Chicago WIHS Concept Sheets and Substudies

Exploratory Examination of Respiratory Sinus Arrhythmia and Cognitive Function in Women with HIV (W17051) – William Chance Nicholson, Kathleen Weber, David Vance

Despite improvements in HIV treatment, persons with HIV are at risk for cognitive impairments which could result from disrupted autonomic nervous system function. Under normal conditions, the vagus nerve helps stabilize the autonomic nervous system and regulate cognitive function. However, conditions like HIV interfere with the vagus nerve’s ability to maintain a healthy nervous system. As women age, they demonstrate a more significant loss of vagus nerve function when compared to males; therefore, they are at an increased risk for cognitive impairments over time. Considering HIV’s ability to interfere with the vagus nerve and women’s decrease in vagus nerve function, HIV-infected women could be at an increased risk for cognitive problems when compared to HIV-negative women. In support of this, studies suggest HIV-infected women perform worse on cognitive tests (e.g., memory, attention) when compared to HIV-negative women. Despite this, little is known about the relationship between the vagus nerve and cognitive function in HIV-infected women. Exploring this relationship could offer a better understanding of autonomic nervous system function in women with HIV. A better understanding of this relationship could provide new insights for cognitive-based interventions, which may reduce the quality of life burdens often imposed by cognitive impairments in this population. The purpose of this study is to explore the relationship between vagus nerve function and cognition in HIV-infected women as compared to HIV-negative women.

The Contribution of Sleep and Circadian Disruption to Kynurenine Pathway Activation and Cardiometabolic Risk in Women with HIV (W17035) – Audrey French, Helen Burgess, Kathleen Weber

It is clear from the medical literature that disrupted or poor sleep patterns are associated with medical problems including heart and other cardiovascular diseases. People with HIV are at higher risk of these diseases as well. There is some preliminary information that sleep disruption leads to increased cardiovascular risk by leading to inflammation. This study is trying to understand the extent of sleep disruption in WIHS women and whether the extent of sleep disruption is affected by HIV status. In addition, this study wants to look at an inflammatory pathway that has been associated with cardiovascular disease, called the IDO pathway, to see how it is affected by sleep quality.

Patterns and cognitive correlates of behavioral health disorders in midlife HIV-infected women (W17016) – Leah H. Rubin, Judith A. Cook

Mental health and substance use disorders are common among people living with HIV and often co-occur. Behavioral health problems are also associated with problems in memory and other mental abilities. Here this study aims to examine the association between behavioral health diagnostic profiles and performance on tasks involving memory and other mental abilities over time. The goal is to use novel approaches to find women with similar behavioral health profiles (e.g., fear, distress, and substance use; fear, distress, and no substance use) and see how they impact performance on memory and other mental abilities over time.

The prevalence and etiology of protracted amenorrhea and resumption of menses in the WIHS (W17014) – Helen E. Cetjin

HIV-infected women will often stop having their monthly periods (menses) for lots of different reasons, and it may be hard to know if they have gone through menopause (“the change of life”), or stopped bleeding because of other factors. Other reasons besides menopause that someone may stop regular menses include polycystic ovarian syndrome (PCOS), excessive weight loss, illicit drug or medication use, or stress. Investigators previously looked at women in the WIHS who had not had a period for at least one year and checked their serum follicle stimulating hormone (FSH) levels. This level is expected to go up and be above 25 mIU/ml in a postmenopausal woman, while it stays lower in women who are not menopausal. Investigators saw that around half of the women who were thought to be in menopause actually had FSH levels that were below the menopausal level. Thus it looked like they had stopped having periods for other reasons. Women who stop having periods for other reasons will often start having them again later on. The purpose of this study is to look at women who stopped having menses for at least one year, and to see how many then started having periods sometime after that. This study hopes to understand why they stopped having periods in the first place. This may help to understand menopause and fertility in HIV positive women.

Trauma Symptoms and Resilience in HIV infected and uninfected Chicago Men and Women (W17013) – Audrey French, Lisa Barnes, Kathleen Weber

Early life and ongoing trauma is common among men and women with and at risk for HIV and is associated with poor health in adulthood. Given the increasing number of individuals aging with HIV, trauma associated morbidity is a growing public health concern. It remains unclear whether differences exist in psychosocial resources and resilience between men and women but women are more likely to report greater trauma symptom burden. This study will analyze data collected from a NIMHD nested study of Chicago men and women participating in the Center of Excellence on Disparities in HIV and Aging and women from the Cook County site of Chicago WIHS to examine sex/gender differences in rates of trauma exposure and symptom burden and their relationship with resilience and health outcomes.

