Results of cervical cytology screening showing atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL) indicate risk for high-grade cervical intraepithelial neoplasia (CIN 2 or 3). In a community-based randomized trial we compared the test performance of human papillomavirus (HPV) DNA testing with that of 6-month repeat Papanicolaou (Pap) test in detecting histologically confirmed CIN 2 or 3.
We randomly assigned 212 women aged 16-50 years with ASCUS or LSIL on cervical cytology screening to undergo either immediate HPV DNA testing or a repeat Pap test in 6 months. Cervical swabs for the HPV DNA testing and the Pap smears were obtained by their familiy physicians. We tested the swabs for oncogenic HPV using the Hybrid Capture II assay (Digene Corp., Beltsville, Md.). Community-based pathologists examined the Pap smears. All women were referred for colposcopy by their family physicians. Two gynecological pathologists assessed the histology findings. We calculated test performance in women who completed the trial using CIN 2 or 3 as the reference standard.
A total of 159 women completed the study. Compared with HPV DNA testing, which detected 87.5% (7/8) of the cases of CIN 2 or 3, repeat Pap smear showing high-grade intraepithelial neoplasia (HSIL) detected 11.1% (1/9) of cases (p = 0.004), and repeat Pap smear showing ASCUS, LSIL or HSIL detected 55.6% (5/9) (p = 0.16). Corresponding specificities were 50.6%, 95.2% (p = 0.002) and 55.6% (p = 0.61). Loss to follow-up was 17.1% in the HPV test group and 32.7% in the repeat Pap group (p = 0.009). Given the 7 cases of CIN 2 or 3 detected by HPV testing and the 5 cases detected by the repeat Pap smear, the incremental cost of HPV testing was calculated to be $3003 per additional case of CIN identified.
HPV DNA testing was more costly but was associated with significantly less loss to follow-up. It may detect more cases of CIN 2 or 3 in women with low-grade cytologic abnormalities.
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
Strong evidence now supports the adoption of cervical cancer prevention strategies that explicitly focus on persistent infection with the causal agent, human papillomavirus (HPV). To inform an evidence-based transition to a new public health approach for cervical cancer screening, we summarize the natural history and cervical carcinogenicity of HPV and discuss the promise and uncertainties of currently available screening methods. New HPV infections acquired at any age are virtually always benign, but persistent infections with one of approximately 12 carcinogenic HPV types explain virtually all cases of cervical cancer. In the absence of an overtly persistent HPV infection, the risk of cervical cancer is extremely low. Thus, HPV test results predict the risk of cervical cancer and its precursors (cervical intraepithelial neoplasia grade 3) better and longer than cytological or colposcopic abnormalities, which are signs of HPV infection. The logical and inevitable move to HPV-based cervical cancer prevention strategies will require longer screening intervals that will disrupt current gynecologic and cytology laboratory practices built on frequent screening. A major challenge will be implementing programs that do not overtreat HPV-positive women who do not have obvious long-term persistence of HPV or treatable lesions at the time of initial evaluation. The greatest potential for reduction in cervical cancer rates from HPV screening is in low-resource regions that can implement infrequent rounds of low-cost HPV testing and treatment.
HIV-infected women are at a higher risk of cervical intraepithelial neoplasia (CIN) and cancer than women in the general population, partly due to a high prevalence of persistent human papillomavirus (HPV) infection. The aim of the study was to assess the burden of HPV infection, cervical abnormalities, and cervical cancer among a cohort of HIV-infected women as part of a routine screening in an urban overpopulated slum setting in Mumbai, India.
From May 2010 to October 2010, Médecins Sans Frontières and Tata Memorial Hospital Mumbai offered routine annual Pap smears and HPV DNA testing of women attending an antiretroviral therapy (ART) clinic and a 12-month follow-up. Women with abnormal test results were offered cervical biopsy and treatment, including treatment for sexually transmitted infections (STIs).
Ninety-five women were screened. Median age was 38 years (IQR: 33–41); median nadir CD4-count 143 cells/μL (IQR: 79–270); and median time on ART 23 months (IQR:10–41). HPV DNA was detected in 30/94 women (32%), and 18/94 (19%) showed either low-grade or high-grade squamous intraepithelial lesions (LSIL/HSIL) on Pap smear. Overall, >50% had cervical inflammatory reactions including STIs. Of the 43 women with a cervical biopsy, eight (8.4%) had CIN-1, five (5.3%) CIN-2, and two (2.1%) carcinoma in situ. All but one had HPV DNA detected (risk ratio: 11, 95% confidence interval: 3.3–34). By October 2011, 56 women had completed the 12-month follow-up and had been rescreened. No new cases of HPV infection/LSIL/HSIL were detected.
