1 Abt Associates Inc., Cambridge, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Research Center, Seattle, WA.
4 Department of Biostatistics, University of Washington, Seattle, WA.
5 University of Pennsylvania/VA Center for Studies of Addiction, Philadelphia, PA.
6 Philadelphia Veterans Affairs Medical Center, Philadelphia, PA.
7 Laboratory of Epidemiology, New York Blood Center, New York, NY.
8 Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
9 University of Washington, Seattle, WA.
10 Departments of Environmental Medicine and Medicine, New York University School of Medicine, New York, NY.
11 Research Department, Fenway Community Health Center, Boston, MA, and Brown University, Providence, RI.
12 Denver Department of Public Health, Denver, CO.
13 Department of Psychology, University of Illinois and Howard Brown Health Center, Chicago, IL.
14 University of Michigan, Ann Arbor, MI.
15 AIDS Office, San Francisco Department of Public Health, San Francisco, CA.
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ABSTRACT |
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cohort studies; HIV infections; incidence; vaccination; vaccines
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; HIVNET, HIV Network for Prevention Trials; IDU, injection drug use(r); MSM, men who had sex with men; PY, person-years.
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INTRODUCTION |
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One of the most important elements of a successful HIV prevention trial is the identification of populations with high HIV seroincidence. For a definitive phase III HIV-1 vaccine trial, with 95 percent power to evaluate a 60 percent effective vaccine, as many as 3,000 persons per study arm would be needed in a population with a 2 percent annualized seroincidence (20). In the United States, on the basis of both reported data and projections, Holmberg estimated a wide range of HIV seroincidence, 0.14.9/100 person-years (PY), which varied by population and location (21
). Other longitudinal cohort studies have reported an HIV seroincidence ranging from 0.12 to 10.7/100 PY (22
28
). These reported seroincidence rates have varied by population and geography as well as over time. Thus, optimization of eligibility criteria and recruitment strategies may lead to cohorts with high HIV seroincidence that are of sufficient size for HIV vaccine efficacy trials. Of particular importance is whether populations with high HIV seroincidence are willing to join intervention trials and can be followed for the time necessary to complete the trial. In 1996, Buchbinder et al. found that gay/bisexual men reporting the greatest interest in enrolling in HIV vaccine trials also had a high seroincidence rate (3.7/100 PY) (27
). However, many of the populations at highest risk have proven difficult to retain; in the US literature reviewed, retention has been as low as 36 percent at 1 year (28
).
A number of US initiatives have sought to identify and recruit populations at high risk of HIV to assess the feasibility of implementing preventive vaccine trials (2931
). While these initiatives were successful, previous recruitment efforts did not include women at risk from heterosexual contact. Protocols and risk assessment instruments varied across populations, making cross-group comparisons problematic. Moreover, earlier studies were conducted prior to the widespread use of needle exchange programs or highly active antiretroviral therapy, two factors that might influence infection rates among high-risk, uninfected cohorts. Rapid recruitment of very large cohorts at high risk for HIV using the same protocol across different study sites, settings, and populations is critical to the success of randomized clinical trials of HIV vaccine efficacy. It is important to determine whether HIV seroincidence declines significantly over time in high-risk cohorts followed under conditions comparable to those of a vaccine trial, including the provision of risk-reduction counseling. This issue was assessed by the Vaccine Preparedness Study of the HIV Network for Prevention Trials (HIVNET), a prospective cohort study of 4,892 persons at high risk of HIV infection recruited from nine cities in the United States.
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MATERIALS AND METHODS |
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To enroll a cohort with high HIV incidence willing to disclose HIV risk behaviors, we established the following eligibility criteria: 1) men who had sex with men (MSM) (receptive or insertive anal intercourse) during the previous year; 2) injection drug users (IDUs) who used drugs intravenously or intramuscularly at least once in the previous 6 months; and 3) women at high risk through heterosexual contact. Because of limited HIV seroincidence data evaluating risk factors for heterosexual transmission among women, the following broad entry criteria were used to enroll women: 1) had a current male sex partner who was infected with HIV; had sex with other men; was diagnosed with gonorrhea, syphilis, or chlamydia in the last year; and/or injected drugs in the last 5 years; 2) had five or more sexual partners in the past year; 3) was diagnosed with either syphilis, gonorrhea, pelvic inflammatory disease, Trichomonas, or chancroid and/or had a first episode of genital herpes in the last year; 4) exchanged sex for money or drugs in the last year; or 5) used crack cocaine in the last year. All eligible participants had to be aged 18 years or older, be HIV seronegative according to licensed enzyme-linked immunosorbent assay (ELISA), and provide informed consent.
