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1.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
Context
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.
Objective
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.
Results
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.
Conclusion
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.
doi:10.1001/jama.2012.5664
PMCID: PMC3556987  PMID: 22820789
2.  Comparison of human papillomavirus DNA testing and repeat Papanicolaou test in women with low-grade cervical cytologic abnormalities: a randomized trial 
Background
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.
Methods
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.
Results
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.
Interpretation
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.
PMCID: PMC80165  PMID: 11022584
3.  Clinical Implications of the Cervical Papanicolaou Test Results in the Management of Anal Warts in HIV-Infected Women 
PLoS ONE  2013;8(11):e81751.
The Papanicolaou test (or Pap test) has long been used as a screening tool to detect cervical precancerous/cancerous lesions. However, studies on the use of this test to predict both the presence and change in size of genital warts are limited. We examined whether cervical Papanicolaou test results are associated with the size of the largest anal wart over time in HIV-infected women in an on-going cohort study in the US. A sample of 976 HIV-infected women included in a public dataset obtained from the Women’s Interagency HIV Study (WIHS) was selected for analysis. A linear mixed model was performed to determine the relationship between the size of anal warts and cervical Pap test results. About 32% of participants had abnormal cervical Pap test results at baseline. In the adjusted model, a woman with a result of Atypia Squamous Cell Undetermined Significance/Low-grade Squamous Intraepithelial Lesion (ASCUS/LSIL) had an anal wart, on average, 12.81 mm2 larger than a woman with normal cervical cytology. The growth rate of the largest anal wart after each visit in a woman with ASCUS/LSIL was 1.56 mm2 slower than that of a woman with normal cervical results. However, they were not significant (P = 0.54 and P = 0.82, respectively). This is the first study to examine the relationship between cervical Pap test results and anal wart development in HIV-infected women. Even though no association between the size of anal wart and cervical Pap test results was found, a screening program using anal cytology testing in HIV-infected women should be considered. Further studies in cost-effectiveness and efficacy of an anal cytology test screening program are warranted.
doi:10.1371/journal.pone.0081751
PMCID: PMC3842937  PMID: 24312348
4.  Human Papillomavirus Typing in HIV-Positive Women 
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 low-risk subtypes.
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.
doi:10.1155/S1064744901000163
PMCID: PMC1784640  PMID: 11495559
5.  Self-reported history of Pap-smear in HIV-positive women in Northern Italy: a cross-sectional study 
BMC Cancer  2010;10:310.
Background
The incidence of invasive cervical cancer in HIV-positive women is higher than in the general population. There is evidence that HIV-positive women do not participate sufficiently in cervical cancer screening in Italy, where cervical cancer is more than 10-fold higher in women with AIDS than in the general population. The aim of the present study was to evaluate the history of Pap-smear in HIV-positive women in Italy in recent years. We also examined the sociodemographic, clinical, and organizational factors associated with adherence to cervical cancer screening.
Methods
A cross-sectional study was conducted between July 2006 and June 2007 in Emilia-Romagna region (Northern Italy). All HIV-positive women who received a follow-up visit in one of the 10 regional infectivology units were invited to participate. History of Pap-smear, including abnormal smears and subsequent treatment, was investigated through a self-administered anonymous questionnaire. The association between lack of Pap-smear in the year preceding the interview and selected characteristics was assessed by means of odds ratios (OR) and 95% confidence intervals adjusted for study centre and age.
Results
A total of 1,002 HIV-positive women were interviewed. Nine percent reported no history of Pap-smear, and 39% had no Pap-smear in the year prior to the date of questionnaire (last year). The lack of Pap-smear in the last year was significantly associated with age <35 years (OR = 1.4, compared to age ≥45 years), lower education level (OR = 1.3), first HIV-positive test in the last 2 years (OR = 1.4), and CD4 count <200 cells/μl (OR = 1.6). Conversely, when women were advised by a gynecologist rather than other health workers to undergo screening, it significantly increased adherence. Non-significantly higher proportions of lack of Pap-smear in the last year were found in women born in Central-Eastern Europe (OR = 1.8) and Africa (OR = 1.3). No difference in history of Pap-smear emerged by mode of HIV-acquisition or AIDS status.
Three hundred five (34%) women reported a previous abnormal Pap-smear, and of the 178 (58%) referred for treatment, 97% complied.
Conclusions
In recent years the self-reported history of Pap-smear in HIV-positive women, in some public clinics in Italy, is higher than previously reported, but further efforts are required to make sure cervical cancer screening is accessible to all HIV-positive women.
doi:10.1186/1471-2407-10-310
PMCID: PMC2904281  PMID: 20565935
6.  Prevalence of cervical neoplastic lesions and Human Papilloma Virus infection in Egypt: National Cervical Cancer Screening Project 
Background
Data from Egyptian studies provide widely varying estimates on the prevalence of pre-malignant and malignant cervical abnormalities and human papilloma virus (HPVs) infection. To define the prevalence and risk factors of pre-invasive and invasive cervical cancer (cacx), a community based full-scale cross sectional, household survey including 5453 women aged between 35 and 60 years was conducted.
Methods
The study period was between February 2000 and December 2002. Initially, conventional Papanicolaou (Pap) smears were evaluated using the Bethesda system (TBS), followed by colposcopic guided biopsy (CGB) for all epithelial abnormalities (EA). In a third step, HPV was tested on all EA by in-situ hybridization (ISH) using first the broad spectrum HPV probe recognizing HPVs 6, 11, 16, 18, 30, 31, 35, 45, 51 and 52 followed by subtyping with probes 6/11, 16/18 and 31/33. Lastly, unequivocal cases were immunostained for herpes simplex type-2 (HSV-2), cytomegalovirus (CMV), and human immunodeficiency virus (HIV).
