Kathleen M. Weber

The Women's Interagency HIV Study: an Observational Cohort Brings Clinical Sciences to the Bench

The Womens Interagency HIV Study (WIHS) is an ongoing long-term observational study of 3,772 women who are either infected with human immunodeficiency virus (HIV) or considered to be at risk for acquiring HIV. Since 1994, the WIHS (pronounced like “wise”) has developed a large database and specimen repository that serve as resources for WIHS investigators as well as for nonaffiliated researchers working on HIV-related or HIV coinfection issues. The purpose of this report is to update researchers on the progress of the WIHS and to provide information on WIHS resources, the methods by which they were obtained, and background for any new potential researchers interested in conducting collaborative research through shared use of these resources.

Determinants of HIV-1 shedding in the genital tract of women

BACKGROUND Plasma HIV-1 RNA concentration has been the best predictor for risk of heterosexual and perinatal transmission. However, direct contact with HIV-1 present locally in the genital tract might be necessary for transmission. We aimed to assess the relation between HIV-1 shedding (RNA or culturable virus) in female genital secretions and other factors that might affect HIV-1 shedding. METHODS This was a cross-sectional study within the Womens Interagency HIV Study (WIHS), a prospective longitudinal cohort study of HIV-infected women. We enrolled 311 HIV positive women from Jan 30, 1997 to July 1, 1998. We did clinical assessments, cultured HIV-1, and measured RNA in peripheral blood mononuclear cells (PBMC) and genital secretions. We compared the results with univariate and multivariate analyses. Presence of HIV-1 RNA or culturable virus in genital secretions was defined as HIV-1 shedding. FINDINGS HIV-1 RNA was present in genital secretions of 57% (152/268) of women whereas infectious virus was detected only in 6% (17/271). Genital tract HIV-1 shedding was found in 80% (130/163) of women with detectable plasma RNA and 78% (116/148) of women with positive PBMC cultures. 33% (27/83) of women with less than 500 copies/mL plasma RNA and 39% (35/90) of those with negative PBMC cultures also had genital tract shedding. INTERPRETATION Plasma RNA concentration, both qualitatively and quantitatively, was the most important factor in predicting genital HIV-1 shedding, even among women receiving potent antiretroviral therapy. However, HIV-1 shedding did occur in women with less than 500 copies/mL plasma HIV-1 RNA. This finding suggests that a separate reservoir of HIV-1 replication may exist in some women.

Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women

Objective: To assess the association between protease inhibitor (PI) use and the incidence of diabetes mellitus (DM) among participants in the Womens Interagency HIV Study. Design: Prospective multicenter cohort study. The diagnosis of DM was based on self‐report at semiannual interviews conducted from 1994 to 1998. Setting: Six inner‐city clinical sites in the United States (Brooklyn, NY; Bronx, NY; Washington, DC; Chicago, IL; San Francisco, CA; and Los Angeles, CA). Participants: A total of 1785 nonpregnant women who had no history of prior DM. The women made up four groups: 1) PI users (n = 609, person‐years [PY] at risk = 707); 2) reverse transcriptase inhibitor (RTI)‐only users (n = 932, PY = 1486); 3) HIV‐infected women reporting no antiretroviral therapy (ART) ever (n = 816, PY = 1480): and 4) HIV‐uninfected women (n = 350, PY = 905). Main Outcomes: Incidence of DM and median body mass index (BMI) from 1995 to 1998 were compared among the four groups. Results: Sixty‐nine incident cases of DM occurred among 1785 women (1.5 cases per 100 PY; 95% CI: 1.2‐1.9). The incidence of DM among PI users was 2.8 cases per 100 PY (2.8%) versus 1.2% among both RTI users and women on no ART (95% CI: 1.6‐4.1 [PI]; 0.7‐1.8 [RTI and no ART]; P = 0.01 for comparison of the PI group with the RTI group) and 1.4% among HIV‐uninfected women (95% CI: 0.7‐2.2, P = 0.06 for comparison with PI group). Weight gain was not associated with either PI or RTI use. Multivariate models identified PI use (hazard ratio [HR] = 2.90 [95% CI: 1.50‐5.60]; P = 0.002), age (HR = 1.75 per 10 years [95% CI: 1.31‐2.34]; P = 0.0002) and BMI as independent risk factors for DM. Conclusions: PI use was associated with a threefold increase in the risk of reporting incident DM. Routine screening for diabetes, particularly among older and heavier patients using PI therapy, is advisable.