Opiate use, medical assisted therapy and mortality in WIHS (W17008) – Mardge Cohen

The opioid epidemic is an important public health problem in the U.S. Drug overdose deaths and opioid-involved deaths are increasing in the United States. Since 1999, the number of overdose deaths involving prescription opioids and heroin has quadrupled with more than half a million people dying from drug overdoses. Every day, on average, 91 Americans die from an opioid overdose. There is geographic, racial and age variation in the impact of this epidemic in the U.S. While there is evidence-based treatment for opiate use disorder, the treatment, including medical assisted therapy like methadone and buprenorphine, is not always accessed by those in need. This study would like to explore if participants in the WIHS (majority older black women) have changing rates of prescription opiate and illicit opiate use and whether there has been an increased uptake of medical assisted therapy like methadone and buprenorphine. In addition, the study would like to examine causes of death in WIHS over the last 15 years to see if drug overdose has become more prominent. From this study we can learn more about the extent of opiate use, opiate use treatment and opiate related deaths. This might enable us to better understand how the opioid epidemic is affecting women in WIHS and encourage more medical assisted treatment to reduce deaths.

Marijuana’s effects on stress and cognition among HIV-infected and HIV-uninfected women (W16053) – Natania A. Crane, Leah H. Rubin, Jessica Fogel, Pauline Maki

Many individuals with HIV use marijuana and have high levels of stress. Importantly, HIV, marijuana use, and stress/trauma are each associated with poorer cognitive, psychological, and social functioning. However, little is known about how HIV, marijuana use, and stress/trauma may interact to impact neural, neurocognitive, and functional outcomes, especially among predominantly minority, urban-dwelling women who may be at greater risk for cognitive decline as they age. This study focuses on how marijuana use is associated with stress and trauma among HIV-infected women versus HIV-uninfected women. The study also focuses on how marijuana use and stress/trauma over time are related to cognition in HIV-infected women versus HIV-uninfected women. Furthermore, the investigators will examine how marijuana use is associated with brain structure and function in HIV infected versus HIV-uninfected women. The study will use self-report and cognitive, and magnetic resonance imaging (MRI)/functional MRI (fMRI) measures already collected on a subset of women in the WIHS to assess how marijuana, stress/trauma, and cognition, and brain markers are related among HIV-infected women compared to HIV-uninfected women.

Intestinal microbiome and immune activation in HIV positive women in the WIHS cohort (W16042) – Brett Williams, Audrey French

Despite better treatment, people with HIV still have increased immune activation compared to people without HIV. This increased immune activation appears to lead to more diseases and death. Previous studies have suggested that the increased immune activation in HIV patients comes from the leaking of gut bacteria into the blood. Since individuals with HIV may have different gut bacteria than those without, these different bacteria (microbiome) living in the gut of people with HIV may cause more inflammation. Previous studies have found that people with HIV have different bacteria in their intestines than people without HIV but almost all of the people tested in these studies were men. It is not clear whether the difference in gut bacteria (microbiome) is due to differences in lifestyle and environment or because of HIV itself. Investigators hope to better understand whether the microbiome is different in HIV infected women compared to women in the WIHS who are not infected but have similar lifestyle and environment. Investigators also hope to determine if there is a certain type of microbiome which is associated with more immune activation.

Glucocorticoid Receptor Biology and Cognition in HIV-infected women (W16039) – Leah H. Rubin and Gretchen Neigh

HIV frequently causes problems with memory and attention and the effects of HIV on these abilities may differ for men and women. Moreover, the factors that cause memory and attention problems may differ for men and women. Here the study focuses on one factor that may contribute to memory problems in HIV-infected (HIV+) women, the stress response system. This study will focus on this risk factor as it tends to have more negative effects on memory in women compared to men. Rather than focus on the stress response system at the broadest level, the study will focus here on the molecular level. Specifically, focusing on the glucocorticoid receptor. The glucocorticoid receptor controls the expression of genes and is necessary for the appropriate supply of energy to cells in the body. Here investigators examine the degree to which the glucocorticoid receptor may be altered in HIV+ women compared HIV- women. Additionally, investigators examine the degree to which the glucocorticoid receptor plays a role in memory difficulties in HIV+ and HIV-uninfected (HIV-) women over time. These findings will inform the design of interventions to improve cognitive function in HIV+ women.