Results
EA representing 7.8% (424/5453), were categorized into atypical squamous cell of undetermined significance (ASCUS) (34.4%), atypical glandular cell of undetermined significance (AGCUS) (15.3%), combined ASCUS and AGCUS (3.1%), low grade squamous intraepithelial lesions (SIL) (41.0%), high grade SIL (5.2%) and invasive lesions (1%). CGB of EA (n = 281) showed non neoplastic lesions (12.8%), atypical squamous metaplasia (ASM) (19.2%), cervical intraepithelial neoplasia I (CIN) (44.4%), CIN II (4.4%), CINIII (2.8%), endocervical lesions (5.2%), combined squamous and endocervical lesions (10.0%), invasive squamous cell carcinoma (SCC) (0.02%) and extranodal marginal zone B cell lymphoma (MZBCL) (0.02%). The overall predictive value of cytology was 87% while the predictive value for high grade lesions was 80%. On histological basis, HPVs were present in 94.3% of squamous lesions while it was difficult to be identified in endocervical ones. ISH revealed positivity for pan HPV in 65.9% of the studied biopsies (n = 217), with incorporation of the viral genome HPV 6/11, 16/18 and 31/33 in 11.1%, 33.3% and 17.1% respectively. Multiple HPVs infections were identified in 0.02%.
Conclusion
Pre-invasive high grade lesions and invasive cervical carcinoma represent 0.5% and 0.04% respectively in Egyptian women. HPV mostly 16/18 as a risk factor (p < 0.001), was frequently associated with mixed infections (p < 0.001) and bilharzial infestation (p < 0.001).
doi:10.1186/1750-9378-2-12
PMCID: PMC1945019  PMID: 17610742
7.  Comparison of Conventional Cervical Cytology versus Visual Inspection with Acetic Acid (VIA) among HIV-Infected Women in Western Kenya 
Objective
To determine the accuracy of visual inspection with Acetic Acid (VIA) versus conventional Pap smear as a screening tool for cervical intraepithelial neoplasia (CIN)/cancer among HIV-infected women.
Materials and Methods
150 HIV-infected women attending the Moi Teaching and Referral Hospital HIV clinic in Eldoret underwent conventional Pap smear, VIA, colposcopy and biopsy. VIA and Pap smears were done by nurses while colposcopy and biopsy were done by a physician. Receiver Operating Characteristic (ROC) analysis was conducted to compare the accuracies between VIA and Pap smear in sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
Results
Among the study participants: VIA was abnormal in 55.3% (83/150, CI=47.0–63.5%); Pap smear showed atypical squamous cells of undetermined significance (ASCUS) or worse in 43.7% (59/135, CI=35.2–52.5%) and 10% (15/150) of the Pap smears were unsatisfactory. Of the abnormal Pap smears, 3% (2/59) had ASCUS, 7% (4/59) had ASC-high grade, 60% (35/59) had low-grade squamous intraepithelial lesions (SIL), 29% (17/59) had high grade SIL, and 2% (1/59) was suspicious for cervical cancer. Using cervical intraepithelial neoplasia (CIN) 2 or higher disease on biopsy as an end point, VIA has a sensitivity of 69.6% (CI=55.1–81.0%), specificity of 51.0% (CI=41.5–60.4%), PPV of 38.6% (CI=28.8–49.3%) and NPV of 79.1% (CI=67.8–87.2%). For conventional Pap smear, sensitivity was 52.5% (CI=42.1–71.5%), specificity 66.3% (CI=52.0–71.2%), PPV 39.7% (CI=27.6–51.8%), and NPV 76.8% (CI=67.0–85.6%).
Conclusion
VIA is comparable to Pap smear and acceptable for screening HIV-infected women in resource limited settings such as Western Kenya.
doi:10.1097/LGT.0b013e3182320f0c
PMCID: PMC3289722  PMID: 22126834
Visual Inspection with Acetic Acid (VIA); Pap smear; Kenya; HIV
8.  Anal Dysplasia Screening 
Executive Summary
Objective
This review considered the role of the anal Pap test as a screening test for anal dysplasia in patients at high risk of anal SCC. The screening process is now thought to be improved with the addition of testing for the human papillomavirus (HPV) in high-risk populations. High-resolution anoscopy (a method to view the rectal area, using an anoscope, a lighted instrument inserted into the rectum) rather than routine anoscopy-guided biopsy, is also now considered to be the diagnostic standard.
Clinical Need: Target Population and Condition
Anal cancer, like cervical cancer, is a member of a broader group of anogenital cancers known to be associated with sexually transmitted viral HPV infection. Human papillomavirus is extremely prevalent, particularly in young, sexually active populations. Sexual practices involving receptive anal intercourse lead to significantly elevated risk for anal dysplasia and cancer, particularly in those with immune dysfunctions.
Anal cancer is rare. It occurs at a rate of about 1 to 2 per 100,000 in the general population. It is the least common of the lower gastrointestinal cancers, representing about 4% of them, in contrast to colorectal cancers, which remain the third most commonly diagnosed malignancy. Certain segments of the population, however, such as HIV-positive men and women, other chronic immune-suppressed patients (e.g., after a transplant), injection drug users, and women with genital dysplasia /cancer, have a high susceptibility to anal cancer.
