Sandra Melnick

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.

Domestic Violence and Childhood Sexual Abuse in HIV-Infected Women and Women at Risk for HIV

OBJECTIVES The purpose of this study was to determine the prevalence and effect of domestic violence and childhood sexual abuse in women with HIV or at risk for HIV infection. METHODS Participants with HIV or at risk for HIV infection enrolled in the Womens Interagency HIV Study. Childhood sexual abuse; all physical, sexual, and coercive violence by a partner; HIV serostatus; demographic data; and substance use and sexual habits were assessed. RESULTS The lifetime prevalence of domestic violence was 66% and 67%, respectively, in 1288 women with HIV and 357 uninfected women. One quarter of the women reported recent abuse, and 31% of the HIV-seropositive women and 27% of the HIV-seronegative women reported childhood sexual abuse. Childhood sexual abuse was strongly associated with a lifetime history of domestic violence and high-risk behaviors, including using drugs, having more than 10 male sexual partners and having male partners at risk for HIV infection, and exchanging sex for drugs, money, or shelter. CONCLUSIONS Our data support the hypothesis of a continuum of risk, with early childhood abuse leading to later domestic violence, which may increase the risk of behaviors leading to HIV infection.

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women

ObjectiveCervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DesignCohort study. The Womens Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). MethodsHIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participants consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. ResultsWomen with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4–81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52–0.88) to demonstrate progression ConclusionsHAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

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.

WOMEN AND HIV: Epidemiology and Global Overview

The global HIV-1 epidemic in women continues to expand at an alarming rate. More than 11 million women are currently estimated to be HIV-infected, with the majority living in sub-Saharan Africa. The primary risk factor for HIV infection in women is unprotected heterosexual intercourse. Several cofactors may influence a womans risk for HIV acquisition. These include the presence of other STDs, the prevalence of HIV in the population, engagement in high-risk sexual behaviors at a young age, an increased number of sexual partners, HIV illness severity in an infected partner, host immunogenetic responses, hormonal and other local effects in the female genital tract, and viral characteristics. The general clinical findings in women with HIV disease are similar to those in HIV-infected men. Some studies have noted higher rates of esophageal candidiasis and decreased rates of Kaposis sarcoma in women when compared with men. Overall disease progression and survival in women and men are similar once an adjustment is made for other important risk factors such as the time of seroconversion, the receipt of antiretrovirals, and baseline CD4 cell counts. Women with HIV have a high frequency of a number of diseases of the reproductive tract, including low-grade cervical dysplasia and vulvovaginal candidiasis. Despite progress in understanding the risk factors for HIV transmission to women and the variables related to disease progression, major research questions remain. These include the role of hormonal contraceptives in the risk for HIV acquisition, the primary mechanism of infection, and host systemic as well as local hormonal and immune responses in the female reproductive tract that may alter the risk of HIV infection. Over the next decade, it is anticipated that the quality of life and length of survival will improve dramatically for both HIV-infected women and men in settings in which new highly active combination antiretroviral therapy is available and affordable. Unfortunately, in most of the world, these antiretroviral drugs are not available for the treatment of the vast numbers of individuals infected by HIV. Therefore, development of successful strategies for primary prevention of HIV infection in women must be a top public health priority.

Cancer risk among participants in the women's interagency HIV study.

Background:The HIV epidemic has been associated with an increased incidence of specific cancers. However, less is known about cancers occurring in HIV-infected women than men. Methods:To determine the risk of cancer among HIV-infected and at-risk HIV-uninfected women, cancer incidence data from the Women’s Interagency HIV Study (WIHS) were compared with data from the population-based United States Surveillance, Epidemiology, and End Results (SEER) registry. Age- and race-adjusted standardized incidence ratios (SIRs) were computed and exact statistical tests were used to measure significance. Results:Among the 1950 women participants (1554 HIV infected, 391 HIV uninfected, and 5 HIV seroconverters), 48 cancers were diagnosed during study follow-up. Among HIV-infected women, significantly (P < 0.05) increased incidence rates were observed for all cancer types (SIR = 1.9), Kaposi sarcoma (SIR = 213.5), non-Hodgkin lymphoma (NHL) (SIR = 19.0), and lung cancer (SIR = 6.3) when compared with SEER rates. Lung cancer incidence was also elevated (P = 0.07) among the HIV-uninfected women (SIR = 6.9), when compared with SEER rates, and was similar to the SIR for HIV-infected women. While the incidence rate of NHL among HIV-infected women was significantly lower during the era of highly active antiretroviral therapy (HAART) compared with the pre-HAART era (relative risk = 0.15, P = 0.005), the incidence of NHL among HIV-infected WIHS participants remained significantly higher than in the US population (SIR = 6.4, 95% CI = 1.3–15.5). Conclusion:In the HAART era, the higher rates of cancer among HIV-infected women, coupled with increased life expectancy, should lead to more intensive cancer screening and prevention efforts in this population.

Low incidence of invasive cervical cancer among HIV-infected US women in a prevention program.

