Adolescents and young adults are behaviorally at risk for HIV infection and are therefore important targets for emerging biomedical HIV prevention approaches such as vaccines, microbicides, and pre-exposure prophylaxis. It follows that inclusion of adolescents in HIV prevention biomedical clinical trials will be essential. In this article, we review the behavioral and developmental justifications for involving adolescents in clinical trials research. We discuss, as well, the need to minimize behavioral risks potentially associated with clinical trial participation.
Justifications for Adolescent Participation in Prevention-Focused HIV Clinical Trials
HIV Infection and Behavioral Considerations
In the United States, it is estimated that at least 14% of all new HIV/AIDS diagnoses are among people younger than 25 years, and the vast majority of these infections occur through sexual activity.1 Additionally, due to the long delay in developing symptoms associated with HIV infection, many of the young adults in the 25-29 age groups were probably infected during adolescence or young adulthood. From 2001 to 2006, male-to-male sex was the largest HIV transmission category in the United States with rates among young, ages 13-24, increasing by 93%.1 These epidemiological data demonstrate that despite multiple prevention efforts aimed at thwarting the spread of HIV, significant numbers of adolescents and young adults are engaging in risk behaviors and becoming infected with HIV on a consistent basis.
Sexual risk behavior data from the 2007 Youth Risk Behavior Surveillance System2 show that 47.8% of the high school students surveyed have had sexual intercourse during their lifetime. Approximately 35% of students surveyed had sexual intercourse in the 3 months preceding the survey (ie, currently sexually active). Of sexually active students, 14.9% had more than 4 sexual partners and 7% of students had sexual intercourse before the age of 13. Just more than 60% sexually active students reported using a condom during their last sexual intercourse.2
To better understand the context of these risk behaviors, it is important to review the developmental period of adolescence along with the cognitive, psychological, and social changes that occur during this time.
Adolescent and Young Adult Development
Adolescence is a time of many biological, social, and psychological transitions. One of the earlier contributions toward understanding the adolescent developmental period came from Erik Erikson,3 who recognized the unique importance of, and struggles with, identity formation during the adolescent years.
More recently, Jeffrey Arnett4 proposed a distinct developmental phase called “emerging adulthood” that spans the late teens through the mid twenties. This phase is characterized by change, instability, and an exploration of love, work, and worldviews.4 Although there is a tendency to think of risk behaviors within adolescence, there is evidence that many risky behaviors, including unprotected sex and substance use, actually peak during emerging adulthood.4,5 Thus, this article will outline the cognitive, psychological, and social considerations of both developmental periods (henceforth called “youth”) when engaging youth in HIV clinical research.
Cognitively, adolescence and young adulthood is the developmental period when youth may develop the capacity for more complex conceptual thinking. In a study of HIV-infected youth, however, Hosek et al6 found that 69% of the sample had yet to begin the transition from concrete thinking to formal or abstract reasoning, suggesting that sophisticated cognitive processing cannot be assumed, even among young adults.
