Christine Colie

Cellular immune factors associated with mother-to-infant transmission of HIV

ObjectiveTo study a possible correlate of protection in mother-to-infant transmission of HIV infection. In particular, to determine whether lack of HIV-specific T-helper (TH) function as indicated by HIV and non-HIV antigen-stimulated interleukin (IL)-2 production of mother and/or newborn peripheral blood leukocytes (PBL) is associated with mother-to-infant transmission of HIV. MethodsPBL from 21 HIV-seropositive pregnant women and 23 cord blood leukocytes (CBL) from their offspring were studied for in vitro TH function by IL-2 production in response to HIV and non-HIV antigens. Polymerase chain reaction (PCR) and viral culture assays were performed to determine HIV infection of the infants. ResultsPBL from 10 out of 21 (48%) mothers and from eight out of 23 (35%) CBL samples responded to two or more out of five synthetic gp160 envelope (env) peptides. Three of the 23 (13%) offspring were shown to be HIV-infected by PCR and/or viral culture on follow-up. All three infected infants were from a subset whose CBL did not exhibit env-specific TH immunity. ConclusionOur results demonstrate that fetal T cells can be primed to HIV env determinants in utero, suggest that HIV-specific TH immunity may be protective in newborns, and provide a possible means for identifying newborns who are at risk for HIV infection.

Squamous cervical lesions in women with human immunodeficiency virus: long-term follow-up.

OBJECTIVE: To estimate the frequency of and trends in abnormal Pap test results in women with human immunodeficiency virus (HIV) and HIV-uninfected women. METHODS: In a cohort study of HIV-infected and uninfected women, Pap tests were obtained every 6 months. Results of atypical squamous cells of undetermined significance (ASC-US) or worse were considered abnormal. RESULTS: Over a median of 8.4 years, 23,843 Pap tests were obtained from 1,931 HIV-positive women with 6,828 Pap tests from 533 HIV-negative women (13 women seroconverted during the study). Among women with HIV, Pap test results were ASC-US in 4,462 (19%), low-grade squamous intraepithelial lesion (LSIL) in 3,199 (13%), high-grade squamous intraepithelial lesion (HSIL) in 267 (1%), and cancer in 11 (0.05%). The incidence of abnormal Pap test results was 179 in 1,000 person-years for HIV-positive and 75 in 1,000 person-years for HIV-negative women (incidence rate ratio 2.4, 95% confidence interval 2.0–2.8). The incidence of HSIL or cancer was 4.4 in 1,000 person-years for HIV-positive and 1.3 in 1,000 person-years for HIV-negative women (incidence rate ratio 3.4, 95% confidence interval 1.2–9.5). CONCLUSION: Among women with HIV in a cervical cancer prevention program, Pap test abnormalities are common, but high-grade abnormalities are infrequent. LEVEL OF EVIDENCE: II

Long-term incidence of cervical cancer in women with human immunodeficiency virus.

The objective of this study was to estimate the incidence of invasive cervical cancer (ICC) in women with human immunodeficiency virus (HIV) and compare it with the incidence in HIV‐uninfected women.

Risk of cervical precancer and cancer among HIV-infected women with normal cervical cytology and no evidence of oncogenic HPV infection.