Immunologic and Clinical Consequences of Hepatitis C Cure (W15040) – Audrey French

While treatment for hepatitis C has been available for many years, up until recently the treatment was difficult to take, had many serious side effects and didn’t always work well. Now there are oral drugs with few side effects that are highly effective at curing hepatitis C. This study looks at the effect of cure of hepatitis C on several important outcomes. The WIHS has shown that active hepatitis C is associated with worse performance on certain tests of neurocognitive function such as memory and fine motor skills, this study would like to see if any of those effects are reversed or improved with cure of hepatitis C. In addition, investigators will look at the effect of cure of hepatitis C on certain blood markers of inflammation that have been shown to affect HIV outcomes.

Incarceration among HIV positive and at-risk women (W14095) – Mardge Cohen, Kathleen Weber

Studies have shown that experiences of incarceration are associated with health and social problems. Following release from prison, health needs are often overshadowed by competing priorities including finding housing and employment. This study will look at the impact of incarceration on health outcomes among HIV positive and at risk women (including HIV treatment outcomes among HIV positive women).

Chicago WIHS Psychoneuroimmunology Study (W14092) – Kathleen Weber, Mardge Cohen, Audrey French

This study’s goal is to better understand how WIHS participant’s stress response systems function during everyday life and during certain physical and mental challenges presented in our research lab setting. Investigators will examine stress response system activity, both physiological and hormonal, in relation to HIV specific factors and other social, environmental, behavioral, psychological, and physical health conditions experienced by women in the Chicago WIHS. The study will examine the associations between measures of stress response systems and stress response profiles, markers of immune function and cellular aging, and the gut microbiome. Investigators will assess functioning of the “Social Engagement System”, a model that links social function to how the nervous system controls the heart and facial expression. Impairments in the Social Engagement System could cause problems with how individuals respond to stress and how they relate to others in their social environment. If this system is not functioning properly, as we recently reported in Chicago WIHS women, this could lead to poorer overall health and greater risks for cardiovascular, metabolic, and cognitive disorders.

Brain Aging in HIV-Infected Women: The Role of Reproductive Aging and Cardiovascular Risk Factors (W14041) – Minjie Wu

As people age, they experience declines in mental abilities, including memory. These declines are associated with changes in the structure and function of the brain. There is some debate about whether individuals with HIV experience more rapid declines in mental abilities and brain function/structure as they age. Most of the studies on how HIV and age affect the brain have been done in samples of mostly men. This proposal uses brain imaging techniques to compare brain structure and function among HIV-infected and HIV-uninfected women across different ages. As they age, women go through the menopausal transition. Investigators are therefore examining how menopause might affect brain structure and function in HIV-infected women and HIV-uninfected women. As a third aim, this study is examining whether risk factors for heart disease are associated with brain structure and function in HIV-infected women. The project involves women only at the Chicago WIHS Consortium. These women will be invited to participate in a separate study visit during which they will complete brain scans. The study will provide important new insights into the patterns and predictors of brain aging in HIV-infected women.

Bioenergetics and white matter integrity of advanced brain aging in women with HIV (W14040) – Melissa Lamar

Individuals with HIV are living longer but they are not necessarily living well and many suffer age-related diseases at earlier ages. Brain aging seems to occur earlier in women with HIV and may be associated with a general marker of disease burden known as mitochondrial dysfunction. Studies have associated mitochondrial dysfunction with physical frailty (walking speed) in aging humans and cognitive impairment (executive dysfunction) in aging monkeys. This study will build upon work being done at the Pepper Center of Wake Forest University and Chicago’s Developmental Center for AIDS Research and the Chicago WIHS to extend the concept of frailty to include brain aging in HIV and integrate unique bioenergetics of mitochondrial dysfunction and brain imaging of myelin or white matter which is important for brain function. This study will address cognition as a form of frailty combining cutting edge bioenergetics and imaging markers in aging and HIV.

Sex Differences in Neurocognitive Performance among WIHS and MACS Participants (W14014) – Eileen Martin, Pauline Maki

HIV frequently causes problems with memory and attention but its effects on these abilities may not be the same for men and women. This question has not been addressed previously, since neurocognitive test scores of HIV+ men and HIV+ women have not been compared directly. It is important to investigate if HIV causes similar or different types of cognitive problems among men and women, since HIV may affect brain function differently for these groups. This proposed study will compare scores on the Symbol Digit Modalities Test, the Stroop Task, the Grooved Pegboard and the Trail Making Test between WIHS participants and MACS participants matched on age, education, and ethnic background. The study will also investigate the association of neurocognitive performance with use of alcohol and street drugs.

