Maria Cecília Costa

Human Papillomavirus Infections with Multiple Types and Risk of Cervical Neoplasia

Background: Besides an established role for certain human papillomavirus (HPV) genotypes in the etiology of cervical cancer, little is known about the influence of multiple-type HPV infections on cervical lesion risk. We studied the association between multiple HPV types and cervical lesions among 2,462 Brazilian women participating in the Ludwig-McGill study group investigation of the natural history of HPVs and cervical neoplasia. Methods: Cervical specimens were typed by a PCR protocol. The cohorts repeated-measurement design permitted the assessment of the relation between the cumulative and concurrent number of HPV types and any-grade squamous intraepithelial lesions (SIL) and high-grade SIL (HSIL). Result: At individual visits, 1.9% to 3.2% of the women were infected with multiple HPVs. Cumulatively during the first year and the first 4 years of follow-up, 12.3% and 22.3% were infected with multiple types, respectively. HSIL risk markedly increased with the number of types [odds ratio (OR), 41.5; 95% confidence interval (95% CI), 5.3-323.2 for single-type infections; OR, 91.7; 95% CI, 11.6-728.1 for two to three types; and OR, 424.0; 95% CI, 31.8-5651.8 for four to six types, relative to women consistently HPV-negative during the first year of follow-up]. The excess risks for multiple-type infections remained after exclusion of women infected with HPV-16, with high-risk HPV types, or persistent infections, particularly for any-grade SIL. Coinfections involving HPV-16 and HPV-58 seemed particularly prone to increase risk. Conclusion: Infections with multiple HPV types seem to act synergistically in cervical carcinogenesis. These findings have implications for the management of cervical lesions and prediction of the outcome of HPV infections. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1274–80)

Type-Specific Duration of Human Papillomavirus Infection: Implications for Human Papillomavirus Screening and Vaccination

BACKGROUND Understanding the duration of human papillomavirus (HPV) infection may help find suitable end points for vaccine trials and testing intervals in screening studies. We studied genotype-specific infection duration among 2462 women enrolled in the Ludwig-McGill cohort study. METHODS Cervical specimens collected every 4-6 months were tested by a polymerase chain reaction protocol. Actuarial techniques were used to estimate the duration of HPV infection and to investigate the influence of age, number of sexual partners, and coinfection with multiple HPV types. RESULTS At enrollment, the prevalence of infection with high-risk HPV types was 10.6%, and the prevalence of infection with low-risk HPV types was 6.1%; incidence rates were 6.1 and 5.0 infections per 1000 women-months, respectively. Prevalent infections took longer to clear than incident infections (mean time to clearance, 18.6 months vs. 13.5 months). The mean duration of incident infection with high- and low-risk HPV varied according to the analytic approach used to measure this variable and showed considerable variation by HPV type (range, 5.1-15.4 months). Age and number of partners did not influence infection duration, whereas coinfection was associated with increased infection duration. The mean duration of HPV-16 monoinfection was 11.0 months, and the mean duration of HPV-16 coinfection was 15.4 months. CONCLUSION There was considerable variation among HPV types with regard to the duration of infection. Coinfection with multiple types contributed to an increased infection duration.

Human Papillomavirus Infection and Reinfection in Adult Women: the Role of Sexual Activity and Natural Immunity

There is a paucity of data on whether or not women can be reinfected with human papillomavirus (HPV) types to which they were exposed to earlier in life and on the role of natural immunity. The observation of HPV infection at older ages may be explained by the reactivation of a latent infection or new exposure from sexual activity. Our objective was to analyze the association between reinfection and sexual activity. We analyzed data from 2,462 women enrolled in the Ludwig-McGill cohort and followed every 4 to 6 months for up to 10 years. We performed HPV typing and viral load measurements via PCR and determined HPV-16 seroreactivity at enrollment. Incidence of infection and reinfection were estimated for individual types. Adjusted relative risks (RR) for the association between infection/reinfection and new sexual partners were calculated using Cox regression. Rates of initial infection and reinfection postclearance were statistically comparable. RRs of initial infection or reinfection were consistently associated with new sexual partners [2.4 (95% confidence intervals; 95% CI, 2.0-3.1) for first infection, 3.7 (1.1-13.8) for reinfection with the same type, and 2.3 (1.5-3.7) for reinfection with a different type]. Reinfection in older women was also associated with new sexual partners (RR, 2.8; 95% CI, 1.4-5.3) as were new infections with HPV-16 among women with serologic evidence of prior HPV-16 exposure (RR, 3.0; 95% CI, 1.6-5.3). Viral loads at initial infection and at reinfection were comparable. HPV infection and reinfection were strongly associated with sexual activity. This study suggests that natural immunity does not play a role in controlling the extent of reinfections.

