1 Department of Medicine, University of California, San Francisco, CA.
2 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
3 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
4 Georgetown University Medical Center, Washington, DC.
5 University of Southern California Medical Center, Los Angeles, CA.
6 Health Science Center, State University of New York, Brooklyn, NY.
7 Montefiore Medical Center, Bronx, NY.
8 Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
9 The Core Center, Cook County Hospital, Chicago, IL.
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ABSTRACT |
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cohort studies; HIV; prospective studies; women
Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; WIHS, Women's Interagency HIV Study
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INTRODUCTION |
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Even though women, people of color, and injection drug users represent a growing number of new AIDS cases, few clinical and epidemiologic research studies of HIV and AIDS have included them (5). If these groups are not included in research studies, the ability to generalize the results to all HIV-infected persons may be limited and important considerations ignored. Reasons for a lack of inclusion of women, people of color, and injection drug users in research studies vary and may be due to study design considerations or hesitancy on the part of potential participants. The belief that certain groups of people may be more difficult to recruit and retain in a prospective study than other groups may have also resulted in fewer research studies that include these populations (6
).
In any prospective study, participants lost during follow-up can potentially bias the results because of differences between those who are lost and those who continue to participate. The higher the attrition rate, the greater the chance for bias. Assessing the group of persons who have dropped out of the study and comparing them with those who are retained can help to clarify the nature of any bias and can then be used to guide future analysis of the data and interpretation of the study results. The characteristics of research participants who are more likely to drop out can also be valuable in designing methods to reduce further loss to follow-up.
In this paper, we describe the successful recruitment and retention of women with HIV infection and women at risk for acquisition of HIV infection in a 10-year prospective study operating in six sites across the United States. Methods used to minimize loss to follow-up in this cohort are also described.
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MATERIALS AND METHODS |
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Recruitment was performed at a variety of venues. Nationally, these included HIV primary care clinics, hospital-based programs, research programs, community outreach sites, women's support groups, drug rehabilitation programs, HIV testing sites, and referrals from enrolled participants. As published previously, the demographic and HIV exposure risk characteristics of the seropositive cohort were comparable with characteristics of nationally reported AIDS cases in US women (7). The HIV-infected and -uninfected women were recruited from similar sources and were well matched on demographic and key risk factors for acquisition of HIV infection. However, site-specific recruitment sources differed, with some sites recruiting more heavily from primary care clinics and existing research studies.
The study protocol allowed for sites to either administer the screening procedures as a separate visit or combine it with the baseline visit. Most sites opted for performing both screening and baseline as one visit; however, one site chose to screen the women first and then bring them back for the baseline visit once they determined participant eligibility.
A total of 2,628 women (2,059 HIV-infected and 569 HIV-uninfected women) were enrolled in the WIHS at six locations within the United States: New York City (two sites), the Washington, DC, metropolitan area, Chicago, southern California, and northern California. Every 6 months, WIHS participants were interviewed using a structured questionnaire and received a physical and gynecologic examination. Multiple gynecologic and blood specimens were collected at each visit. The length of time for a full visit was approximately 3 hours. Follow-up data through September 30, 1999 (WIHS visit 10), were included in the analyses.
Retention strategies
From the start of the study, certain standardized procedures were put into place at all WIHS sites, such as the creation of national and local community advisory boards and monetary compensation to participants for their 6-month study visits. During the course of the study, the different WIHS sites shared other strategies for helping to keep participants in follow-up. Sites were flexible and adopted techniques that proved to be successful, even if it meant using or seeking additional resources. Retention was continually monitored at both the national and local levels. Sites frequently revisited retention strategies to make them women friendly and to keep up with changing study protocols.
Scheduling appointments and tracking techniques. All sites sent reminder letters or made reminder phone calls for study appointments and were flexible about rescheduling missed or canceled appointments. At each 6-month visit, participants were asked to complete a locating form with contact person information for friends, family, and providers. If a woman could not be reached at her home phone or address, study staff would contact her referrals to try reaching her. If a woman was too ill to have a full visit or if she was in detention, an abbreviated interview was an option.
To find women who were lost from study follow-up, several sites performed periodic clinic and street outreach to places where women were originally recruited or were known to "hang out." Computer searches of medical databases were also done to try to get updated locating information on study participants. Some WIHS sites periodically checked with county jails and state prisons to see if participants were there and, if so, either performed the study visit at the incarceration facility or conducted the interview portion of the study visit over the phone. Where consent was obtained, some WIHS sites contacted primary care providers or monitored patient admission records to determine the participant's status and to abstract contact information.
