Kathryn Anastos

Association between Renal Disease and Outcomes among HIV-Infected Women Receiving or Not Receiving Antiretroviral Therapy

BACKGROUND The associations of proteinuria and an elevated creatinine level with progression to acquired immunodeficiency syndrome (AIDS) and death in the era of highly antiretroviral therapy (HAART) have not been fully described. METHODS This analysis includes 2038 human immunodeficiency virus (HIV)-infected women from the Womens Interagency HIV Study. Time to the development of a new AIDS-defining illness (ADI) and death was modeled using proportional hazards regression before the widespread availability of HAART and after initiation of HAART. RESULTS Of the 2038 subjects, the 14.1% of women with proteinuria had lower CD4 lymphocyte counts and higher viral loads (P<.0001 for all) at baseline and before initiation of HAART. Before the widespread availability of HAART, proteinuria was associated with an increased risk for development of ADI (hazard ratio [HR], 1.37; P=.005), and proteinuria and an elevated creatinine level were both associated with an increased risk of death (for proteinuria: HR, 1.35 [P=.04]; for creatinine: HR, 1.72 per decrease in the inverse unit [P=.02]). Among women initiating HAART, an elevated creatinine level remained associated with an increased risk of development of ADI (HR, 1.54 per decrease in the inverse unit; P=.03), and proteinuria and an elevated creatinine level were associated with an increased risk of death (for proteinuria: HR, 2.07 [P=.005]; for creatinine: HR, 1.96 per decrease in the inverse unit [P=.04]). CONCLUSIONS Proteinuria and an elevated creatinine level were associated with an increased risk of death and development of ADI. These associations may reflect the direct role of the kidney in modulating HIV disease, or they may act as markers of greater comorbidity.

Hypertension in Women: What is Really Known?: The Women's Caucus, Working Group on Women's Health of the Society of General Internal Medicine

PURPOSE To determine whether there is sufficient information in the medical literature to guide appropriate treatment of hypertensive women. DATA IDENTIFICATION Epidemiologic surveys of hypertension, clinical trials of antihypertensive therapy, and studies of selected adverse effects of antihypertensive agents were identified through a computerized search using MEDLINE and by identifying all studies cited in current medical textbooks as supporting evidence for the guidelines for the treatment of hypertensive individuals. All epidemiologic studies selected were cross-sectional or longitudinal, multicenter, population-based surveys. All clinical trials were large, randomized studies comparing one or more antihypertensive agents with a placebo or nonplacebo control group. Epidemiologic studies and clinical trials were reviewed to assess the quantity and quality of information available regarding important aspects of hypertension in women. Data pertaining to epidemiology, natural history, results of treatment, and two significant side effects of antihypertensive treatment were examined. RESULTS OF DATA ANALYSIS The prevalence of hypertension is greater in black women than in black men and is about equal in white women and men. Because women outnumber men in the population, there are more hypertensive women than men. The attributable risk percent (the proportion of end points that could be eliminated by removing hypertension) for cardiovascular complications of hypertension is higher for women than men. Clinical trials show clear benefit of therapy for black women but no clear benefit for white women; some studies suggest that treatment of white women is harmful. Lipid profiles and their relation to ischemic heart disease differ for women and men; there is currently no information on the effects of antihypertensive agents on serum lipids in women. Few data have been published on the frequency of sexual dysfunction in treated hypertensive women. CONCLUSIONS Hypertension in women and its related cardiovascular outcomes are a major public health problem. Clinical trials of antihypertensive therapy do not fully support current guidelines for the treatment of hypertensive women. Research concerning adverse effects of antihypertensive agents has largely excluded women from consideration; further studies are required to guide appropriate treatment.

Patterns and Predictors of Changes in Adherence to Highly Active Antiretroviral Therapy: Longitudinal Study of Men and Women

BACKGROUND Adherence to therapy is a dynamic behavior. However, few studies have identified factors associated with changes in adherence to highly active antiretroviral therapy (HAART) among men and women. METHODS From 1999 through 2004, self-reported adherence to HAART was recorded twice yearly as part of 2 prospective cohort studies. At each study visit, participants were categorized as being 100% adherent if they reported full adherence with their HAART regimen over the past 4 days (for men) and 3 days (for women). Repeated-measures logistic regression models were used to identify predictors for changes in adherence between consecutive visits. RESULTS Of the participants, 640 men and 1304 women contributed 2803 and 5972 visit-pairs, respectively. Among white men, the prevalence of 100% adherence decreased from 91% in 1998 to 80% in 2003. Among women and African American men, the prevalence of full adherence was lower (75% and 77% on average, respectively) and stable over time (P>.6). In both cohorts, the presence of clinical symptoms was independently associated with decreasing adherence (odds ratio [OR], 1.38 in men and 1.48 in women). Depression in men (OR, 1.44) and use of alcohol in women (OR, 1.81, 1.52, and 1.29, for binge drinking, moderate-to-heavy drinking, and low consumption, respectively) also predicted decreasing adherence. In addition, the use of drugs by men and women (OR, 0.61 and 0.58, respectively) and alcohol binging by women (OR, 0.41) were negatively associated with improving adherence. CONCLUSIONS Adherence to antiretroviral treatment is a dynamic process; modifiable risk factors are associated with increasing and decreasing adherence, suggesting specific interventions. Moreover, the association of these risk factors with changes in adherence may differ by sex.