Objective: To measure the incidence of invasive cervical cancer (ICC) in US women infected with HIV. Design: Multicenter prospective cohort study, conducted between October 1994, and September 2001. Setting: HIV research centers operating as six urban consortia in the Womens Interagency HIV Study. Subjects: A total of 2131 women (462 HIV seronegative, 1661 HIV seropositive, and eight seroconverters). Women with a history of hysterectomy or of cervical cancer at baseline evaluation were excluded. Intervention: Cervical cytology obtained at 6-month intervals, with a colposcopy referral threshold of atypia, followed by individualized treatment. Main outcome measure: ICC diagnoses obtained from study databases and regional cancer registries and confirmed by a gynecologic pathologist. Results: No incident ICC were observed in HIV seronegative women during 2375 woman-years of observation. During 8260 woman-years of observation, eight putative incident cases of cervical cancer were identified in HIV seropositive women, but only one was confirmed, yielding an incidence rate of 1.2/10 000 woman-years (95% confidence interval, 0.3–6.7/10 000 woman-years). The difference in incidence between HIV seropositive and seronegative women was not significant (P = 1.0). Conclusion: ICC is uncommon in HIV-infected US women participating in a regular prevention program.

The relative value of CD4 cell count and quantitative HIV-1 RNA in predicting survival in HIV-1-infected women: results of the women's interagency HIV study.

OBJECTIVES To determine factors associated with survival and to assess the relative strength of CD4 cell count and HIV-1 RNA in predicting survival in a cohort of HIV-1-infected women. DESIGN Prospective cohort, enrolled during 1994-1995, with median follow-up of 29 months RESULTS Of 1769 HIV-infected women 252 died. In multivariate analyses, lower CD4 cell count, higher quantitative plasma HIV-1 RNA, and the presence of a self-reported AIDS-defining (Class C) condition were significantly associated with shorter survival: the relative hazard (RH) of dying was 1.17, 3.27, and 8.46, respectively for women with baseline CD4 cell count of 200-349, 50-199, and < 50 x 10(6) cells/l, compared with women with CD4 cell count of > or = 350 x 10(6) cells/l. Compared with women with HIV-1 RNA levels of < 4000 copies/ml plasma, the RH of dying for women with baseline quantitative HIV-1 RNA measurements of 4000-20,000, 20,000-100,000, 100,000-500,000 and > 500,000 copies/ml, was 2.19, 2.17, 3.16, and 7.25, respectively. CD4 cell count had as strong a prognostic value as HIV-1 RNA level, particularly among participants with more advanced immunodeficiency. When the analysis was adjusted to eliminate the distortion created by having disproportionately sized strata of the categorized variables, the relative hazard of death associated with CD4 cell count became even larger in comparison with that for HIV-1 RNA. Eliminating from the analysis all follow-up time during which participants could have received highly active antiretroviral therapy did not change these findings. Age was not a predictor of survival after adjustment for covariates. CONCLUSIONS CD4 cell count and HIV-1 RNA had similar prognostic value in this cohort of HIV-1-infected women. Even in the presence of a low viral burden, a substantially decreased CD4 cell count remained a strong predictor of mortality.

HPV testing for triage of HIV-infected women with papanicolaou smears read as atypical squamous cells of uncertain significance.

PURPOSE To assess the utility of testing for high-risk human papillomavirus (HPV) DNA as a triage strategy for detecting cervical intraepithelial neoplasia (CIN) grade 2/3 in women with human immunodeficiency virus-1 (HIV-1) infection and cytology read as atypical cells of uncertain significance (ASCUS). METHODS Conventional cervical cytology and cervicovaginal lavage were obtained at 6-month intervals between October 1, 1994, and September 30, 2002, from women enrolled in the Womens Interagency HIV Study, a multicenter cohort studying the natural history of HIV in women. HPV typing was performed by PCR. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 were classified as carrying high oncogenic risk. Women with ASCUS smears were referred for colposcopy. Analyses of the sensitivity of HPV testing were cross-sectional, using colposcopy results within 90 days of first ASCUS result. RESULTS Of the 270 women evaluated, 7 (3%) had CIN 2, and 3 (1%) had CIN3 or adenocarcinoma in situ. High-risk HPV DNA was found in 81 (30%) of the 270 participants. The sensitivity of high-risk HPV DNA detection for CIN 2/3 was 50% (95% CI 0.19, 0.81), the specificity was 71% (95% CI 0.65, 0.76), the positive predictive value was 6% (95% CI 0.01, 0.11), and the negative predictive value was 97% (95% CI 0.95, 1.00). HPV of any risk type was found in 176 (65%) of the 270 women, including 9 of 10 women with CIN 2/3, for a sensitivity of 90% (95% CI 0.56, 1.00), a specificity of 36% (95% CI 0.30, 0.42), a positive predictive value of 5% (95% CI 0.02, 0.08), and a negative predictive value of 99% (95% CI 0.94, 1.00). CONCLUSIONS For women with HIV and Papanicolaou smears read as ASCUS, DNA testing for high risk HPV may not be sensitive enough for clinical use.