Changes in type‐specific human papillomavirus load predict progression to cervical cancer

Depuydt, Christophe; Criel, A.; Benoy, Ina; Arbyn, Marc; Vereecken, Annie; Bogers, Johannes

doi:10.1111/j.1582-4934.2012.01631.x

Cited by 53 publications

(94 citation statements)

References 33 publications

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“…In contrast to a slight decrease among women who did not develop CIN2-3 under observation, the viral loads were higher and tended to increase even further among women who had a diagnosis of CIN2-3 at the last positive visit. This agrees with previous reports on clinical outcomes with respect to changes in HPV16 DNA loads (6,14), suggesting that sustained higher viral loads may signal the progression of cervical lesions.…”

Section: Discussionsupporting

confidence: 82%

“…Most previous studies were limited by small sample sizes and a cross-sectional study design. To date, published data on longitudinal changes in HPV31 DNA loads, stratified according to whether there was a subsequent diagnosis of CIN2-3, are even more rare (14,15). The profile of changes in viral loads over time may help to distinguish infections that tend to resolve from those that lead to the development of cervical lesions.…”

mentioning

confidence: 99%

“…Data on oncogenic types other than HPV16 are much less common. Some reports suggest that the viral-load-related risk of CIN2-3 may be HPV type specific (12, 13); others show that differences in slopes (daily changes in viral loads) between transient infections and infections leading to CIN3 are constant across types (14,15). HPV31 is one of the oncogenic types and is phylogenetically closely related to HPV16 (16).…”

mentioning

confidence: 99%

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Association of Human Papillomavirus 31 DNA Load with Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3

et al. 2015

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eThe association between human papillomavirus 31 (HPV31) DNA loads and the risk of cervical intraepithelial neoplasia grades 2 and 3 (CIN2-3) was evaluated among women enrolled in the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS), who were monitored semiannually over 2 years and who had HPV31 infections detected at >1 visit. HPV31 DNA loads in the first HPV31-positive samples and in a random set of the last positive samples from women with >2 HPV31-positive visits were measured by a real-time PCR assay. CIN2-3 was histologically confirmed at the same time as the first detection of HPV31 for 88 (16.6%) of 530 women. After adjustment for HPV31 lineages, coinfection with other oncogenic types, and the timing of the first positive detection, the odds ratio (OR) per 1-log-unit increase in viral loads for the risk of a concurrent diagnosis of CIN2-3 was 1.5 (95% confidence interval [CI], 1.2 to 1.9). Of 373 women without CIN2-3 at the first positive visit who had >1 later visit, 44 had subsequent diagnoses of CIN2-3. The initial viral loads were associated with CIN2-3 diagnosed within 6 months after the first positive visit (adjusted OR, 1.5 [95% CI, 1.0 to 2.4]) but were unrelated to CIN2-3 diagnosed later. For a random set of 49 women who were tested for viral loads at the first and last positive visits, changes in viral loads were upward and downward among women with and without follow-up CIN2-3 diagnoses, respectively, although the difference was not statistically significant. Results suggest that HPV31 DNA load levels at the first positive visit signal a short-term but not long-term risk of CIN2-3. C ervical infection with oncogenic human papillomavirus (HPV) is a prerequisite for cervical cancer and its precursor lesions, which have typically been defined for clinical purposes as cervical intraepithelial neoplasia grades 2 and 3 (CIN2-3) (1). However, most infections are transient, with only a small proportion leading to the development of treatable cervical precancerous lesions (2, 3). It is still largely undetermined why, for a given type of HPV, some infections progress while others do not. The HPV DNA load, as measured in an exfoliated cervical scraping sample, reflects the number of free virions, the number of infected cells with either productive infection or clonal expansion, and the numbers of viral copies in individual cells. Whether HPV DNA load levels are associated with the risk of CIN2-3 deserves consideration.Studies of the clinical relevance of HPV DNA loads have focused mainly on HPV16 (4-8), the type that possesses the greatest oncogenic potential (9-11). Data on oncogenic types other than HPV16 are much less common. Some reports suggest that the viral-load-related risk of CIN2-3 may be HPV type specific (12, 13); others show that differences in slopes (daily changes in viral loads) between transient infections and infections leading to CIN3 are constant across types (14,15). HPV31 is one of the oncogenic typ...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Association of Human Papillomavirus 31 DNA Load with Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3