The high prevalence of HPV infection, STIs, and cervical lesions among women attending an ART clinic demonstrates a need for routine screening. Simple, one-stop screening strategies are needed. The optimal screening interval, especially when resources are limited, needs to be determined.
HIV/AIDS; HPV; women’s health; cervical cancer; operational research; India
Human papillomavirus (HPV) infection is associated with almost all cases of cervical cancer, and cervical cancer is a common malignancy in women living in developing countries. A cross-sectional study was conducted to determine the prevalence of HPV infection, human immunodeficiency virus (HIV) infection, and cervical cytologic abnormalities in women presenting to a sexually transmitted infections clinic in Kampala, Uganda. In June and July, 2002, 135 women underwent complete physical exams including Papanicolaou (Pap) smears. HIV status was evaluated by serology. Cervical and vaginal swabs were obtained by clinicians and tested for HPV genotypes by PCR/reverse blot strip assay. Of the 106 women with cervical swabs adequate for HPV testing, the HPV prevalence was 46.2% (49/106). HIV prevalence was 34.9% (37/106). High risk genotypes 52, 58, and 16 were the genotypes detected most commonly. Eighteen percent (9/49) of women infected with HPV were found to have genotypes 16 and/or 18. Seventy-three percent (27/37) of HIV-positive women versus 16% (10/63) of HIV-negative women had abnormal Pap smears (P <0.0001). Among HIV-positive women, abnormal Pap smears were associated with the presence of high risk HPV genotypes (P <0.001). The majority of women infected with HPV attending this sexually transmitted infections clinic in Uganda were infected with high risk HPV genotypes other than 16 and 18. Future studies should focus on whether current HPV vaccine formulations, that are limited to high risk genotypes 16 and 18, would be effective at decreasing the burden of cervical cancer in this population.
human papillomavirus (HPV); human immunodeficiency virus (HIV); HPV genotypes; cervical cytologic abnormalities; cervical cancer
Worldwide, cervical cancer is a leading cause of cancer related morbidity and mortality. For over 50 years, cervical cytology has been the gold standard for cervical cancer screening. Because of its profound effect on cervical cancer mortality in nations that have adopted screening programs, the Pap smear is widely accepted as the model screening test. Since its introduction, many studies have analyzed the Pap smear and found that it is not without its shortcomings including low sensitivity for detection of cervical intraepithelial neoplasia 2/3. Additionally, the discovery of infection with the human papillomavirus (HPV) as a necessary step in the development of cervical cancer has led to the development of HPV testing as an adjunct to cytology screening. More recently, researchers have compared HPV testing and cytology in the primary screening of cervical cancer. In this review, we will discuss cytologic testing limitations, the role of HPV DNA testing as an alternative screening tool, the impact of the HPV vaccine on screening, and future directions in cervical cancer screening.
Co-testing; Cytology; HPV vaccine; Pap smear limitations; Screening
Human papillomavirus (HPV) infection as of now has been beyond doubt to be the causative agent for cervical carcinoma. Its morphological identification in Pap smear is important.
To define the validity of classical and non-classical cellular changes indicative of low-grade squamous intraepithelial lesion (SIL) encompassing HPV infection in relation to positivity for ‘high risk’ HPV16 as well as for ‘low risk’ HPV6/11.
Materials and Methods:
A total of 3000 Papanicolaou smears were screened, of which 150 were reported as low grade-SIL encompassing HPV infection (LSIL-HPV). Subsequently cervical scrapes from these 150 subjects, along with equal number of normal women as controls, were collected and processed for HPV deoxy-ribonucleic acid testing by polymerase chain reaction (PCR).
On the basis of cytomorphological characteristics in Pap smears, HPV infection were categorized into the following two groups: Classical (koilocytic) changes (CC) encountered in 30 women and non-classical changes (NCC) encountered in 120 women. It was observed that 21 (70%) CC and 46 (38.3%) NCC of HPV infection were positive for HR-HPV16; however only 12 cases (10%) of NCC and two cases (6.6%) of CC were positive for LR-HPV 6/11. Majority (41.7%) of HPV positive cases were reported in the age group of 25 to 30 years and HPV positivity decreased with the increasing age.
