Cervical cancer is the second-most prevalent cancer in young women around the world. Infection with human papillomavirus (HPV), especially high-risk HPV types (HR-HPV), is necessary for the development of this cancer. HPV-DNA detection is increasingly being used in cervical cancer screening programs, together with the Papanicolau smear test. We evaluated the usefulness of introducing this new array-based HPV genotyping method (i.e., Clinical Arrays Papillomavirus Humano) in the cervical cancer screening algorithm in our center. The results obtained using this method were compared to those obtained by the hybrid capture II high-risk HPV DNA test (HC-II) and Papanicolau in a selected group of 408 women. The array-based assay was performed in women that were HC-II positive or presented cytological alterations. Among 246 array-positive patients, 123 (50%) presented infection with ≥2 types, and HR-HPV types were detected in 206 (83.7%), mainly HPV-16 (24.0%). Up to 132 (33.2%) specimens were classified as ASCUS (for atypical squamous cells of undetermined significance), and only 48 (36.4%) of them were HPV-DNA positive by either assay; however, 78.7% of these cases were caused by HR-HPV types. The agreement between both HPV-DNA detection techniques was fairly good (n = 367). Screening with Papanicolau smear and HC-II tests, followed by HPV detection and genotyping, provided an optimal identification of women at risk for the development of cervical cancer. Furthermore, with the identification of specific genotypes, either in single or multiple infections, a better prediction of disease progression was achieved. The array method also made allowed us to determine the possible contribution of the available vaccines in our setting.
Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide. About 75 to 80% of sexually active Americans will be infected with HPV at some point in their lifetime. The risk of HPV infection seems to be related with age at first intercourse, younger age and number of sexual partners. HPV infection is limited to the basal cells of stratified epithelium of the skin or mucous membranas. There is a wide latency period, from months to years, before squamous intraepithelial lesions develop. Most HPV infections are cleared within 2 years by the immune system. Only in 5% to 10% of infected women with “high risk” types the infection persists determining a high risk of developing intraepithelial neoplasias, as cervical cancer, vulvar cancer, penile cancer, and/or anal cancer. The gynecological evaluation and Papanicolau smear are the primary screening tools for detecting HPV infection. There is currently no specific treatment for HPV infection. The Transfer Factor (TF) or Dialyzable Leukocyte Extract is an immunomodulator that has been successfully used as an adjuvant in the treatment of intracelular infections such as recurrent herpes virus diseases. TF induces the expression of RNAm and IFN-γ and increases CD4+ cells. The IFN-γ activates macrophages, neutrophils, B lymphocytes, NK cells, and favours the differentiation of T cells into Th1 lymphocytes that are requiried for the control of intracellular patho gens.
We used TF in a group of patients with persistent genital human papillomavirus infection.
We included 12 patients, aged 19 to 45 years old (mean 30), with 14 to 23 years at first intercourse and a mean of 3 sexual partners in their lifetime. All of them had persistent HPV that had been treated before with local and ablative therapeutic options (including cervical freezing, cauterizing loop, imiquimod, podophyllin and/or cervical conization). Transfer factor was administered daily for 5 days, and subsequently at 7-day intervals for 5 weeks. We found an important improvement in the gynecological evaluation of cervix and perineal lesions and a significant reduction in the frequency of relapses.
Transfer factor could be used as an adjuvant in patients with persistent genital human papillomavirus infection.
The raw incidence of cancer of the uterine cervix is Spain is 7,8 per 100.000 inhabitants (adjusted incidence is 5.6). The incidence of this tumor is still low, but a steady increase has been seen, probably related to increasing risk factors.
To determine the frequency of infection by different types of human papillomavirus (HPV) in Papanicolau smears from women with and without cancer of the uterine cervix in Spain.