CONTEXT US cervical cancer screening guidelines for human immunodeficiency virus (HIV)-uninfected women 30 years or older have recently been revised, increasing the suggested interval between Papanicolaou (Pap) tests from 3 years to 5 years among those with normal cervical cytology (Pap test) results who test negative for oncogenic human papillomavirus (HPV). Whether a 3-year or 5-year screening interval could be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown. OBJECTIVE To determine the risk of cervical precancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as 2 separate end points, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test result 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 US cohort of the Womens Interagency HIV Study, between October 1, 2001, and September 30, 2002, with follow-up through April 30, 2011. Semiannual visits at 6 clinical sites included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using polymerase chain reaction. The primary analysis was truncated at 5 years of follow-up. MAIN OUTCOME MEASURE Five-year cumulative incidence of cervical precancer and cancer. RESULTS No oncogenic HPV was detected in 369 (88% [95% CI, 84%-91%]) HIV-infected women and 255 (91% [95% CI, 88%-94%]) HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women, 2 cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500 cells/μL or greater. Histologic data were obtained from 4 of the 6 clinical sites. There were 6 cases of CIN-2+ in 145 HIV-uninfected women (cumulative incidence, 5% [95% CI, 1%-8%]) and 9 cases in 219 HIV-infected women (cumulative incidence, 5% [95% CI, 2%-8%]). This included 1 case of CIN-2+ in 44 oncogenic HPV-negative HIV-infected women with CD4 cell count less than 350 cells/μL (cumulative incidence, 2% [95% CI, 0%-7%]), 1 case in 47 women with CD4 cell count of 350 to 499 cells/μL (cumulative incidence, 2% [95% CI, 0%-7%]), and 7 cases in 128 women with CD4 cell count of 500 cells/μL or greater (cumulative incidence, 6% [95% CI, 2%-10%]). One HIV-infected and 1 HIV-uninfected woman had CIN-3, but none had cancer. CONCLUSION The 5-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.

Incidence of cervical precancers among HIV-seropositive women.

OBJECTIVE The objective of the study was to estimate the impact of human immunodeficiency virus (HIV) infection on the incidence of high-grade cervical intraepithelial neoplasia (CIN). STUDY DESIGN HIV-seropositive and comparison seronegative women enrolled in a prospective US cohort study were followed up with semiannual Papanicolaou testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer) and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using a Cox analysis. Median follow-up (interquartile range) was 11.0 (5.4-17.2) years for HIV-seronegative and 9.9 (2.5-16.0) for HIV-seropositive women. RESULTS CIN3+ was diagnosed in 139 HIV-seropositive (5%) and 19 HIV-seronegative women (2%) (P<.0001), with CIN2+ in 316 (12%) and 34 (4%) (P<.0001). The annual CIN3+ detection rate was 0.6 per 100 person-years in HIV-seropositive women and 0.2 per 100 person-years in seronegative women (P<.0001). The CIN3+ detection rate fell after the first 2 years of study, from 0.9 per 100 person-years among HIV-seropositive women to 0.4 per 100 person-years during subsequent follow-up (P<.0001). CIN2+ incidence among these women fell similarly with time, from 2.5 per 100 person-years during the first 2 years after enrollment to 0.9 per 100 person-years subsequently (P<.0001). In Cox analyses controlling for age, the hazard ratio for HIV-seropositive women with CD4 counts less than 200/cmm compared with HIV-seronegative women was 8.1 (95% confidence interval, 4.8-13.8) for CIN3+ and 9.3 (95% confidence interval, 6.3-13.7) for CIN2+ (P<.0001). CONCLUSION Although HIV-seropositive women have more CIN3+ than HIV-seronegative women, CIN3+ is uncommon and becomes even less frequent after the initiation of regular cervical screening.

Knowledge of cervical cancer prevention and human papillomavirus among women with HIV

OBJECTIVE To assess knowledge of and attitudes towards human papillomavirus (HPV), Pap testing, and the HPV vaccine. METHODS In a multicenter U.S. cohort study, women with the human immunodeficiency virus (HIV) and at-risk comparison women completed 44-item standardized self-report questionnaires exploring their knowledge of cervical cancer prevention, HPV, and HPV vaccination. Results were correlated with demographic variables, measures of education and attention, and medical factors. Data were clustered using principal component analysis. Significant associations were assessed in multivariable models. RESULTS Among 1588 women, HIV seropositive women better understood facts about cervical cancer prevention and HPV than seronegative women, but both had substantial knowledge deficits. Almost all women considered Pap testing important, although 53% of HIV seropositive and 48% of seronegative women considered cervical cancer not preventable (P=0.21). Only 44% of HIV seropositive women knew Paps assess the cervix, versus 42% of HIV seronegative women (P=0.57). Both groups understood that HPV causes genital warts and cervical cancer (67% of HIV seropositive vs. 55% of seronegative women, P=0.002). About half of both groups considered HPV vaccination extremely important for cervical cancer prevention. HIV seronegative women were more likely to report learning of HPV vaccination through advertising than from clinicians (81% vs. 64%, P<0.0001). CONCLUSION High risk women need effective education about cervical cancer prevention, HPV, and HPV vaccination.