Classical cellular changes are not the only diagnostic features for HPV infection in Pap smear, non-classical diagnostic features also support the diagnosis of HPV infection and may be positive for HR-HPV16.
HPV deoxyribonucleic acid; koilocytes; LSIL-HPV; Pap smear; PCR
Human papillomavirus (HPV) is the main risk factor for invasive cervical cancer. High risk ratios are found in cross-sectional data on HPV prevalence. The question raised is whether this present evidence is sufficient for making firm recommendations on HPV screening. A validated cervical cancer screening model was extended by adding HPV infection as a possible precursor of cervical intraepithelial neoplasia (CIN). Two widely different model quantifications were constructed so that both were compatible with the observed HPV risk ratios. One model assumed a much longer duration of HPV infection before progressing to CIN and a higher sensitivity of the HPV test than the other. In one version of the model, the calculated mortality reduction from HPV screening was higher and the (cost-)effectiveness was much better than for Pap smear screening. In the other version, outcomes were the opposite, although the cost-effectiveness of the combined HPV + cytology test was close to that of Pap smear screening. Although small follow-up studies and studies with limited strength of design suggest that HPV testing may well improve cervical cancer screening, only large longitudinal screening studies on the association between HPV infection and the development of neoplasias can give outcomes that would enable a firm conclusion to be made on the (cost-)effectiveness of HPV screening. Prospective studies should address women aged 30-60 years.
To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction.
Cervicovaginal lavages collected from 19,512 women attending a health maintenance program were retrospectively tested for HPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a research test. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance (ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively with routine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervical intraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated.
A baseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up than a normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who would develop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+ 10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevated risk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk of CIN3+ compared with women with a low-grade squamous intraepithelial Pap.
HPV testing to rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16 and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficient algorithm for cervical cancer screening, especially in women age 30 years or older.
Persistent cervical infections by approximately 15 carcinogenic genotypes of human papillomavirus (HPV) cause virtually all cases of cervical cancer and its immediate precancerous precursor, cervical intraepithelial neoplasia grade 3 or carcinoma in situ. As is shown in a meta-analysis by Koshiol et al. (Am J Epidemiol 2008;168:123–137), detection of carcinogenic HPV viral persistence could be used to identify women at the greatest risk of cervical precancer. Specifically, women who have carcinogenic HPV infection that persists for at least 1 year versus those whose infections clear are at significantly elevated risk of having or developing cervical precancer. However, before detection of HPV persistence can be used in cervical cancer screening, several considerations need to be addressed: 1) validation and Food and Drug Administration approval of a reliable HPV genotyping test, 2) rational clinical algorithms based on risk of precancer and cancer for the clinical management of HPV persistence, 3) clinician and patient acceptability of monitoring of HPV infections (including not responding excessively to the first positive HPV test and waiting 1–2 years for infections to either persist or resolve), and 4) patient compliance with recommended follow-up. Investigators will need to address these and other key issues in order to realize the potential utility of HPV viral monitoring for improving the accuracy of cervical cancer screening.
human papillomavirus 16; human papillomavirus 18; longitudinal studies; papillomavirus infections; uterine cervical neoplasms
Despite the availability of preventive strategies (screening tests and vaccines), cervical cancer continues to impose a significant health burden in low- and medium-resourced countries. HIV-infected women are at increased risk for infection with human papillomavirus (HPV) and thus development of cervical squamous intraepithelial neoplasia (CIN).
Study participants included HIV-infected women enrolling the prospective open cohort of Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (IPEC/FIOCRUZ). At cohort entry, women were subjected to conventional Papanicolaou test, HPV-DNA test and colposcopy; lesions suspicious for CIN were biopsied. Histopathology report was based on directed biopsy or on specimens obtained by excision of the transformation zone or cervical conization. Poisson regression modeling was used to assess factors associated with CIN2+ diagnosis.
