Nancy B. Kiviat

A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection.

Abstract Background. Human papillomavirus (HPV) has been associated with cervical intraepithelial neoplasia, but the temporal relation between the infection and the neoplasia remains unclear, as does the relative importance of the specific type of HPV, other sexually transmitted diseases, and other risk factors. Methods. We studied prospectively a cohort of 241 women who presented for evaluation of sexually transmitted disease and had negative cervical cytologic tests. The women were followed every four months with cytologic and colposcopic examinations of the uterine cervix and tests for HPV DNA and other sexually transmitted diseases. Results. Cervical intraepithelial neoplasia grade 2 or 3 was confirmed by biopsy in 28 women. On the basis of survival analysis, the cumulative incidence of cervical intraepithelial neoplasia at two years was 28 percent among women with a positive test for HPV and 3 percent among those without detectable HPV DNA. The risk was highest among those with HPV type 16 or 18 infe...

Comparison of Human Papillomavirus Types 16, 18, and 6 Capsid Antibody Responses Following Incident Infection

The relationship between human papillomavirus (HPV) DNA in the genital mucosa and serum IgG to HPV-16, -18, and -6 was studied in a cohort of 588 college women. Among women with incident HPV infections, 59.5%, 54.1%, and 68.8% seroconverted for HPV-16, -18, or -6, respectively, within 18 months of detecting the corresponding HPV DNA. Transient HPV DNA was associated with a failure to seroconvert following incident HPV infection; however, some women with persistent HPV DNA never seroconverted. Antibody responses to each type were heterogeneous, but several type-specific differences were found: seroconversion for HPV-16 occurred most frequently between 6 and 12 months of DNA detection, but seroconversion for HPV-6 coincided with DNA detection. Additionally, antibody responses to HPV-16 and -18 were significantly more likely to persist during follow-up than were antibodies to HPV-6.

Development and Duration of Human Papillomavirus Lesions, after Initial Infection

BACKGROUND To determine the potential value of human papillomavirus (HPV) vaccines, information concerning the incidence and duration of clinically important lesions is needed. METHODS A total of 603 female university students were followed for a mean duration of 38.8 months. Triannual gynecologic examinations included cervical and vulvovaginal specimen collection for Pap and HPV DNA testing. Women with cytologic evidence of a high-grade squamous intraepithelial lesion (SIL) were referred for colposcopically directed biopsy. RESULTS Among women with incident HPV infection, the 36-month cumulative incidence of cervical SILs found by cytologic testing (47.2%; 95% confidence interval [CI], 38.9%-56.4%) was higher than that of vaginal SILs (28.8%; 95% CI, 21.3%-38.2%). The median time to clearance of cervical and vaginal SILs was 5.5 and 4.7 months, respectively. Among women with incident HPV-16 or HPV-18 infection, the 36-month cumulative incidence of cervical intraepithelial neoplasia (CIN) grade 2 was 20.0% (95% CI, 10.8%-35.1%), and that of CIN grade 3 was 6.7% (95% CI, 2.5%-17.0%). The 36-month cumulative incidence of clinically ascertained genital warts among women with incident HPV-6 or HPV-11 infection was 64.2% (95% CI, 50.7%-77.4%). CONCLUSIONS Intraepithelial lesions are common early events among women with incident HPV infection, and the interval between incident HPV-16 or HPV-18 infection and biopsy-confirmed CIN grade 2-3 appears to be relatively short.

Mucopurulent cervicitis--the ignored counterpart in women of urethritis in men.

Among 100 randomly selected nonmenstruating women attending a clinic for sexually transmitted diseases, we assessed objective criteria for the clinical diagnosis of mucopurulent cervicitis. Visualization of yellow mucopurulent endocervical secretions on a white swab and the presence of 10 or more polymorphonuclear leukocytes per microscopical field (at a magnification of 1000) in satisfactory gram-stained endocervical smears were independently correlated with cervical Chlamydia trachomatis infection. Neither finding correlated with gonorrhea or genital herpes, although herpes caused characteristic cervical ulcerations. C. trachomatis was isolated from the cervix of 20 of 40 women with mucopurulent cervicitis but of only 2 of 60 without it. The overall prevalence of mucopurulent cervicitis among women attending the clinic (40 per cent) exceeded that of nongonococcal urethritis among men in the same clinic, and the prevalence of C. trachomatis infection was higher in mucopurulent cervicitis than in nongonococcal urethritis, a condition that is conventionally treated with tetracyclines. These findings support recommendations for the treatment of mucopurulent cervicitis and should guide the selective use of confirmatory diagnostic tests for C. trachomatis infection.