Patients and methods
A case-control study was performed in women with and without cervical cancer from Zaragoza, Spain. Pap smears from 600 cases (540 women with cervical intraepithelial neoplasms (CIN) and 60 with invasive cancer) and 1200 controls (women without those lesions) were tested by polymerase chain reaction (PCR) and typed by oligonucleotide microarray-based detection.
HPV was detected in 93.3% of all samples with invasive cancer versus 17.5% of controls. OR for invasive cancer was 55 (95% CI 21.5–140,5). Statistically significant associations were also found for different grades of cervical dysplasia.
The strong association found between HPV infection, specifically types 16 and 18 and cancer of the uterine cervix in Zaragoza, Spain, stresses the importance of ongoing efforts to institute a vaccine program with recently approved HPV vaccines in order to prevent cervical cancer in this population.
Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma.
At the baseline examination in 1991–1992, 11 923 participants (aged 30–65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993–1995. For HPV testing, we used a polymerase chain reaction–based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan–Meier method.
Of 10 123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30–44 years, 45–54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age.
HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test.
Cervical cancer is the second most prevalent female cancer worldwide. The majority of cases appear between the age of 30 and 50. Human papillomavirus (HPV) plays a central role in cervical cancer with 99.7% of HPV DNA identified in invasive cervical carcinomas. The prevalence of the HPV infection varies substantially among countries and according to age and lifestyle. HPV is a common sexually transmitted infection among males and females with a 70% higher incidence in sexually active females. This study aimed to determine the prevalence of human papillomavirus in young university women by analyzing the correlation between Papanicolaou (PAP)-stained cervical tests and HPV detection by genotyping, as well as other risk factors. A total of 200 women aged between 18 and 25 years were enrolled in this study, which took place between September 2008 and May 2009 at the Universidad de Tarapacá, Arica, Chile. Results of the PAP smears showed that 97.5% of cells had normal characteristics, although an inflammatory pattern was noted. The prevalence of generic HPV infection was 3.5% when testing for HPV DNA using the polymerase chain reaction (PCR) method. An analysis of the genotype of infected female individuals indicated that high-risk HPV types, such as HPV 16 and 31 were present in 42.84 and 14.29% of females, respectively, and low-risk types such as HPV 6, in 14.29%. Only one sample with differentiated non-HPV (14.29%) was found. A 95% correlation between PAP-stained cervical tests and the method of testing for HPV was observed. Using the PCR method, it was found that of the 195 negative PAP smears, 5 were positive for HPV and two of the samples that were positive for ASC-US were also positive. A significantly increased (P<0.05) HPV infection risk was observed in the 18–21 age group with a higher prevalence (71.40%) when compared to the 22–25 age group (28.6%). A significant (P<0.042) difference was found between smoking and HPV infection. In conclusion, a significant (P<0.05) correlation was found between PAP and PCR methods for HPV testing in young university women. A significant correlation between smoking and HPV was detected, whereas no difference was noted with other parameters.
human papillomavirus; prevalence
Few natural history studies of cervical human papillomavirus (HPV) incidence and duration have been conducted among older women, especially from multiethnic populations. Viral and nonviral determinants of HPV acquisition and clearance were examined among 972 sexually active women, ages 18 to 85 years, recruited from clinics on Oahu, Hawaii, and followed for a mean duration of 15 months (range, 2–56 months). Interviews and cervical cell specimens for cytology and HPV DNA detection by PCR, using the PGMY09/PGMY11 primer system, were obtained at baseline and at 4-month intervals. The prevalence of cervical HPV infection was 25.6% at study entry. A total of 476 incident genotype-specific infections were observed during the follow-up period. The incidence of high-risk (HR) HPV types (9.26 per 1,000 woman-months) was similar to low-risk (LR) HPV types (8.24 per 1,000 woman-months). The most commonly acquired HR-HPV types were HPV-52, HPV-16, and HPV-31; and their incidence was increased significantly with a coexisting cervical HPV infection. Cervical HPV acquisition decreased with age, income, and long-term use of oral contraceptives and increased with number of sexual partners, use of hormonal creams, alcohol drinking, and condom use by a sexual partner. Cohort participants cleared 265 of the 476 incident infections during follow-up. LR-HPV infections cleared more rapidly than did HR-HPV infections (median, 180 days versus 224 days). Clearance times were enhanced among older women and women with multiple infections. Our data suggest several viral and nonviral determinants of cervical HPV acquisition and clearance that might be used in cervical cancer prevention programs.