The median age of the 366 HIV-infected women included in the study was 34 years (interquartile range: 28–41 years). The prevalence of CIN1, CIN2 and CIN3 were 20.0%, 3.5%, and 2.2%, respectively. One woman was found to have cervical cancer. The prevalence of CIN2+ was 6.0%. Factors associated with CIN2+ diagnosis in the multivariate model were age < years compared to ≥35 years (aPR = 3.22 95%CI 1.23–8.39), current tobacco use (aPR = 3.69 95%CI 1.54–8.78), nadir CD4 T-cell count <350 cells/mm3 when compared to ≥ 350 cells/mm3 (aPR = 6.03 95%CI 1.50–24.3) and concomitant diagnosis of vulvar and/or vaginal intraepithelial lesion (aPR = 2.68 95%CI 0.99–7.24).
Increased survival through wide-spread use of highly active antiretroviral therapy might allow for the development of cervical cancer. In Brazil, limited cytology screening and gynecological care adds further complexity to the HIV-HPV co-infection problem. Integrated HIV care and cervical cancer prevention programs are needed for the prevention of cervical cancer mortality in this group of women.
To review concepts, information, obstacles, and approaches to cervical cancer screening and prevention as vaccination against human papillomavirus (HPV) types 16 and 18 is adopted.
Expert forum, conducted September 12–13, 2008, hosted by the Society of Gynecologic Oncologists, including 56 experts in cervical cancer and titled Future Strategies of Cervical Cancer Prevention: What Do We Need to Do Now to Prepare?
The current approach to cervical cancer screening in the U.S. is limited by its opportunistic nature. If given to women before exposure, a vaccine against HPV 16, 18 can decrease cervical cancer risk by up to 70%. The impact on abnormal cytology and cervical intraepithelial neoplasia (CIN) will be less but still substantial. As the prevalence of high-grade CIN falls, fewer women with positive screening tests will have truly preinvasive disease. To minimize harm from false-positive tests in women who are at low risk for cancer because of early vaccination, later initiation of and longer intervals between screenings are ideal. However, the vaccine is less effective when administered after first intercourse, and delivering and documenting HPV vaccination to girls at optimal ages may prove difficult.
Until population-based data on the performance of cytology, HPV testing, and alternate screening or triage interventions become available, modifying current screening guidelines is premature. Current recommendations to initiate screening as late as age 21 and to screen less often than annually are appropriate for young women known to have been vaccinated before first intercourse.
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
Objective: Human papillomavirus (HPV) is the major cause of cervical carcinoma and cervical intraepithelial neoplasia worldwide. Certain HPV types have a strong association with and probably a causative role in the
pathogenesis of premalignant cervical lesions. Epidemiologic studies in women infected by the human immunodeficiency
virus (HIV) have shown an increased incidence of squamous intraepithelial lesions (SILs), whichwere predominantly
high-grade. Six to 30 per cent of women diagnosed with atypical squamous cells of undetermined
significance (ASCUS) on a Papanicolaou (Pap) smear harbor SIL in normal screening populations. This study was
undertaken to determine the presence of low- and high-risk HPV types in women infected by HIV and to correlate
the results to those of the Pap smear.
Study design: HPV DNA typing (low- and high-risk) by Digene™ (Digene Corporation, Gathesburg, MD) hybrid capture methodology was performed on cervical swabs from 209 HIV-positive women. The results of HPV typing
were correlated with those of the Pap smear in a retrospective analysis.
Results: One hundred and one women (48%) tested positive for HPV subtypes by DNA typing by the hybrid capture method. Of these, 64 patients (63%) had Pap smears whichwere read as being normal, having benign cellular
changes, or having ASCUS (favor reactive process). Of these, 19 patients tested positive for both high-risk and
low-risk subtypes, 32 patients tested positive only for high-risk subtypes, and 13 patients tested positive only for
Conclusion: HPV subtyping identifies a significant group of HIV-positive women who are at risk for developing cervical intraepithelial neoplasia, although they may not show significant abnormalities on their Pap smears.
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
Immunosuppressive therapy protects the transplanted organ but predisposes the recipient to chronic infections and malignancies. Transplant patients are at risk of cervical intraepithelial neoplasia (CIN) and cervical cancer resulting from an impaired immune response in the case of primary infection or of reactivation of a latent infection with human papillomavirus of high oncogenic potential (HR-HPV).
