Unprotected vaginal sex with known HIV-seropositive male partners decreased from the baseline to the 12-month visit (OR = 0.50, 95% CI = 0.32-0.81) and then remained steady from the 12- to 36-month visits (OR = 0.73, 95% CI = 0.42-1.27). At 36 months, unprotected vaginal sex with HIV-seropositive partners remained below that reported at the baseline visit (OR = 0.42, 95% CI = 0.23-0.75). Women who enrolled later in the trial were less likely to report unprotected vaginal sex with HIV-infected partners than were women who enrolled earlier. Race, age, and education were not related to unprotected vaginal sex with HIV-infected partners; nor were perceived vaccine efficacy or joining the trial to protect oneself from HIV. Women who consistently did not have an idea as to their assignment status were more likely to report unprotected vaginal sex with HIV-infected partners than were women who perceived assignment to placebo (Table 5).
Participants enrolled in the phase 3 efficacy trial of an rgp120 vaccine containing 2 subtype B antigens (MN and GNE8) reported substantial HIV risk, both at the baseline visit and during 36 months of follow-up, underscoring the critical need for HIV vaccines. Contrary to speculation that participating in HIV vaccine efficacy trials might increase HIV sexual risk behavior,1 sexual risk behavior did not increase beyond that reported at baseline among participants in this trial. The highest-risk behaviors, unprotected anal sex with HIV-infected partners among the men and unprotected vaginal sex with HIV-infected partners among the women, decreased over the duration of the trial. Unprotected anal sex among the men and unprotected vaginal sex among the women initially decreased and later returned to baseline levels but did not exceed baseline levels at any point during the trial.
The reported decrease in unprotected anal sex among MSM in this trial approximates the observed reductions in risk behavior reported in a recent meta-analysis evaluating 1- to 6-month postintervention effects of HIV risk reduction interventions among MSM (OR = 0.69, 95% CI = 0.56-0.86).22 Also, the reduction in unprotected vaginal sex from the baseline to the 12-month visit exceeds that observed in similar meta-analyses of HIV risk reduction interventions among drug users (OR = 0.86, 95% CI = 0.76-0.98)23 and heterosexuals (OR = 0.81, 95% CI = 0.69-0.95).24 Lastly, the overall decrease in unprotected anal sex from the baseline to 36-month visit among all men in the trial (7%) is almost identical to that observed among participants randomized to the enhanced intervention arm (∼10%) of a large-scale randomized controlled behavioral intervention trial that enrolled >4000 MSM in 6 US cities.25 The results from these studies demonstrate that the reductions in HIV risk behavior observed among the participants in this efficacy trial are similar to those observed across multiple HIV risk reduction intervention studies.
However, although risk behavior did not exceed that reported at baseline at any time during follow-up and generally declined over time, both younger MSM and MSM who perceived that they had received vaccine reported levels of unprotected anal sex at follow-up that were statistically indistinguishable from those reported at baseline; older men and men who perceived that they had received placebo or who did not have a clear perception of their assignment did not return to risk levels reported at baseline. The effect of age on risk behavior change over time is not unanticipated because younger age has been associated with greater HIV risk in other studies of MSM.26,27
The MSM who perceived that they received the vaccine consistently reported at baseline and over time a greater amount of unprotected anal sex than did men who did not perceive that they received vaccine which suggests that this may be an individual-level behavioral phenomenon unrelated to trial participation per se. This conclusion is supported by the lack of an observed perceived assignment × visit interaction effect on risk behavior. Thus, the difference in risk behavior between participants who perceived that they received vaccine and those who did not is, on average, about the same over time. If an increased probability of risk behavior were attributable to trial participation, the hypothesis would be that risk behavior would not differ by perceived assignment status at baseline but that participants who perceived that they received vaccine would increase their risk behavior over time relative to those who perceived that they received placebo.
Psychologic theory may help explain why the participants at highest risk were consistently more likely to perceive that they received vaccine than were participants at lower risk. Cognitive dissonance theory28-30 suggests that when a person engages in a behavior that is inconsistent with their beliefs, that person is motivated to reduce the uncomfortable state of arousal (dissonance) that results. Because beliefs are often easier to change than behavior, a dissonance-reducing change in beliefs may be more likely to occur than behavior change. One way that trial participants could reduce dissonance associated with risk behavior is to establish a belief that they have received vaccine and that the vaccine is efficacious. In fact, among these trial participants, perceptions of HIV vaccine efficacy and assignment status were significantly correlated. This phenomenon may be suggestive of additional counseling strategies and underscores the need for continued counseling emphasizing that the product being tested is of unknown efficacy, that participants may receive placebo, that infections have occurred in the trial, and that participants should maintain lower risk behavior.
