Reproductive factors, oral contraceptive use, and human papillomavirus infection: pooled analysis of the IARC HPV prevalence surveys.

High parity, early age at first full-term pregnancy (FTP), and long-term oral contraceptive (OC) use increase cervical cancer risk, but it is unclear whether these variables are also associated with increased risk of acquisition and persistence of human papillomavirus (HPV) infection, the main cause of cervical cancer. Information on reproductive and menstrual characteristics and OC use were collected from 14 areas worldwide, among population-based, age-stratified random samples of women aged 15 years or older. HPV testing was done using PCR-based enzyme immunoassay. Unconditional logistic regression was used to estimate the odds ratios (OR) of being HPV-positive according to reproductive and menstrual factors and corresponding 95% confidence intervals (CI). When more than two groups were compared, floating CIs (FCI) were estimated. A total of 15,145 women (mean age, 40.9 years) were analyzed. Women with >or=5 FTPs (OR, 0.90; 95% FCI, 0.76-1.06) showed a similar risk of being HPV-positive compared with women with only one FTP (OR, 1.00; 95% FCI, 0.86-1.16). However, nulliparous women showed an OR of 1.40 (95% CI, 1.16-1.69) compared with parous women. Early age at first FTP was not significantly related to HPV positivity. HPV positivity was similar for women who reported >or=10 years of use of OCs (OR, 1.16; 95% FCI, 0.85-1.58) and never users of OCs (OR, 1.00; 95% FCI, 0.90-1.12). Our study suggests, therefore, that high parity, early age at first FTP, and long-term OC use are not associated with HPV prevalence, but rather these factors might be involved in the transition from HPV infection to neoplastic cervical lesions.     

Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study

To determine whether Chlamydia trachomatis infection is consistently associated with an increased risk of invasive cervical carcinoma (ICC) after accounting for the strong effect of human papillomavirus (HPV) infection, a case-control study of 1,238 cases of ICC and 1,100 control women from 7 countries was carried out (hospital-based studies in Thailand, the Philippines, Morocco, Peru, Brazil and population-based studies in Colombia and Spain, all coordinated by the International Agency for Research on Cancer, Lyon, France). C. trachomatis serum antibody detection was made by means of a microfluorescence assay. Among HPV DNA-positive cases and controls, the risk of squamous cell ICC was elevated in C. trachomatis seropositive women (OR = 1.8; 95% CI = 1.2-2.7) after adjustment for age, center, oral contraceptive use, history of Pap smears, number of full-term pregnancies and herpes simplex virus 2 seropositivity. The effect of C. trachomatis seropositivity on squamous cell ICC risk increased with increasing C. trachomatis antibody titers and was higher in women under 55 years of age. C. trachomatis antibodies were not associated with adeno- or adenosquamous cell carcinoma (OR = 1.0; 95% CI = 0.53-1.9) in HPV DNA-positive women. An association of C. trachomatis with squamous cell ICC was found among all cases and control women with or without adjustment for HPV.     

Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis

Objective

We conducted a pooled analysis of published studies to compare the performance of human papillomavirus (HPV) testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3).

Methods

Source articles presenting data on posttreatment HPV testing were identified from the National Library of Medicine (PubMed) database. We included 5,319 cases from 33 articles published between 1996 and 2013.

Results

The pooled sensitivity of high-risk HPV testing (0.92; 95% confidence interval [CI], 0.90 to 0.94) for detecting posttreatment CIN 2 or worse (CIN 2+) was much higher than that of cytology (0.76; 95% CI, 0.71 to 0.80). Co-testing of HPV testing and cytology maximized the sensitivity (0.93; 95% CI, 0.87 to 0.96), while HPV genotyping (detection of the same genotype between pre- and posttreatments) did not improve the sensitivity (0.89; 95% CI, 0.82 to 0.94) compared with high-risk HPV testing alone. The specificity of high-risk HPV testing (0.83; 95% CI, 0.82 to 0.84) was similar to that of cytology (0.85; 95% CI, 0.84 to 0.87) and HPV genotyping (0.83; 95% CI, 0.81 to 0.85), while co-testing had reduced specificity (0.76; 95% CI, 0.75 to 0.78). For women with positive surgical margins, high-risk HPV testing provided remarkable risk discrimination between test-positives and test-negatives (absolute risk of residual CIN 2+ 74.4% [95% CI, 64.0 to 82.6] vs. 0.8% [95% CI, 0.15 to 4.6]; p<0.001).