Background. Although the prevalence of human papillomavirus (HPV) genital infection is similarly high in males and females, seroprevalence is lower in males. This study assessed rates and determinants of seroconversion after detection of genital HPV infection in young men.
Methods. We investigated HPV type-specific seroconversion in a cohort of heterosexual male university students who had an α9 HPV type (HPV-16, -31, -33, -35, -52, -58, or -67) detected in the genital tract (n = 156). HPV DNA and antibodies were detected and typed using liquid bead-based multiplex assays. We calculated seroconversion using Kaplan–Meier survival analysis. Cox proportional hazards models with generalized estimating equations were used to examine associations with seroconversion.
Results. Within 24 months of detecting genital HPV infection, type-specific seroconversion ranged from 4% for HPV–52 to 36% for HPV-31. HPV-16 seroconversion at 24 months was 13% (95% confidence interval [CI], 7%–25%). Among incident HPV infections, ever cigarette smoking and infection site(s) (shaft/scrotum and glans/urine vs shaft/scrotum or glans/urine only) were positively associated with type-specific seroconversion.
Conclusions. For each of the α9 HPV types, type-specific seroconversion within 24 months was observed in 36% or less of infected men. Seroconversion might be related to cigarette smoking and genital site(s) infected.
The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.
While infections with human papillomavirus (HPV) are highly prevalent among sexually active young women in Uganda, information on incidence, clearance and their associated risk factors is sparse. To estimate the incidence, prevalence and determinants of HPV infections, we conducted a prospective follow-up study among 1,275 women aged 12-24 years at the time of recruitment. Women answered a questionnaire and underwent a pelvic examination at each visit to collect exfoliated cervical cells. The presence of 42 HPV types was evaluated in exfoliated cervical cells by a polymerase chain based (PCR) assay (SPF10-DEIA LiPA).
Three hundred and eighty (380) of 1,275 (29.8%) women were followed up for a median time of 18.5 months (inter-quartile range 9.7-26.6). Sixty-nine (69) women had incident HPV infections during 226 person-years of follow-up reflecting an incidence rate of 30.5 per 100 person-years. Incident HPV infections were marginally associated with HIV positivity (RR = 2.8, 95% CI: 0.9 - 8.3). Clearance for HPV type-specific infections was frequent ranging between 42.3% and 100.0% for high- and 50% and 100% for low-risk types. Only 31.2% of women cleared all their infections. Clearance was associated with HIV negativity (Adjusted clearance = 0.2, 95% CI: 0.1 - 0.7) but not with age at study entry, lifetime number of sexual partners and multiplicity of infections. The prevalence of low-grade squamous intraepithelial lesions (LSILs) was 53/365 (14.5%). None of the women had a high-grade cervical lesion (HSIL) or cancer. Twenty-two (22) of 150 (14.7%) HPV negative women at baseline developed incident LSIL during follow-up. The risk for LSIL appeared to be elevated among women with HPV 18-related types compared to women not infected with those types (RR = 3.5, 95% CI: 1.0 - 11.8).
Incident HPV infections and type-specific HPV clearance were frequent among our study population of young women. These results underscore the need to vaccinate pre-adolescent girls before initiation of sexual activity.
Carcinogenic human papillomavirus (HPV) infections are very common after sexual debut and nearly all become undetectable (“clear”) within a few years. Following clearance, the long-term risks of type-specific HPV re-appearance and subsequent risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are not well defined.