Some have suggested that individuals whose motivation to participate in efficacy trials is to gain protection from HIV should possibly be excluded from participating.31 Given that about half of the participants in this trial endorsed protection as a reason for participating,15 excluding such individuals from trials could significantly increase the time and cost of enrollment, decrease HIV incidence of trial cohorts, and increase the sample size and follow-up requirements to determine efficacy. Furthermore, excluding such individuals from trials may raise ethical issues regarding fair and equal access to trials.31 The data from this trial indicate that the motivation of protection is not associated with increased risk among trial participants and, thus, would not support excluding such participants from future trials.
Finally, that MSM who became infected later in the trial reported increases in unprotected anal sex with HIV-infected partners from the 18- to 36-month visits may suggest that avoidance of infection up to 18 months of trial participation could potentially result in increasing optimism about vaccine efficacy and increased risk behavior. While this is speculation, the possibility suggests an additional counseling message to consider for future trials. In addition to the messages that low-risk behavior should be maintained during the trial because the vaccine may not be effective and participants may receive placebo, future trials should consider incorporating an additional message to mitigate the potentially negative impact of increasing participant optimism. For example, in addition to the standard messages, participants might also be told that infections have occurred in the trial, that we do not know in which treatment arm the infections have occurred, and that participants should continue safer sex practices. Such a message could serve to counterbalance optimistic perceptions among trial participants not only potentially related to their avoidance of infection, but also to contextual influences such as news reports of successful trial enrollment, Data Safety Monitoring Board (DSMB) reviews, and retention. Care should be taken when delivering such a message, however, as there is a chance that it could affect study compliance and retention.
This study has several limitations. Notably, we were unable to attribute risk behavior change to trial participation because there was no comparison group that did not receive an injection of either vaccine or placebo. Without such a comparison group, interpretation of either upward or downward trends in risk behavior is limited. Similarly, without such a comparison group we cannot make comparative statements about the magnitude of behavior change we observed in this study. For example, it may be that although trial participation did not cause an increase in HIV sexual risk behavior, it could attenuate the declining slope of risk behavior over time. In other words, the rate of decrease for trial participants could be less than that for a similar cohort of participants who do not receive an injection of vaccine or placebo. Unless contrast groups that do not receive an injection are included in future trial designs, quasi-experimental nonequivalent group designs may be the only way to evaluate the relationship of trial participation to HIV risk behavior. Despite the possible confounds associated with these designs,32 comparing vaccine efficacy trial cohorts to those enrolled using similar eligibility criteria could provide convergent validity as to the relationship between trial participation and HIV sexual risk behavior. The Centers for Disease Control and Prevention has enrolled such a contrast group at a subset of VaxGen trial sites and results are expected in the near future.
We were also limited with regard to sample size of both minority MSM and female participants. The small sample of women constrained our ability to calculate parameter estimates with reasonable CIs and to evaluate interaction effects related to unprotected vaginal sex and perceived vaccine efficacy and assignment over time. Also, the small sample of women participating in the trial limited our ability to evaluate heterogeneity among these women with regard to motivations to participate in trials, risk behavior, education, and trial-related perceptions of vaccine efficacy and assignment. In general, these same limitations apply to our ability to understand the risk behavior dynamics of people in high-risk communities of color who will be recruited for enrollment in future HIV vaccine efficacy trials.
Our ability to assess changing perceptions of vaccine efficacy and perceived assignment was limited by infrequent measures. It was not possible to evaluate how changing perceptions may be related to risk behavior change over time. Future trials should measure these perceptions at each visit to assess and monitor changing perceptions and associated risk behavior change.
Despite limitations, this study provides the first descriptive data on HIV sexual risk behavior among phase 3 HIV vaccine efficacy trial participants. These data may alleviate some concerns about increasing HIV sexual risk behavior by trial participants; however, they also suggest areas for future evaluation. There is a need for additional analyses to evaluate how substance use may vary as a result of trial participation and to identify mediators and moderators of risk behavior of trial participants. It will also be important to assess perceived assignment to vaccine or placebo and the extent to which these perceptions may lead to unblinding and differential risk behavior change. Finally, despite the methodologic challenges, quasi-experimental nonequivalent control group analyses, such as that being conducted by the Centers for Disease Control and Prevention, will provide a more complete picture of HIV sexual risk behavior within the context of HIV vaccine efficacy trials.
The authors thank the study coordinators at each of the trial sites for their perseverance and dedication to this trial. Furthermore, the authors thank Marta Ackers, Alan Greenberg, John Williamson, Eleanor McLellan, Markus Durham, Bill Heyward, and Marc Gurwith for their support and review of the manuscript and Marlene Chernow, Gina Rossen, John Jermano, and Nzeera Ketter for their critical contributions to the design and implementation of the trial. Most importantly, the authors thank the VAX004 volunteers for their participation and commitment.