Occurrence of cervical infection with multiple human papillomavirus types is associated with age and cytologic abnormalities.

Background Few aspects of the occurrence of infections with multiple HPV types have been described. Since the immunity conferred by vaccines is type-specific, the epidemiology of such coinfections needs to be addressed. Goal The goal of the study was to document the prevalence and incidence of infection with multiple HPV types and the distribution of HPV types in coinfections. Study Design In a prospective cohort of 2075 Brazilian women, cervical specimens were collected for cytology and HPV detection. Information on potential risk factors was obtained by interview. Results The prevalence of HPV coinfections was 3% among cytologically normal women, 10% among women with ASCUS, 23% among those with LSIL, and 7% among those with HSIL. The incidence rate of coinfection declined markedly with age (Ptrend < 0.001). Some HPV types co-occurred less frequently than expected, namely, HPV 16 and 18 occurring with other oncogenic HPV types and HPV 6/11. Conclusion We have observed that occurrence of HPV coinfection was dependent both on age and on the presence of cytologic abnormalities. These results may have implications for vaccine development and for public health decisions about vaccination programs.

Association of HPV infection and Chlamydia trachomatis seropositivity in cases of cervical neoplasia in Midwest Brazil

High‐risk human papillomavirus (HPV) is considered the main etiological agent for cervical neoplasia. However, the presence of a single type HPV infection alone is unlikely to be sufficient to cause cervical cancer. There is epidemiologic evidence suggesting that HPV and Chlamydia trachomatis play a central role in the etiology of cervical intraepithelial neoplasia and subsequent cervical cancer. To evaluate the HPV prevalence and the seropositivity for C. trachomatis in women referred to the colposcopy clinic due to an abnormal cervical smear and to examine the effect of this association on the severity of cervical neoplasia. Following enrollment, 131 patients underwent colposcopy and biopsies when necessary. HPV DNA was detected by the polymerase chain reaction (PCR) and genotyping was performed by reverse line‐blot hybridization assay. C. trachomatis seropositivity was tested by ELISA for the detection of IgG antibodies. The prevalence of HPV infection was 86.3%. Seropositivity for C. trachomatis was 26%. Thirty‐one women (27.4%) were positive for C. trachomatis antibodies and HPV‐DNA. The most prevalent HPV type in C. trachomatis‐seropositive women were HPV 16 (51.6%) and this HPV type was present mainly in neoplasia cases. Positivity for HPV, particularly HPV types 16 and 18, and C. trachomatis seropositivity was significantly associated with a diagnosis of high grade neoplasia. Borderline significance was observed after adjustment for HPV. C. trachomatis seropositivity is associated with high grade neoplasia in women infected with HPV, mainly when the types 16 and 18 were involved. J. Med. Virol. 84: 1143–1150, 2012.