Those with the highest identified risk for anal cancer are HIV-positive homosexual and bisexual men, at a rate of 70 per 100,000 men. The risk for anal cancer is reported to be increasing dramatically in HIV-positive males and females, particularly since the introduction of highly active antiretroviral therapy in the mid-1990s. The introduction of effective viral therapy has been said to have transformed the AIDS epidemic in developed countries into a chronic disease state of long-term immunosuppression. In Ontario, there are about 25,000 people living with HIV infection; more than 6,000 of these are women. About 28% of the newly diagnosed HIV infections are in women, a doubling since 1999. It has also been estimated that 1 of 3 people living with HIV do no know it.
Health Technology Description
Anal Pap test screening involves the blind insertion of a swab into the anal canal and fixing cells either on a slide or in fluid for cytological examination. Anal cytology classified by the standardized Bethesda System is the same classification used for cervical cytology. It has 4 categories: normal, atypical squamous cells of uncertain significance, or squamous intraepithelial lesions which are further classified into low- or high-grade lesions. Abnormal cytological findings are subjected to further evaluations by high-resolution anoscopy, a technique similar to cervical colposcopy, and biopsy. Several HPV deoxyribonucleic acid detection technologies such as the Hybrid 11 Capture and the polymerase chain reaction are available to detect and differentiate HPV viral strains.
Unlike cervical cancer, there are no universally accepted guidelines or standards of care for anal dysplasia. Moreover, there are no formal screening programs provincially, nationally, or internationally. The New York State Department of Health AIDS Institute has recently recommended (March 2007) annual anal pap testing in high-risk groups. In Ontario, reimbursement exists only for Pap tests for cervical cancer screening. That is, there is no reimbursement for anal Pap testing in men or women, and HPV screening tests for cervical or anal cancer are also not reimbursed.
Methods
The scientific evidence base was evaluated through a systematic literature review. Assessments of current practices were obtained through consultations with various agencies and individuals including the Ministry of Health and Long-Term Care AIDS Bureau; Public Health Infectious Diseases Branch, Ministry of Health and Long-Term Care; Cancer Care Ontario; HIV/AIDS researchers; pathology experts; and HIV/AIDS clinical program directors. An Ontario-based budget impact was also done.
Findings
No direct evidence was found for the existence of controlled studies evaluating the effectiveness of anal Pap test screening programs for impact on anal cancer morbidity or mortality. In addition, no studies were found on the use of HPV DNA testing in the screening or diagnostic setting for anal dysplasia. The reported prevalence of HPV infection in high-risk groups, particularly HIV-positive males, however, was sufficiently high to preclude any utility of HPV testing as an adjunct to anal Pap testing.
Nine reports involving studies in the United States, United Kingdom, and Canada were identified that evaluated the performance characteristics of anal Pap test screening for anal dysplasia. All involved hospital-based specialty HIV/AIDS care clinics with mainly HIV-positive males. All studies involved experienced pathologists, so the results generally represent best-case scenarios. Estimates of anal Pap test sensitivity and specificity were highly variable, and depended on the varying prevalence of cytology abnormality and differential thresholds for abnormality for both cytology and histopathology.
In the largest study of HIV-positive males, sensitivity varied from 46% (95% confidence interval [CI], 36%–56%) to 69% (95% CI, 60%–78%). Specificity ranged from 59% (95% CI, 53%–65%) to 81% (95% CI, 76%–85%). In the only study of HIV-negative males, sensitivity ranged from 26% (95% CI, 5%-47%) to 47% (95% CI, 26%–68%). Specificity ranged from 81% (95% CI, 76%–85%) to 92% (95% CI, 89%–95%).
In comparison, cervical Pap testing has also been evaluated mainly in settings where there is a high prevalence of the disease, and estimates of sensitivitykij and specificity were also low and highly variable. In a systematic review involving cervical Pap testing, sensitivity ranged from 30% to 87% (mean, 47%) and specificity from 86% to 100% (mean, 95%).
Conclusions
No direct evidence exists to support the effectiveness of an anal Pap test screening program to reduce anal cancer mortality or morbidity. There are, however, strong parallels with cervical pap testing for cervical cancer. Sexually transmitted HPV viral infection is currently the acknowledged common causative agent for both anal and cervical cancer. Anal cancer rates in high-risk populations are approaching those of cervical cancer before the implementation of Pap testing.
The anal Pap test, although it has been mainly evaluated only in HIV-positive males, has similar operating characteristics of sensitivity and specificity as the cervical Pap test. In general, the treatment options for precancer dysplasia in the cervix and the anus are similar, but treatment involving a definitive surgical resection in the anus is more limited because of the higher risk of complications. A range of ablative therapies has been applied for anal dysplasia, but evidence on treatment effectiveness, tolerability and durability, particularly in the HIV-positive patient, is limited.
PMCID: PMC3377578  PMID: 23074504
9.  Human papillomavirus genotype distribution in Madrid and correlation with cytological data 
BMC Infectious Diseases  2011;11:316.
Background
Cervical cancer is the second most common cancer in women worldwide. Infection with certain human papillomavirus (HPV) genotypes is the most important risk factor associated with cervical cancer. This study analysed the distribution of type-specific HPV infection among women with normal and abnormal cytology, to assess the potential benefit of prophylaxis with anti-HPV vaccines.
Methods
Cervical samples of 2,461 women (median age 34 years; range 15-75) from the centre of Spain were tested for HPV DNA. These included 1,656 samples with normal cytology (NC), 336 with atypical squamous cells of undetermined significance (ASCUS), 387 low-grade squamous intraepithelial lesions (LSILs), and 82 high-grade squamous intraepithelial lesions (HSILs). HPV detection and genotyping were performed by PCR using 5'-biotinylated MY09/11 consensus primers, and reverse dot blot hybridisation.