Evaluating Immune Mechanisms Contributing to Cognitive Impairment in HIV Infected Women (12033) – Seema Desai & Alan Landay

With new available potent antiretroviral drugs, HIV associated dementia has become rare and more common is a milder form of neurocognitive illnesses called HIV associated neurological disorder (HAND) which occurs in 25-30% of HIV infected subjects even when HIV replication is under control with the highly active antiretroviral therapy. This study will examine whether persistent microbial translocation and activation of innate cells namely monocytes/macrophages over period of time will contribute to current overall cognitive impairment in HIV infected and uninfected WIHS women. They will examine markers that are resultant of a leaky gut: LPS, LBP, and innate immune markers of monocyte/macrophage activation sCD14 and sCD163 in HIV infected and uninfected women who perform at extremes of global measures of cognition. The study findings will add new information on the mechanisms that lead to cognitive impairment despite viral control with potent antiretroviral therapy.

Smoking reduction, cessation and recidivism in the WIHS (W12028) – Mardge Cohen, Nancy Hessol

Cigarette smoking is the number one cause of preventable disease and death; in the United States over 400,000 deaths each year are due to smoking. In people with HIV, smoking weakens the immune system and can make it more difficult to fight off serious infections, especially lung disease. Among the women in the WIHS, the rates of cigarette smoking are more than twice as high as the national averages. A recent study of women in the WIHS also found that both HIV-infected and uninfected women have lower smoking quit rates than the general population. Quitting smoking might be the most important intervention for preventing morbidity and mortality among HIV-infected and uninfected smokers. The goal of this project is to investigate factors that predict smoking reduction (cutting down the number of cigarettes per day), smoking cessation (not smoking for 12 or more months), and smoking recidivism (starting to smoke again after having quit) among the HIV-infected and HIV-uninfected women in the WIHS. The investigators hope that the results from this study will help to guide more effective smoking cessation programs for the women.

Effects of stress on cognition in HIV-infected women (W12026) – Leah H. Rubin, Pauline M. Maki, Mardge Cohen, Kathleen Weber, Judith Cook

The negative impact of stress on memory is important for memory is well established in the literature on healthy aging. To date, there is very little scientific data about the impact of stress on memory in women affected by HIV. Such data are important to understanding memory function in women with HIV because women affected by HIV report high rates of life stress and acute stress associated with childhood sexual abuse and domestic violence. A demonstration of a link between stress and memory difficulties in women with HIV will provide a strong foundation for future intervention studies aimed at lowering stress and thereby improving memory function. Thus, the present study aims to examine the role of stress on memory in HIV-infected women and HIV-uninfected women.

Immune Dys-regulation in HIV-infected women with heavy alcohol consumption (W11008) – Seema Desai

Heavy or long term use of alcohol can have a negative impact on the immune system. Alcohol can damage the gut and cause organisms to leak out thereby activating the immune system. Continuous stimulation of the immune system for long periods of time can exhaust (tire) it, making the immune system less functional and “age” earlier than it should. Investigators want to examine the relationship between alcohol use and the immune system in HIV-infected women to see if there is a way to improve or preserve the immune system in those who drink alcohol.

Hair Cortisol as a Biomarker of Chronic Stress among Women living with HIV (W10048) – Joel Milam, Kathleen Weber

Exposure to traumatic events, especially early in life, and repeated psychological stressors related to adverse social environments has been linked with poor adaptation to disease. Until recently, there has been no biological marker of chronic stress suitable for large epidemiological studies, therefore large cohort studies of stress have relied on self-report surveys. However, a neuroendocrine lab in Germany (Dr. Clemens Kirshbaum) recently validated a laboratory procedure to reliably measure cortisol, the major stress hormone of the HPA axis, in human hair. This approach provides a better estimate of chronic stress by measuring cumulative cortisol exposure for the prior 1-3 month time period depending on the length of hair collected. This study proposes to examine hair cortisol, as a biomarker of chronic stress in 300 WIHS women at the Los Angeles, Chicago, and Brooklyn sites (100 per site) to examine HPA axis activity and its relationship to soluble immune markers (pro-inflammatory cytokines IL-1β, IL-6, TNFa & the anti-inflammatory regulatory cytokine IL- 10), cellular aging markers (telomere length and telomerase) and self-reported indices of stress and stress resistant characteristics (e.g., optimism). Examining the construct validity of hair cortisol as a biomarker of chronic stress will inform a more extensive research initiative to explore HPA axis dysfunction and other inflammatory mediated outcomes in HIV infected WIHS women.