Conclusion

Our findings recommend the addition of high-risk HPV testing, either alone or in conjunction with cytology, to posttreatment surveillance strategies. HPV testing can identify populations at greatest risk of posttreatment CIN 2+ lesions, especially among women with positive section margins.     

Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: A pooled analysis of 17 population-based studies

High-risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR-HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly informs on the cervical cancer burden in the country. A total of 30,207 women from 17 population-based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen, Gaithersburg, MD), visual inspection with acetic acid and liquid-based cytology. Women positive for any test received colposcopy-directed or four-quadrant biopsies. A total of 29,579 women had HR-HPV testing results, of whom 28,761 had biopsy confirmed (9,019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR-HPV prevalence was 17.7%. HR-HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25–29 (11.3%) in rural and at age 35–39 (11.3%) in urban women. In rural and urban women, age-standardized CIN2 prevalence was 1.5% [95% confidence interval (CI): 1.4–1.6%] and 0.7% (95% CI: 0.7–0.8%) and CIN3+ prevalence was 1.2% (95% CI: 1.2–1.3%) and 0.6% (95% CI: 0.5–0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR-HPV-positive women steadily increased with age, peaking in 45- to 49-year-old women. High prevalence of HR-HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group of 45–49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is underreported.     

The prevalence of human papillomavirus infection in Mombasa,Kenya

Objectives  

A human papillomavirus (HPV) prevalence survey was done in Mombasa, Kenya, to improve the knowledge of HPV prevalence and genotype distribution in sub-Saharan African countries overall, and in women of different ages.     

International correlation between human papillomavirus prevalence and cervical cancer incidence.

Data from population-based human papillomavirus (HPV) surveys in regions of low, intermediate, and high cervical cancer incidence were used to study the ecologic correlation between high-risk HPV prevalence and cervical cancer incidence. All the surveys were conducted by the IARC according to a standardized protocol for the collection of female population samples and detection of HPV DNA using PCR assay in a central laboratory. Cervical cancer incidence data were extracted, when available, from a cancer registry covering the surrounding or nearby area of the prevalence survey. Thirteen areas were included in this analysis. The relation between high-risk HPV prevalence and cervical cancer incidence was investigated within 10-year age groups from age 25 to 65 years. A Poisson regression model was used to predict cervical cancer incidence from HPV prevalence, and the strength of the correlation was assessed using Spearman's rank correlation coefficient. The rank correlation was weakest in women ages 25 to 34 years and strongest in women ages 55 to 64 years. In addition, the prevalence of high-risk HPV was not able to predict cervical cancer incidence accurately in every country. Nevertheless, our data raise a concern about the cervical cancer burden in areas where reliable cervical cancer statistics do not exist but where the prevalence of high-risk HPV in women over age 45 is high.     

Population-based prevalence and age distribution of human papillomavirus among women in Santiago, Chile.

More than 18 types of human papillomavirus (HPV) are associated with cervical cancer, the relative importance of the HPV types may vary in different populations.OBJECTIVE: To investigate the types of HPV, age distribution, and risk factors for HPV infection in women from Santiago, Chile.METHODS: We interviewed and obtained two cervical specimens from a population-based random sample of 1,038 sexually active women (age range, 15-69 years). Specimens were tested for the presence of HPV DNA using a GP5+/6+ primer-mediated PCR and for cervical cytologic abnormalities by Papanicolaou smears.RESULTS: 122 women tested positive for HPV DNA, 87 with high risk types (HR), and 35 with low risks (LR) only. Standardized prevalence of HPV DNA was 14.0% [95% confidence interval (95% CI), 11.5-16.4]. HR HPV by age showed a J reverse curve, whereas LR HPV showed a U curve, both statistically significant in comparison with no effect or with a linear effect. We found 34 HPV types (13 HR and 21 LR); HPV 16, 56, 31, 58, 59, 18, and 52 accounted for 75.4% of HR infections. Thirty-four (3.6%) women had cytologic lesions. Main risk factor for HPV and for cytologic abnormalities was number of lifetime sexual partners, odds ratios for > or =3 versus 1 were 2.8 (95% CI, 1.6-5.0) and 3.8 (95% CI, 1.3-11.4), respectively.CONCLUSIONS: LR HPV presented a clear bimodal age pattern; HR HPV presented a J reverse curve. HPV prevalence was similar to that described in most Latin American countries.     