Recruitment
Eight of the sites had cohorts that had participated in either MSM (Boston, Chicago, Denver, New York Blood Center, San Francisco) or IDU (New York University, Philadelphia) HIV seroincidence studies (22, 24
, 25
, 27
33
). However, none had enrolled women exclusively at heterosexual risk. Recruitment strategies for new participants included targeting sexually transmitted disease clinics, advertising, conducting targeted outreach on street corners and in gay bars and clubs, and obtaining subjects through participant referral. After providing informed consent, persons were screened for eligibility by using a brief, confidential questionnaire. Those eligible were interviewed by a trained interviewer who used a detailed, standardized questionnaire to inquire about sociodemographic characteristics, alcohol and drug use, and HIV-1 sexual and injection-related risk behaviors. In addition, participants were given a brief description of a hypothetical vaccine efficacy trial and were asked to indicate, using a four-point Likert scale ranging from "definitely" to "definitely not" willing to participate (34
), how willing they would be to enroll.
Potential participants then underwent HIV-1 antibody counseling and testing. Those whose specimens were repeatedly reactive to HIV-1 enzyme immunoassay, confirmed by positive Western blot, were counseled and were referred for appropriate care. HIV-1 seronegative participants were requested to return every 6 months over an 18-month study period for repeat HIV-1 antibody counseling, testing, and follow-up interviews.
Analysis
Loss to follow-up was defined as the proportion of eligible study participants for whom we were not able to obtain a study endpoint. To evaluate factors associated with loss to follow-up, crude odds ratios and their 95 percent confidence intervals were estimated by using chi-square analysis for enrollment site, gender, eligibility criteria, stability of housing in the 6 months prior to enrollment, frequency of moving in the past 6 months, educational attainment, race/ethnicity, and age. To control for confounding, a logistic regression model was developed that included all of these variables.
A parametric survival regression model was used to calculate stratified HIV-1 seroincidence rates and 95 percent confidence intervals (35). Person-years of follow-up were calculated by summing the years in the study defined as time from enrollment to date of last completed Vaccine Preparedness Study visit across participants. For seroconverters, the midpoint between the last known HIV seronegative visit and the date of the seroconversion visit was used to estimate the date of seroconversion. HIV-1 seroincidence rates were calculated stratified by baseline demographic and behavioral variables and by specific behavioral data obtained at the initial interview to assist in identifying new eligibility criteria for future HIV vaccine trials. Standardized mortality rates were calculated by using the initial eligibility criteria adjusted for age and gender to the 1996 US population (36
).
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RESULTS |
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Lost to follow-up were 6, 11, and 12 percent (cumulative) of the participants at 6, 12, and 18 months, respectively. Significant differences in loss were observed by study site, gender, frequency of moving before enrollment, unstable housing, educational attainment, race/ethnicity, and age (table 1). In multivariate analysis, gender, enrollment criteria, study site, frequency of moving, age, education, race/ethnicity, and unstable housing remained significantly associated with loss to follow-up.
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We also examined HIV-1 seroincidence according to a participant's stated level of willingness to enroll in future HIV preventive vaccine trials. Although no trend was observed in HIV-1 seroincidence by level of willingness, persons who indicated that they were definitely willing to enroll in a future vaccine trial had the highest HIV-1 seroincidence rate (1.96/100 PY, 95 percent CI: 1.41, 2.73) (table 4), with 82 percent of the participants stating that they were either probably or definitely willing to participate in HIV vaccine efficacy trials.