Genetic Predictors of Cognition, Mood and Menopause Symptoms in HIV+ Women (W10047) – Pauline Maki & Jeffrey Bishop

Recent studies have identified genetic factors that influence mood and mental abilities in healthy women. These genetic factors influence hormone and other brain chemicals that play a role in mood and mental abilities. The present study analyzes the influence of common and well characterized genetic variants or “polymorphisms” in the ESR1, ESR2, COMT, CYP1A1, CYP1B1, BDNF, SLC6A4, and APOE genes – in relation to memory function, depressive symptoms, menopausal symptoms and perceived stress in HIV positive women. By identifying these relationships in a population of HIV positive women, investigators can identify risk factors for depression, persistent menopause symptoms and cognitive impairment that may help us to target more intensive cognitive evaluations or intervention studies for women.

Evaluating Determinants of Immune Activation in HIV Disease (W09048) – Seema Desai

HIV infection causes the immune system to not function well. Although Highly Active Antiretroviral Therapy (HAART) can control viral load and increase the number of CD4 cells, the immune system does not always return to normal functioning. This reduction in functioning is called immune activation. Different chemicals may be causing the activation of the immune system. Investigators will study two of them, a chemical produced by a process called “microbial translocation” which occurs when bacteria leak from the lining of the gut and something called IFN- that affects the cell surface to influence the CD 4 cell. This is a lab based study which will help investigators understand how HIV affects the immune system over chronic disease.

Associations between drug abuse dependence, anxiety, and depression, and their impact on likelihood of engaging in high risk sexual and drug use behaviors in HIV+ and HIV- women (W09023) – Judith A. Cook, Mardge H. Cohen

Disorders such as depression, anxiety, and drug and alcohol abuse/dependence are serious problems for HIV positive and HIV negative women in the WIHS cohort. Prior research suggests that all three problems may be related to a woman’s tendency not to seek or follow through with health care services. By using WIHS study data, investigators will explore how these problems are related to whether women engage in high risk HIV transmission behaviors, as well as the likelihood that they receive mental health and drug use treatment. In 2010, the PI and colleagues began to interview active members of the HIV positive WIHS cohort using a valid and reliable diagnostic assessment for mental health and substance use disorders called the World Mental Health – Composite International Diagnostic Interview (WMH-CIDI). So far, over 1,000 HIV positive women have completed this interview. The proposed study would extend these interviews to the rest of the WIHS cohort (N=1,329) including HIV negative and newly enrolled HIV positive and negative women, as well as women from the 4 new Southern sites. The assessment lasts about two hours, and would be done only with the woman’s permission, during a separate study visit. The interview is conducted using a laptop computer which prompts the interviewer to ask questions, and responses are entered into the computer, which also records the interview. Women would receive a research honorarium for the study visit as well as travel costs. A random sample of 5% of the women (about 66 across all WIHS sites) would also be asked to participate in a brief (3-5 minute) anonymous phone interview in which they provide feedback about the CIDI interview. The CIDI interview would be a one-time assessment and information about diagnoses would remain strictly confidential.

HIV Pathogenesis & Aging Pilot (W09016) – Seema Desai

Decline in immune function is a hallmark of aging, resulting in increased susceptibility of elderly individuals to many infectious diseases and possibly cancers leading to increased morbidity and mortality. The underlying mechanism of immune decline that results in senescence in aging individuals is thought to be due to inflammation and activation, a consequence of constant stimulation of the immune system with infectious agents over lifetime. Several immunological alterations that characterize HIV-1-infected individuals are remarkably similar to those accumulated with age in the HIV-1-uninfected elderly indicating accelerated aging in HIV infected individuals. Chronic HIV infection is associated with aberrant immune activation and microbial translocation (release of bacteria and bacterial products into systemic circulation). This in turn activates cells of innate and adaptive immune system resulting in release of inflammatory cytokines. Whether these immune perturbations cause accelerated aging in HIV infection needs to be examined. The investigator’s goal is to study accelerated aging in HIV infected individuals which is likely outcome of activation and inflammation. The concept of aging as activation induced inflammatory syndrome (AIIS) is novel and will advance the field of HIV/aging by integrating strategies to control inflammatory responses rather than treat individual diseases and conditions associated with aging in HIV infected individuals. The mechanism by which immunological damage occurs in HIV infected aging individuals will also be examined.