In the 7-year, population-based cohort study in Guanacaste, Costa Rica, we studied how often type-specific carcinogenic HPV infections re-appeared after clearance, and how often re-appearance led to CIN2+. We considered 1740 carcinogenic HPV infections detected by MY09/11 PCR among 2805 women (18-91 years old, median 34) who were actively followed at 6- or 12-month intervals. We identified women with 1 or more type-specific HPV infections that cleared and re-appeared, and further defined a subgroup of “definite clearance and re-appearance” (≥ 2 intervening negative results over a period of ≥ 1 year). We determined the absolute risk of CIN2+ among the different groups. P values are two sided.
Only 7.7% (81/1052) of HPV-infected women had intervening negative results. Very few (3.7%, 39/1052) had “definite clearance and re-appearance”, of which 5.1% (2/39) subsequently persisted to a diagnosis of CIN2. There were zero CIN3+ lesions.
Extremely few women (2/2805 of women in our cohort) had a type-specific carcinogenic HPV infection clear, re-appear and lead to CIN2+. If confirmed, this argues against vaccination to avoid re-appearance that leads to precursor lesions and against the need of frequent HPV screening after initial negative results.
HPV infection re-appearance; CIN2+ risk after re-appearance; HPV infection epidemiology
We describe type-specific progression, regression and persistence of incident human papillomavirus (HPV)-6-11-16 and -18 infections, along with type distribution in cervical intra-epithelial neoplasia (CIN) lesions.
The study population consisted of 16–23 year-old women undergoing Pap testing and cervical swab polymerase chain reaction testing for HPV DNA at approximate 6 month intervals for up to 4 years in the placebo arm of a clinical trial of an HPV 16-vaccine. HPV types in incident infections were correlated with types in lesion biopsy specimens.
56.7% of CIN-1 and nearly one-third of CIN-2/3 lesions following incident HPV-6-11-16 or -18 infections did not correlate with the incident infection HPV type. Cumulative 36-month progression rates to CIN-2/3 testing positive for the relevant HPV type were highest for HPV-16 infections (16.5%), followed by HPV-18 (8.2%). Overall, 26.0% of CIN-1, 50.0% of CIN-2 and 70.6% of CIN-3 biopsies tested positive for HPV-6-11-16-18 infections.
Women with a given HPV type may often be co-infected or subsequently infected with other types which may lead to subsequent cervical lesions. This issue has been addressed in this study reporting data for the natural history of HPV-6-11-16 and -18 infections and is a relevant consideration in designing future studies to evaluate the incidence/risk of CIN following other type-specific HPV infections.
Infection with multiple types of human papillomavirus (HPV) is one of the main risk factors associated with the development of cervical lesions. In this study, cervical samples collected from 1,810 women with diverse sociocultural backgrounds, who attended to their cervical screening program in different geographical regions of Colombia, were examined for the presence of cervical lesions and HPV by Papanicolau testing and DNA PCR detection, respectively.
The negative binomial distribution model used in this study showed differences between the observed and expected values within some risk factor categories analyzed. Particularly in the case of single infection and coinfection with more than 4 HPV types, observed frequencies were smaller than expected, while the number of women infected with 2 to 4 viral types were higher than expected. Data analysis according to a negative binomial regression showed an increase in the risk of acquiring more HPV types in women who were of indigenous ethnicity (+37.8%), while this risk decreased in women who had given birth more than 4 times (−31.1%), or were of mestizo (−24.6%) or black (−40.9%) ethnicity.
According to a theoretical probability distribution, the observed number of women having either a single infection or more than 4 viral types was smaller than expected, while for those infected with 2–4 HPV types it was larger than expected. Taking into account that this study showed a higher HPV coinfection rate in the indigenous ethnicity, the role of underlying factors should be assessed in detail in future studies.