The aim of this study was to assess the prevalence of HR-HPV cervical infections and CIN in 60 female kidney graft recipients of reproductive age in comparison to that in healthy controls. Cervical swabs were analyzed for the presence of HR-HPV DNA. HR-HPV-positive women remained under strict observation and were re-examined after 24 months for the presence of transforming HR-HPV infection by testing for HR-HPV E6/E7 mRNA. All the HR-HPV-positive patients were scheduled for further diagnostic tests including exfoliative cytology, colposcopy and cervical biopsy.
The prevalence of HR-HPV did not differ significantly between the study group and the healthy controls (18% vs 25%, p = 0.37). There was no correlation between HR-HPV presence and the immunosuppresive regimen, underlying disease, graft function or time interval from transplantation. A higher prevalence of HR-HPV was observed in females who had had ≥2 sexual partners in the past. Among HR-HPV-positive patients, two cases of CIN2+ were diagnosed in each group. In the course of follow-up, transforming HR-HPV infections were detected in two kidney recipients and in one healthy female. Histologic examination confirmed another two cases of CIN2+ developing in the cervical canal.
Female kidney graft recipients of reproductive age are as exposed to HR-HPV infection as are healthy individuals. Tests detecting the presence of HR-HPV E6/E7 mRNA offer a novel diagnostic opportunity in those patients, especially in those cases where lesions have developed in the cervical canal.
Renal transplantation; HPV mRNA; HR-HPV; Immunosuppressive therapy; Cervical intraepithelial neoplasia
HIV-infected women are at increased risk for developing cervical cancer. Women living in resource-limited countries are especially at risk due to poor access to cervical cancer screening and treatment. We evaluated three cervical cancer screening methods to detect cervical intraepithelial neoplasia grade 2 and above (CIN 2+) in HIV-infected women in South Africa; Pap smear, visual inspection with 5% acetic acid (VIA) and human papillomavirus detection (HPV).
HIV-infected women aged 18–65 were recruited in Johannesburg. A cross-sectional study evaluating three screening methods for the detection of the histologically-defined gold standard CIN-2 + was performed. Women were screened for cervical abnormalities with the Digene HC2 assay (HPV), Pap smear and VIA. VIA was performed by clinic nurses, digital photographs taken and then later reviewed by specialist physicians. The sensitivity, specificity and predictive valves for CIN-2 + were calculated using maximum likelihood estimators.
1,202 HIV-infected women participated, with a median age of 38 years and CD4 counts of 394 cells/mm3. One third of women had a high grade lesion on cytology. VIA and HPV were positive in 45% and 61% of women respectively. Estimated sensitivity/specificity for HPV, Pap smear and VIA for CIN 2+ was 92%/51.4%, 75.8%/83.4% and 65.4/68.5% (nurse reading), respectively. Sensitivities were similar, and specificities appeared significantly lower for the HPV test, cytology and VIA among women with CD4 counts ≤200 cells/mm3 as compared to CD4 counts >350 cells/mm3.
Although HPV was the most sensitive screening method for detecting CIN 2+, it was less specific than conventional cytology and VIA with digital imaging review. Screening programs may need to be individualized in context of the resources and capacity in each area.
Persistent infections with high-risk types of human papillomavirus (HPV) are associated with the development of cervical neoplasia. Compared to cytology HPV testing is more sensitive in detecting high-grade cervical cancer precursors, but with lower specificity. HPV based primary screening for cervical cancer is currently discussed in Germany. Decisions should be based on a systematic evaluation of the long-term effectiveness and cost-effectiveness of HPV based primary screening.
What is the long-term clinical effectiveness (reduction in lifetime risk of cervical cancer and death due to cervical cancer, life years gained) of HPV testing and what is the cost-effectiveness in Euro per life year gained (LYG) of including HPV testing in primary cervical cancer screening in the German health care context? How can the screening program be improved with respect to test combination, age at start and end of screening and screening interval and which recommendations should be made for the German health care context?
A previously published and validated decision-analytic model for the German health care context was extended and adapted to the natural history of HPV infection and cervical cancer in order to evaluate different screening strategies that differ by screening interval, and tests, including cytology alone, HPV testing alone or in combination with cytology, and HPV testing with cytology triage for HPV-positive women. German clinical, epidemiological and economic data were used. In the absence of individual data, screening adherence was modelled independently from screening history. Test accuracy data were retrieved from international meta-analyses. Predicted outcomes included reduction in lifetime-risk for cervical cancer cases and deaths, life expectancy, lifetime costs, and discounted incremental cost-effectiveness ratios (ICER). The perspective of the third party payer and 3% annual discount rate were adopted. Extensive sensitivity analyses were performed in order to evaluate the robustness of results and identify areas of future research.