The human papillomavirus infection in men study: human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States

Male sexual behavior influences the rates of cervical dysplasia and invasive cervical cancer, as well as male human papillomavirus (HPV) infection and disease. Unfortunately, little is known regarding male HPV type distribution by age and across countries. In samples combined from the coronal sulcus, glans penis, shaft, and scrotum of 1,160 men from Brazil, Mexico, and the United States, overall HPV prevalence was 65.2%, with 12.0% oncogenic types only, 20.7% nononcogenic types only, 17.8% both oncogenic and nononcogenic, and 14.7% unclassified infections. Multiple HPV types were detected in 25.7% of study participants. HPV prevalence was higher in Brazil (72.3%) than in the United States (61.3%) and Mexico (61.9%). HPV16 (6.5%), HPV51 (5.3%), and HPV59 (5.3%) were the most commonly detected oncogenic infections, and HPV84 (7.7%), HPV62 (7.3%), and HPV6 (6.6%) were the most commonly detected nononcogenic infections. Overall HPV prevalence was not associated with age. However, significant associations with age were observed when specific categories of HPV, nononcogenic, and unclassified HPV infections were considered. Studies of HPV type distribution among a broad age range of men from multiple countries is needed to fill the information gap internationally with respect to our knowledge of HPV infection in men.     

Determinants of prevalence, acquisition, and persistence of human papillomavirus in healthy Mexican military men.

BACKGROUND: Human papillomavirus (HPV) infection is sexually transmitted, but the nature of the infection in males is poorly understood. We sought to identify determinants of HPV infection, acquisition, and persistence in 1,030 healthy military men in Mexico. METHODS: From July 2000 to July 2003, trained interviewers administered a questionnaire, conducted a genital examination, and collected samples. The presence of multiple HPV types in genital cells from the urethra, urethral meatus, scrotum, penile shaft, and coronal sulcus was evaluated. At baseline 1,030 participants and after 1-year follow-up 336 individuals were sampled using a highly sensitive DNA reverse blot strip assay. RESULTS: HPV prevalence was 44.6%; infection with high-risk types was observed in 34.8% participants and 51.1% were multiply infected. After 1-year follow-up, 165 men remained free of HPV, 68 cleared their infection, 45 acquired one, and 37 remained infected with the same HPV type. The period prevalence was 50.9%, the incidence rate was 17.9/1,000 men-months [95% confidence interval (95% CI), 13.0-23.9], clearance was 54%, and persistence was 29.4%. At baseline, the number of partners before age 20 years, a history of a sexually transmitted disease, and the presence of condilomas significantly increased the association with HPV infection. Having anal intercourse with males was associated with the risk of acquiring a HPV infection (odds ratio, 5.2; 95% CI, 1.2-23). The odds ratio for persistent infection was 0.10 (95% CI, 0-0.87) in men who reported being circumcised compared with those who did not. CONCLUSIONS: High-risk sexual behavior increases the risk of HPV infection in males, whereas circumcision may lower the risk of persistence.     

Human papillomavirus type 16 and TP53 mutation in oral cancer: matched analysis of the IARC multicenter study

TP53 mutations were analyzed in 35 human papillomavirus (HPV) type 16 DNA-positive cancers of the oral cavity and oropharynx and in 35 HPV DNA-negative cancers matched by subsite, country, sex, age, and tobacco and alcohol consumption. Wild-type TP53 was found more frequently in cancer specimens that contained HPV16 DNA than in those that did not. All 14 HPV16 DNA-positive cancers in HPV16 E6 antibody-positive patients contained wild-type TP53, compared with 50% of corresponding HPV DNA-negative cancers (matched odds ratio, infinity; 95% confidence interval, 1.4- infinity ). In contrast, for HPV16 DNA-positive cancers in E6-negative patients, wild-type TP53 frequency was similar to that in corresponding HPV DNA-negative cancers (matched odds ratio, 1.0; 95% confidence interval, 0.2-5.4). TP53 inactivation is a major mechanism of HPV-related carcinogenesis in the oral cavity and oropharynx. The role of HPV in cancers also containing TP53 mutations remains to be clarified.     

Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing

There is justifiable excitement about the recent introduction of prophylactic vaccines against human papillomavirus (HPV) types 16 (HPV-16) and HPV-18. Preventing these infections theoretically could avert approximately 70% of cervical cancer cases worldwide. In the U.S., numerous influential advocates are calling for universal vaccination of adolescent females. Given the promise of the vaccines, perhaps it is inevitable that vaccine introduction is proceeding before full consideration of how universal vaccination would affect existing, successful cervical cancer prevention programs. Determining the impact and cost effectiveness of the vaccines unavoidably will require time. Nevertheless, it is worth describing in broad terms for the readers of Cancer Cytopathology how successful, broad HPV vaccination of adolescent girls may affect cytology and HPV testing.     

Geographic heterogeneity in the prevalence of human papillomavirus in head and neck cancer

Human papillomavirus (HPV) causes oropharyngeal squamous cell carcinoma (OPSCC), although strongly divergent results have been reported regarding the prevalence of HPV16 in different countries, whether this represents important differences in etiology remains unclear. Applying rigorous protocols for sample processing, we centrally evaluated 1,420 head and neck tumors (533 oropharynx, 395 oral cavity and 482 larynx) from studies conducted in the US, Europe and Brazil for mucosal HPV DNA and p16^INK4a expression to evaluate regional heterogeneity in the proportion of HPV16‐associated OPSCC and other head and neck cancer, and to assess covariates associated with the risk of HPV16‐positive OPSCC. While majority of OPSCC in the US (60%) were HPV16‐positive, this proportion was 31% in Europe and only 4% in Brazil (p < 0.01). Similar differences were observed for other head and neck tumors, ranging from 7% in the US and 5% in Europe, to 0% in South America. The odds of HPV16‐positive OPSCC declined with increasing pack years of smoking (OR: 0.75; 95% CI: 0.64–0.87) and drink years of alcohol use (OR: 0.64; 95% CI: 0.54–0.76). These results suggest that while the contribution of HPV16 is substantial for the oropharynx, it remains limited for oral cavity and laryngeal cancers.     

High prevalence of human papillomavirus infection in the female population of Guatemala

The costs of computed tomographic colonography (CTC) are not yet established for screening use. In our study, we estimated the threshold costs for which CTC screening would be a cost‐effective alternative to colonoscopy for colorectal cancer (CRC) screening in the general population. We used the MISCAN‐colon microsimulation model to estimate the costs and life‐years gained of screening persons aged 50–80 years for 4 screening strategies: (i) optical colonoscopy; and CTC with referral to optical colonoscopy of (ii) any suspected polyp; (iii) a suspected polyp ≥6 mm and (iv) a suspected polyp ≥10 mm. For each of the 4 strategies, screen intervals of 5, 10, 15 and 20 years were considered. Subsequently, for each CTC strategy and interval, the threshold costs of CTC were calculated. We performed a sensitivity analysis to assess the effect of uncertain model parameters on the threshold costs. With equal costs ($662), optical colonoscopy dominated CTC screening. For CTC to gain similar life‐years as colonoscopy screening every 10 years, it should be offered every 5 years with referral of polyps ≥6 mm. For this strategy to be as cost‐effective as colonoscopy screening, the costs must not exceed $285 or 43% of colonoscopy costs (range in sensitivity analysis: 39–47%). With 25% higher adherence than colonoscopy, CTC threshold costs could be 71% of colonoscopy costs. Our estimate of 43% is considerably lower than previous estimates in literature, because previous studies only compared CTC screening to 10‐yearly colonoscopy, where we compared to different intervals of colonoscopy screening. © 2008 Wiley‐Liss, Inc.     

Variations in the age-specific curves of human papillomavirus prevalence in women worldwide

An inverse relationship between age and human papillomavirus (HPV) prevalence has been reported in many developed countries, but information on this relationship is scarce in many other parts of the world. We carried out a cross-sectional study of sexually active women from the general population of 15 areas in 4 continents. Similar standardised protocols for women's enrolment, cervical specimen collection and PCR-based assays for HPV testing were used. HPV prevalence in different age groups was compared by study area. 18,498 women aged 15-74 years were included. Age-standardised HPV prevalence varied more than 10-fold between populations, as did the shape of age-specific curves. HPV prevalence peaked below age 25 or 35, and declined with age in Italy, the Netherlands, Spain, Argentina, Korea and in Lampang, Thailand and Ho Chi Minh, Vietnam. This was not the case in Songkla, Thailand nor Hanoi, Vietnam, where HPV prevalence was low in all age groups. In Chile, Colombia and Mexico, a second peak of HPV prevalence was detected among older women. In the poorest study areas in Asia (Shanxi, China and Dindigul, India), and in Nigeria, HPV prevalence was high across all age groups. The substantial differences observed in age-specific curves of HPV prevalence between populations may have a variety of explanations. These differences, however, underline that great caution should be used in inferring the natural history of HPV from age-specific prevalences.     