et al. 2015

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“…Furthermore, we encourage the use of primers targeting the E6 or E7 region and not L1, as L1-negative cancers have been described (27). And finally, we recommend the use of individual type-specific and normalized (for the number of cells) HPV tests which allow monitoring of individual patients over time (12). Such serial measurements without clinical threshold constraints (9,12,16), in comparison to a fixed single viral load threshold (24,25), could allow earlier detection of CIN2ϩ and improve clinical sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Clinical Validation of a Type-Specific Real-Time Quantitative Human Papillomavirus PCR against the Performance of Hybrid Capture 2 for the Purpose of Cervical Cancer Screening

Depuydt¹,

Benoy²,

Beert³

et al. 2012

J Clin Microbiol

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cTo be acceptable for use in cervical cancer screening, a new assay that detects DNA of high-risk human papillomavirus (hrHPV) types must demonstrate high reproducibility and performance not inferior to that of a clinically validated HPV test. In the present study, a real-time quantitative PCR (qPCR) assay targeting the E6 and E7 genes of hrHPV was compared with Hybrid Capture 2 (hc2) in a Belgian cervical cancer screening setting. In women >30 years old, the sensitivity and specificity for intraepithelial neoplasias of grade 2 or worse (93 cases of cervical intraepithelial neoplasias of grade 2 or worse (CIN2؉) and 1,207 cases of no CIN or CIN1) were 93.6% and 95.6%, respectively, and those of hc2 were 83.9% and 94.5%, respectively {relative sensitivity of qPCR/hc2 ‫؍‬ 1.12 [95% confidence interval (CI), 1.01 to 1.23]; relative specificity ‫؍‬ 1.01 [95% CI, 0.99 to 1.03]}. A score test showed that the sensitivity (P < 0.0001) and specificity (P < 0.0001) of the qPCR assay were not inferior to those of hc2 at the required thresholds of 90% and 98%, respectively. The overall agreement of hrHPV positivity between the two runs of the qPCR tests was 98.7% (95% CI, 97.5 to 99.4%), with a kappa value of 0.96 (95% CI, 0.83 to 1.00). The qPCR assay used in this study can be considered a reliable HPV assay that fulfills the clinical validation criteria defined for use in cervical cancer screening.

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“…It is generally estimated that it takes several years to decades from the time of an initial HPV infection until development of a high-grade lesion and eventually formation of a tumor (96,97). On average, a CIN 3ϩ lesion is 9.4 years only when detected (97).…”

Section: Cervical Cancermentioning

confidence: 99%

Human Papillomavirus Laboratory Testing: the Changing Paradigm

2016

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SUMMARYHigh-risk human papillomaviruses (HPVs) cause essentially all cervical cancers, most anal and oropharyngeal cancers, and some vaginal, vulvar, and penile cancers. Improved understanding of the pathogenesis of infection and the availability of newer tests are changing the approach to screening and diagnosis. Molecular tests to detect DNA from the most common high-risk HPVs are FDA approved for use in conjunction with cytology in cervical cancer screening programs. More-specific tests that detect RNA from high-risk HPV types are now also available. The use of molecular tests as the primary screening tests is being adopted in some areas. Genotyping to identify HPV16 and -18 has a recommended role in triaging patients for colposcopy who are high-risk HPV positive but have normal cytology. There are currently no recommended screening methods for anal, vulvar, vaginal, penile, or oropharyngeal HPV infections. HPV testing has limited utility in patients at high risk for anal cancer, but p16 immunohistochemistry is recommended to clarify lesions in tissue biopsy specimens that show moderate dysplasia or precancer mimics. HPV testing is recommended for oropharyngeal squamous cell tumors as a prognostic indicator. Ongoing research will help to improve the content of future guidelines for screening and diagnostic testing.

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Changes in type‐specific human papillomavirus load predict progression to cervical cancer

Cited by 53 publications

References 33 publications

Association of Human Papillomavirus 31 DNA Load with Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3

Association of Human Papillomavirus 31 DNA Load with Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3

Clinical Validation of a Type-Specific Real-Time Quantitative Human Papillomavirus PCR against the Performance of Hybrid Capture 2 for the Purpose of Cervical Cancer Screening

Human Papillomavirus Laboratory Testing: the Changing Paradigm

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