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DISCUSSION |
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Previous work has suggested that a definitive phase III HIV-1 vaccine trial, with 95 percent power to evaluate a 60 percent effective vaccine in populations with a 2 percent annualized seroincidence, will require sample sizes of approximately 3,000 per study arm (20) followed for 3 years. Rida et al. proposed testing HIV-1 vaccines using an intermediate trial design to allow for efficient screening to eliminate products with no or low (
30 percent) efficacy (20
). By using the existing, less-restrictive eligibility criteria from the Vaccine Preparedness Study, it would be feasible to conduct an intermediate-sized HIV-1 vaccine trial among 2,475 participants per study arm (1,375 women at risk at 1.18/100 PY, 1,100 MSM at 1.55/100 PY) followed over 18 months, allowing for a 10 percent loss to follow-up (20
). On the basis of the Vaccine Preparedness Study results, either the classic phase III or intermediate trial design approach appears feasible in the United States.
Temporal changes in incidence rates, which are critical in trial planning, have been problematic in other prevention trials. During a randomized clinical trial of isoniazid to prevent tuberculosis in persons with anergy and HIV-1, the incidence of tuberculosis declined from 6.6/100 PY to 0.9/100 PY in the placebo group, with a 17.8/100 PY death rate (37). The decline in the placebo group was due to dramatic changes in tuberculosis control, particularly the reestablishment of directly observed therapy that has been credited with a decline in community-acquired tuberculosis. Extending the trial was not a viable option, since the overall mortality rate was so high. Thus, despite a well-designed and well-conducted trial, the result was a noninformative null finding.
Likewise, our observed HIV-1 seroincidence rate among MSM was slightly lower than that reported previously (27), although this difference was not statistically significant. Among rollover participants followed at the three original Vaccine Preparedness Initiative sites (Chicago, Denver, and San Francisco), HIV seroincidence was nearly unchanged (1.96/100 PY, 95 percent CI: 1.39, 2.76) compared with the previous rate (2.3/100 PY, 95 percent CI: 1.7, 2.9) (27
). These data suggest that in this cohort, introduction of highly effective antiretroviral treatment, postexposure prophylaxis, or other interventions have not yet had a significant effect on temporal trends of HIV-1 seroincidence. Continued monitoring of MSM by using large, population-based cohort studies is needed for trial planning, particularly so as to not repeat the experience of the tuberculosis prophylactic trial mentioned above (37
).
Our observed seroincidence rates among women at risk for HIV infection were somewhat lower than those observed among MSM (1.18 vs. 1.55). Our initial eligibility criteria were intentionally broad, reflecting the lack of HIV-1 incidence and risk information for women in late 1994. Our data establish that some women in the United States, including crack-cocaine-using women who do not also inject drugs, have multiple risks for HIV-1 infection, and those multiple risks are associated with high HIV-1 incidence (1.42/100 PY). The fact that a large fraction of the women in the Vaccine Preparedness Study have multiple risks may make it difficult to disentangle the attributable risk of various risk factors. Thus, interventions to supplement condoms, particularly woman-controlled methods such as microbicides, as well as behavioral strategies that will be effective against both parental and sexual exposures, are urgently needed.
Among male injectors, however, HIV-1 seroincidence was too low in this cohort (0.38/100 PY) and mortality rates from competing risks too high to enable an HIV preventive vaccine trial to be conducted, despite high retention. These rates are in sharp contrast to those observed earlier at the same and similar sites (range, 1.385.30/100 PY) (21, 38
); in Baltimore, Maryland (3.80/100 PY) (23
); in Montreal, Canada (5.1/100 PY) (39
); and at four high-HIV-prevalence National AIDS Demonstration Research Sites (5.311.2/100 PY (28
)). The eligibility criteria for the Vaccine Preparedness Study were developed in late 1994 and were based on HIV seroincidence data then available for IDUs. While controversy surrounds the potential effects of community interventions among IDUs, such as expanded access to needle exchange programs (28
, 39
, 40
), our data suggest that HIV seroincidence is labile among male IDUs. Further observational studies in which eligibility criteria and recruitment methods are modified, combined with very aggressive approaches to retention, are needed to determine whether HIV vaccine trials are feasible in male IDU populations in the United States.