A recent body of neurobiological research and imaging studies has begun to provide evidence of the developmental changes in overlapping areas of the brain that impact the cognition of youth and may further explain why youth are prone to risk behavior. Casey et al7-9 describe the ability to suppress inappropriate thoughts and actions in favor of goal-directed ones as a cornerstone of cognitive development and report that there are distinct neural systems that underlie the constructs of impulse control and risky decisions. Specifically, impulsivity is associated with immature prefrontal cortex development, whereas risk processing involves an increase in the activity of subcortical systems, accumbens and amygdale.7,10,11 Thus, the combination of a heightened responsiveness to rewards and the immaturity in behavioral control areas bias youth to seek immediate gains, which may explain the increase in risky decisions and emotional reactivity that is characteristic of adolescents and young adults.10
Psychologically, the formation of a sense of identity is considered by many theorists to be the primary developmental goal of the adolescent years.3,12,13 Erikson13 described adolescence as the period in the lifespan during which an individual must establish a sense of personal identity and avoid the dangers of role diffusion and identity confusion. Arnett4 proposes that most identity exploration actually takes place during emerging adulthood, and research has shown that identity achievement is rarely reached by the end of high school.12,14,15 In many ways, risk behaviors can be seen as apart of identity exploration as youth seek out a wide range of experiences and desire those that are novel, intense, and filled with sensation.16
Adolescence is also a time when the symptoms of many psychiatric disorders begin to manifest. In the 2007 Youth Risk Behavior Survey,2 29% of youth reported that they had experienced an episode lasting 2 or more weeks where they had felt so sad or hopeless that they stopped engaging in normal activities. For youth, depression can be a temporary response to a variety of situations and stressors, including impaired school performance or difficulties in relationships.17 The common and episodic nature of depression among youth may also be related to the neurobiological changes in the adolescent brain and the subsequent emotional reactivity associated with those changes.10 Adolescent depression and anxiety may also be related to the stress of identity development, the conflicts with parents that are inherent in the development of independence, and the influence of sex hormones. For example, pubertal timing has been linked to adolescent onset psychopathology, with early female maturers demonstrating elevated rates of psychological disorders and late male maturers demonstrating elevated rates of disruptive behavior and substance abuse disorders.18
Socially, as adolescents search for a sense of belonging, they become attached to a specific peer group and begin to conform to the norms of that group. For youth, the peer group offers a network of social and emotional support although also allowing them to experiment with different roles and values. Fearful of criticism, youth often rely on their peer group's approval of their choices, views, and behaviors. As a result, rigid conformity to peer groups often occurs. In fact, peer group norms and peer pressure have been shown to influence adolescent risk behavior, including sexual debut, sexual behavior, and substance use.19-21 On the other hand, youth are also in need of structure and stability during this time of exploration. Parent-child relationships often provide the needed guidance balanced with necessary discipline. In fact, autonomy and relatedness are complementary rather than opposing dimensions of the youth-parent relationship.22
The sexual relationships of today's youth involve a wide range of behaviors, and youth are considerably more likely to use a variety of sexual techniques than previous generations.23 Relationships during young adulthood have previously been characterized by serial monogamy, a series of long-term or short-term exclusive sexual relationships. However, a growing body of literature points to the frequency of sexual concurrency among youth, which is characterized by maintaining sexual partnerships that overlap in time.24-26 Concurrency is often driven by the need for a “back-up” partner in case the “primary” partner does not work out, and these partners may be socially distinct (ie, boyfriend at school versus guy from the neighborhood). Brady et al24 found that sexually concurrent youths who engaged in inconsistent condom use with other partners were more likely to engage in inconsistent condom use and a greater number of unprotected sexual episodes with main partners. Furthermore, Lenoir et al26 found that among adolescent couples, agreement between perceptions of sex-partner concurrency was low and that youth who perceived themselves to be in mutually monogamous relationships often underestimated their risk for sexually transmitted disease.
Thus, there are well-established cognitive, psychological, and social changes that occur during the adolescent and young adult years that influence the risk-taking behaviors of youth. Given the rising prevalence of HIV in the population, young people will continue to be at risk for contracting HIV and other sexually transmitted infections (STIs). Therefore, the development and testing of both behavioral and biomedical interventions to reduce risk behaviors, prevent HIV acquisition, and decrease secondary transmission are vitally important to the survival of a generation. To involve youth in these studies, the aforementioned cognitive, psychological and social changes need to be considered within the context of HIV clinical trials.19
Adolescents and Reduction of Risk in Clinical Trials
Recruitment of adolescents into HIV prevention clinical trials poses unique challenges. On the one hand, inclusion of adolescents is necessary from both scientific and ethical perspectives. On the other hand, individuals younger than 18 years are considered a vulnerable population, requiring particular attention to protection from harm related to research participation. To balance the need to include adolescents in HIV prevention trials with the requirement to provide added protection from harm, several issues must be addressed, including efforts to minimize the problem of “preventive misconception” and its potential negative sequela, risk compensation. Broadly speaking, these efforts fall into 2 categories: interventions designed to improve awareness about randomized clinical trials (ie, minimization of preventive misconception) and interventions designed to directly encourage self-protective sexual behaviors within the context of the clinical trial. In the following sections, the concepts of risk compensation and preventive misconception will be described, with recommendations made for future research and practice.