Plasma and Mucosal HIV Viral Loads Are Associated with Genital Tract Inflammation In HIV-Infected Women

Background: Systemic and mucosal inflammation may play a role in HIV control. A cross-sectional comparison was conducted among women in the Womens Interagency HIV Study to explore the hypothesis that compared with HIV-uninfected participants, women with HIV, and, in particular, those with high plasma viral load (PVL) have increased levels of mucosal and systemic inflammatory mediators and impaired mucosal endogenous antimicrobial activity. Methods: Nineteen HIV-uninfected, 40 HIV-infected on antiretroviral therapy (ART) with PVL ⩽ 2600 copies/mL (low viral load) (HIV+-LVL), and 19 HIV-infected on or off ART with PVL >10,000 (high viral load) (HIV+-HVL) were evaluated. Immune mediators and viral RNA were quantified in plasma and cervicovaginal lavage (CVL). The CVL antimicrobial activity was also determined. Results: Compared to HIV-uninfected participants, HIV+-HVL women had higher levels of mucosal but not systemic proinflammatory cytokines and chemokines, higher Nugent scores, and lower Escherichia coli bactericidal activity. In contrast, there were no significant differences between HIV+-LVL and HIV-uninfected controls. After adjusting for PVL, HIV genital tract shedding was significantly associated with higher CVL concentrations of IL-6, IL-1&bgr;, MIP-1&agr;, and CCL5 (RANTES) and higher plasma concentrations of MIP-1&agr;. High PVL was associated with higher CVL levels of IL-1&bgr; and RANTES, as well as with higher Nugent scores, lower E. coli bactericidal activity, smoking, and lower CD4 counts; smoking and CD4 count retained statistical significance in a multivariate model. Conclusions: Further study is needed to determine if the relationship between mucosal inflammation and PVL is causal and to determine if reducing mucosal inflammation is beneficial.

Genital Warts and Vulvar Intraepithelial Neoplasia: Natural History and Effects of Treatment and Human Immunodeficiency Virus Infection

OBJECTIVE: To describe the natural history of genital warts and vulvar intraepithelial neoplasia (VIN) in women with human immunodeficiency virus (HIV). METHODS: A cohort of 2,791 HIV-infected and 953 uninfected women followed for up to 13 years had genital examinations at 6-month intervals with biopsy for lesions suspicious for VIN. RESULTS: The prevalence of warts was 4.4% (5.3% for HIV-seropositive women and 1.9% for HIV-seronegative women, P<.001). The cumulative incidence of warts was 33% (95% confidence interval [CI] 30–36%) in HIV-seropositive and 9% (95% CI 6–12%) in HIV-seronegative women (P<.001). In multivariable analysis, lower CD4 lymphocyte count, younger age, and current smoking were strongly associated with risk for incident warts. Among 501 HIV-seropositive and 43 HIV-seronegative women, warts regressed in 410 (82%) seropositive and 41 (95%) seronegative women (P=.02), most in the first year after diagnosis. In multivariable analysis, regression was negatively associated with HIV status and lower CD4 count as well as older age. Incident VIN of any grade occurred more frequently among HIV-seropositive than HIV-seronegative women: 0.42 (0.33–0.53) compared with 0.07 (0.02–0.18) per 100 person-years (P<.001). Positivity for VIN 2 was found in 58 women (55 with and three without HIV, P<.001). Two women with HIV developed stage IB squamous cell vulvar cancers. CONCLUSION: Although genital warts and VIN are more common among HIV-seropositive than HIV-seronegative women, wart regression is common even in women with HIV, and cancers are infrequent. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00000797. LEVEL OF EVIDENCE: II