Retention is of critical importance in conducting randomized clinical trials of prophylactic vaccines or nonvaccine interventions. Our overall retention rate, 88 percent after 18 months, is high for an observational study among healthy, uninfected populations at risk for HIV and is similar to retention rates among HIV-infected populations in clinical trial networks of treatment for acquired immunodeficiency syndrome (41). Low follow-up rates have hampered randomized clinical trials of prevention interventions in the United States and internationally, with follow-up rates ranging from 46 percent at 2 years in a peer-led behavioral intervention in Zimbabwe (W. C. McFarland et al., University of California, unpublished manuscript), to 78 percent at 4 months in a phase II trial of a herpes vaccine (42
), and to 7884 percent in studies of nonoxynol-9 (43
, 44
). Innovations in retention methods, such as the use of home specimen collection techniques for remote follow-up (45
), and the motivation associated with being in an intervention trial may be expected to result in even-higher retention in HIV-1 vaccine or other intervention trials at sites with experience working with populations at risk for HIV.
Although our study found sufficient HIV-1 seroincidence to support future HIV-1 vaccine efficacy trials, our data also suggest a cautionary note. HIV-1 seroincidence rates within populations in different communities may change over time as a result of changing HIV seroprevalence, sexual practices, competing morbidity and mortality, and implementation of effective prevention strategies in the community. For example, the substantial decrease in HIV seroincidence in the male IDU population relative to previous studies at these sites may reflect a competing mortality on the one hand and, on the other, the introduction of syringe exchange programs in those cities. Alternatively, "saturation" with HIV-1 infection of those persons at the highest risk in those cities may result in low incidence without mortality or prevention successes. In addition, some have speculated that introducing highly active antiretroviral therapy in the HIV-infected community and offering postexposure chemoprophylaxis following nonoccupational exposures among high-risk persons may lead to decreased HIV-1 seroincidence among uninfected persons in those communities (because of decreased infectiousness) or increased HIV-1 seroincidence (if risk activity increases) (4648
). Although we found no significant decline in HIV-1 seroincidence over time in our cohort, it is possible that such changes may occur in the future. Monitoring of trends in HIV-1 incidence within at-risk populations, including the provision of risk-reduction counseling and high retention, will be critical in planning future HIV-1 vaccine efficacy trials.
Our results indicate that recruitment, retention, and, with minor modifications in eligibility, HIV-1 incidence among MSM and women at heterosexual or injection risk for HIV-1 infection are sufficient to conduct HIV-1 vaccine efficacy and other HIV prevention trials in the United States, with HIV-1 infection as an endpoint. In addition, the procedures and processes implemented in the Vaccine Preparedness Study have resulted in the rapid enrollment of participants in a phase II vaccine trial as well as enrollment in a phase III vaccine trial. Among male IDUs, recruitment and retention were successful; however, additional work will be needed to recruit IDUs with HIV-1 seroincidence levels sufficient to enable prevention interventions to be evaluated. The results of this study, along with studies from the Vaccine Preparedness Study of informed consent (49), willingness to participate in HIV vaccine trials (34
), lack of serious social harms in a previous phase II trial (15
), and successful conduct of a phase II HIV vaccine trial, indicate that the major feasibility concerns raised in 1994 have been addressed successfully.
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ACKNOWLEDGMENTS |
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The following institutions and persons associated with HIVNET participated in the Vaccine Preparedness Study Protocol Team: Domestic Master Contractor: Abt Associates Inc.: Drs. G. Seage and M. Gross; Statistical and Clinical Coordinating Center: Fred Hutchinson Cancer Research Center and University of Washington: Drs. T. Fleming and S. Self; Central Laboratory: Viral and Rickettsial Disease Laboratory, California Department of Health Services: Drs. H. Sheppard and M. Ascher; Repository Contractor: Biomedical Research Inc.: Dr. J. Leff; Denver Department of Public Health: Dr. F. N. Judson; Fenway Community Health Center: Dr. K. Mayer; Howard Brown Health Center: Dr. D. McKirnan; New York Blood Center: Drs. C. Stevens and B. Koblin; New York University Medical Center: Dr. M. Marmor and S. Titus; Beth Israel Medical Center, New York: Dr. D. Des Jarlais; San Francisco Department of Public Health: Drs. E. Stone and S. Buchbinder; University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center: Drs. D. Metzger and G. Woody; University of Washington: Dr. C. Celum; National Institute of Allergy and Infectious Diseases: Dr. R. Hoff, M. McCauley, and Dr. Z. Rosenberg.
The authors are grateful for the editorial assistance of Dr. Sherry Marts, the efforts of the Vaccine Preparedness Study site staff, and the contributions of HIVNET Community Advisory Board members.
The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
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NOTES |
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REFERENCES |
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