Effect of Nicotine on HIV Pathogenesis (W09015) – Seema Desai

This study will investigate the effect smoking has on HIV pathogenesis. Nicotine, the active ingredient of cigarette is known to cause deleterious effects on cells of our body in absence of infection. Cigarette smoking predisposes a person to microbial infection and this process is enhanced in HIV infected smokers. Studies conducted have presented pro as well as anti-inflammatory role of nicotine, though in HIV disease the outcome of nicotine use may vary based on concurrent diseases and immune function. This study will explore the effects of nicotine on immune cells of healthy and HIV infected individuals as well as study the effects of smoking on immune perturbations associated with HIV disease especially immune activation and inflammation to understand the causes that alter competence of the immune system in HIV infected smokers. The results of this study will further help design intervention strategies in WIHS participants.

Traditional Gender Role Attitudes, Health-Promoting Behaviors, and Sexual Risk Taking Behaviors in a population of HIV+ Women and Women at Risk for HIV/AIDS (W08002) – Mardge Cohen, Leslie R. Brody

The goal of the proposed study is to investigate the impact that traditional gender role traits and attitudes have on health-promoting and risk-taking behaviors in a sample of HIV+ women and women at risk for HIV infection. Since a large percentage of women contract HIV from heterosexual partners, their perceived roles in their relationships with men are critical to understand. To date, more research has been done on the relationship between traditional gender role attitudes and risk-taking behaviors in seronegative populations than in seropositive populations. The present study will focus on both groups of women. It is believed that the latter group’s level of traditional gender role attitudes will be related to both their sexual risk-taking behaviors as well as their health promoting behaviors. For example, one avenue of exploration will be whether or not traditional gender role attitudes predict lower HAART adherence and mental health services utilization. Research has found links between both HAART regimen adherence and reduced AIDS-related mortality and between mental health service use and reduced AIDS-related mortality (Cook et al., 2004; Palacio et al., 2004). For example, Palacio et al. (2004) found that those women who use HAART and even those who had used, but then stopped HAART reported more PCP visits and fewer emergency room visits and hospitalizations than women who were HAART naïve. These research studies indicate that it is important to understand factors that make health-promoting behaviors less likely to happen.

Risk Factors for Liver Disease Progression in HIV-Infected Women (W05051) – Audrey French, Andrea Kovacs, Marion Peters, Eric Seaberg, Gerald Sharp

Rates of liver fibrosis and cirrhosis are increased in HIV-positive patients, especially those with hepatitis C virus (HCV) infections. This study will assess the relationships between risk factors for these diseases and more rapid progression to fibrosis and cirrhosis and will assess the effects of long-term exposure to anti-HIV therapy (HAART, including types of HAART therapy) for patients with and without HCV or HIV infections. Rates of fibrosis and cirrhosis will be measured by comparing several serum measures that are well correlated with assessment of fibrosis and cirrhosis as measured by liver biopsy. Using these serum tests, investigators will calculate the difference in degree of fibrosis/cirrhosis at baseline, at beginning of HAART therapy for women who receive it, and at the most recent WIHS visit, and they will calculate the rate of liver disease progression by dividing the amount of change in fibrosis/cirrhosis by the amount of time in each interval. This will tell investigators the rate of liver disease progression from baseline to beginning of HAART and from then to the time of the most recent WIHS visit. The study will then compare women who are rapid liver disease progressors to those who are slow progressors to determine the risk factors or combinations of risk factors that are most important in causing more rapid progression to fibrosis and cirrhosis. Investigators will also examine the rate of liver disease progression for HIV-positive women before and after beginning HAART therapy. Our serum measures of fibrosis/cirrhosis will be validated by comparing them to the results of liver biopsies for WIHS subjects for whom this information is available and by determining the relationship of these rates of progression to the later occurrence of cirrhosis and other end stage liver disease. One advantage of using serum tests, as opposed to liver biopsies, to assess liver disease progression is that these measures will be available for all WIHS subjects, making it possible to measure the effects of long-term HAART exposure, as well as the other risk factors under consideration, among HCV-negative women for whom liver biopsies would not be clinically justified.