Results
HPV infection was detected in 1,062 women (43.2%). Out of these, 334 (31%) samples had normal cytology and 728 (69%) showed some cytological abnormality: 284 (27%) ASCUS, 365 (34%) LSILs, and 79 (8%) HSILs. The most common genotype found was HPV 16 (28%) with the following distribution: 21% in NC samples, 31% in ASCUS, 26% in LSILs, and 51% in HSILs. HPV 53 was the second most frequent (16%): 16% in NC, 16% in ASCUS, 19% in LSILs, and 5% in HSILs. The third genotype was HPV 31 (12%): 10% in NC, 11% in ASCUS, 14% in LSILs, and 11% in HSILs. Co-infections were found in 366 samples (34%). In 25%, 36%, 45% and 20% of samples with NC, ASCUS, LSIL and HSIL, respectively, more than one genotype was found.
Conclusions
HPV 16 was the most frequent genotype in our area, followed by HPV 53 and 31, with a low prevalence of HPV 18 even in HSILs. The frequency of genotypes 16, 52 and 58 increased significantly from ASCUS to HSILs. Although a vaccine against HPV 16 and 18 could theoretically prevent approximately 50% of HSILs, genotypes not covered by the vaccine are frequent in our population. Knowledge of the epidemiological distribution is necessary to predict the effect of vaccines on incidence of infection and evaluate cross-protection from current vaccines against infection with other types.
doi:10.1186/1471-2334-11-316
PMCID: PMC3231944  PMID: 22081930
10.  High grade squamous intraepithelial lesion in inmates from Ohio: cervical screening and biopsy follow-up 
CytoJournal  2006;3:15.
Background
Cervical carcinoma remains the second leading cause of cancer death in women worldwide and sexual behavior is regarded as the main contributing factor. We studied cervical cytology screening with surgical biopsy follow-up in women prisoners and compared the findings to those in the general population.
Methods
We reviewed 1024 conventional cervical smears, 73 cervical biopsies and 2 loop electrosurgical excision procedure (LEEP) specimens referred to us from the Correctional Center in Columbus, Ohio during a 12-month period. The results were compared to 40,993 Pap smears from the general population for the same 12-month period.
Results
High grade squamous intraepithelial lesion (HGSIL) was diagnosed in 1.3% of the cervical smears from the inmate population versus 0.6% in the general population (p < 0.01). The unsatisfactory rate was 1.6% compared to 0.3% in the general population (p < 0.01). Among the study population, follow-up tissue diagnosis was obtained in 24.3% of the abnormal cytology results (ASCUS, LGSIL, and HGSIL). Of the HGSIL Pap smears, 61.5% had a subsequent tissue diagnosis. Thirty-nine biopsies (52% of the all inmate biopsies and LEEP) showed CIN II/III (cervical intraepithelial neoplasia II/III). Eight of these thirty-nine follow-up biopsies diagnosed as CIN II/III had a previous cervical cytology diagnosis of ASCUS. The average age for HGSIL was 30.5 years (S.D. = 5.7) and for low grade squamous intraepithelial lesion (LGSIL) was 27.2 years (S.D. = 6.1).
Conclusion
A significantly higher prevalence of HGSIL cervical cytology and unsatisfactory smears was encountered in female inmates, with tissue follow-up performed in less than two thirds of the patients with HGSIL. These results are in keeping with data available in the literature suggesting that the inmate population is high-risk and may be subject to less screening and tissue follow-up than the general population. Clinicians should proceed with urgency to improve screening and follow-up with treatment. The inmate population should be targeted for HPV vaccination promptly after FDA approval.
doi:10.1186/1742-6413-3-15
PMCID: PMC1475623  PMID: 16686955
11.  Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India 
Human immunodeficiency virus (HIV)-infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)-induced cervical cancer remains unabated because of lack of cost-effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV-infected women. We evaluated 303 nonpregnant HIV-infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low-grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high-grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV-positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 µL−1. Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV-infected women. Implementing VIA-based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low-cost HPV-based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.
doi:10.1002/ijc.25971
PMCID: PMC3516675  PMID: 21387289
cervical cancer; visual inspection; cytology; screening; HIV/AIDS; India
12.  Complementary Procedures in Cervical Cancer Screening in Low Resource Settings 
Objective
To evaluate the efficacy of pap smear, HPV DNA testing and colposcopy and to determine the approach for cervical cancer screening in low resource settings.
Methods
Eight hundred non pregnant married women above 30 years of age were studied and subjected to pap smear examination. Hysterectomised women were excluded from the study. Selected patients were followed by HPV DNA testing by Hybrid Capture II method, colposcopy and biopsy. Sensitivity, specificity, Positive predictive value (PPV), Negative predictive value (NPV), diagnostic accuracy and kappa value (k) were calculated for each screening test.
Result
Out of eight hundred women with mean age 36.5 ± 5.94 years undergoing pap smear, ASCUS was found in 66(8.25%), ASC-H in 2(0.25%), LSIL in 48(6%), HSIL in 8(1%), inflammatory in 540(67.5%). Out of 260 women who underwent HPV DNA testing, 120 (46.15%) had abnormal cytology and/or positive HPV DNA test (Group I, n = 120) and 140(53.8%) had dual negative results (Group II, n = 140) HPV DNA test was found positive in 64 women (53.3%) in Group I. Sensitivity and specificity of pap smear was 69.2 and 63.72% while for HPV DNA testing was 92.3 and 84% respectively. PPV and NPV of pap smear, HPV DNA testing and colposcopy was 18, 40, 76.4% and 94.7, 98.9, 100% respectively. Diagnostic accuracy of pap smear (k = 0.14), HPV DNA test (k = 0.70) and colposcopy (k = 0.81) was 64.29, 84.9, and 96.8% respectively. Combining pap smear & HPV DNA testing (k = 0.25) increased the sensitivity and NPV to 100%.
