Sepideh Farhat

Persistence of Human Papillomavirus Infection in HIV-Infected and -Uninfected Adolescent Girls: Risk Factors and Differences, by Phylogenetic Type

BACKGROUND High rates of persistence of human papillomavirus (HPV) infection have been reported for adult women with human immunodeficiency virus (HIV) infection. Although most women are first infected with HPV during adolescence, persistence of specific HPV types has not been carefully examined among HIV-infected adolescents. The objective of this study was to examine the rates of and risk factors for persistence of HPV types among HIV-infected and -uninfected adolescent girls. METHODS This is a prospective cohort study of female adolescents, aged 13-18 years, participating in the Reaching for Excellence in Adolescent Care and Health project, a national study of HIV-infected and -uninfected adolescents. The main outcome measured was type-specific loss of initial HPV DNA detected. Loss of HPV DNA was defined for the following categories of HPV DNA types: low risk, which included types 6, 11, 42, 44, 54, 40, 13, 32, 62, 72, 2, 57, and 55; and high risk, which included types 16-like (16, 31, 33, 35, 52, 58, and 67), 18-like (18, 39, 45, 59, 68, 70, 26, 69, and 51), and 56-like (56, 53, and 66). RESULTS Prevalent or incident HPV infection was detected in 334 girls. When type-specific loss of HPV was examined, HIV-uninfected girls had a shorter mean time to loss of initial infection than did HIV-infected girls (403 days vs. 689 days, respectively; P<.0001). By means of multivariate analysis, CD4 immunosuppression and the presence of multiple HPV-type subgroups were found to be associated with persistence of HPV. CONCLUSION Since persistence of high-risk HPV types has been strongly linked with the development of invasive cancer, the prolonged persistence of HPV observed among HIV-infected adolescents who are relatively healthy underscores the importance of prevention of HPV infection in this group.

Cytotoxic T Lymphocyte Responses to E6 and E7 Proteins of Human Papillomavirus Type 16: Relationship to Cervical Intraepithelial Neoplasia

Cytotoxic T lymphocyte (CTL) responses to the human papillomavirus (HPV) type 16 E6 and E7 proteins were measured in 20 women with known HPV and cervical disease status. CTL assays were performed after stimulation with E6 or E7 fusion proteins using autologous B lymphoblastoid cells infected with vaccinia viruses expressing E6 or E7. CTL responses to E6 and E7 were detected in 6 (75%) of 8 and 5 (56%) of 9 HPV-16-positive women without cervical intraepithelial neoplasia (CIN), respectively. Responses to E6 or E7 were each detected in only 2 (29%) of 7 HPV-16-positive women with CIN. Responses to both antigens were found in 63% of women without CIN and 14% of those with CIN. CTL responses to E6 or E7 are more commonly detectable in HPV-16-positive women without CIN than in HPV-16-positive women with CIN, suggesting that CTL response may play a role in disease protection.

Persistence of Human Papillomavirus Type 16 Infection Is Associated with Lack of Cytotoxic T Lymphocyte Response to the E6 Antigens

Our cross-sectional study suggested that cytotoxic T lymphocyte (CTL) responses have a protective effect in squamous intraepithelial lesion (SIL) development. More CTL responses in women with human papillomavirus type 16 (HPV 16) infection without SILs than with SILs were detected. In the current longitudinal study, the role of CTL in clearing HPV 16 infection in women without SILs was investigated. Women with HPV 16 infection (n=51) were enrolled, along with HPV 16-negative control women (n=3). Twenty-two (55%) of 40 women who cleared HPV 16 infection had an E6 CTL response at least once, compared with none of 9 women who had HPV 16 persistence (P=.003). Such a difference was not demonstrated for E7; 25 (63%) of 40 women who cleared HPV 16 infection responded, versus 5 (56%) of 9 women with persistence (P=.720). It appears that lack of response to E6 is important in the persistence of HPV 16 infection.

Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women.

OBJECTIVE: To describe the natural history of cervical intraepithelial neoplasia (CIN) 2 in a prospective study of adolescents and young women, and to examine the behavioral and biologic factors associated with regression and progression. METHODS: Adolescents and women aged 13 to 24 years who were referred for abnormal cytology and were found to have CIN 2 on histology were evaluated at 4-month intervals. Risks for regression were defined as three consecutive negative cytology and histology visits, and progression to CIN 3 was estimated using Cox proportional hazards regression models. RESULTS: Ninety-five patients with a mean age of 20.4 years (±2.3) were entered into the analysis. Thirty-eight percent resolved by year 1, 63% resolved by year 2, and 68% resolved by year 3. Multivariable analysis found that recent Neisseria gonorrhoeae infection (hazard ratio 25.27; 95% confidence interval [CI] 3.11–205.42) and medroxyprogesterone acetate use (per month) (hazard ratio 1.02; 95% CI 1.003–1.04) were associated with regression. Factors associated with nonregression included combined hormonal contraception use (per month) (hazard ratio 0.85; 95% CI 0.75–0.97) and persistence of human papillomavirus (HPV) of any type (hazard ratio 0.40; 95% CI 0.22–0.72). Fifteen percent of patients showed progression by year 3. HPV 16/18 persistence (hazard ratio 25.27; 95% CI 2.65–241.2; P=.005) and HPV 16/18 status at last visit (hazard ratio 7.25; 95% CI 1.07–49.36; P<.05) were associated with progression Because of the small sample size, other covariates were not examined. CONCLUSION: The high regression rate of CIN 2 supports clinical observation of this lesion in adolescents and young women. LEVEL OF EVIDENCE: II