Risk Compensation and Preventive Misconception
Risk compensation or risk homeostasis theory is based on the presumption that persons have an inherent set point that determines their willingness to take risks.27,28 According to this theory, any modification in the environment that reduces the external probability of risk will lead an individual to increase their risk-related behaviors (ie, behavioral disinhibition) to maintain the homeostatic set point, thereby neutralizing the benefits of risk-reduction strategies.
A number of researchers have challenged the assumptions of risk homeostasis theory, and the empirical evidence for the existence of risk compensation is mixed at best.29,30 Pless et al30 point out that the theory, if true to any extent, may vary among different subgroups and with different risk reduction strategies.29 In reviewing the literature on risk compensation/homeostasis theory, Pinkerton31 notes that it has been applied, with varying results, to such diverse behaviors as automobile driving, drinking, and taking precautions against computer viruses.
The possibility of compensatory risk behavior in response to implementation of STI/HIV prevention strategies has received a good deal of attention.31 For instance, questions have been raised about whether condom-promotion programs or the introduction of an HIV vaccine may lead to increased sexual risk behaviors in other areas (eg, increased number of partners) that will neutralize the salutatory effects of these program.31-33 In a review of the literature on condom promotion programs, accompanied by comprehensive mathematical modeling strategies, Pinkerton31 concluded that some degree of risk compensation may occur in response to condom-promotion interventions, but there was no compelling empirical evidence that the beneficial effects of increased condom use were neutralized by increased risk in other areas.31 Again, it is important to note that different prevention strategies (eg, condom use, vaccination) that have different targets (eg, HIV, Human Papillomavirus) are likely to have different effects with respect to risk compensation or homeostasis. Nonetheless, concerns about possible risk compensation have been raised with respect to repeat HIV testing, Human Papillomavirus vaccination, postexposure prophylaxis, male circumcision, and future implementation of HIV vaccination, pre-exposure prophylaxis, and microbicides for HIV/STI prevention.32,34-36
Risk-Compensation and Biomedical HIV Prevention Clinical Trials
Most of the research on risk compensation or behavioral disinhibition has focused on behavioral responses to implementation of new or anticipated biomedical interventions. Risk compensation in the context of clinical trials, however, has at least two unique elements that differentiate it from risk compensation in response to the implementation of proven prevention strategies. Essentially, two errors in cognition or understanding must occur: (1) The trial participant has to overestimate the probability that she/he has been assigned to the experimental condition; and (2) The trial participant has to assume that the experimental biomedical intervention, which is unproven, has some significant degree of efficacy. This set of errors has been referred to as “preventive misconception,”37 which will be discussed in more detail below. Evidence for risk compensation in HIV prevention clinical trials is mixed. A number of qualitative studies, for example, carried out in conjunction with microbicide/diaphragm clinical trials report that many participants believed that the experimental condition/device was effective at HIV prevention.38-41 Nonetheless, there generally was no clear indication from quantitative data of a concomitant decrease in condom use (ie, condom migration), which would have suggested some degree of risk compensation.38,39,41 One study, however, found that women reported decreased use of condoms when interviewed through focus groups upon completion of the clinical trial.41 These reports were inconsistent with more conventional self-report measures of condom use through the course of the trial, which indicated no notable reduction in condom use. It is possible that the quantitative self-report data was subject to social desirability bias, such that the women did not admit to decreased condom use. Alternatively, the focus group format, with its attendant (and unpredictable) group dynamics, may have resulted in inaccurate reports regarding decreased condom use.42 The results of a randomized open-label clinical trial of diaphragm use with lubricant gel did suggest the possibility of some degree of disinhibition (reduced condom use) in the experimental versus the control group, though the results were not conclusive.43
Several research studies found that a common motivation of adult participants for enrollment in HIV vaccine clinical trials was a desire for protection from infection, a belief that could translate into compensatory risk behavior.44-47 An early study, in fact, found some increase in risk behavior (eg, unprotected anal intercourse) among adult clinical trial participants.44 Another study reported that among men who have sex with men participating in an HIV vaccine efficacy trial, younger age (<30 years old), perceptions of assignment to the experimental condition, and non-black race were associated with increased reports of unprotected anal intercourse.48 However, most recent research has not found that HIV vaccine clinical trial participants have increased their sexual risk behaviors.49,50
The research on risk-compensation in HIV vaccine and microbicide clinical trials is inconclusive and has focused, by necessity, on adult participants. In addition, across several research studies, findings indicate that many participants enroll because of the hope that the vaccine or microbicide will provide protection from HIV or come to believe that the experimental intervention is, in fact, providing protection.38,46,51-55 There remains a need for research on risk compensation among adolescents. Even if increased risk behavior in the context of HIV vaccine (or microbicide) clinical trials is relatively rare, or confined to specific subgroups, there remains an ethical responsibility to work to reduce the potential for risk compensation as much as possible.56 These efforts are particularly important when recruiting adolescent minors into biomedical HIV prevention clinical trials.
