Clinical and Diagnostic Laboratory Immunology, September 2005, p. 1013-1019, Vol. 12, No. 9
1071-412X/05/$08.00+0 doi:10.1128/CDLI.12.9.1013-1019.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
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Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland,1 Georgetown University Medical Center, Washington, D.C.,2 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland,3 Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland,4 Montefiore Medical Center, Bronx, New York,5 University of California, San Francisco, California,6 University of Southern California Medical Center, Los Angeles, California,7 Health Science Center at Brooklyn, State University of New York, Brooklyn, New York,8 John H. Stroger Hospital of Cook County, Chicago, Illinois9
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In response, NIAID was joined by the National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute of Drug Abuse (NIDA), and the National Institute of Dental and Craniofacial Research (NIDCR) to fund six sites across the country to study the natural history of HIV in women. These sites initially enrolled 2,059 HIV-positive women and 569 HIV-negative women between 1 October 1994 and 15 November 1995, making the WIHS the largest study in the United States to focus on HIV infection among women.
The proportion of AIDS cases occurring in women has continued to rise in the United States (7). Highly active antiretroviral therapy (HAART) became available in 1996, greatly increasing life expectancy and quality of life for those with HIV. By 2001, however, 554 women of the original cohort had died, and among the 1,618 (78%) survivors who remained active in the study, the median age was 42 years, and 23% of the cohort reported being postmenopausal. To ensure the ability of WIHS to study HIV and its therapies in the HAART era, recruitment was reopened from 1 October 2001 to 30 September 2002; the cohort was expanded by another 1,144 women to a total of 2,762 women with a median age of 32 years. The larger cohort enables the WIHS to better define the effects of infection and therapy across both reproductive and postmenopausal periods of women's lives.
Each WIHS consortium is supported by a community advisory board (CAB) comprised of study participants, and these local CAB members select representatives for the national WIHS CAB (NCAB). Participating in WIHS EC meetings and working group conference calls, NCAB members review plans and rationales for protocol changes and assist researchers in understanding what new initiatives are likely to be supported by study participants and what questions are of importance to the HIV-infected community.
Protection of Human Subjects and Informed Consent Despite 20 years of growing awareness about HIV and AIDS, there remains a stigma associated with the diagnosis and a fear of disclosure among many infected women. HIV-negative participants worry that they will be thought to be HIV positive if identified with an HIV study. Hence, confidentiality is carefully guarded in the WIHS. A certificate of confidentiality from the U.S. Department of Health and Human Services protects study staff from being required to respond to requests for information on participants from any persons or organizations unrelated to the study. Participants are assigned study identification numbers and names are not used on any WIHS documentation except consent and locator forms and medical record requests. Forms with identifying information are maintained separately from data files in a secured file cabinet.
WIHS participants provided written informed consent, in English or Spanish, both for screening and for enrollment. For those unable to read, the consent form is read to them and this is documented on the consent form prior to obtaining signatures. WIHS consent forms include information on current study procedures and on the storage of specimens in the repository for future studies as approved by the WIHS EC. Each subsite within the WIHS consortia has consent forms approved by its institutional review board. Significant changes in the protocol and new substudies are reviewed by institutional review boards prior to initiation; women may choose whether or not to participate in new substudies without jeopardizing their status as core WIHS participants.
Recruitment At the time of the original WIHS recruitment, there were few inclusion and exclusion criteria. Adult women able and willing to consent to participation in the study, complete the interview in English or Spanish, travel to the research site for an interview and physical examination every six months, and have blood drawn for laboratory testing by venous or arterial access were enrolled into one of two groups: HIV positive or HIV negative. Prior to 1996, HAART exposure was limited to early clinical trials; therefore, most enrollees were naïve to highly active therapy and many had already been diagnosed with an AIDS-defining illness. A detailed description of the original recruitment was published by Barkan et al. in 1998 (4).
The goals of expansion in the period from 2001 to 2002 were to recruit a younger group with limited disease progression and to identify two groups related to treatment exposurethose who had been on HAART and those who had never been exposed to HAARTas well as a control group of HIV-negative women of similar ages and backgrounds. To obtain a representative sample of the population of HIV-infected women in the community, recruitment focused on African-American and Latina women. Eligibility criteria for the expansion cohort included the following: (i) documented results from an HIV enzyme-linked immunosorbent assay and a confirmatory Western blot for each of those who were HIV positive or documented HIV-negative results obtained within 30 days prior to enrollment for HIV-negative women; (ii) no history of clinical AIDS-related conditions, confirmed by medical record abstraction; (iii) documentation of laboratory reports of HIV RNA levels and CD4 counts surrounding the period of HAART initiation for those enrolled as HAART exposed; and (iv) consent from the woman to have her specimens stored in the WIHS national repository.