Association between toll‐like receptor expression and human papillomavirus type 16 persistence

The mechanisms involved in mucosal immune control of cervical human papillomavirus (HPV) infection remain ill defined. Because toll‐like receptors (TLRs) are key players in innate immune responses, we investigated the association between TLR expression and viral persistence or clearance in young women with incident infections with oncogenic HPV types 16 or 51. Messenger RNA expression of TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, TLR8 and TLR9 was measured by quantitative reverse transcription‐PCR using human endocervical specimens, collected before and after viral acquisition, in a cohort well characterized for HPV infections. Wilcoxon rank sum test was used to compare the change seen from preinfection to incident infection between women who subsequently cleared infection with those who did not. HPV 16 infections that cleared were significantly (p < 0.05) associated with an increase in expression of the four viral nucleic acid‐sensing TLRs (TLR3, TLR7, TLR8 and TLR9) as well as TLR2 upon viral acquisition. Similar associations were not observed for HPV 51. In women who subsequently cleared their HPV 16 infection, changes in TLR1, TLR3, TLR7 and TLR8 expression levels between preincident and incident visits were significantly correlated with parallel changes in the levels of interferon‐α2, measured by immunoassay in cervical lavage specimens. This study suggests that dampened TLR expression in the cervical mucosa is a type‐specific mechanism by which HPV 16 interferes with innate immune responses, contributing to viral persistence, and that TLR upregulation and resultant cytokine induction is important in subsequent viral clearance.

Concordance and Transmission of Human Papillomavirus Within Heterosexual Couples Observed Over Short Intervals

BACKGROUND Because many human papillomavirus (HPV) infections are transient, rates of transmission may be miscalculated if the interval between testing spans several months. We examined rates of concordance and transmission in heterosexual couples over short intervals. METHODS  Twenty-five adult couples were enrolled and sampled for HPV DNA from the genitals, hand, and mouth 5 times over a 6-week period, including 24 hours after sexual intercourse and after 48 hours of abstinence. Concordance and transmission patterns were described. RESULTS Concordance between the couples genital sites ranged from 64% to 95% for at least 1 HPV type. The highest rates of concordance were observed 24 hours after sexual intercourse. A similar peak in concordance was not seen between genital and nongenital anatomic sites. Transmission rates for female genital to male genital ranged from 26.8 to 187.5 per 100 person-months and for male genital to female genital from 14.5 to 100 per 100 person-months. CONCLUSIONS High rates of concordance shortly after intercourse suggest that some DNA detections in the genital area are contaminants from a partner and not established HPV infections. Female-to-male transmission appeared more common than male-to-female transmission.

Cell-mediated immune responses to human papillomavirus 16 E6 and E7 antigens as measured by interferon gamma enzyme-linked immunospot in women with cleared or persistent human papillomavirus infection.

Cell-mediated immune responses have been thought to be important in the control of human papillomavirus (HPV) infections. We examined cell-mediated immune responses to HPV-16 E6 and E7 in the peripheral blood using interferon gamma (IFN-&ggr;) enzyme-linked immunospot assay (Cellular Technology Ltd, Cleveland, Ohio) in women with HPV-16 infection who showed clearance and compared these women to women with HPV-16 persistence. Women participating in a longitudinal study of cervical HPV were recruited once cervical HPV-16 infection was detected by polymerase chain reaction. Four groups of women were examined: (1) persistent, (2) intermittent, (3) transient, and (4) cleared. Ninety-six samples from 55 women were compared. Comparing IFN-&ggr; enzyme-linked immunospot to the HPV-16 clearance of 10 women with recent persistence, none had response to either E6 or E7; of 24 women with recent clearance, 14 had E6 and 8 had E7 response. Women with intermittent persistence behaved similarly to the clearance group than recent persistors: 50% were positive to E6 and 20% to E7. In summary, anti-E6 responses seem critical in the immediate control of HPV, and in some women, an immune tolerance eventually develops if HPV is not eliminated soon after infection.