Six-month natural history of oral versus cervical human papillomavirus infection

Human papillomavirus (HPV) infection is etiologically associated with a subset of oral cancers, and yet, the natural history of oral HPV infection remains unexplored. The feasibility of studying oral HPV natural history was evaluated by collecting oral rinse samples on 2 occasions at a 6‐month interval from 136 HIV‐positive and 63 HIV‐negative participants. Cervical vaginal lavage samples were concurrently collected for comparison. HPV genomic DNA was detected in oral and cervical samples by consensus primer PCR and type‐specified for 37 HPV types. The six‐month cumulative prevalence of oral HPV infection was significantly less than for cervical infection (p < 0.0001). HIV‐positive women were more likely than HIV‐negative women to have an oral (33 vs. 15%, p = 0.016) or cervical (78 vs. 51%, p < 0.001) infection detected. Oral HPV infections detected at baseline were as likely as cervical infections to persist to 6 months among HIV‐negative (60% vs. 51%, p = 0.70) and HIV‐positive (55% vs. 63%, p = 0.27) women. Factors that independently elevated odds for oral HPV persistence differed from cervical infection and included current smoking (OR = 8, 95% CI = 1.3–53), age above 44 years (OR = 20, 95% CI = 4.1–83), CD4 < 500 (OR = 6, 95% CI = 1.1–26), use of HAART therapy (OR = 12, 95% CI = 1.0–156), and time on HAART therapy (trend p = 0.04). The rate of oral HPV infections newly detected at follow‐up was significantly lower than cervical infection among HIV‐positive (p < 0.001) and HIV‐negative women (p < 0.001). Our study not only demonstrates that it is feasible to study the natural history of oral HPV infection with oral rinse sampling, but also indicates that oral and cervical HPV natural history may differ.

Risk Factors for Oral HPV Infection among a High Prevalence Population of HIV-Positive and At-Risk HIV-Negative Adults

Introduction: Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals. Methods: This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis. Results: Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6–2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each Ptrend < 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (Ptrend < 0.001) and higher number of lifetime sexual partners (Ptrend = 0.03) were strong risk factors. Conclusions: Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV. Impact: Immunosuppression may contribute to increased persistence or progression of oral HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 122–33. ©2011 AACR.

Relationship between prevalent oral and cervical human papillomavirus infections in human immunodeficiency virus-positive and -negative women.

ABSTRACT Human papillomavirus (HPV) is an etiologic agent for both oropharyngeal and cervical cancers, yet little is known about the interrelationship between oral and cervical HPV infections. Therefore, we compared the prevalences and type distributions of oral and cervical HPV infections and evaluated infection concordance in a cross-sectional study within the Womens Interagency HIV Study cohort. Oral rinse and cervical-vaginal lavage samples were concurrently collected from a convenience sample of 172 human immunodeficiency virus (HIV)-positive and 86 HIV-negative women. HPV genomic DNA was detected by PGMY09/11 L1 consensus primer PCR and type specified by reverse line blot hybridization for 37 HPV types and β-globin. Only 26 of the 35 HPV types found to infect the cervix were also found within the oral cavity, and the type distribution for oral HPV infections appeared distinct from that for cervical infections (P < 0.001). Oral HPV infections were less common than cervical infections for both HIV-positive (25.2% versus 76.9%, P < 0.001) and HIV-negative (9.0% versus 44.9%, P < 0.001) women. Oral HPV infections were more common among women with a cervical HPV infection than those without a cervical HPV infection (25.5% versus 7.9%, P = 0.002). The majority of women (207; 93.7%) did not have simultaneous oral and cervical infections by the same HPV type; however, the number of women who did (14; 6.3%) was significantly greater than would be expected by chance (P = 0.0002). Therefore, the oral and cervical reservoirs for HPV infection are likely not entirely independent of one another.

Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States

Background:Vitamin D deficiency is of increasing concern in HIV-infected persons because of its reported association with a number of negative health outcomes that are common in HIV. We undertook this study to determine the prevalence and predictors of vitamin D deficiency among a nationally representative cohort of middle-aged, ethnically diverse, HIV-infected and HIV-uninfected women enrolled in the Womens Interagency HIV Study (WIHS). Methods:Vitamin D testing was performed by Quest Diagnostics on frozen sera using the liquid chromatography/mass spectroscopy method. Vitamin D deficiency was defined as 25(OH)D ≤20 ng/mL. Comparisons of continuous and categorical characteristics among HIV-infected and HIV-uninfected women were made by Wilcoxon tests and Pearson χ2 tests, respectively. Results:One thousand seven hundred seventy-eight women (1268 HIV positive) were studied. Sixty-three percent had vitamin D deficiency (60% HIV positive vs. 72% HIV negative; P < 0.001). Multivariable predictors of vitamin D deficiency were being African American (adjusted odds ratio 3.02), Hispanic (adjusted odds ratio 1.40), body mass index (adjusted odds ratio 1.43), age (adjusted odds ratio 0.84), HIV positive (adjusted odds ratio 0.76), glomerular filtration rate <90·mL−1·min−1 (adjusted odds ratio 0.94), and WIHS sites Los Angeles (adjusted odds ratio 0.66) and Chicago (adjusted odds ratio 0.63). In the HIV-positive women, multivariate predictors were undetectable HIV RNA (adjusted odds ratio 0.69), CD4 50-200 cells per cubic millimeter (adjusted odds ratio 1.60), CD4 <50 cells per cubic millimeter (adjusted odds ratio 1.94), and recent protease inhibitor use (adjusted odds ratio 0.67). Conclusions:In this study of more than 1700 women in the United States, most women with or without HIV infection had low vitamin D levels and African American women had the highest rates of vitamin D deficiency. An understanding of the role that vitamin D deficiency plays in non-AIDS-related morbidities is planned for investigation in WIHS.

Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women: a preliminary study.

Objective: Neurocognitive studies of HIV typically target executive functions dependent on frontostriatal circuitry. The integrity of medial temporal systems has received considerably less attention despite high hippocampal viral load. Studies also predominately involve HIV+ men, though HIV+ women may be at increased risk for cognitive dysfunction due to the high prevalence of psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk uninfected women. Methods: Participants included 54 HIV+ and 12 HIV− women (mean age = 43 years; 86% African American) recruited from the Chicago site of the Womens Interagency HIV Study. Participants completed standardized tests of verbal and visual episodic memory, working memory, and executive function. A subset of 11 women also underwent functional MRI during a delayed verbal episodic memory task. Results: HIV serostatus predicted significantly lower immediate and delayed verbal episodic memory, working memory, and visual memory. Preliminary neuroimaging findings revealed group differences in bilateral hippocampal function, with HIV+ women showing decreased activation during encoding and increased activation during delayed recognition. These alterations correlated with worse episodic verbal memory. Conclusions: Verbal episodic memory deficits are evident in HIV+ women and may be associated with hippocampal dysfunction at both encoding and retrieval.

Free Glycogen in Vaginal Fluids Is Associated with Lactobacillus Colonization and Low Vaginal pH

Objective Lactobacillus dominates the lower genital tract microbiota of many women, producing a low vaginal pH, and is important for healthy pregnancy outcomes and protection against several sexually transmitted pathogens. Yet, factors that promote Lactobacillus remain poorly understood. We hypothesized that the amount of free glycogen in the lumen of the lower genital tract is an important determinant of Lactobacillus colonization and a low vaginal pH. Methods Free glycogen in lavage samples was quantified. Pyrosequencing of the 16S rRNA gene was used to identify microbiota from 21 African American women collected over 8–11 years. Results Free glycogen levels varied greatly between women and even in the same woman. Samples with the highest free glycogen had a corresponding median genital pH that was significantly lower (pH 4.4) than those with low glycogen (pH 5.8; p<0.001). The fraction of the microbiota consisting of Lactobacillus was highest in samples with high glycogen versus those with low glycogen (median = 0.97 vs. 0.05, p<0.001). In multivariable analysis, having 1 vs. 0 male sexual partner in the past 6 months was negatively associated, while BMI ≥30 was positively associated with glycogen. High concentrations of glycogen corresponded to higher levels of L. crispatus and L. jensenii, but not L. iners. Conclusion These findings show that free glycogen in genital fluid is associated with a genital microbiota dominated by Lactobacillus, suggesting glycogen is important for maintaining genital health. Treatments aimed at increasing genital free glycogen might impact Lactobacillus colonization.

Assessing the effect of HAART on change in quality of life among HIV-infected women

BackgroundThe impact of highly active antiretroviral therapy (HAART) on health-related quality of life (QOL) of HIV-1 infected individuals in large prospective cohorts has not been well studied.ObjectiveTo assess the effect of HAART on QOL by comparing HIV-infected women using HAART with HIV-infected women remaining HAART naïve in the Womens Interagency HIV Study (WIHS), a multicenter prospective cohort study begun in 1994 in the US.MethodsA 1:1 matching with equivalent (≤ 0.1%) propensity scores for predicting HAART initiation was implemented and 458 pairs were obtained. HAART effects were assessed using pattern mixture models. The changes of nine QOL domain scores and one summary score derived from a shortened version of the MOS-HIV from initial values were used as study outcomes.ResultsThe background covariates of the treatment groups were well-balanced after propensity score matching. The 916 matched subjects had a mean age of 38.5 years and 42% had a history of AIDS diagnosis. The participants contributed a total of 4,292 person visits with a median follow-up time of 4 years. In the bivariate analyses with only HAART use and time as covariates, HAART was associated with short-term improvements of 4 QOL domains: role functioning, social functioning, pain and perceived health index. After adjusting for demographic, socioeconomic, biological and clinical variables, HAART had small but significant short-term improvements on changes in summary QOL (mean change: 3.25; P = 0.02), role functioning (6.99; P < 0.01), social functioning (5.74; P < 0.01), cognitive functioning (3.59; P = 0.03), pain (6.73; P < 0.01), health perception (3.67; P = 0.03) and perceived health index (4.87; P < 0.01). These QOL scores typically remained stable or declined over additional follow-up and there was no indication that HAART modified these trends.ConclusionOur study demonstrated significant short-term HAART effects on most QOL domains, but additional use of HAART did not modify long-term trends. These changes could be attributed to the direct effect of HAART and indirect HAART effect mediated through clinical changes.