Testing for high-risk human papillomavirus (HPV) in primary screening for cervical cancer is considered more sensitive, but less specific, in comparison with Pap-smear cytology. Women with persistent HPV infections have a higher risk of developing cervical intraepithelial neoplasia 2+ (CIN2+) lesions. This study was performed to evaluate the gain in specificity for detection of histologically confirmed CIN2+ lesions achieved by short-time repeat testing for high-risk HPV in women aged 30–65 years, with the primary sample for HPV analysis taken by self-sampling.
A total of 8000 women in Uppsala County, aged 30–65 years, who had not attended organised screening for 6 years or longer, were offered self-sampling of vaginal fluid at home and the samples sent for HPV typing. Of these, 8% (669) were not possible to contact or had performed hysterectomy. Women positive for high-risk HPV in the self-sampling test were invited for a follow-up HPV test and a cervical biopsy on average 3 months after the initial HPV test.
In all, 39% (2850/7331) of invited women chose to perform self-sampling of vaginal fluid at home. High-risk HPV infection was found in 6.6% (188) of the women. In all, 89% of the women testing HPV positive performed a follow-up examination, on average 2.7 months, after the first test and 59% of these women were HPV positive in the follow-up test. The prevalence of CIN2+ lesions in women with an initial HPV-positive test was 23% (95% CI 18–30%) and in women with two consecutive HPV-positive tests was 41% (95% CI 31–51%). In women with two positive HPV tests, the prevalence of CIN2+ lesions varied from 49% in women at age 30–39 years to 24% in women at age 50–65 years. Short-time repeat HPV testing increased the specificity for detection of CIN2+ lesions from about 94.2% to 97.8%. The most prevalent HPV types were HPV16 (32%), followed by HPV18/45 (19%) and HPV 33/52/58 (19%).
The short-time persistence of high-risk HPV infection in this age group was about 60%. Repeat testing for high-risk HPV using self-sampling of vaginal fluid can be used to increase the specificity in the screening for cervical cancer in women aged 30–65 years.
cervix; screening; carcinoma; HPV test; persistence; self-sampling
Infection with multiple human papillomavirus (HPV) types is common. However, it is unknown whether viral DNA load is related to the coexistence of other types.
Study subjects were 802 and 303 women who were positive for HPV16 and HPV18, respectively, at enrollment into the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study. HPV16 and HPV18 E7 copies per nanogram of cellular DNA in cervical swab samples were measured by real-time polymerase chain reaction in triplicate.
Concurrent coinfection was common in this population of women with minor cervical lesions; multiple HPV types were detected in 573 (71.4%) of 802 HPV16-positive women and 227 (74.9%) of 303 HPV18-positive women. The adjusted odds ratio associating coinfection with per 1 log unit increase in HPV16 DNA load was 0.78 (95% confidence interval (CI), 0.68-0.89); it was 0.64 (95% CI, 0.52-0.79) for a similar analysis of HPV18 DNA load. Women with, compared to without, coinfection of A9 species possessed a significantly lower HPV16 DNA load (p < 0.001) whereas women with, compared to without, coinfection of A7 species types possessed a significantly lower HPV18 DNA load (p = 0.001). A trend of decrease in HPV16 DNA load with increasing number of the coexisting non-HPV16 A9 species types was statistically significant (p for trend = 0.001).
Coinfection with other types was associated with lower HPV16 and HPV18 DNA load. The extent of reduction was correlated to phylogenetic distance of the coexisting types to HPV16 and HPV18, respectively.