To ensure comparability with the HIV-positive women, site recruitment targeted women who engaged in high-risk behaviors for enrollment in the HIV-negative group. High-risk behaviors were defined as reporting one or more of the following criteria within the past year: (i) injection drug use; (ii) having a sexually transmitted disease; (iii) having unprotected sex with three or more men or protected sex with more than five men; or (iv) having exchanged sex for drugs, money, or shelter.
Recruitment methods used in both the original and expansion cohorts emphasized face-to-face techniques. Infectious disease, internal medicine, and obstetric and gynecology offices throughout the community were contacted for referrals. Outreach to HIV community organizations, churches and HIV ministries, and social-service organizations was conducted. Women who were part of the original cohort recruited friends and family members, women with whom they shared support groups and counseling sessions, and friends of friends.
Loss to follow-up between baseline and the first follow-up visit was 10.3% among original enrollees. For this reason, five of the six sites chose a two-step enrollment process for the period from 2001 to 2002 which required an initial screening visit and then a second baseline study visit. Due to the high loss to follow-up at some consortia among those recruited from residential drug rehabilitation centers during the 1994-to-1995 period, many sites did not recruit at drug treatment centers but did enroll women in rehabilitation who were referred by a physician or friends. These changes resulted in a loss to follow-up between baseline and first follow-up visits of only 5.3% among the expansion cohort.
Retention After the baseline visit, the new cohort was merged into the original cohort's protocol and visit schedule. One year after the expansion recruitment was completed, the retention rate for the combined cohort was 76% for seronegative and 83% for seropositive women. One-year retention rates for new recruits were 91% among HIV-negative women and 95% among those who were HIV positive. An analysis of the successful WIHS retention efforts from 1994 through 1999 was detailed in a paper by Hessol et al. (11).
The WIHS is structured with a 6-calendar-month period for visit windows. For example, visit 16 occurred between 1 April 2002 and 30 September 2002. Ideally, visits are scheduled 6 months apart plus or minus 6 weeks. Because of the importance of identifying long-term outcomes, women are never withdrawn from the study due to missed visits. Those who move out of the area may remain active by transferring to a closer WIHS site, or long-distance transportation may be provided for annual visits. Abbreviated visits may be conducted over the phone for ill or incarcerated participants, with data collection limited to the participant's medical and therapeutic history for the preceding 6 months.
Locator information.
At each visit, WIHS participants are asked to provide the name and contact information of a friend or family member in addition to someone in their home along with instructions regarding the limit or extent of messages that can be left. This helps to track and retain those who may have unstable living situations.
Interview.
Centrally scripted interviews were conducted at each 6-month WIHS visit. Self-reported data include general medical history; antiretroviral therapy; obstetric and gynecologic history; use of drugs, alcohol, and cigarettes; sexual behaviors; health care utilization; beliefs regarding HIV and treatments; and psychological status. Changes are submitted to the EC for approval and then are included in the protocol starting in the next visit window.
To ensure the highest-quality data, centralized training was conducted for all study interviewers at the start of the WIHS and again prior to its expansion. A designated interviewer from each consortium completed additional training that enabled them to orient new staff and evaluate all interviewers at their sites on an annual basis. Additionally, question-by-question guidance forms are distributed at the start of each visit to assist interviewers with new questions and their abilities to objectively prompt participants to clarify answers when needed.
Additional surveillance.
All reports of AIDS-related diagnoses are followed up with medical record abstractions. State cancer registries, local and state tuberculosis registries, and the National Death Registry are utilized to add to and confirm the outcome data collected.
Clinical examination.
Physical examinations conducted at each core visit include a standardized assessment of vital signs with blood pressure; anthropometric measures; a skin and oral examination; an examination of the breasts, lymph nodes, and abdomen; and a gynecological examination that includes a Pap test and the collection of specimens for testing and storage as described below. The WIHS protocol includes colposcopic examination and biopsy when indicated. Women needing further treatment are referred for care outside of the WIHS, and sites have referral mechanisms which take into account each participant's insurance coverage and ability to pay.
Laboratory testing.