In the base case analysis screening resulted in a 53% to 97% risk reduction for cervical cancer with a discounted ICER between 2,600 Euro/LYG (cytology alone every five years) and 155,500 Euro/LYG (Annual cytology age 20 to 29 years, and annual HPV age 30 years and older). Annual cytology, the current recommended screening strategy in Germany, was dominated. In sensitivity analyses variation in the relative increase in the sensitivity of HPV testing as compared to cytology, HPV test costs, screening adherence, HPV incidence, and annual discount rate influenced the ICER results. Variation in the screening start age also influenced the ICER. All cytology strategies were dominated by HPV screening strategies, when relative sensitivity increase by HPV testing compared to cytology was higher (scenario analysis with data for test accuracy from German studies). HPV testing every one, two or three years was more effective than annual cytology. With increased screening adherence a longer screening interval and with low screening adherence a shorter interval would be more cost-effective. With a reduction in HPV incidence of more than 70% triennial HPV screening in women aged 30 years and older (and biennial Pap screening in women aged 20 to 29 years) is cost-effective. The discounted ICER increases with increasing annual discount rate. Increasing screening start age to 25 years had no relevant loss in effectiveness but resulted in lower costs. An optimal strategy may be biennial HPV testing age 30 years and older with biennial cytology at age 25 to 29 years (ICER of 23,400 Euro/LYG).
Based on these results, HPV-based cervical cancer screening is more effective than cytology and could be cost-effective if performed at intervals of two years or greater. Increasing the age at screening start to 25 years causes no relevant loss in effectiveness but saves resources. In the German context an optimal screening strategy could be biennial HPV testing at age 30 years and older with biennial cytology at the age of 25 to 29 years. An extension to a three-yearly screening interval requires substantially improved screening adherence or a higher relative increase in the sensitivity of HPV testing as compared to cytology. The implementation of an organised screening program for quality-controlled introduction of HPV-screening and -vaccination with continued systematic outcome evaluation is recommended.
cervix; cervix of uterus; cervical carcinoma; carcinoma; cancer; cytology; human papillomavirus; HPV; DNA; HPV-DNA diagnosis; diagnosis; early finding; screening; primary screening; test; decision-analytical modelling; Markov model; effectiveness; systematic review; meta-analysis; Health Technology Assessment; long-term effectiveness; cost-effectiveness; health economic evaluation
Smoking has been associated with cervical cancer. We examined whether smoking increases the risk for high-grade cervical lesions in women with high-risk human papillomavirus (HPV) infection.
In a population-based cohort study, 8,656 women underwent a structured interview, and subsequently cervical cells were obtained for HPV DNA testing. Women with high-risk HPV infection and no prevalent cervical disease at baseline (n=1,353) were followed through the Pathology Data Bank for cervical lesions for up to 13 years. Separate analyses of women with persistent high-risk HPV infection were also conducted. Hazard ratios (HRs) for a diagnosis of cervical intraepithelial neoplasia grade 3 or worse/high-grade squamous intraepithelial lesions or worse (CIN3+) and the corresponding 95% confidence intervals (CIs) were calculated in the 2 groups.
Among high-risk HPV positive women an increased risk for CIN3+ was associated with long-term smoking (≥10 years) and heavy smoking (≥20 cigarettes/day). In the subgroup of women with persistent HPV infection heavy smoking was also associated with a statistically significantly higher risk for CIN3+ than never smoking (HR, 1.85; 95% CI, 1.05–3.22, adjusted for length of schooling, parity and HPV type at baseline). The average number of cervical cytology screening tests per year during follow-up did not explain the differences in risk in relation to smoking (p=0.4).
Smoking is associated with an increased risk for subsequent high-grade cervical lesions in women with persistent high-risk HPV infection.