A population‐based study of human papillomavirus genotype prevalence in the United States: Baseline measures prior to mass human papillomavirus vaccination

Currently, two prophylactic human papillomavirus (HPV) vaccines targeting HPV 16 and 18 have been shown to be highly efficacious for preventing precursor lesions although the effectiveness of these vaccines in real‐world clinical settings must still be determined. Toward this end, an ongoing statewide surveillance program was established in New Mexico to assess all aspects of cervical cancer preventive care. Given that the reduction in cervical cancer incidence is expected to take several decades to manifest, a systematic population‐based measurement of HPV type‐specific prevalence employing an age‐ and cytology‐stratified sample of 47,617 women attending for cervical screening was conducted prior to widespread HPV vaccination. A well‐validated polymerase chain reaction (PCR) method for 37 HPV genotypes was used to test liquid‐based cytology specimens. The prevalence for any of the 37 HPV types was 27.3% overall with a maximum of 52% at age of 20 years followed by a rapid decline at older ages. The HPV 16 prevalences in women aged ≤20 years, 21–29 years or ≥30 years were 9.6, 6.5 and 1.8%, respectively. The combined prevalences of HPV 16 and 18 in these age groups were 12.0, 8.3 and 2.4%, respectively. HPV 16 and/or HPV 18 were detected in 54.5% of high‐grade squamous intraepithelial (cytologic) lesions (HSIL) and in 25.0% of those with low‐grade SIL (LSIL). These baseline data enable estimates of maximum HPV vaccine impact across time and provide critical reference measurements important to assessing clinical benefits and potential harms of HPV vaccination including increases in nonvaccine HPV types (i.e., type replacement).     

Response of experimental animals to human carcinogens: an analysis based upon the IARC Monographs programme

Only the results of epidemiological studies can be used to establisha causal relationship between an exposure to an agent and humancancer; however, such studies often cannot be carried out dueto limitations of population or latent period or to the presenceof mixed exposures. It is essential, therefore, that the validitybe established of extrapolating to humans the results obtainedfrom long-term carcinogenicity tests in animals. The responsesof experimental animals to known and suspected human carcinogens,as evaluated in the IARC Monographs series, were analysed asan indication of the sensitivity of animal tests for predictinghuman carcinogens. Although the response was high - 84% - itwould have been even higher had all the compounds been adequatelytested experimentally. An additional finding was that for manyexposures causally related to human cancer, there is a targetorgan in common between humans and at least one animal species,despite many inherent physiological differences. These findingsshow clearly the importance of experimental carcinogenicitystudies in the primary prevention of cancer.     

High prevalence of human papillomavirus types 16 and 18 in middle-ear carcinomas

Chronic suppurative otitis media, averaging 20 or more years of duration, has been associated with cancer in this region in 40%–80% of cases. Although human papillomaviruses (HPV) have been implicated in many human squamous-cell neoplasms, their role in the pathogenesis of middle-ear malignancies remains unexplored. In this study, we investigated the presence and subtypes of HPV in middle-ear carcinomas. Formalin-fixed and paraffin-embedded tumor tissues were sampled for DNA extraction. PCR was done with consensus primers, capable of detecting HPV 16, 18, 31, 33, 52b and 58. Typing of the products generated by consensus primers was performed with restriction enzyme digestion. It was found that a resulting 89% (8/9) of the middle-ear carcinomas contained HPV DNA. Coexistence of HPV 16 and 18 was detected in 3 squamous-cell carcinomas. HPV 16 was detected in 4 squamous-cell carcinomas and I adenocarcinoma. The high prevalence of high-risk-type HPV in carcinomas of the middle ear suggests that viral infection may be an important etiologic component in the carcinogenic process. Int. J. Cancer 71:208–212, 1997. © 1997 Wiley-Liss, Inc.