Human Papillomavirus; Viral Load; Coinfection
The time course of cell-mediated and humoral immune responses was elucidated in eight women with human papillomavirus type 16 (HPV-16) infection by performing serial HPV-16 E6 and E7 cytotoxic T-lymphocyte (CTL) assays and HPV-16 virus-like particle (VLP) antibody analyses. Four subjects had a single incident of HPV-16 DNA detection, and four subjects had two periods of HPV-16 DNA detection. In two of the women in the latter group, the second episode of HPV-16 detection occurred in the presence of high titers of HPV-16 VLP antibody, bringing into question the protective role of humoral immunity in preventing repeated infection. However, all four subjects rapidly became HPV-16 DNA negative following the second detection of HPV-16 DNA, suggesting the presence of immunological memory. In addition, one subject rapidly became negative for HPV-16 DNA despite having no evidence of CTL or VLP antibody response prior to the second HPV-16 DNA detection, suggesting the presence of immunological responses at an undetectable level. Overall, seven of eight subjects (88%) had detectable HPV-16 E6 and/or E7 CTL responses and seven of eight women (88%) had detectable HPV-16 VLP antibody responses.
There are no previous longitudinal studies on genotype-specific natural history of human papillomavirus (HPV) infections in oral mucosa of women.
In the Finnish Family HPV Study, 329 pregnant women were enrolled and followed up. HPV-genotyping of oral scrapings was performed with nested PCR and Multimetrix® test (Progen, Heidelberg, Germany). Incidence and clearance times and rates for each HPV-genotype identified in oral mucosa were determined. Predictors for incident and cleared HPV infections for species 7/9 genotypes were analyzed using Poisson regression model.
Altogether, 115 baseline HPV-negative women acquired incident oral HPV infection, and 79 women cleared their infection. HPV16 and multiple HPVs most frequently caused incident infections (65% and 12%) in 13.3 and 17.1 months respectively, followed by HPV58, HPV18 and HPV6 (close to 5% each) in 11–24 months. HPV58, HPV18 and HPV66 were the most common to clear. HPV6 and HPV11 had the shortest clearance times, 4.6 months and 2.5 months, and the highest clearance rates, 225.5/1000 wmr and 400/1000 wmr, respectively. The protective factors for incident oral HPV-species 7/9 infections were 1) new pregnancy during follow-up and 2) having the same sexual partner during FU. Increased clearance was related with older age and a history of atopic reactions, whereas previous sexually transmitted disease and new pregnancy were associated with decreased clearance.
HPV16 was the most frequent genotype to cause an incident oral HPV-infection. Low risk HPV genotypes cleared from oral mucosa more quickly than high risk HPV genotypes. Pregnancy affected the outcome of oral HPV infection.
Human papillomavirus (HPV) is the cause of cervical cancer. To better understand the natural history of HPV, we assessed the incidence of type-specific HPV infection and examined risk factors for acquisition of high-risk (HR) HPV infection in Danish women.
A population-based prospective cohort study of women aged 20 – 29 years was conducted. Participants were interviewed and underwent two gynaecological examinations 2 years apart. Women for whom Hybrid Capture 2 results were available at both visits were included in the analysis (n = 7454).
A HR HPV infection was acquired by 12.8% of the women during follow-up. The incidence decreased with increasing age. The commonest types were HPV16, HPV31 and HPV52. HPV66, HPV58 and HPV53 were mainly acquired with other HR types. Multiple HR types were acquired in 50% of the women who became HPV positive during follow-up. In initially HPV negative women age, number of sexual partners and oral contraceptive use were the main risk factors for acquisition, particularly of multiple HR HPV types.
HPV infections were commonly acquired. We confirmed the sexually transmitted nature of the infection. Our findings show that both the level of potential exposure and other behavioural factors increase the risk for HR HPV acquisition.
