Ruth M. Greenblatt

The Women's Interagency HIV Study

The Womens Interagency HIV Study comprises the largest U.S. cohort to date of human immunodeficiency virus (HIV)-seropositive women (N = 2,058) with a comparison cohort of seronegative women (N = 568). The methodology, training, and quality assurance activities employed are described. The study population, enrolled between October 1994 and November 1995 through six clinical consortia throughout the United States (totaling 23 sites) represents a typically hard-to-reach study population. More than half of the women in each cohort were living below the federally defined levels of poverty. The women ranged in age from 16 to 73 years; approximately one-quarter self-identified as Latina or Hispanic, over one-half as African-American not of Hispanic origin, and less than 20% as white, non-Hispanic origin. Self-reporting of HIV exposure risk included injection drug use by 34% of the seropositive women and 28% of the seronegative women, heterosexual contact (42% vs 26%), transfusion risk (4% vs 3%) and no identified risk (20% vs 43%). Demographic and HIV exposure risk characteristics of the seropositive cohort were comparable with characteristics of nationally reported AIDS cases in U.S. women. This well characterized cohort of HIV-seropositive and high-risk seronegative women represents a rich opportunity for future studies of HIV disease progression and pathogenesis.

Prevalence and Risk Factors for Anal Human Papillomavirus Infection in Human Immunodeficiency Virus (HIV)—Positive and High-Risk HIV-Negative Women

Little is known about the epidemiology of anal human papillomavirus (HPV) infection in women. We studied 251 human immunodeficiency virus (HIV)-positive and 68 HIV-negative women for the presence of anal HPV by use of polymerase chain reaction (PCR) and hybrid capture. Medical and behavioral risk factors were evaluated; 76% of HIV-positive and 42% of HIV-negative women were found to have anal HPV DNA via analysis by PCR (relative risk [RR], 1.8; 95% confidence interval [CI], 1.3-2.5). Among 200 women for whom there were concurrent anal and cervical HPV data, anal HPV was more common than cervical HPV in both HIV-positive (79% vs. 53%) and HIV-negative women (43% vs. 24%). By multivariate analysis of HIV-positive women, CD4(+) cell counts </=200 cells/mm(3), compared with counts >500 cells/mm(3) (RR, 1.4; 95% CI, 1.1-1.5), and cervical HPV infection (RR, 1.3; 95% CI, 1.1-1.4) were associated with anal HPV infection. Women >45 years old had reduced risk, compared with women <36 years old (RR, 0.80; 95% CI, 0.50-0.99), as did African American women (RR, 0.86; 95% CI, 0.72-1.0), compared with white women. Anal HPV infection is underrecognized in HIV-positive and high-risk HIV-negative women.

Prevalence and predictors of squamous cell abnormalities in papanicolaou smears from women infected with HIV-1

Background Cervical neoplasia occurs with increased frequency among women infected with HIV-1. Objective To characterize prevalence of and risk factors for abnormal cervical cytology among women with HIV and to compare them to uninfected women. Methods Baseline cervical cytology was obtained from 1713 women seropositive for HIV and 482 at-risk control women who were enrolled in the Womens Interagency HIV Study, a multicenter prospective cohort study conducted in six U.S. cities. Associations with sociodemographic, medical, and sexual variables were assessed by Fishers exact test, Mantel extension test, and logistic regression analysis. Results Cervical cytology was abnormal in 38.3% of HIV-infected women (atypical squamous cells of uncertain significance [ASCUS] 20.9%, low-grade squamous cells of uncertain significance [LSIL] 14.9%, high-grade squamous cells of uncertain significance [HSIL] 2.3%, cancer 0.2%) and 16.2% of HIV-uninfected women (ASCUS 12.7%, LSIL 2.3%, HSIL 1.2%, cancer 0.0%). Risk factors for any abnormal cytology in multivariate analysis included HIV infection, CD4 cell count, HIV RNA level, detection of human papillomavirus (HPV), a prior history of abnormal cytology, employment, and number of male sex partners within 6 months of enrollment. Prior abortion was associated with a decreased risk of cytologic abnormality. Conclusions Cervical cytologic abnormalities were frequent among women infected with HIV, although high-grade changes were found in only 2.5%. Factors linked to sexual and reproductive history, HPV infection, and HIV disease all influenced risk.

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.