Our study adds to the understanding of the role of smoking in the natural history of HPV and cervical carcinogenesis.
cervical intraepithelial lesions; smoking; human papillomavirus
This chapter addresses the natural history of anogenital human papillomavirus (HPV) infection. Cervical infections are the best understood HPV infection. Cervical HPV persistence is the known necessary event for the development of cervical cancer. New infections appearing at any age are benign unless they persist. Several long-term natural history studies have now shed light on the very low risk of cervical intraepithelial neoplasia (CIN) 3+ in women past the peak of HPV acquisition (e.g., 30 or older) who are HPV-negative or clear their HPV. Although data on transmission of HPV are finally emerging, rates of transmission between heterosexual couples vary widely among studies. Factors that affect the calculations of these rates include a) intervals between testing points, b) rates of concordance or discordance at baseline, and c) difficulty in defining established infections versus contamination. Both cervix to anus and anus to cervix autoinoculation in the same woman appears to be quite common. Whether either site serves as a long-term reservoir is unknown. Studies show that anal infections in women and in men who have sex with men are quite common with cumulative rates up to 70–90%. Similarly, clearance of anal HPV is also common, with few individuals showing persistence unless they are human immunodeficiency virus (HIV)-infected. HIV strongly influences the development of anal intraepithelial neoplasia (AIN). The few studies on the natural history of AIN in HIV-infected men suggest that high-grade AIN is a precursor to invasive anal cancer. Although no natural history studies of AIN are available in women, women with other HPV-associated lesions, including CIN3+ and vulvar cancer, have higher rates of anal cancer. Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia is poorly understood. Cumulative rates of HPV are extremely high in men and risks are associated with sexual behavior. Unlike women, prevalence rates are steady across all ages, suggesting that men do not develop protection against reinfection.
HPV; Natural history; Transmission; Male infections; Anal disease
Objective: HIV-positive women are known to be at high-risk of human papillomavirus (HPV) infection and its associated cervical pathology. Here, we describe the prevalence and distribution of HPV genotypes among HIV-positive and -negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN).
Methods: We report data on 1,371 HIV-positive women and 8,050 HIV-negative women, aged 17–65 years, recruited into three sequential studies in Cape Town, South Africa, conducted among women who had no history of cervical cancer screening recruited from the general population. All women were tested for HIV. Cervical samples were tested for high-risk HPV DNA (Hybrid Capture 2) with positive samples tested to determine the specific genotype (Line Blot). CIN status was determined based on colposcopy and biopsy.
Results: The HPV prevalence was higher among HIV-positive women (52.4%) than among HIV-negative women (20.8%) overall and in all age groups. Younger women, aged 17–19 years, had the highest HPV prevalence regardless of HIV status. HIV-positive women were more likely to have CIN 2 or 3 than HIV-negative women. HPV 16, 35, and 58 were the most common high-risk HPV types with no major differences in the type distribution by HIV status. HPV 18 was more common in older HIV-positive women (40–65 years) with no or low grade disease, but less common in younger women (17–29 years) with CIN 2 or 3 compared to HIV-negative counterparts (p < 0.03). Infections with multiple high-risk HPV types were more common in HIV-positive than HIV-negative women, controlling for age and cervical disease status.
Conclusion: HIV-positive women were more likely to have high-risk HPV than HIV-negative women; but, among those with HPV, the distribution of HPV types was similar by HIV status. Screening strategies incorporating HPV genotyping and vaccination should be effective in preventing cervical cancer in both HIV-positive and -negative women living in sub-Saharan Africa.
HIV-infections; HPV; genotype; HPV vaccine; cervical cancer screening
There have been no published studies of carcinogenic human papillomavirus (HPV)--the necessary cause of cervical cancer--in Haiti, a nation that has one of the greatest burdens of cervical cancer globally.
Characterize prevalence of carcinogenic HPV and the prevalence of individual carcinogenic HPV genotypes in women with cervical precancer or cancer, cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+).
Women (n=9,769; aged 25-60 years) were screened for carcinogenic HPV by Hybrid Capture 2 (HC2; Qiagen, Gaithersburg, MD). Carcinogenic HPV positives underwent colposcopy and visible lesions were biopsied. A subset of carcinogenic HPV positives was tested for individual HPV genotypes using a GP5+/6+ assay.
The prevalence of carcinogenic HPV was 19.0% (95% confidence interval: 18.4%-19.9%) and decreased with increasing age (ptrend < 0.001). Women with 3 or more sexual partners and who started sex before the age of 18 years had twice the age-adjusted prevalence of carcinogenic HPV of women with one partner and who started sex after the age of 21 (24.3% vs. 12.9%, respectively). HPV16 and HPV35 were the most common HPV genotypes detected in CIN2+ and more common in women with CIN2+ than those without CIN2+. HPV16 and/or HPV18 were detected in 21.0% of CIN2 (n = 42), 46.2% of CIN3 (n = 52), and 80% of cancers (n = 5).