Human papillomavirus; type-specific incidence; multiple HR HPV types; risk factors
Certain high-risk (HR) human papillomavirus (HPV) types are a necessary cause for the development of cervical disorders. Women with persistent HR HPV infections have an increased risk of developing high-grade cervical lesions, compared with those who have no or low-risk HPV infections. Therefore, implementation of HPV detection into cervical screening programs might identify women at risk of cervical cancer. Several HPV detection methods with different sensitivities and specificities are available. Recently, a new PCR-based technique, the Roche AMPLICOR HPV Test, was developed. This test recognizes a group of 13 HR HPV types simultaneously. This study was undertaken to validate and compare HPV detection in 573 cervical scrape specimens by the AMPLICOR HPV Test and the INNO-LiPA HPV detection/genotyping assay (SPF10-LiPA system version 1). Human β-globin was not detected in nine specimens, which were therefore excluded from the comparison. Eleven scrape specimens containing HPV type 53 or 66 were also excluded from the comparison because these (probably) HR HPV types cannot be detected by the AMPLICOR HPV Test. The results of HPV detection by the Roche AMPLICOR HPV Test were confirmed by INNO-LiPA HPV detection/genotyping assay in 539/553 cases, showing an absolute agreement of 97.5% with a Cohen's kappa of 0.9327, indicating almost complete similarity of the two tests. Like the INNO-LiPA HPV detection/genotyping assay, the AMPLICOR HPV Test was sensitive, specific, feasible, and easy to handle. The value of the Roche AMPLICOR HPV Test with a broad-spectrum HR HPV detection has to be determined in prospective clinical studies.
Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type–specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types.
A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time.
For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%).
HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA–negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.
Persistent infection with carcinogenic human papillomavirus (HPV) is linked to high-grade lesions and cervical cancer. To better understand the natural history of HPV, we sought to determine the rates of incident and cleared carcinogenic HPV infection, by age, among women aged 15–49 years and to explore risk factors for incident infection.
Women enrolled in an earlier HPV prevalence survey (500 of 800 who were HPV-negative and all 121 who were HPV-positive) were invited to participate in follow-up HPV testing at their periodic health examination one year later. A cervical soft-brush specimen for HPV testing and a smear for cytologic examination were obtained, and participants completed a questionnaire on their demographic characteristics and sexual history.
Two hundred and fifty-three (50.6%) previously HPV-negative women and 54 (44.6%) previously HPV-positive women were retested. The mean interval between visits was 14.0 (standard deviation 2.0, median 13.5, range 9.0–21.3) months. Incident HPV infection occurred in 11.1% (28/253) of the women overall, with the highest rate, 25.0% (6/24), in the 15–19-year age group. In the univariate analyses, risk factors for incident HPV were the median number of sexual partners in the past year (≤ 1 v. ≥ 2: odds ratio [OR] 8.2, 95% confidence interval [CI] 3.0–22.2; p < 0.001) and the median number of sexual partners over a lifetime (> 3 v. ≤ 3: OR 3.0, 95% CI 1.2–7.2; p = 0.014). In multivariate logistic regression modelling adjusted for age, median number of sexual partners in the past year, median number of sexual partners over a lifetime, marital status, current smoking and current use of oral contraceptives, only the median number of sexual partners in the past year remained significantly associated with incidence (OR 6.2, 95% CI 1.6–24.5; p = 0.009). Of the previously HPV-positive women, 51.9% (28/54) had cleared the infection.
Incident infection with carcinogenic HPV was highest in women aged 15–19 years, and risk factors were consistent with a sexually transmitted infection. A large proportion of the women who were HPV-positive appeared to have cleared the infection after one year.
Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.
Cervical cancer; genetics; HPV; polymorphism; progression
The influence of multiple human papillomavirus (HPV) types on detection of concordant incident HPV infections of the cervix or anus following infection at the other anatomic site was examined in a cohort of 897 women. Multiple HPV infections at the anus were not significantly associated with subsequent acquisition of a concordant cervical infection, whereas prior coinfections in the cervix increased risk of a new cervical HPV infection. Incident anal HPV infections following concordant cervical HPV infections increased significantly among women with preexisting cervical or anal coinfections. Potential synergy in acquisition of cervical and anal HPV infections has implications for prophylactic vaccine effectiveness.
Background. Data on the natural history of human papillomavirus (HPV)–related genital warts (GWs) in men are sparse. We described the distribution of HPV types in incident GWs and estimated GW incidence and time from type-specific incident HPV infections to GW detection in a multinational cohort of men aged 18–70 years.