Reimbursements and incentives. At each 6-month visit, women were reimbursed, in cash, for their time. The cash amounts varied among the six WIHS consortia, ranging from $20 to $50. If needed, women were also given transportation assistance, such as bus tokens, train tickets, money for gasoline, and cab vouchers. Most sites provided meals or snacks and gift incentives, which included dental kits, cosmetics, male and female condoms, and food coupons. Some sites provided child care while study participants completed their visit. Occasionally sites provided gifts for the children of study participants. To help keep participants interested in returning, sites varied their incentives from one visit to the next and, in some cases, increased the cash amount that participants were reimbursed.
Establishing trust and communicating with participants. A variety of things were done to help participants feel at ease and connected to the study. All WIHS sites provided safe, comfortable environments in which to conduct their study visits, and study staff members treated participants with respect and were nonjudgmental. Sensitive matters were handled confidentially, and study staff established a continuing relationship with participants over time. The WIHS employed female interviewers, and all WIHS sites had bilingual staff so that the study visit could be conducted in either English or Spanish. All six WIHS sites had local newsletters that were handed out or mailed to study participants. These newsletters helped to keep participants informed of general HIV information, study results, protocol and staff changes, and enrollment into other related studies. Some sites mailed birthday and holiday cards to participants and occasionally included movie or museum passes or grocery coupons. Some sites also had holiday parties and special events, such as educational forums.
Each WIHS consortium has its own local community advisory board that meets with varying frequency. The local community advisory boards were very helpful in suggesting strategies for recruitment and improving retention. Both the local and national community advisory boards were periodically consulted to aid with protocol design, study visit satisfaction, and better participant compliance with study protocols.
Participants were also given personalized attention at each visit and were helped with referrals to social and medical services. They were counseled regarding abnormal laboratory results, abnormal examination findings, and unsafe sexual or drug use behaviors. When appropriate, participants were also helped with linkages and access to care. With participant consent, study test results, for example, HIV viral load and T-cell counts, were also sent to primary care providers.
Missed visits and disenrollment. Women who did not have a 6-month interview and were not known to be deceased were considered missed, and a missed visit form was completed. This form included information as to why the visit was missed, such as the participant moved out of town or was unable to be located. Women who moved and transferred to another WIHS site were considered to be a participant of the new site. Women who asked to be disenrolled from the study had a disenrollment form completed and were considered lost for all future visits.
Death information. When information that a study participant had died was received, a disenrollment form was completed, and the participant was removed from all future retention statistics. The National Death Index was searched for information on women not seen in the past 12 months. At some sites, local death registries were also checked for new death information. National death registry data were available through 1998 and local data through 1999.
Statistical methods
The primary dependent variable in these analyses was attrition, defined as having missed the interview portion of the study visit in more than 12 months or, if deceased, in more than 12 months prior to their date of death. The retention rate was calculated as the number of women interviewed in the last 12 months divided by the number of women enrolled at visit 1 minus women who have died. Therefore, retention rates can increase from one visit to the next if either the number of women interviewed in the last 12 months has increased or if the number of women who have died has increased. Retention rates were determined for each WIHS visit cycle (visits 210) and for each of the six WIHS centers, stratified by HIV serostatus. By using the 12-month retention definition, if a woman was seen for visit 3 in May 1996 but missed visit 4 in November 1996 but returned for visit 5 in May 1997, she would not be considered lost at visit 4 because she had been interviewed in the past 12 months.
The following independent variables were assessed for their effect on study attrition using Cox proportional hazards models (8): demographic characteristics (age, race/ethnicity, education, household income, employment, housing, had a primary care provider, had health insurance, past experience in studies of HIV/AIDS, and HIV risk category), health status (HIV serostatus, self-reported clinical AIDS, HIV medication history, and depression), behavioral factors (cigarette smoking, alcohol and recreational drug use, and high risk sexual activity) as reported at study entry, and WIHS site of enrollment. Only those variables that had p values of <0.10, in unadjusted analyses, were included in the final multivariate models.