Conclusion
Sensitivity and diagnostic accuracy of HPV DNA test is more than that of pap smear and the test is not influenced by inflammatory conditions of vagina. In low resource settings, women with ASCUS and LSIL on cervical cytology should be subjected to HPV DNA test and only if found positive should be referred for colposcopy thereby reducing colposcopy referrals. Women with HSIL should be directly subjected to colposcopy guided biopsy. Using this approach, most of the preinvasive cervical lesion will be detected but few cases will still be missed among inflammatory smears, if HPV DNA testing is not supplemented.
doi:10.1007/s13224-011-0067-y
PMCID: PMC3295876  PMID: 22851828
HPV testing; Pap smear; Cervical cancer
13.  Associations between oral HPV16 infection and cytopathology: evaluation of an oropharyngeal “Pap-test equivalent” in high-risk populations 
Human papillomavirus (HPV) is responsible for the rising incidence of oropharyngeal squamous cell cancers (OSCC) in the United States (U.S.), and yet, no screening strategies have been evaluated. Secondary prevention by means of HPV detection and cervical cytology has led to a decline in cervical cancer incidence in the U.S. Here, we explored an analogous strategy by evaluating associations between HPV16 infection, cytopathology and histopathology in two populations at elevated risk for OSCC. In the first, a cross-sectional study population (PAP1), cytology specimens were collected by means of brush biopsy from patients presenting with oropharyngeal abnormalities. In the second (PAP2), a nested case-control study, bilateral tonsillar cytology samples were collected at 12-month intervals from HIV-infected individuals. The presence of cytopathological abnormality in HPV16-positive tonsil brush biopsies (cases) was compared to HPV16-negative samples (controls) matched on age and gender. HPV16 was detected in samples by consensus primer PCR and/or type-specific PCR. Univariate logistic regression was used to evaluate associations. In PAP1, HPV16 alone (OR 6.1, 95%CI 1.6–22.7) or in combination with abnormal cytology (OR 20, 95%CI 4.2–95.4) was associated with OSCC. In PAP2, 4.7% (72 of 1524) of tonsillar cytology specimens from HIV-infected individuals without oropharyngeal abnormalities were HPV16-positive. Tonsillar HPV16 infection was not associated with atypical squamous cells of unknown significance (ASCUS), the only cytological abnormality identified. Therefore, HPV16 was associated with OSCC among individuals with accessible oropharyngeal lesions, but not with cytological evidence of dysplasia among high-risk individuals without such lesions. An oropharyngeal Pap-test equivalent may not be feasible, likely due to limitations in sampling the relevant tonsillar crypt epithelium.
doi:10.1158/1940-6207.CAPR-11-0284
PMCID: PMC3380432  PMID: 21836021
oral HPV; tonsillar HPV; head and neck squamous cell cancer; cervical HPV; head and neck cancer screening
14.  Cytology and Human Papillomavirus Testing 6 to 12 Months after ASCUS or LSIL Cytology in Organized Screening To Predict High-Grade Cervical Neoplasia between Screening Rounds 
Journal of Clinical Microbiology  2012;50(6):1927-1935.
We carried out a prospective study comparing the performance of human papillomavirus (HPV) E6/E7 mRNA (PreTect HPV-Proofer; NorChip, Klokkarstua, Norway) and DNA (Amplicor HPV test; Roche Diagnostics, Basel, Switzerland) triage testing of women 6 to 12 months after atypical-squamous-cells-of-undetermined-significance (ASCUS) or low-grade-squamous-intraepithelial-lesion (LSIL) cytology in organized screening to predict high-grade cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) between screening rounds. Between January 2005 and April 2008, 692 study women with screening-detected ASCUS/LSIL cytology 6 to 12 months earlier returned for HPV mRNA and DNA testing and repeat cytology. The median follow-up time was 3 years, using existing health care facilities. Follow-up test results were available for 625 women. Of the 145 CIN2+ cases detected during the study period, 95 (65.5%) were HPV mRNA positive 6 to 12 months after screening-detected ASCUS/LSIL, 44 (30.4%) were HPV mRNA negative, and 6 (4.1%) were invalid. The corresponding HPV DNA results were 139 (95.9%), 5 (3.4%), and 1 (0.7%), respectively. The cumulative incidences of CIN2+ 3 years after a negative HPV mRNA and DNA test were 10.3% (95% confidence interval [CI], 7.2 to 13.3%) and 1.8% (95% CI, 0.0 to 3.6%), respectively. The cumulative incidences of CIN2+ 3 years after positive HPV mRNA and DNA tests were 52.8% (95% CI, 40.1 to 60.1%) and 41.3% (95% CI, 35.5 to 46.6%), respectively. In conclusion, both positive HPV mRNA and DNA test results have a high enough long-term prediction of CIN2+ risk to consider referral to colposcopy as good practice when performed in delayed triage of women with ASCUS/LSIL cytology. In addition, the low CIN2+ risk among women with a negative Amplicor HPV test in our study confirms its safe use in a clinical setting.
doi:10.1128/JCM.00265-12
PMCID: PMC3372167  PMID: 22518869
15.  Detection of abnormal cervical cytology in Papanicolaou smears 
Background:
Cervical cytology by Papanicolaou (Pap) smears is an effective means of screening for cervical premalignant and malignant conditions. Cervical intra-epithelial neoplasia (CIN) and cervical cancer remain important health problems for women worldwide.