Methods. Participants included 2487 men examined for GWs and tested for HPV every 6 months and followed up for a median of 17.9 months. Samples were taken from 112 men with incident GWs to test for HPV DNA by polymerase chain reaction.
Results. Incidence of GWs was 2.35 cases per 1000 person-years, with highest incidence among men aged 18–30 years (3.43 cases per 1000 person-years). HPV 6 (43.8%), HPV 11 (10.7%), and HPV 16 (9.8%) were the genotypes most commonly detected in GWs. The 24-month cumulative incidence of GWs among men with incident HPV 6/11 infections was 14.6% (95% confidence interval [CI], 7.5%–21.1%). Median time to GW detection was 17.1 months (95% CI, 12.4–19.3 months), with shortest time to detection among men with incident infections with HPV 6/11 only (6.2 months; 95% CI, 5.6–24.2 months).
Conclusions. HPV 6/11 plays an important role in GW development, with the highest incidence and shortest time to detection among men with incident HPV 6/11 infection.
Human papillomavirus (HPV) type-specific distribution was evaluated in genital samples collected from 654 women from the South of Italy undergoing voluntary screening and correlated with cyto-histological abnormalities. HPV DNA was detected in 45.9% of the samples, 41.7% of which had multiple infection and 89.0% had high-risk HPV infection. The prevalence of HPV infection and the rate of multiple infections decreased with age, suggesting natural selection of HPV types with better fitness. In line with other Italian studies, the most common HPV types were HPV-6 and HPV-16, followed by HPV-51, HPV-31, HPV-53, and HPV-66, in women with both normal and abnormal cytology. Cervical intraepithelial lesions grade 2 or 3 were associated with high-risk HPV-16, HPV-18, HPV-31, and HPV-51 infection. These data indicate that prophylactic HPV vaccination is expected to reduce the burden of HPV-related cervical lesions in this population, but also suggest the potential utility of new vaccines with larger type coverage.
Cervical cancer is the leading gynecological malignancy worldwide, and the incidence of this disease is very high in American Indian women. Infection with the Human Papillomavirus (HPV) is responsible for more than 95% of cervical squamous carcinomas. Therefore, the main objective of this study was to analyze oncogenic HPV infections in American Indian women residing in the Northern Plains.
Cervical samples were collected from 287 women attending a Northern Plains American Indian reservation outpatient clinic. DNA was extracted from the cervical samples and HPV specific DNA were amplified by polymerase chain reaction (PCR) using the L1 consensus primer sets. The PCR products were hybridized with the Roche HPV Line Blot assay for HPV genotyping to detect 27 different low and high-risk HPV genotypes. The chi-square test was performed for statistical analysis of the HPV infection and cytology diagnosis data.
Of the total 287 patients, 61 women (21.25%) tested positive for HPV infection. Among all HPV-positive women, 41 (67.2%) were infected with high-risk HPV types. Of the HPV infected women, 41% presented with multiple HPV genotypes. Additionally, of the women infected with oncogenic HPV types, 20 (48.7%) were infected with HPV 16 and 18 and the remaining 21 (51.3%) were infected with other oncogenic types (i.e., HPV59, 39, 73). Women infected with oncogenic HPV types had significantly higher (p=0.001) abnormal Papanicolaou smear tests (Pap test) compared to women who were either HPV negative or positive for non-oncogenic HPV types. The incidence of HPV infection was inversely correlated (p<0.05) with the age of the patients, but there was no correlation (p=0.33) with seasonal variation.
In this study, we observed a high prevalence of HPV infection in American Indian women residing on Northern Plains Reservations. In addition, a significant proportion of the oncogenic HPV infections were other than HPV16 and 18.
Human Papillomavirus; American Indian; Northern Plains; Cervical cancer; Cervical cancer diagnosis