30–64 (5.2%, p=0.0002). Although 5-year CIN3+ risk for HPV-negative/ASC-US was similar across all 3 groups (0.57% vs. 0.59% vs. 0.43%, p=1), risk for HPV-positive/ASC-US was lower for age 21–24 (4.4%) than 25–29 (7.1%, p<0.0001) or 30–64 (6.8%, p<0.0001).
Women aged 21–24 had almost zero cancer risk, and positive Pap test results predicted low CIN3+ risk except for the 0.6% of Pap results that were high-grade. The generally low risk supports conservative management of women aged 21–24.
PMCID: PMC3616448  PMID: 23519307
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); young women
Journal of lower genital tract disease  2013;17(5 0 1):S69-S77.
The majority of women referred for colposcopy are not diagnosed with CIN2+ but, nonetheless, are typically asked to return much sooner than their next routine screening interval in 3-5 years. An important question is how many subsequent negative Pap results, or negative Pap and HPV cotest results, are needed prior to returning to an extended retesting interval.
We estimated 5-year risks of CIN2+ for 3 follow-up management strategies after colposcopy (Pap-alone, HPV-alone and cotesting) for 20,319 women aged 25 and older screened from 2003-2010 at Kaiser Permanente Northern California who were referred for colposcopy but for whom CIN2+ was not initially diagnosed (i.e., “Women with CIN1/negative colposcopy”).
Screening results immediately antecedent to CIN1/negative colposcopy influenced subsequent 5-year CIN2+ risk: women with an antecedent HPV-positive/ASC-US or LSIL Pap had a lower risk (10%) than those with antecedent ASC-H (16%, p<0.0001) or HSIL+ (24%, p<0.0001). For women with an antecedent HPV-positive/ASC-US or LSIL, a single negative cotest approximately 1 year post-colposcopy predicted lower subsequent 5-year risk of CIN2+ (1.1%) than 2 sequential negative HPV tests (1.8%, p=0.3) or 2 sequential negative Pap results (4.0%, p<0.0001). For those with an antecedent ASC-H or HSIL+ Pap, 1 negative cotest after 1 year predicted lower subsequent 5-year risk of CIN2+ (2.2%) than 1 negative HPV test (4.4%, p=0.4) or 1 negative Pap (7.0%, p=0.06); insufficient data existed to calculate risk after sequential negative cotests for women with high grade antecedent cytology.
After CIN1/negative colposcopy followed by negative post-colposcopy tests, women did not achieve sufficiently low CIN2+ risk to return to 5-year routine screening. For women with antecedent HPV-positive/ASC-US or LSIL, a single negative post-colposcopy cotest reduced risk to a level consistent with a 3-year return. For women with antecedent ASC-H or HSIL+, no single negative test result sufficed to reduce risk to a level consistent with a 3-year return.
For women with CIN1/negative colposcopy and antecedent HPV-positive/ASC-US or LSIL, a single negative post-colposcopy cotest reduced risk to a level consistent with a 3-year return.
PMCID: PMC3616505  PMID: 23519308
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); colposcopy
Journal of lower genital tract disease  2013;17(5 0 1):S36-S42.
New screening guidelines recommend that HPV-negative/ASC-US results be considered as equivalent to HPV-negative/Pap-negative results, leading to rescreening in 5 years. However, despite ample research data, the routine clinical performance of HPV testing of women with ASC-US has not been adequately documented.
We estimated 5-year risks of CIN3+ and cancer for 2 groups between 2003-2010 at Kaiser Permanente Northern California: 27,050 women aged 30-64 who underwent HPV and Pap cotesting and had an ASC-US Pap result, and 12,209 women aged 25-29 who underwent HPV triage of ASC-US.