Human Papillomavirus-specific Genotypes in Cervical Lesions of Women Referred for Smears With Atypical Glandular Cells or Adenocarcinoma In Situ

This study was designed to analyze whether specific human papillomavirus (HPV) genotypes may predict histologic outcomes in women with glandular abnormalities in their cervical smears. Of the 160 women included, 111 were diagnosed with atypical glandular cells, 35 had both atypical glandular cells and high-grade squamous intraepithelial lesions, whereas 14 women had AIS, in 1 case associated with high-grade squamous intraepithelial lesions. All women underwent colposcopic examinations and biopsy was performed in 129/160 (80.6%). Thirty-one women (19.3%) were considered negative for neoplasia and scheduled for follow-up. All specimens were tested for 27 HPV genotypes by Roches polymerase chain reaction-reverse line blot assay. Histologic diagnoses were either cervical intraepithelial neoplasia or invasive carcinoma in 75 (58%) women, and negative for neoplasia in 54 (42%). The overall prevalence of HPV was 43%. HPV 16 was the most prevalent type followed by HPV 18. HPV 16 was significantly associated with squamous and glandular neoplasia and HPV 18 with glandular neoplasia. In women with cervical intraepithelial neoplasia 2 or 3, 11 different HPV genotypes were found, whereas in those who had invasive glandular or invasive carcinoma HPV 16 and HPV 18 were found predominantly. The detection of HPV 16 in women with glandular abnormalities in cervical smears did not help differentiating squamous from glandular lesions. However, the detection of HPV 53 in abnormal smears can predict squamous neoplasia, whereas HPV 18 can predict glandular neoplasia as histologic diagnoses.

Value of HPV-DNA test in women with cytological diagnosis of atypical glandular cells (AGC).

OBJECTIVE This study analyzed whether HPV (human papillomavirus) testing contributes towards defining histological abnormalities in women with atypical glandular cells (AGC) diagnosed at cervical cytology. STUDY DESIGN One hundred and eight women with conventional cervical cancer screening smears suggestive of AGC not otherwise specified (AGC-NOS) and favor neoplastic (AGC-FN) were consecutively enrolled. All women underwent colposcopic examinations and biopsy was performed according to the cytopathologic and/or colposcopic abnormalities present. All specimens were tested for high risk HPV genotypes by Roches polymerase chain reaction reverse line blot assay. The chi-square test was used to evaluate the association between HPV findings and a diagnosis of high-grade pre-invasive or invasive disease (CIN 2 or worse) taking negative tests or CIN 1 as a reference. Odds ratios (OR) with their respective 95% confidence intervals (95%CI) were used to evaluate the magnitude of the association between HPV testing and CIN 2 or worse. Sensitivity, specificity and their respective 95% confidence intervals (95%CI), positive predictive values (PPV) and negative predictive values (NPV) were also calculated. RESULTS Final diagnosis revealed a negative outcome in 80 cases (74%), cervical epithelial neoplasia 1 (CIN 1) in 13 cases (12%), CIN 2 or worse in 12 cases (11%) and glandular neoplasia in 3 (3%) cases. The overall detection rate of HPV was 21% (23/108). Neoplasia was significantly associated with positive HPV-DNA in women with AGC-NOS (OR=15.21; 95%CI: 2.64-87.50); however, there was no significant association between a histological diagnosis of neoplasia and HPV positivity in women with AGC-FN (OR=3.00; 95%CI: 0.36-24.92). The sensitivity, specificity, positive predictive value and negative predictive value of HPV-DNA testing for the detection of CIN 2 or worse in women with AGC-NOS were 71%, 86%, 29% and 97%, respectively. In women with AGC-FN, these values were 50%, 75%, 66% and 60%, respectively. CONCLUSIONS HPV testing at the time of colposcopy for patients with AGC in whom no colposcopic abnormality is found may be a powerful ancillary tool for identifying women at a high risk of underlying significant cervical lesions.

Prognostic Value of DNA and mRNA E6/E7 of Human Papillomavirus in the Evolution of Cervical Intraepithelial Neoplasia Grade 2