Risks for cervical intraepithelial neoplasia 3 among adolescents and young women with abnormal cytology.

OBJECTIVE: To estimate the risks of cervical intraepithelial neoplasia (CIN) 3 among girls and women aged 13 to 24 years who were referred for abnormal cytology while receiving care in a large health maintenance organization. METHODS: At the time of referral, patients had a colposcopic examination and biopsy if needed. Histology was sent to a centralized laboratory. Patients were interviewed for risk behaviors. Data analysis included multinomial logistic regression analysis to compare three groups: CIN 3 to CIN 1 or less, CIN 3 to CIN 2, and CIN 2 to CIN 1 or benign. RESULTS: Cervical intraepithelial neoplasia-3 was found in 6.6% (95% confidence interval [CI] 4.6–8.6%) of the 622 girls and women referred and no cancers were detected. Risk for CIN 3 compared to CIN 1 or less included human papillomavirus 16 or 18 (odds ratio [OR] 30.93, 95% CI 6.95–137.65), high-risk, non-16/18 human papillomavirus (OR 6.3, 95% CI 1.3–29.4), and time on oral contraceptives (OR 1.36 per year of use, 95% CI 1.08–1.71). CONCLUSION: Our data support conservative care for adolescents and young women with abnormal cytology since CIN 3 was rare and cervical cancer was never found. Human papillomavirus 16 or 18 was strongly associated with for CIN 3, and testing for these types may be warranted for triage of abnormal cytology in this age group. LEVEL OF EVIDENCE: II

Human Papillomavirus Concordance in Heterosexual Couples

PURPOSE Few studies have examined the relationships between sexual or hygienic behaviors and human papillomavirus (HPV) transmission. Our objectives were to (1) describe HPV concordance between the anogenital, oral, and palmar areas of monogamous heterosexual couples; and (2) determine sexual behaviors, hygienic practices, sexual histories, and subject characteristics associated with HPV anogenital concordance. METHODS Couples were recruited from women who developed an incident HPV infection while being enrolled in a longitudinal HPV natural history study that recruited from two family-planning clinics. Men were their monogamous partners of at least 3 months. Samples were tested for HPV-DNA of 37 high- and low-risk genotypes. Questionnaires completed privately assessed health, sexual, hygienic history, and behaviors. RESULTS A total of 25 couples enrolled between February 2006 and July 2007; none had received HPV vaccine. The average age was 25 years (SD, 6) for men and 23 years (SD, 3) for women. HPV-84 was the most commonly shared HPV type in the anogenital and palmar areas. HPV-16 was the only shared oral-HPV type. Sixty-eight percent of couples had type-specific anogenital concordance. Receiving finger-anal sex (p = .05), sharing towels (p = .04), longer time since last intercourse (women: p = .03, men: p = .02 men), and men washing their genitals after sex (p = .03) were associated with decreased likelihood of concordance. Persistence of incident HPV types in women was associated with HPV in men (p = .002). CONCLUSIONS Our findings show that certain hygienic and sexual behaviors are associated with anogenital concordance between healthy, monogamous, heterosexual couples. Future studies are needed to see whether these detections reflect contamination, transient, or established infections.

The Role of Sexual Behavior and Human Papillomavirus Persistence in Predicting Repeated Infections with New Human Papillomavirus Types

Background: Although human papillomavirus (HPV) infections are common in young women, the rate of and risk for repeated new infections are not well documented. We examined the rate of and risks for new HPV detection in young women. Methods: We used data from an ongoing study of HPV, initiated in 1990. Sexually active women ages 12 to 22 years were eligible. Interviews on behaviors and HPV testing were done at 4-month intervals; sexually transmitted infection (STI) testing was annual or if symptomatic. Starting with first HPV detection, time to the next (second) visit (event) with detection of new HPV types, and then the second event to time to third event was calculated. Risks were determined using Cox proportional hazard model. Results: Sixty-nine percent of 1,125 women had a second event, and of those with a second event, 63% had a third event by 3 years, respectively. Women with HPV persistence from initial visit to second event [hazard ratio (HR) = 4.51 (3.78-5.37)], an STI [HR = 1.47 (1.00-2.17)], bacterial vaginosis [HR = 1.60 (1.07-2.39)], and number of new sex partners [HR = 1.10 (1.05-1.15 per partner/mo)] were independent associations for HPV. Risks for third event were similar. Conclusion: This study documents the repeated nature of HPV infections in young women and their association with sexual risk behaviors. Impact: This finding underscores the lack of clinical utility of HPV testing in young women. Further studies are needed to examine host factors that lead to HPV acquisition and persistence. Cancer Epidemiol Biomarkers Prev; 19(8); 2055–65. ©2010 AACR.