Aim:
To study the role of Pap smear in detecting premalignant and malignant lesions of cervix; and to determine the prevalence of various lesions.
Materials and Methods:
This study is based on 300 patients who attended the out-patient Department of Obstetrics and Gynaecology. Pap smears were prepared from patients presenting with complaints like vaginal discharge, post-coital bleeding, inter-menstrual bleeding, dyspareunia, and pain lower abdomen. After fixation and staining, each smear was carefully examined.
Results:
Epithelial cell abnormalities were found in 5% smears, atypical squamous cells of undetermined significance (ASCUS) in 0.3%, squamous intraepithelial lesion (SIL) in 3.4% which includes low grade squamous intraepithelial lesion (LSIL) (2.7%) and high grade squamous intraepithelial lesion (HSIL) 0.7%. Invasive carcinoma was seen in 1.3% cases. Mean age of the patients with diagnosis of LSIL was 32.3 years and for HSIL, it was 40.5 years. The mean age of the patients with invasive carcinoma was 57 years.
Conclusion:
Premalignant and malignant lesions of cervix are not uncommon in our set up and can be diagnosed early by Pap smears.
doi:10.4103/0970-9371.93222
PMCID: PMC3307451  PMID: 22438616
Cervical cancer; cervical intraepithelial neoplasia; papanicolaou smear
16.  Association between cervical dysplasia and human papillomavirus in HIV seropositive women from Johannesburg South Africa 
Cancer Causes & Control   2009;21(3):433-443.
Objective
To examine the association between CD4 counts, HPV infection and the risk of cervical neoplasia among HIV-seropositive women.
Methods
A cross-sectional observational study was conducted among 1,010 HIV-seropositive women using cytology-based Pap smears. HPV DNA testing using Linear Array genotyping assay (Roche) was carried out in a subset of 191 patients. Multivariable-adjusted prevalence ratios (mPR) and 95% confidence intervals (CIs) were estimated with log-binomial regression.
Results
Among 1,010 HIV-seropositive women, the prevalence of AGC/ASCUS, LSIL and HSIL or greater was 8.3, 23.5 and 18.0%, respectively. The risk of cervical lesions was higher with CD4 < 200 cells/mm3 vs. CD4 levels > 500/mm3. HPV types 16 (41.7%) and HPV 56 (22.2%) were the most common types in HSIL cases. Women with CD4 levels < 200/mm3 had a higher prevalence of HPV types 16 (p < 0.01) and 66 (p = 0.04). No statistical relationship between cervical lesions and HAART use was found.
Conclusion
The burden of HPV infection and HSIL was high and correlated with HIV-induced immunosuppression. HPV 16 was the most common type in HSIL and increased in prevalence with greater immune suppression. Prophylactic HPV 16 vaccination could prevent approximately 40% of HSIL cases. Strengthening screening programs is imperative in this population.
doi:10.1007/s10552-009-9475-z
PMCID: PMC2835728  PMID: 19949850
Cervical dysplasia; HIV; South Africa; Human papillomavirus
17.  HPV infection, cervical abnormalities, and cancer in HIV-infected women in Mumbai, India: 12-month follow-up 
Background
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.2147/IJWH.S47710
PMCID: PMC3746789  PMID: 23976867
HIV/AIDS; HPV; women’s health; cervical cancer; operational research; India
18.  Frequency of Precancerous Changes and Cervical Cancer Recorded in Three Health Centres in Tuzla Canton in Period 2010-2011 
Materia Socio-Medica  2013;25(4):259-261.
Cervical cancer is the second most common cancer in the world and the leading cause of death. Frequency and mortality are significantly reduced thanks to cytological Papanicolau test (PAP). Regular PAP test can reduce approximately 80% of cases of this cancer
Aim of the study:
To examine frequency of cervical cancer and changes of cervix, the age of risk for the changes and effect of frequency of PAP test.
Materials and methods:
3383 PAP (cytological) findings have been retrospectively ana lysed in three Health Centres of Tuzla Canton: Tuzla, Srebrenik and Sapna. During 2010 and 2011 protocols of Health Centers have been analyzed.
Results:
Analysis of 3383 smears detected the following: abnormal PAP tests in 20.8% (705) and without abnormalities in 79.1% (2678). Normal findings in 9.1% (311), inflammatory changes in 69.6% (2357), ASCUS in 12.9% (438), ASC-H in 0.3% (11), LSIL in 5.4% (183), HSIL in 1.4% (49) and Squamous cell carcinoma in 0.7% (24). Cervical cancer has mostly been found in women from Srebrenik 1.1% (15) and least in women from Tuzla 0.3%(4).The highest number of abnormal findings (ASCUS, ASC-H , LSIL, H SIL and Cc) was also found in women from Srebrenik 39.5% (279). The average age of the examinees with the cancer was 41.7. In 62.5% (15) of women PAP test was performed for the first time and they were diagnosed with cervical cancer. Cervical cancer hasn’t been found in women who had PAP test once a year or more.
Conclusion:
Women with the abnormal findings in their first PAP test and should be persuaded to accept the treatment in order to prevent development of cervical cancer.
doi:10.5455/msm.2013.25.259-261
PMCID: PMC3914754  PMID: 24511270
Cervical cancer; PAP test; Regular examination.
19.  Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer 
PLoS ONE  2012;7(10):e47755.
Background
High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women.
Methods
We enrolled 479 HIV-1–infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis.
Results
Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1–5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200cells/mm3 versus >500cells/mm3 (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1–infected women had had one Pap smear within the last 2 years.