Five-year risks of CIN3+ and of cancer for women aged 30-64 testing HPV-negative/ASC-US and for 923,152 women testing Pap-negative alone were similar although statistically distinguishable (CIN3+: 0.43% vs. 0.26% (p=0.001); Cancer: 0.050% vs. 0.025% (p=0.1, respectively)). The cancer risk increase for HPV-negative/ASC-US versus Pap-negative alone was confined to women aged 60-64 (0.26% vs. 0.035%, p=0.3). Five-year risks of CIN3+ and of cancer for women with HPV-negative/ASC-US were substantially higher than those for women testing HPV-negative/Pap-negative (CIN3+: 0.43% vs. 0.08% (p<0.0001); Cancer: 0.050% vs. 0.011% (p=0.003, respectively)). For women aged 30-64 testing HPV-positive/ASC-US, 5-year risks of CIN3+ and cancer were slightly higher than for the 9,374 women with LSIL (CIN3+: 6.8 % vs. 5.2% (p=0.0007); Cancer: 0.41% vs. 0.16% (p=0.04)). Similar patterns were seen for women aged 25-29.
Women with HPV-negative/ASC-US had similar risk as women testing Pap-negative alone, but had higher risk than women testing HPV-negative/Pap-negative. Based on the principle of “equal management of equal risks”, our findings support equal management of women with HPV-negative/ASC-US and those with Pap-negative alone, except for exiting women from screening because cancer risks at ages 60-64 may be higher for HPV-negative/ASC-US. Our findings also support managing HPV-positive/ASC-US and LSIL similarly.
Women testing HPV-negative/ASC-US have similar risk of CIN3+ or cancer as women testing Pap-negative alone, but have higher risk than women testing HPV-negative/Pap-negative.
PMCID: PMC3616508  PMID: 23519303
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); ASC-US
Journal of lower genital tract disease  2013;17(5 0 1):S43-S49.
LSIL Pap results do not typically lead to HPV testing. HPV triage is not cost-effective because most cases are HPV-positive. However, under new national guidelines recommending cotesting for women ages 30–64, clinicians will increasingly receive the HPV test result for LSIL Pap results. Some authors have suggested that HPV triage might be effective at older ages, when the percentage of HPV positivity among women with LSIL declines.
We estimated 5-year risks of CIN2+ and CIN3+ for 9,033 women aged 30–64 who had both an HPV test and an LSIL Pap result.
HPV-positivity of LSIL decreased only slightly with age (30–34: 88% vs. 60–64: 72%, p<0.0001). The 5-year risks of CIN2+ and CIN3+ for women aged 30–64 testing HPV-positive/LSIL were larger than those for women testing HPV-negative/LSIL (CIN2+: 19% vs. 5.1%, p<0.0001; CIN3+: 6.1% vs. 2.0%, p<0.0001). The 5-year CIN3+ risk in HPV-negative/LSIL women was similar to that for women with ASC-US Pap without knowledge of HPV test results (2.0% vs. 2.6%, p=0.4).
HPV-negative/LSIL posed lower risk than other Pap results that guidelines currently recommend for referral to immediate colposcopy. By the principle of “equal management of equal risks,” women with HPV-negative/LSIL might reasonably be managed similarly to those with ASC-US Pap results without knowledge of HPV testing, i.e., re-testing at 6–12 months, rather than immediate colposcopy. Although the HPV test result for LSIL Pap results provides actionable information to clinicians who screen with cotesting, the high HPV-positivity of LSIL at even the oldest ages suggests the lack of cost-effectiveness of HPV triage of LSIL for clinicians who do not use routine cotesting.
PMCID: PMC3637971  PMID: 23519304
Human Papillomavirus (HPV); cancer prevention; cytology; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); LSIL
This short review outlines our understanding of cervical cancer precursors, concentrating on the central etiologic role of persistent human papillomavirus (HPV) infection. The stages of cervical carcinogenesis are better understood than for most other major cancers, providing a successful cancer etiology and prevention model.
PMCID: PMC3711590  PMID: 23549399
Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (≥CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of ∼2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent ≥CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR = 19.2, 95% CI = 4.4–83.2) and single non-16 carcinogenic infections (OR = 9.2, 95% CI = 2.1–39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR = 27.2, 95% = 3.5-213.5) had a strong association between high viral load and incident ≥CIN2; non-16 carcinogenic high viral load was not associated with incident ≥CIN2 (OR = 0.7, 95% CI = 0.2–1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident ≥CIN2 (OR = 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent ≥CIN2; however HPV16 was uniquely associated with incident ≥CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident ≥CIN2.
PMCID: PMC3962984  PMID: 17722112
human papillomavirus; viral load; genotype; screening

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