Association of race and gender with HIV-1 RNA levels and immunologic progression

Context: HIV‐1 RNA and lymphocyte subset levels are the principal indications for antiretroviral treatment. Past reports have differed with regard to the effect of gender and race on these measures and in measures of disease progression. Objective: To assess racial and gender differences in HIV‐1 RNA levels and CD4+ lymphocyte decline. Design: A longitudinal study based in the two largest HIV natural history cohort studies conducted in 7 metropolitan areas of the United States. Results: In all, 1256 adult women and 1603 adult men for whom multiple data points were available prior to initiation of antiretroviral therapy were included. Women were more likely to be nonwhite, to have a history of injection drug use, and to have HIV‐associated symptoms. After adjustment for differences in measurement method, baseline CD4+ cell count, age, and clinical symptoms, HIV‐1 RNA levels were 32% to 50% lower in women than in men at CD4+ counts >200 cells/mm3 (p < .001) but not at CD4+ cell counts <200 cells/mm3. HIV‐1 RNA levels were also 41% lower in nonwhites than in whites (p < .001) and 21% lower in persons reporting a prior history of injection drug use (p < .001). Women had more rapid declines in CD4+ cell counts over time than men (difference in slope of 46 cells/year) and nonwhite individuals had slower decline in CD4 cell counts than whites (difference of 39 cells/year). Conclusions: Both race and gender influence the values of HIV‐1 RNA and the rate of HIV‐1 disease progression as indicated by decline in CD4 cell counts over time. These effects could provide clues regarding the factors that influence HIV‐disease progression and may indicate that guidelines for therapy should be adjusted for demographic characteristics.

Evolution of cervical abnormalities among women with HIV-1: Evidence from surveillance cytology in the Women's Interagency HIV Study

Objective: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. Methods: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV‐seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T‐cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. Results: At least one abnormal smear was found during all of follow‐up among 73.0% of HIV‐seropositive patients and 42.3% of seronegatives (p < .001). Only 5.9% of seropositives ever developed high‐grade lesions, and the proportion with high‐grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV‐seropositive patients and seronegative patients was 26.4 and 11.0/100 woman‐years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9‐3.0), whereas that of at least low‐grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6‐6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p < .05); HPV detection and HIV RNA level predicted progression (p < .01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p < .001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm3 and HIV RNA levels <4000/ml of similar HPV status. Conclusions: Although HIV infected women were at high risk for abnormal cytology, high‐grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.

Patterns of the hazard of death after AIDS through the evolution of antiretroviral therapy: 1984-2004

Objective:To characterize changing survival patterns after development of clinical AIDS from 1984 to 2004, when different antiretroviral therapies were being introduced. Design:Cohort of homosexual men since 1984 and cohort of women since 1994. Methods:A total of 1504 men and 461 women were followed for all-cause mortality after an incident AIDS diagnosis. Relative hazards of death and relative times to death were determined in five therapy eras: no/monotherapy (July 1984–December 1989), monotherapy/combination therapy (January 1990–December 1994), HAART introduction (January 1995–June 1998), short-term stable HAART use (July 1998–June 2001), and moderate-term stable HAART use (July 2001–December 2003). Results:A total of 1057 (54%) study participants died. The time at which 25% of individuals died after an AIDS diagnosis increased significantly from 0.56 years [95% confidence interval (CI), 0.50–0.64] in the no/monotherapy era to 0.74 (95% CI, 0.67–0.82), 1.78 (95% CI, 1.29–2.44), 4.22 (95% CI, 2.94–6.05) and 5.08 years (95% CI, 2.39–10.79) in the four subsequent therapy eras, respectively. Inferences on the beneficial effects of HAART were confirmed after adjustment by age, sex, type of AIDS diagnosis and CD4 cell count at diagnosis. The pattern of the hazard of death after AIDS changed from increasing in the pre-HAART era to being lower and non-increasing in the eras of HAART. Conclusions:The sustained beneficial effect of HAART, even in individuals with clinical AIDS and extensive treatment histories, attenuates concerns about emergence of resistance but augurs that a substantial number of HIV-infected individuals may require care for very long periods.