All WIHS participants had blood, urine, and cervicovaginal swab and lavage fluid specimens taken for baseline laboratory tests; follow-up lab work is done at each 6-month visit. As the study evolves, new areas of testing are identified and included. The collection of fasting samples was added in 2000 to allow for cardiovascular and metabolic research. Table 1 details these tests.
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TABLE 1. WIHS laboratory testing
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TABLE 2. WIHS repository specimensa
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Characteristics of the Cohort The characteristics of the HIV-positive women in the WIHS cohort are similar to those seen in the national statistics on HIV maintained by the CDC. Table 3 shows the racial distribution and exposure categories for AIDS cases (the CDC did not report HIV infection in 1995) reported in the United States in 1995 and for those women recruited into the WIHS in the original recruitment period. Table 4 shows the same breakdown for HIV-only cases (AIDS free) from areas with confidential HIV reporting through 2001 and for new WIHS recruits enrolled in 2001 and 2002. The higher percentage of Latina women in the WIHS relative to that shown in CDC statistics may reflect the fact that confidential HIV reporting was not required until 2002 in any jurisdictions where WIHS sites are located and where there tend to be larger Hispanic populations. In the expansion cohort, Latinas comprised 64% of those enrolled in Southern California and 42% in Bronx, NY.
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TABLE 3. Cumulative female adult/adolescent AIDS and HIV infection cases in the United States and WIHS through 1995
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TABLE 4. Cumulative reported HIV cases only (no AIDS) in the United States through 2001 and new WIHS HIV-positive recruits for 2001 and 2002
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TABLE 5. Clinical markers in the WIHS
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TABLE 6. Comorbidity at baseline in the WIHS cohort
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TABLE 7. Social demographic characteristics of study population
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Examples of work by researchers working with the WIHS include the determination that, in contrast to findings in studies of male cohorts, there may be partial protection against HIV-1 associated with the CCR5
32 heterozygotes in women (20), the description of the presence of antibody-dependent cell-mediated cytotoxicity in cervicovaginal lavage fluids at levels that were unpredicted by serum titers and that can contribute to mucosal defense against HIV-1 (5), and the suggestion of the possible existence of a separate reservoir of HIV-1 replication in a small percentage of women who were found to have vaginal shedding of HIV-1 despite plasma HIV-1 RNA levels below 500 copies/ml (16).
Due to the long-term nature of the study, the need to avoid overburdening participants prevents the WIHS from requesting more-frequent visits and specimen collection from the entire cohort. Because biannual visits may be insufficient to answer some research questions, short-term substudies have been utilized to gain more-frequent sampling from a limited portion of the cohort.
To date, WIHS publications have addressed HIV therapy prescription and adherence patterns (8, 9, 10, 15, 19) as well as the effects of initiating HAART at different stages of HIV disease activity (1, 2). These studies could not have been done in the context of the controlled regimens and adherence requirements necessary for clinical trials. Collaborative work on coinfections such as hepatitis C (3) and human papillomavirus (21, 23, 18) in the HIV-positive cohort; on the risk of developing other comorbidities related to HIV and antiretroviral therapies, such as cancer (12), diabetes (13), and lipodystrophy (22); and on IVDU (17) and changes in sexual risk behaviors (24) have benefited largely by having a control group of HIV-negative women who match the infected cohort in sociodemographic and behavioral characteristics as well as by having both groups of HIV-positive women: those treated with HAART and those who are HAART naïve.
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As treatment options and outcomes change over time, the WIHS is the only study in the United States with the power of size and longevity to provide a more accurate picture of how these changes are affecting women's lives. There is significant value added for each investigator who chooses to collaborate with ongoing cohort studies, as there is the capacity to do both retrospective and prospective work utilizing the collected data, stored specimens, and the core visit structure with a proven, ongoing study population. As the course of HIV becomes increasingly complex, we believe that more of these types of collaborations will be required to answer the many questions that will need to be addressed. This cohort continues to accumulate a wealth of resources available for use by collaborating investigators and welcomes researchers who are dedicated to a better understanding of HIV infection in women.
Information and guidelines for researchers interested in utilizing these resources can be found on the WIHS website at http://statepiaps.jhsph.edu/wihs/.
Data presented in this work were collected by the WIHS Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, D.C., Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Coordinating Center (Alvaro Munoz).
The WIHS is funded by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute of Dental and Craniofacial Research (grants U01-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590). Funding is also provided by the National Institute of Child Health and Human Development (grant UO1-CH-32632) and the National Center for Research Resources (grants MO1-RR-00071, MO1-RR-00079, and MO1-RR-00083).
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