Conclusions
The high prevalence of HPV infection and cervical lesions in the HIV-1–infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1–infected women.
doi:10.1371/journal.pone.0047755
PMCID: PMC3484159  PMID: 23118894
20.  Negative Predictive Value of Pap Testing: Implications for Screening Intervals for Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2012;120(4):791-797.
Objective
To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value.
Methods
Participants in the Women’s Interagency HIV Study were followed with conventional Pap smears every 6 months. After excluding those with abnormal Pap tests before study, cervical disease, or hysterectomy, women with negative enrollment Pap results were followed for development within 15 or within 39 months of precancer, defined as a Pap read as high grade squamous intraepithelial lesion, atypical glandular cells favor neoplasia, or adenocarcinoma in situ, or a cervical biopsy read as cervical intraepithelial neoplasia 2+. Correlations between one or more consecutive negative Pap results and subsequent precancer were assessed using Cox proportional hazards models.
Results
Among 942 HIV infected women with negative baseline Pap tests, 8 (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap tests, precancer was rare, with no cases within 15 months and 10/539 (2%) within 39 months. No women developed precancer or cancer within 39 months after 10 consecutive negative Pap tests. Risks for precancer within 15 months after negative Pap included current smoking (aHR 1.5, 95% CI 1.2, 2.0 vs nonsmokers), younger age (aHR=1.5, 95% CI 1.1, 2.1 for women aged younger than 31 years vs older than 45 years) and lower CD4 count (aHR 11.8, 95% CI 1.3, 2.3 for CD4 200–500, aHR 2.2, 95% CI 1.6, 2.9 for CD4 <200/cmm, vs CD4 >500/cmm).
Conclusion
Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate.
doi:10.1097/AOG.0b013e31826a8bbd
PMCID: PMC3448928  PMID: 22996096
21.  HPV DNA and Pap smear test results in cases with and without cervical pathology 
Objective
The aim of the study was to determine the HPV prevalance and its relation to Pap smear, colposcopy and colposcopy directed biopsy in our region of Eskisehir, Turkey.
Material and Methods
A total of 615 women who applied to the outpatient clinic between December 2009 and December 2010 constituted our study population. All patients underwent pelvic examination and Pap smear sampling. Patients who had pathological cervical appearance or Pap smear results of ASCUS, AGUS, LSIL or HSIL were referred to colposcopy. Cervical samples for HPV DNA were taken from the patients before Pap smear sampling during the routine examination or before the colposcopic evaluation.
Results
Twenty six of 615 patients (4%) were HPV positive. Of these 26 patients, 12 were positive for HPV type 16, 3 for type 18, 3 for type 51, 2 for type 6, 1 for type 52, 1 for type 33, 1 for type 16 and type 31, 1 for type 6 and 52, 1 for type 56 and 90, 1 for type 39 and 66. In 4 patients with cervical cancer, and in 3 of 4 CIN III cases both HPV DNA and Pap smear were positive. In the Pap smear examination of 615 patients, cytology revealed 35 ASCUS (5.6%) 4 AGUS (0.6%), 2 CIN I (0.3%) results who were negative for HPV DNA. These patients with abnormal cytology (n=41) underwent colposcopy directed biopsy, there were 3 CIN I and 1 CIN III and all the other cervical biopsy results of these patients were benign (inflammation, chronic cervicitis).
Conclusion
HPV positivity in our hospital setting is low which is compatible with other studies in Turkey. In positive HPV cases there is a good correlation between HPV type and positive cervical biopsy results.
doi:10.5152/jtgga.2011.69
PMCID: PMC3940231  PMID: 24627668
HPV DNA; Pap smear; colposcopy directed biopsy
22.  Frequency of Cervical Cancer and Breast Cancer Screening in HIV–Infected Women in a County-Based HIV Clinic in the Western United States 
Journal of Women's Health  2010;19(4):709-712.
Abstract
Background
Women's primary-care services are frequently dispensed to HIV-infected women through HIV specialty clinics. Our objective was to evaluate cervical cancer and breast cancer screening practices in a county-based HIV clinic in San Mateo, California.
Methods
This was a retrospective cohort study of medical records of HIV-infected women obtaining HIV care at this site.
Results
Between January 1, 2002 and December 31, 2006, 69 women were documented to have at least 12 months of medical care at the clinic. Median followup time was 51 months. Over 253 person-years of followup, there were 656 pap smears performed per 1,000 person-years; 77.9% of women had at least one Pap smear during the study time period. A total of 59.5% (47/79) of normal pap smears had a followup pap smear within 18 months; 62.0% of abnormal pap smears had a followup pap smear within 12 months. A CD4 count of less than 200 cells/mm3 was associated with not receiving a pap smear in multivariable analysis. Mammogram screening was performed on 64.7% of women aged 40 or older.
Conclusions
Based on the results of this study, the majority of HIV-infected women at this clinic received cervical and breast cancer screening at some point during their care. Only two-thirds of abnormal pap smear results had followup pap smear screening within a year. With the increased risk of cervical cancer in HIV-infected women, efforts should be made to promote cervical cancer screening, particularly in high-risk women.
doi:10.1089/jwh.2009.1412
PMCID: PMC2867552  PMID: 20201703
23.  Assessment of effectiveness and cost-effectiveness of HPV testing in primary screening for cervical 
Introduction
The introduction of a screening programme for cervical carcinoma in Germany has led to a significant reduction in incidence of the disease. To date, however, diagnosis in Germany has been based solely on cervical cytology, which has been criticised because of a low sensitivity and consequently high rate of false negative results. Because an infection with the human papillomavirus (HPV) previously was found to be a necessary aetiological factor in the development of cervical cancer, there has been some discussion that HPV testing should be included in cervical cancer screening.