The prevalence of carcinogenic HPV in Haiti was much greater than the prevalence in other Latin American countries. High carcinogenic HPV prevalence and a lack of cervical cancer screening may explain the high burden of cervical cancer in Haiti.
Few data are available on the epidemiology of HPV and cervical cancer among Chinese women younger than 25 years old. This study aimed to estimate the HPV infection rate and the prevalence of cervical intraepithelial neoplasia (CIN) in women aged 18-25, as well as their knowledge of and attitudes towards HPV vaccination.
A population-based cervical cancer screening study was conducted on women aged 18-25 in Jiangsu province in 2008. Participants provided socio-demographic, reproductive and behavioral information and completed a survey about their knowledge of and attitudes towards HPV vaccination. Women then underwent a gynecologic exam to provide two cervical exfoliated cell samples for high risk HPV DNA testing and liquid-based cytology (LBC) as well as visual inspection with acetic acid (VIA). Women testing positive for any test were referred to colposcopy and biopsy. The gold standard for diagnosis of cervical lesions was directed or random biopsies.
Within the sample of 316 women, 3.4% of them were diagnosed with CIN grade 2 or worse lesions and 17.1% were found to be positive for HPV DNA. Among these young women, extra-marital sexual behavior of them (OR=2.0, 95%CI: 1.1-3.8) or their husbands (OR=2.6, 95%: 1.4-4.7) were associated with an increased risk of HPV positivity. Although overall HPV awareness was low, after a brief educational intervention, 98.4% reported they would electively receive HPV vaccination and would also recommend that their daughters be vaccinated. However, most urban and rural women reported their ideal maximum out-of-pocket contribution for HPV vaccination to be less than 500 RMB and 50-100 RMB, respectively.
Our study indicates cervical disease burden is relatively high among sampled Chinese women aged 18-25. Appropriate educational interventions for female adolescents and strategies to subsidize vaccine costs are definitely needed to ensure the effectiveness of vaccination campaigns in China.
Cervical cancer; Cervical intraepithelial neoplasia; Human papillomavirus; Knowledge; Attitude
Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+).
In 2005, 710 HIV+ Rwandan women ≥25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women.
Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included ≥7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and ≥7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm3, CI = 0.40-0.97).
In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women.
Cervical cytology and human papillomavirus (HPV) DNA co-testing is recommended as a screening method for detecting cervical lesions. However, for women who are HPV-positive but cytology-negative, the appropriate management and significance of HPV-58 infection remain unknown.
This study of prevalent HPV detected at baseline with a median follow-up of 3.2 years evaluated the risk factors associated with cervical abnormalities and assessed the significance of HPV-58 infection. A total of 265 women were enrolled. All high-grade squamous intraepithelial lesions (HSIL) that were detected by cytology were confirmed by histology. Histological diagnoses of cervical intraepithelial neoplasia 2/3 were classified as HSIL. Women were classified into four groups according to the HPV genotype that was detected at their first visit: HPV-58 (n = 27), HPV-16 (n = 52; 3 women had HPV-58 co-infection), ten other high risk (HR) types (n = 79), or low/undetermined risk types (n = 107).
Of 265 women, 20 (7.5%) had HSIL on their follow-up examinations. There were significant differences in the cumulative incidence of HSIL between the four groups (p<0.001). The 5-year cumulative incidence rates of HSIL were 34.0% (95% CI: 17.3–59.8%) in HPV-58 positive cases, 28.0% (95% CI: 13.8–51.6) in HPV-16 positive cases, 5.5% (95% CI: 2.1–14.0%) in one of the ten other types of HR-HPV positive cases, and 0% in women with low/undetermined risk HPV. When seen in women with HR-HPV (n = 158), persistent HPV infection was a significant factor associated with the development of HSIL (hazard ratio = 15.459, 95% CI: 2.042–117.045). Women with HPV-58 had a higher risk (hazard ratio = 5.260, 95% CI: 1.538–17.987) for the development of HSIL than women with HPV-16 (hazard ratio = 3.822, 95% CI: 1.176–12.424) in comparison with women with other types of HR-HPV.
HPV-58 has a high association with the development of HSIL in women who are HPV-positive and cytology-negative.