Objective This study aimed at evaluating whether human papillomavirus (HPV) groups and E6/E7 mRNA of HPV 16, 18, 31, 33, and 45 are prognostic of cervical intraepithelial neoplasia (CIN) 2 outcome in women with a cervical smear showing a low-grade squamous intraepithelial lesion (LSIL). Methods This cohort study included women with biopsy-confirmed CIN 2 who were followed up for 12 months, with cervical smear and colposcopy performed every three months. Results Women with a negative or low-risk HPV status showed 100% CIN 2 regression. The CIN 2 regression rates at the 12-month follow-up were 69.4% for women with alpha-9 HPV versus 91.7% for other HPV species or HPV-negative status (P < 0.05). For women with HPV 16, the CIN 2 regression rate at the 12-month follow-up was 61.4% versus 89.5% for other HPV types or HPV-negative status (P < 0.05). The CIN 2 regression rate was 68.3% for women who tested positive for HPV E6/E7 mRNA versus 82.0% for the negative results, but this difference was not statistically significant. Conclusions The expectant management for women with biopsy-confirmed CIN 2 and previous cytological tests showing LSIL exhibited a very high rate of spontaneous regression. HPV 16 is associated with a higher CIN 2 progression rate than other HPV infections. HPV E6/E7 mRNA is not a prognostic marker of the CIN 2 clinical outcome, although this analysis cannot be considered conclusive. Given the small sample size, this study could be considered a pilot for future larger studies on the role of predictive markers of CIN 2 evolution.

Association between HPV types and species groups and cervical neoplasia from a high-risk area for cervical cancer, Goiânia, Brazil.

This study was designed to evaluate the effect of single or multiple-human papillomavirus (HPV) infection and phylogenetic groups on the prevalence and severity of cervical intraepithelial neoplasia (CIN) in women undergoing colposcopy after an abnormal cervical smear. Colposcopy was performed in 198 cases and biopsy was performed in 193 patients. All specimens were tested for 27 HPV genotypes using the Roche polymerase chain reaction reverse line blot assay. The overall prevalence of HPV infection in women with an abnormal cervical smear was 86% (171 of 198). The prevalence of HPV 16 in high-grade CIN (2/3) was 52% (40 of 76), being detected in 88.8% of cases (8 of 9) of invasive carcinoma. The prevalence of HPV types 31 and 35 in high-grade CIN was 10.5% (8 of 76) and 6.6% (5 of 76), respectively. Single or multiple-type infection involving HPV 16 were significantly associated with a diagnosis of high-grade neoplasia (≥CIN 2) [odds ratio (OR) 6.49; 95% confidence interval (CI): 1.88-23.44 and OR: 3.65; 95% CI: 1.13-12.15] even after adjustment for HPV-DNA. A statistically significant association was also found between HPV 16 and the other HPV types belonging to species &agr; 9 and a diagnosis of high-grade neoplasia (OR: 7.62; 95% CI: 1.28-51.58); however, no association was found between HPV 16 and the other HPV types belonging to species &agr; 7. HPV 16 is the most important predictor of high-grade cervical neoplasia. Multiple-type infections are predictors of high-grade cervical neoplasia when type 16 is present.

Resultados do exame anátomo-patológico e "Polymerase Chain Reaction (PCR)" na forma clinica e subclinica da infecção anal pelo Papilomavirus Humano (HPV): estudo em quatro grupos de pacientes

The purpose of this study is to analyze the results found in the pathological examination and PCR test for clinical and subclinical HPV anal infections in four groups of patients. Methods: The four groups studied were: ten patients with idiopathic anal pruritus, six with treated HPV genital infection, six with treated anal condyloma, and eight with anal condyloma. Eight patients with condyloma underwent wart biopsy, and high-resolution anoscopy with directed biopsy was performed in the remaining 22 patients. Paraffin wax embedded biopsy specimens were sent to pathological analysis, and later PCR was carried out on the same samples. Results: Through the pathological examination, the presence of HPV is positive in all patients studied: clinically in the eight patients with condyloma, and subclinically in the others 22. Thirteen of these 22 patients presented and associated intraepithelial neoplasia. PCR was positive in 91,9% of the 22 patients those who presented the subclinical infection at pathology examination and 87,5% of the eight patients that presented the clinical infection the most common type of anal subclinical HPV infection was HPV-16 and HPV-11 when warts were presented. Conclusions: Pathological findings related to HPV were presented in all patients studied, and 13 cases were diagnosed two of them were carcinoma in situ. PCR was positive in 91,9% of patients presenting the subclinical infection, and in 87,5% with the clinical infection was HPV-16, and for warts HPV-11.