Laboratory measures included HIV type 1 serology, CD4 counts (cells/mm3), and quantitative HIV RNA. HIV serology was performed by enzyme-linked immunosorbent assay testing and confirmed by Western blot. T-cell subsets were determined by flow cytometry, which was performed in AIDS Clinical Trials Group-certified laboratories. Quantification of HIV RNA in plasma was performed using the isothermal nucleic acid sequence-based amplification method (Organon Teknika Corp., Durham, North Carolina) with a lower limit of detection of 4,000 copies/ml. Among HIV-infected women, the relative prognostic values of CD4 cell counts, quantitative HIV RNA measurements, and HIV medication use (defined as monotherapy, combination therapy, or highly active antiretroviral therapy) were assessed by inclusion as time-dependent covariates in the Cox proportional hazards models.
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RESULTS |
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The retention rate for all sites, for visits 1 through 10, is shown in figure 1. Overall, retention rates decreased over time and were significantly higher (p < 0.001) for HIV-infected women (85 percent through visit 10) as compared with HIV-uninfected women (72 percent through visit 10). Figure 2 shows the retention rates by WIHS site for HIV-infected women. Retention varied significantly by site (p < 0.001) and was highest in Chicago, with a rate of 95 percent at visit 10, and lowest in southern California, with a rate of 79 percent at visit 10. Among HIV-uninfected women (figure 3), retention also varied significantly by site (p < 0.001), with the highest retention in the Brooklyn site (86 percent at visit 10) and the lowest in the Washington, DC, site (58 percent at visit 10). The Brooklyn WIHS site recruited a significantly higher proportion of participants who reported previous HIV/AIDS research study experience (46 percent), compared with the other five WIHS sites (range, 1424 percent). The Chicago site recruited a high proportion of its HIV-infected participants from primary care clinics at the host's institution (91 percent).
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DISCUSSION |
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Similar to other prospective studies of HIV infection (9, 10
), this study found that retention was lowest among younger participants and varied by site of enrollment. Younger participants were more geographically mobile than older participants and may have perceived less benefit from participation in an ongoing cohort study.
In the WIHS, retention varied significantly by site despite standardized quality assurance procedures and a high degree of similarity in the staffing, protocols, and manner in which participants were treated. One difference in recruitment was the two-step process for recruitment used at the Bronx/Manhattan site. Based on the results presented here it is not possible to determine if the two-step recruitment process, or some other unmeasured factor, improved retention of fully recruited women at the Bronx/Manhattan WIHS site. However, a two-step or "phase-in" recruitment strategy may be a useful strategy for reducing the number of fully recruited participants lost to follow-up (11).
Differences in retention by site may also be partially explained by the places where women were initially recruited. In Brooklyn, women were recruited for the WIHS from those already enrolled in another longitudinal study of women with HIV infection. These women had already demonstrated a willingness to participate in HIV research and thus would be less likely to be lost to follow-up. In contrast, in the southern California WIHS site, only 14 percent of participants reported past experience with studies of HIV/AIDS. Another example is the difference in retention rates among the HIV-infected and -uninfected women at the Chicago site, 95 percent and 69 percent at visit 10, respectively. The HIV-infected women enrolled in Chicago were drawn from patients at the host institution's primary care clinics, whereas the HIV-uninfected women were recruited from the community (e.g., drug rehabilitation centers) and HIV/sexually transmitted disease screening clinics in Chicago.
We also found that retention was higher among WIHS African-American women than among women in other racial/ethnic groups. This is similar to results found in a National Institute for Mental Health multisite HIV prevention trial that included women and men (10) but differs from results from the Multicenter AIDS Cohort Study of HIV in men (9
). The reasons for this difference by race/ethnicity are not clear but may be due to a higher perceived benefit for participation among African-American women as compared with women of other races or ethnicities. It may also be that the groundwork was laid to recruit and retain African Americans successfully by performing community outreach, conducting focus groups, and hiring staff that represented this community. Because a higher proportion of injection drug users were White, we checked to see if the association between race and retention could be confounded by injection drug use. The result of this additional analysis showed no evidence of such confounding.
Also similar to results from the National Institute for Mental Health trial (10), our study found unstable housing to be a consistently significant predictor for attrition. The consistency of this unstable housing finding within our analyses and in other studies suggests that more extensive contact information should be obtained from these women at enrollment and that more needs to be done to track, relocate, and welcome back participants who do not live in a permanent residence.