Functional Attributes of Mucosal Immunity in Cervical Intraepithelial Neoplasia and Effects of HIV Infection

The role of mucosal immunity in human papillomavirus (HPV)-related cervical diseases is poorly understood. To characterize the local immune microenvironment in cervical intraepithelial neoplasia (CIN) 2/3 and determine the effects of HIV infection, we compared samples from three groups: normal cervix, CIN 2/3 from immunocompetent women (HIV− CIN 2/3), and CIN 2/3 from HIV seropositive women (HIV+ CIN 2/3). CIN 2/3 lesions contained increased numbers of immune cells from both the acquired and innate arms of the immune response in stroma [CD4+ and CD8+ T cells, macrophages, mast cells, B cells, neutrophils, and natural killer (NK) cells] and dysplastic epithelium (CD4+ T cells, macrophages, and NK cells). Immune cells in CIN 2/3 expressed activation markers, as measured by interleukin-2 receptor (IL-2R) and transcription factor T bet. Interferon-γ production was significantly up-regulated in CIN lesions and was expressed by CD4+ and CD8+ T cells and NK cells, indicating the activation of immune cells. Abundant presence of transforming growth factor-β+ CD25+ cells in the infiltrates associated with CIN lesions, and of immature CD1a+ dendritic cells expressing IL-10 and transforming growth factor-β, indicate that CIN is associated with an influx of immune cells that produce a mixture of proinflammatory and regulatory cytokines. In HIV+ CIN, immune cell densities (CD4+ T cells, macrophages, neutrophils, and NK cells) and expression of interferon-γ were significantly decreased compared with HIV− CIN. Regulatory cytokines were also down-regulated in this group. Therefore, both pro- and anti-inflammatory responses present in CIN 2/3 lesions are suppressed in HIV-seropositive women.

Evolution and Taxonomic Classification of Human Papillomavirus 16 (HPV16)-Related Variant Genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67

Background Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies. Methods DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types. Results The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%–1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1. Conclusions These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions.

Variations in Serum Mullerian Inhibiting Substance Between White, Black and Hispanic Women

OBJECTIVE To compare serum müllerian inhibiting substance (MIS) levels between white, black, and Hispanic women to determine whether ovarian aging occurs at a different time course for women of different racial groups. DESIGN Longitudinal study of serum MIS levels in women of different race and ethnicity over two different time points. SETTING Womens Interagency HIV Study, a multicenter prospective cohort study. PATIENT(S) Serum samples obtained from 809 participants (122 white, 462 black, and 225 Hispanic women). INTERVENTION(S) Comparison of serum MIS between women of different race and ethnicity at two time points (median age 37.5 years and 43.3 years). MAIN OUTCOME MEASURE(S) Variation in MIS by race and ethnicity over time, controlling for age, body mass index, HIV status, and smoking. RESULT(S) Compared with white women, average MIS values were lower among black (25.2% lower) and Hispanic (24.6% lower) women, adjusting for age, body mass index, smoking, and HIV status. CONCLUSION(S) There is an independent effect of race and ethnicity on the age-related decline in MIS over time.

Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy

To initiate infection, HIV-1 requires a primary receptor, CD4, and a secondary receptor, principally the chemokine receptor CCR5 or CXCR4. Coreceptor usage plays a critical role in HIV-1 disease progression. HIV-1 transmitted in vivo generally uses CCR5 (R5), but later CXCR4 (X4) strains may emerge; this shift heralds CD4+ cell depletion and clinical deterioration. We asked whether antiretroviral therapy can shift HIV-1 populations back to R5 viruses after X4 strains have emerged, in part because treatment has been successful in slowing disease progression without uniformly suppressing plasma viremia. We analyzed the coreceptor usage of serial primary isolates from 15 women with advanced disease who demonstrated X4 viruses. Coreceptor usage was determined by using a HOS-CD4+ cell system, biological and molecular cloning, and sequencing the envelope gene V3 region. By constructing a mathematical model to measure the proportion of virus in a specimen using each coreceptor, we demonstrated that the predominant viral population shifted from X4 at baseline to R5 strains after treatment. Multivariate analyses showed that the shift was independent of changes in plasma HIV-1 RNA level and CD4+ cell count. Hence, combination therapy may lead to a change in phenotypic character as well as in the quantity of HIV-1. Shifts in coreceptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs.