Objectives
How do HPV tests compare to cytological tests in terms of sensitivity and specificity, and what are the effects of screening for cervical carcinoma in Germany? Is there health economic evidence that may foster an inclusion of HPV testing into national screening programms?
Methods
A systematic literature review was performed, including studies that compared the HPV test to cervical cytology in terms of sensitivity and specificity in the diagnosis of CIN 2+ (CIN=Cervical Intraepithelial Neoplasia). In addition, a systematic review of the relevant health economic literature was performed to analyze cost-effectiveness in the German setting.
Results
A total of 24 studies fulfilled the inclusion criteria. One study consisted of three substudies. Hence, results of 26 comparisons of HPV and cytology are reported. In 25 of these, the HPV test was more sensitive than cytology, whereas cytology had better specificity in 21 studies. The combination of HPV test and cytology increased sensitivity. Variability in results was considerably larger for cytology than for HPV testing. Results of the economic meta-analysis suggest that in health care settings with already established PAP screening programms, cost-effectiveness strongly depends on screening intervals. In analyses comparing HPV screening to conventional PAP screening with two-yearly intervals, only 25% of the HPV strategies were found to be cost-effective, whereas in comparison with one-, three-, and five-yearly PAP screening, the percentage of overall cost-effective HPV strategies was 83%, 55%, and 92%, respectively. Results for annual screening intervals are based on the assumption of complete screening compliance, which has to be further evaluated in decision analyses in the future adapting to the German health care setting.
Discussion
Including HPV testing in screening procedures for cervical carcinoma could lead to a reduction in false positive results. Doing so would involve one of the following approaches: a) combining the HPV test with cytology, or b) using cytology as triage in HPV-positive women. The most appropriate interval between screening tests and the best age to start or stop screening remains to be determined. At this point a formal health economic decision analyses may help in resolving those questions, additionally incorporating compliance and adherence within different screening scenarios.
Conclusion
Considering medical evidence weighing the question whether HPV testing should be implemented into screening routine may not be if but how to do so. Open questions remain in setting the length of optimal screening intervals, the age range in which to screen, and the combination or sequence of existing cytology and HPV testing. Answers to those questions will be gathered in the very near future through large international clinical trials. Cost-effectiveness of implementing HPV testing is likely to exist in the management of borderline or unclear smears in triage treatment as well as in certain scenarios of primary screening within the German health care setting.
PMCID: PMC3011325  PMID: 21289942
24.  Conventional Pap Smear Screening in HIV Seropositive Women in South India 
Objectives
To assess the prevalence of Pap smear abnormalities and to characterize the associated risk factors in HIV seropositive women.
Material and methods
We conducted a cross-sectional study on 252 HIV seropositive women in and around Krishna district, Andhra Pradesh, India by screening them for cervical cytological abnormalities by means of conventional Pap smear screening and the abnormalities reported as per modified Bethesda system.
Results
The prevalence of Pap smear abnormalities in HIV seropositive women was found to be 7.17 % which was a twofold increased risk as compared to the general population. On analysis of the risk factors like younger age for abnormal pap smears, mean CD4 count, duration of disease, and ART/HAART therapy the difference between the two groups of HIV seropositive women with normal pap smears and seropositive women with abnormal pap smears was found to be not statistically significant.
Conclusion
HIV/AIDS is associated with a twofold increased risk for cervical cytological abnormalities, and hence the need for periodic pap smear screening in this high risk group to reduce the global burden of cervical cancer.
doi:10.1007/s13224-012-0204-2
PMCID: PMC3650154  PMID: 24431601
HIV; Pap smear screening; Anti Retro Viral Therapy (ART); Highly Activated Anti Retro Viral Therapy (HAART); Cervical cytological abnormalities
25.  Liquid-based cytology for primary cervical cancer screening: a multi-centre study 
British Journal of Cancer  2001;84(3):360-366.
The aim of this six-centre, split-sample study was to compare ThinPrep fluid-based cytology to the conventional Papanicolaou smear. Six cytopathology laboratories and 35 gynaecologists participated. 5428 patients met the inclusion criteria (age > 18 years old, intact cervix, informed consent). Each cervical sample was used first to prepare a conventional Pap smear, then the sampling device was rinsed into a PreservCyt vial, and a ThinPrep slide was made. Screening of slide pairs was blinded (n = 5428). All non-negative concordant cases (n = 101), all non-concordant cases (n = 206), and a 5% random sample of concordant negative cases (n = 272) underwent review by one independent pathologist then by the panel of 6 investigators. Initial (blinded) screening results for ThinPrep and conventional smears were correlated. Initial diagnoses were correlated with consensus cytological diagnoses. Differences in disease detection were evaluated using McNemar's test. On initial screening, 29% more ASCUS cases and 39% more low-grade squamous intraepithelial lesions (LSIL) and more severe lesions (LSIL+) were detected on the ThinPrep slides than on the conventional smears (P = 0.001), including 50% more LSIL and 18% more high-grade SIL (HSIL). The ASCUS:SIL ratio was lower for the ThinPrep method (115:132 = 0.87:1) than for the conventional smear method (89:94 = 0.95:1). The same trend was observed for the ASCUS/AGUS:LSIL ratio. Independent and consensus review confirmed 145 LSIL+ diagnoses; of these, 18% more had been detected initially on the ThinPrep slides than on the conventional smears (P = 0.041). The ThinPrep Pap Test is more accurate than the conventional Pap test and has the potential to optimize the effectiveness of primary cervical cancer screening. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1588
PMCID: PMC2363733  PMID: 11161401
cervical smears; CIN; cervical cancer; ThinPrep cytology; cancer screening

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