Cervical Precancer Risk in HIV-Infected Women Who Test Positive for Oncogenic Human Papillomavirus Despite a Normal Pap Test

BACKGROUND Determining cervical precancer risk among human immunodeficiency virus (HIV)-infected women who despite a normal Pap test are positive for oncogenic human papillomavirus (oncHPV) types is important for setting screening practices. METHODS A total of 2791 HIV-infected and 975 HIV-uninfected women in the Womens Interagency HIV Study were followed semiannually with Pap tests and colposcopy. Cumulative risks of cervical intraepithelial neoplasia grade 2 or greater (CIN-2+; threshold used for CIN treatment) and grade 3 or greater (CIN-3+; threshold to set screening practices) were measured in HIV-infected and HIV-uninfected women with normal Pap tests, stratified by baseline HPV results, and also in HIV-infected women with a low-grade squamous intraepithelial lesion (LSIL; benchmark indication for colposcopy). RESULTS At baseline, 1021 HIV-infected and 518 HIV-uninfected women had normal Pap tests, of whom 154 (15%) and 27 (5%), respectively, tested oncHPV positive. The 5-year CIN-2+ cumulative risk in the HIV-infected oncHPV-positive women was 22% (95% confidence interval [CI], 9%-34%), 12% (95% CI, 0%-22%), and 14% (95% CI, 2%-25%) among those with CD4 counts <350, 350-499, and ≥500 cells/µL, respectively, whereas it was 10% (95% CI, 0%-21%) in those without HIV. For CIN-3+, the cumulative risk averaged 4% (95% CI, 1%-8%) in HIV-infected oncHPV-positive women, and 10% (95% CI, 0%-23%) among those positive for HPV type 16. In HIV-infected women with LSIL, CIN-3+ risk was 7% (95% CI, 3%-11%). In multivariate analysis, HIV-infected HPV16-positive women had 13-fold (P = .001) greater CIN-3+ risk than oncHPV-negative women (referent), and HIV-infected women with LSIL had 9-fold (P < .0001) greater risk. CONCLUSIONS HIV-infected women with a normal Pap result who test HPV16 positive have high precancer risk (similar to those with LSIL), possibly warranting immediate colposcopy. Repeat screening in 1 year may be appropriate if non-16 oncHPV is detected.

Changes in knowledge of cervical cancer prevention and human papillomavirus among women with human immunodeficiency virus.

OBJECTIVE: To estimate changes in high-risk womens knowledge of cervical cancer prevention, human papillomavirus (HPV), and HPV vaccination since introduction and marketing of HPV vaccines. METHODS: At study visits in 2007 and 2008–2009, women with the human immunodeficiency virus (HIV) and at-risk comparison women in a multicenter U.S. cohort study completed 44-item self-report questionnaires exploring their knowledge of cervical cancer prevention, HPV, and HPV vaccination. Results from 2007 were compared with those obtained in 2008–2009. Knowledge scores were correlated with demographic variables, measures of education and attention, and medical factors. Significant associations were assessed in multivariable models. RESULTS: HIV-seropositive women had higher knowledge scores than seronegative women at baseline (13.2±5.7 compared with 11.8±6.0, P<.001) and follow-up (14.1±5.3 compared with 13.2±5.5, P=.01), but the change in scores was similar (0.9±5.3 compared with 1.5±5.5, P=.13). Knowledge that cervical cancer is caused by a virus rose significantly (P=.005), but only to 24%. Belief that cervical cancer is preventable only rose from 52% to 55% (P=.04), but more than 90% of women in both periods believed regular Pap testing was important. In analysis of covariance models, higher baseline score, younger age, higher education level, higher income, and former- as opposed to never-drug users, but not HIV status, were associated with improved knowledge. CONCLUSION: High-risk womens understanding of cervical cancer and HPV has improved, but gaps remain. Improvement has been weakest for less educated and lower-income women. LEVEL OF EVIDENCE: II