Several variables thought to be associated with study retention (level of education, employment, and substance use) were not significant predictors of attrition. This finding suggests that excluding certain persons from prospective studies because of fear of attrition may be unfounded. Our two measures of health care (had a primary care provider and health insurance) were significant predictors of retention only in the unadjusted models but failed to predict retention in the multivariate models. This means that, when controlling for other important influences on study retention, our measures of health care were not predictive. We also found that having had a primary care provider was a more important influence on retention for the HIV-infected women than the HIV-uninfected women. Because most HIV-infected women who did not have a primary care provider also reported no therapy use during follow-up, we checked whether having a primary care provider or health insurance could confound the association between therapy and retention. The result of these additional analyses showed no evidence of such confounding.
Similar to the Multicenter AIDS Cohort Study (9), our study found that retention was higher among those who were healthier (AIDS free at baseline, higher CD4 cell counts, and lower HIV viral load at the last study visit). As the WIHS allowed enrollment of women with a history of AIDS, the number of women who experienced morbidity or mortality during follow-up (especially in the first years of the study) was higher than the number of women in most other cohort studies of HIV infection that excluded persons with a history of AIDS (9
, 12
).
This study is among the first cohort studies of HIV infection to find that women who reported HIV combination therapy or highly active antiretroviral therapy use were more likely to return for follow-up, even when controlling for potential confounders such as HIV viral load and CD4 cell count at the last visit. Women may not be on combination therapy for several reasons: 1) it may not be indicated, 2) they may have chosen not to be on therapy, 3) they may not have access to therapy, 4) monotherapy may have failed, or 5) providers may have withheld therapy because of concerns about noncompliance, perhaps due to a prior history of noncompliance with therapeutic regimens. Thus, women not on combination therapy may represent a very heterogeneous population with different reasons for attrition. Use of highly active antiretroviral therapy or other combination therapy may also be a surrogate measure for a variety of factors likely to increase their retention. Women on highly active antiretroviral therapy are capable of following treatment regimens, which indicates that these women are more organized than those who cannot and thus may be better able to keep track of study visits. Women on highly active antiretroviral therapy are connected to health care facilities in a productive manner, and this may increase their interest in participation and may offer study personnel more avenues for contacting the women.
Our finding that retention was lower for HIV-uninfected women, compared with HIV-infected women, may be due to several factors. It is possible that HIV-uninfected women were more mobile and less connected to the health care and delivery system, and therefore we were less able to locate them for follow-up visits. In fact, of the 129 HIV-uninfected women who missed their last study visit, 46 percent were unable to be contacted compared with 36 percent of the 260 HIV-infected women who missed their last study visit. Another possibility is that HIV-uninfected women may not have felt the study was as beneficial to them as it was for the HIV-infected women. Finally, many of the HIV-infected women were recruited from other studies of HIV (27 percent vs. 6 percent of HIV-uninfected women) or from clinics connected with the investigators of that site. This may have resulted in selection of a population easier to retain: Those recruited from other studies had a demonstrated history of study compliance, while those recruited from clinics may have been easier to track because of their clinic ties.
There are limitations to our analysis. Because of the smaller sample size of HIV-uninfected women, we may have had insufficient power to detect statistically significant differences among the various covariates. Additionally, some of the statistically significant predictors of study retention, such as race/ethnicity, are probably surrogates for other unmeasured factors, such as perceived benefit of study participation. Finally, we did not capture specific information regarding the individual sources of recruitment, thus restricting our analysis of recruitment source data.
Enrolling and retaining study participants who are representative of the community at large in cohort studies is extremely important. Without this representation, it is impossible to generalize the findings back to the community of interest. Low-income women, people of color, substance users, and those with unstable housing have traditionally been underrepresented in research studies. Our findings can benefit future research studies by alleviating concerns about recruitment and retention of these population groups. By developing procedures and selecting staff for recruiting a representative sample, overcoming barriers for participation, developing creative fixes to problems that arise, and collecting sufficient anchoring information at initial and subsequent contact to allow adequate retention rates, prospective studies can be successfully accomplished in all communities.
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ACKNOWLEDGMENTS |
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Data in this report were collected by the WIHS Collaborative Study Group with centers (Principal Investigators) at the New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, New York (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); the Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt, Herminia Palacio); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and the Data Coordinating Center (Alvaro Muñoz, Stephen J. Gange). The authors also acknowledge Niloufar Ameli for her assistance with the computer-generated figures and Paula Wichienkuer for her editorial assistance at the University of California, San Francisco.
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NOTES |
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REFERENCES |
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