Does Patient Sex Affect Human Immunodeficiency Virus Levels

We undertook a critical epidemiological review of the available evidence concerning whether women have lower levels of human immunodeficiency virus (HIV) RNA than do men at similar stages of HIV infection. The 13 studies included in this analysis reported viral load measurements in HIV-infected men and women at a single point in time (cross-sectional studies) or over time (longitudinal studies). Seven of the 9 cross-sectional studies demonstrated that women had 0.13-0.35 log(10) ( approximately 2-fold) lower levels of HIV RNA than do men, despite controlling for CD4(+) cell count. Four longitudinal studies revealed that women had 0.33-0.78 log(10) (2- to 6-fold) lower levels of HIV RNA than do men, even when controlling for time since seroconversion. Adjustment for possible confounders of the relationship between sex and viral load, including age, race, mode of virus transmission, and antiretroviral therapy use, did not change this outcome. This finding is significant, because viral loads are frequently used to guide the initiation and modification of antiretroviral therapy.

Anal intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected women.

Objectives:To study anal intraepithelial neoplasia and its associations with anal and cervical human papillomavirus (HPV), cervical neoplasia, host immune status, and demographic and behavioral risk factors in women with and at risk for HIV infection. Design:Point-prevalence analysis nested within a prospective study of women seen at three clinical centers of the Womens Interagency HIV Study. Methods:In 2001–2003 participants were interviewed, received a gynecological examination, anal and cervical cytology testing and, if abnormal, colposcopy-guided or anoscopy-guided biopsy of visible lesions. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV probing. Logistic regression analyses were performed, and odds ratios (ORs) estimated risks for anal intraepithelial neoplasia. Results:Four hundred and seventy HIV-infected and 185 HIV-uninfected women were enrolled. Low-grade anal intraepithelial neoplasia was present in 12% of HIV-infected and 5% of HIV-uninfected women. High-grade anal intraepithelial neoplasia was present in 9% of HIV-infected and 1% of HIV-uninfected women. In adjusted analyses among HIV-infected women, the risk factors for low-grade anal intraepithelial neoplasia were younger age [OR = 0.59, 95% confidence interval (CI) = 0.36–0.97], history of receptive anal intercourse (OR = 3.2, 95% CI = 1.5–6.8), anal HPV (oncogenic types only OR = 11, 95% CI = 1.2–103; oncogenic and nononcogenic types OR = 11, 95% CI = 1.3–96), and cervical HPV (oncogenic and nononcogenic types OR = 3.5, 95% CI = 1.1–11). In multivariable analyses among HIV-infected women, the only significant risk factor for high-grade anal intraepithelial neoplasia was anal HPV infection (oncogenic and nononcogenic types OR = 7.6, 95% CI = 1.5–38). Conclusion:Even in the era of highly active antiviral therapy, the prevalence of anal intraepithelial neoplasia was 16% in HIV-infected women. After controlling for potential confounders, several risk factors for low-grade anal intraepithelial neoplasia differed from risk factors for high-grade anal intraepithelial neoplasia.

Sexual, contraceptive, and drug use behaviors of women with HIV and those at high risk for infection: results from the Women's Interagency HIV Study.

OBJECTIVE To document the sexual and contraceptive practices of women with HIV infection or who are at risk for infection. DESIGN Data on the baseline behaviors of 561 HIV-negative and 2040 HIV-positive women were collected as part of the Womens Interagency HIV Study (WIHS). WIHS is a multisite, longitudinal study following the natural history of HIV infection among women in the United States. METHODS Each participant contributed an interviewer administered, self-report interview including questions on sexual and contraceptive behavior. RESULTS Women with HIV were less likely to report heterosexual activity in the previous 6 months (65% HIV-positive, 76% HIV-negative). Among sexually active women, there were no differences in the proportion of those reporting vaginal (97% HIV-positive, 98% HIV-negative) or anal sex (12% HIV-positive, 10% HIV-negative), although women with HIV were less likely to report cunnilingus (41% HIV-positive, 70% HIV-negative) and fellatio (48% HIV-positive, 57% HIV-negative). Of women with HIV, 63% always used condoms during vaginal sex (versus 28% HIV-negative), with lower rates reported during other sexual activities. Crack, cocaine, or injecting drug use, reported by 27% of HIV-positive and 35% of HIV-negative women, was associated with inconsistent condom use, independent of serostatus. HIV-positive women who reported using condoms and another contraception method were less consistent condom users (57% consistent versus 67%). CONCLUSIONS The prevalence of sexual risk behavior in this sample suggests that, although women with HIV exhibit lower levels of sexual risk behavior than uninfected women, many have not been successfully reached with regard to implementing safer behaviors. These findings have implications for more widespread and effective behavioral intervention efforts.