Evaluation of Genital Sites and Sampling Techniques for Detection of Human Papillomavirus DNA in Men

To evaluate methods for detection of genital human papillomavirus (HPV) DNA in men, samples were obtained from 3 consecutive groups of 10 men attending a sexually transmitted disease clinic by use of (1) a saline-wetted Dacron swab alone, (2) a saline-wetted cytobrush, or (3) emery paper (600A-grit Wetordry Tri-M-ite; 3M) abrasion followed by a saline-wetted Dacron swab. By use of a polymerase chain reaction-based assay, 45% of emery-paper samples were found to be positive for beta-globin, compared with 23% of swab-alone and 0% of cytobrush samples. Subsequently, emery paper and saline-wetted Dacron swabs were used to obtain penile shaft, glans, foreskin, and scrotum samples from 318 male university students. Urine samples were also obtained. Of 1323 samples tested, 1288 (97%) were found to be positive for beta-globin. HPV DNA was detected in samples from 104 men (33%): 24% from the penile shaft, 16% from the glans, 28% from the foreskin, 17% from the scrotum, and 6% in urine. The HPV prevalence was similar for circumcised and uncircumcised men. Testing multiple sites increased the number of men for whom HPV DNA was detected.

Genital Human Papillomavirus Infection in Men: Incidence and Risk Factors in a Cohort of University Students

BACKGROUND In contrast to the wealth of data on human papillomavirus (HPV) infections in women, much less is known about HPV in men. METHODS Between June 2003 and March 2006, a total of 240 heterosexually active male university students 18-20 years of age were recruited for participation in a cohort study of HPV infection. Genital cell samples were collected, at 4-month intervals, for HPV-DNA analysis by polymerase chain reaction. The subjects maintained a Web-based journal of sexual activity. RESULTS At 24 months, the cumulative incidence of new infection of any genital HPV type was 62.4% (95% confidence interval [CI], 52.6%-72.2%). Acquisition rates did not differ by genital site (i.e., glans, penile shaft, or scrotum) of initial detection (P=.86). The most commonly detected types were HPV-84 and HPV-16. In multivariate analysis, a report of a new sex partner during the prior 0-4 (hazards ratio [HR], 2.0 [95% CI, 1.3-3.0]) and 5-8 (HR, 1.8 [95% CI, 1.2-2.7]) months and a history of smoking (HR, 1.6 [95% CI, 1.1-2.4]) were associated with an elevated risk of HPV acquisition. CONCLUSION Genital HPV infection is common and multifocal in young men, and its incidence is higher than that reported for similar cohorts of young women. The high rates of HPV infection in men should be considered when strategies for the prevention of HPV infection in female adolescents and young women are being developed.

p16INK4a Expression Correlates with Degree of Cervical Neoplasia: A Comparison with Ki-67 Expression and Detection of High-Risk HPV Types

Although recent studies have suggested that p16INK4a may be a useful surrogate biomarker of cervical neoplasia, Ki-67 and human papillomavirus testing have also been shown to be useful in detecting neoplasia. To help delineate the utility of p16INK4a, biopsy samples (n = 569: negative, 133; reactive, 75; atypical, 39; low grade, 76; moderate, 80; and severe intraepithelial neoplasia, 113; also, squamous cell carcinoma, 46; adenocarcinoma, 7) were analyzed by immunohistochemistry for expression of p16INK4a and Ki-67 (n = 432), as well as by in situ hybridization for human papillomavirus Type 16 (n = 219). Testing for high-risk human papillomavirus types by polymerase chain reaction and HybridCapture2 was performed on concurrent cervical swab specimens. Recuts of the original blocks were reexamined (n = 198). Endometrial biopsies (n = 10) were also analyzed for p16INK4a expression. Degree of p16INK4a and Ki-67 expression correlated with degree of cervical neoplasia (P < .001) and with presence of high-risk human papillomavirus types (P < .001). There was no relationship between p16INK4a overexpression and inflammation or hormonal status. Ki-67 expression correlated with inflammation (P = 0.003) and was expressed in more reactive and atypical lesions than p16INK4a (P = 0.008). Probes for human papillomavirus 16 stained 54% of cervical neoplastic lesions; the degree of staining correlated significantly with degree of neoplasia (P < .001) and p16INK4a staining (P < .001). Interobserver reproducibility was substantial for p16INK4a and Ki-67 interpretation (weighted κ: 0.74 and 0.70, respectively). Expression of p16INK4a was observed in all endometrial biopsies. Compared with Ki-67 expression and detection of high-risk human papillomavirus, p16INK4a was less likely to be positive in samples from women with negative, reactive, and atypical biopsies. Although expression of p16INK4a in endometrial epithelium may be problematic in terms of screening, the potential of p16INK4a as a screening test warrants investigation.

Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection.

ObjectiveTo determine the risk of developing high grade anal squamous intraepithelial neoplasia (HG-AIN) in relation to HIV infection, and immunosuppression, after controlling for the effects of human papillomavirus (HPV) infection. DesignProspective cohort study of 158 HIV-seropositive, and 147 HIV-seronegative homosexual men presenting to a community-based clinic with initially negative anal cytologic, and colposcopic findings. MethodsSubjects completed self-administered questionnaires, underwent cytologic screening, and standardized unaided, and colposcopic examination of the proximal anal canal for presence of abnormalities suggestive of AIM. Anal specimens were screened for HPV DMA. ResultsHG-AIN developed in eight (5.4%), and 24 (15.2%) HIV-seronegative, and -seropositive men, respectively. Risk of HG-AIN among HIV-seronegative men was associated with detection of anal HPV types 16 or 18 by Southern transfer hybridization (STH), detection of HPV 16 or 18 at the lower levels by polymerase chain reaction but not by STH, and with number of positive HPV tests; HG-AIN risk among HIV-seropositive men was associated with detection of HPV 16 or 18 only by STH, detection of HPV types other than 16 or 18, CD4 count ≤ 500 × 106/l, and number of positive HPV tests. HIV-induced immunosuppression remained an independent predictor of HG-AIN after adjusting for type, and level of detection of HPV; HIV infection predicted HG-AIN risk after adjustment for number of positive HPV tests. ConclusionsThe association of HG-AIN with HIV, independent of HPV type, level of HPV detection, and number of positive HPV tests, suggests that this increased risk cannot be entirely explained by an effect of HIV on HPV detection. Future studies focusing on factors more specific to the local microenvironment in the anal canal should help clarify these issues.

Endometrial histopathology in patients with culture-proved upper genital tract infection and laparoscopically diagnosed acute salpingitis.

To define and quantitate histologic changes in the endometrium that best correlate with documented upper genital tract infection (UGTI) and laparoscopically diagnosed acute salpingitis, we studied endometrial biopsy specimens from 69 consecutive patients with clinically suspected acute pelvic inflammatory disease (PID) who underwent microbiological evaluation for UGTI and laparoscopic examination for acute salpingitis. Both UGTI and acute laparoscopically confirmed salpingitis were present in 37 patients (54%), UGTI without salpingitis in 1 (1%), salpingitis without UGTI in 11 (16%), and neither UGTI nor salpingitis in 20 (29%). Chlamydia trachomatis or Neisseria gonorrhoeae UGTI was found in 34 women, Escherichia coli in two patients, Peptococcus magnus in one woman, and with Streptococcus agalactiae in one woman. The following features were correlated both with UGTI and with salpingitis: presence of any neutrophils in the endometrial surface epithelium; neutrophils within gland lumens; dense subepithelial stromal lymphocytic infiltration; any stromal plasma cells; and germinal centers containing transformed lymphocytes. The simultaneous presence of five or more neutrophils per x400 field in endometrial surface epithelium, together with one or more plasma cell per x 120 field in endometrial stroma, was the best predictor of UGTI plus salpingitis. This combination had a sensitivity of 92% and a specificity of 87% for predicting the diagnosis of both UGTI and laparoscopically confirmable acute salpingitis. Prospective studies are needed to assess the usefulness of these criteria.

Concurrent and Sequential Acquisition of Different Genital Human Papillomavirus Types

Coinfection with multiple types of genital human papillomavirus (HPV) has been reported, but how frequently it occurs and whether prior infection with specific HPV types inhibits subsequent infection by related types are not known. To address this, 518 women were followed for an average of 2.9 years, and behavioral information and cervical and vulvovaginal swabs for HPV DNA assay were obtained at 4-month intervals. A polymerase chain reaction-based method was used to detect types frequently found in cervical cancers (HPV 16, 18, 31, and 45) and in genital warts (HPV 6 and 11). Concurrent acquisition of multiple types occurred more often than expected by chance. However, no 2 types were more or less likely to be acquired concurrently than any other 2 types. When considering sequential acquisition of HPV types, we found that risk of acquiring a new HPV type was not decreased among those with prior infection by a phylogenetically related or unrelated type (hazard ratio [95% confidence interval], 1.0 [0.4-3.0] and 1.3 [0.8-2.1], respectively).