Mortality Among Participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study

BACKGROUND Many studies that have reported decreases in human immunodeficiency virus (HIV)-related mortality since the advent of highly active antiretroviral therapy (HAART) have also reported steady increases in non-HIV-related mortality over the same time periods. We examined temporal trends and risk factors for accident- and injury-related mortality among HIV-infected and -uninfected participants in the Womens Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS). METHODS Information on causes of death was recorded for all participants in the MACS and WIHS cohort studies who died, and causes of death were categorized as accident- or injury-related deaths or not. Mortality rates were calculated by time periods, prior to the widespread use of HAART (before 1997) and after (1997-2002), and risk factors. RESULTS Cause of death information was available for 619 women in the WIHS who died (during the period 1994-2002) and 1830 men in the MACS who died (during the period 1984-2002). The death rates were higher for accident- or injury-related mortality in the WIHS (2.96 deaths per 1000 person-years for the HIV-infected group and 2.96 per 1000 person-years for the HIV-uninfected group), compared with the participants in MACS (0.79 deaths per 1000 person-years for the HIV-infected group and 0.63 per 1000 person-years for the HIV-uninfected group). In the final multivariate analysis, the following factors were associated with significantly higher risk in men: higher education, depressive symptoms, and a greater number of sex partners. Among women, the significant risk factors for death were decreased CD4+ T cell count, unemployment, higher alcohol use, and injection drug use. CONCLUSION The characteristics of the men in the MACS who died and women in the WIHS who died differ, as do the risk factors for mortality. These results characterize important target groups for interventions to reduce accident- and injury-related deaths.

Effects of treated and untreated depressive symptoms on highly active antiretroviral therapy use in a US multi-site cohort of HIV-positive women

Abstract This study examines the effects of treated and untreated depressive symptoms on the likelihood of utilization of highly active antiretroviral therapy (HAART) among a multi-site cohort of HIV-infected women who screened positive for probable depression. Data were collected biannually from 1996 through 2001 in a prospective cohort study. Random-effects regression analysis was used to estimate the longitudinal effects of mental health treatment on the probability of HAART utilization, controlling for clinical indicators (CD4 count, viral load), demographic features (race/ethnicity, income), and behavioural factors (recent crack, cocaine, or heroin use). Use of antidepressants plus mental health therapy, or use of mental health therapy alone significantly increased the probability of HAART utilization, compared to receiving no depression treatment. Use of antidepressants alone did not differ significantly from receiving no depression treatment. African American women and those who used crack, cocaine, or heroin also were less likely to use HAART. These findings suggest that efforts to enhance depressed womens access to psychopharmacologic treatment and therapy may increase their use of the most effective HIV therapies.

The impact of HIV infection and immunodeficiency on human papillomavirus type 6 or 11 infection and on genital warts.

Background HIV infection and associated immunodeficiency are known to alter the course of human papillomavirus (HPV) infections and of associated diseases. Goal This study investigated the association between HIV and HPV and genital warts. Study Design HPV testing and physical examinations were performed in two large prospective studies: the Womens Interagency HIV Study (WIHS) and the HIV Epidemiology Research Study (HERS). Statistical methods incorporating dependencies of longitudinal data were used to examine the relationship between HIV and HPV and genital warts. Results A total of 1008 HIV-seronegative and 2930 HIV-seropositive women were enrolled in the two studies. The prevalence of HPV 6 or 11 was 5.6 times higher in HIV-seropositive women in the WIHS and 3.6 times higher in the HERS. Genital wart prevalence increased by a factor of 3.2 in the WIHS and 2.7 in the HERS in HIV-seropositive women. In the WIHS, infection with HPV type 6 or 11, in comparison with no HPV infection, was associated with odds of genital wart prevalence of 5.1 (95% CI: 2.9–8.8), 8.8 (95% CI: 6.1–12.8), and 12.8 (95% CI: 8.8–18.8) in HIV-seronegative women, HIV-seropositive women with ≥201 CD4 cells/&mgr;l, and HIV-seropositive women with ≤200 CD4 cells/&mgr;l, respectively. In the HERS, infection with HPV type 6 or 11 was associated with odds of 2.7 (95% CI: 1.6–4.6), 4.9 (95% CI: 3.2–7.7), and 5.3 (95% CI: 3.3–8.5) in these same groups. Other HPV types showed a similar dose–response relation, but of substantially lower magnitude and statistical significance. Conclusions HIV infection and immunodeficiency synergistically modified the relation between HPV 6 or 11 infection and genital wart prevalence.