VAX004 Study Group Members and Affiliations
Franklyn Judson, MD, Denver Department of Public Health, Denver, CO; Geoffrey J. Gorse, MD, Saint Louis University, St. Louis, MO; Clayton D. Harro, MD, Johns Hopkins School of Public Health, Baltimore, MD; Kenneth Mayer, MD, Fenway Community Health, Boston, MA; Jay Kostman, MD, Philadelphia Fight, Philadelphia, PA; Harold Kessler, MD, Chicago Center for Clinical Research, Chicago, IL; Stephen J. Brown, MD, AIDS Research Alliance, West Hollywood, CA; Richard DiCarlo, MD, Louisiana State University Health Sciences Center, New Orleans, LA; Michael C. Keefer, MD, University of Rochester, Rochester, NY; Bienvenido G. Yangco, MD, Infectious Disease Research Institute, Inc., Tampa, FL; Javier O. Morales, MD, Clinical Research Puerto Rico, Inc., San Juan, PR; Donald Forthal, MD, University of CA-Irvine Medical Center, Orange, CA; Susan Buchbinder, MD, San Francisco Department of Public Health, San Francisco, CA; Connie Celum, MD, University of Washington/Seattle HPTU, Seattle, WA; Keith Henry, MD, Hennepin County Medical Center, Minneapolis, MN; Jeffrey M. Jacobson, MD, Beth Israel Medical Center, New York, NY; Jerry Cade, MD, Wellness Center, Las Vegas, NV; Elaine Thomas, MD, University of New Mexico Health Sciences Center, Albuquerque, NM; Richard Novak, MD, University of Illinois at Chicago, Chicago, IL; Frank Rhame, MD, Abbott Northwestern Hospital, Minneapolis, MN; Ralph W. Richter, MD, Clinical Pharmaceutical Trials, Inc., Tulsa, OK; Michael C. Caldwell, MD, Dutchess County Department of Health, Poughkeepsie, NY; Beryl Koblin, PhD, New York Blood Center, New York, NY; Michael Marmor, PhD, NYU School of Medicine, New York, NY; Catherine Creticos, MD, Howard Brown Health Center, Chicago, IL; Michael Para, MD, Ohio State University, Columbus, OH; Stephen K. Tyring, MD, UTMB Center for Clinical Studies, Houston, TX; David McKinsey, MD, Antibiotic Research Associates, Kansas City, MO; Neil Flynn, MD, UC Davis Medical Center, Infectious Diseases, Sacramento, CA; Edwin DeJesus, MD, IDC Research Initiative, Altamonte Springs, FL; Steven Santiago, MD, Care Resource, Inc., Coral Gables, FL; Barry M. Miskin, MD, Palm Beach Research Center, West Palm Beach, FL; Cecilia Shikuma, MD, Hawaii AIDS Clinical Trials Unit, Honolulu, HI; Melanie Thompson, MD, AIDS Research Consortium of Atlanta, Atlanta, GA; James O. Kahn, MD, UCSF-Positive Health Program, San Francisco, CA; Ross G. Hewitt, MD, Erie County Medical Center, Buffalo, NY; Michael S. Somero, MD, Office of Michael S. Somero, MD, Palm Springs, CA; Roel A. Coutinho, MD, GG&GD/Municipal Health Service Amsterdam, Amsterdam, NL; Martin Fenstersheib, MD, Crane Center, San Jose, CA; M. Angeli Adamczyk, MD, ACRC/Arizona Clinical Research Center, Inc., Tucson, AZ; Peter Piliero, MD, Albany Medical College, Albany, NY; Ronald Poblete, MD, North Jersey Community Research Initiative, Newark, NJ; Michael Sands, MD, University of Florida-Jacksonville, Jacksonville, FL; Barbara Gripshover, MD, University Hospitals of Cleveland, Cleveland, OH; David Brand, MD, North Texas Center for AIDS & Clinical Research, Dallas, TX; Patrick Daly, MD, Nelson-Tebedo Health Resource Center, Dallas, TX; Mark J. Mulligan, MD, University of Alabama at Birmingham, Birmingham, AL; Robert L. Baker, MD, Community Medical Research Institute, Indianapolis, IN; Peter S. Vrooman, Jr., MD, ALL TRIALS Clinical Research, Winston Salem, NC; Robert Hogg PhD, BC Center for Excellence in HIV/AIDS, Vancouver, BC, Canada; Jean Vincelette, MD, Hopital Saint-Luc du CHUM, Montreal, PQ, Canada; Brian P. Buggy, MD, Wisconsin AIDS Research Consortium, Milwaukee, WI; James H. Sampson, MD, Research & Education Group, Portland, OR; Sharon Riddler, MD, University of Pittsburgh, Pittsburgh, PA; Robert A. Myers, MD, Body Positive, Inc., Phoenix, AZ; Michelle Lally, MD, The Miriam Hospital, Providence, RI; Joseph Jemsek, MD, Jemsek Clinic, Huntersville, NC; Howard Grossman, MD, Polaris Medical Group, New York, NY; Ken Logue, MD, CascAids Research, Toronto, ON, Canada.
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Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
HIV vaccine efficacy trials; HIV risk behavior; clinical trials; sexual risk behavior; MSM; women at risk