“Preventive misconception37” is an adaptation of the notion of therapeutic misconception, a concept that has been intensively discussed and studied in the research ethics literature for more than 20 years.57,58 The term “therapeutic misconception” has typically been applied to treatment-oriented randomized, controlled clinical trials. According to Appelbaum et al,58 therapeutic misconception occurs when clinical research participants incorrectly attribute therapeutic benefits to unproven experimental treatments. The application of therapeutic misconception to preventive trials has been described by several authors.37,56 Simon et al37 propose that “preventive misconception” entails two errors: (1) an overestimate of the probability of being assigned to the experimental condition; and (2) a presumption that the unproven experimental preventive intervention is efficacious. Empirical support for preventive misconception has been found in a shingles vaccine trial37 and in an HIV vaccine trial.47 Schuklenk and Ashcroft56 argue that harm resulting from preventive misconception in the context of an HIV vaccine trial (eg, HIV infection due to risk compensation) should be treated as a trial-related injury. Development of interventions to reduce preventive misconception may translate into an important reduction in social harms associated with vaccine trial participation. Again, there is a particular responsibility to minimize preventive misconception among more vulnerable subject populations, such as adolescents. Kafaar et al59 describe some of the cognitive development issues that affect adolescent decision making and, as a result, require particular attention when recruiting adolescents for HIV vaccine trials.
Research on Modifications of Informed Consent Procedures
Numerous efforts have been made to adapt and simplify consent forms to improve comprehension of clinical trials, modifications that are often necessary when including adolescents in clinical trials research.60,61 The typical approach to enhancing (or simplifying) consent forms involves improving the readability of the forms through shortening sentences, reducing use of technical language, and use of graphic illustrations. Murphy et al62 used this approach in their study of adolescents' understanding about an HIV vaccine clinical trial. In this study, adolescents at behavioral risk for HIV infection were randomized to receive either a standard consent form or a simplified form. Results indicated improved comprehension among the adolescents who received the simplified form. However, the item analysis revealed that several items central to preventive misconception did not differentiate between the 2 groups (eg, side effects do not indicate placebo or vaccine). Similarly, many of the items that did differentiate between the standard and simplified consent groups were not relevant to preventive misconception. An additional limitation is the fact that simplified consent forms may not be acceptable or widely utilized due to institutional and/or legal constraints.
Implications for Biomedical HIV Prevention Clinical Trials with Adolescents
Minimization of Preventive Misconception
Instead of modifying informed consent forms, which can be problematic, it may be more effective to develop supplemental materials that focus specifically on the elements of preventive misconception, such as randomization and the nonproven efficacy of the experimental intervention. An advantage of supplemental material, therefore, is that it could be applied to any biomedical HIV prevention clinical trial, regardless of the nature of the informed consent. Research approaches using health marketing and health communication principles may prove to be very effective at increasing adolescents' knowledge about clinical trials and reducing preventive misconception.
Direct Reduction of Risk Compensation
Behavioral/educational interventions focusing on behavioral aspects of HIV/STI prevention are a standard element of biomedical HIV prevention clinical trials. With trials focused on adolescents, a vulnerable population, it is even more important to effectively address the possibility of risk compensation through developmentally appropriate behavioral interventions. The evidence-based behavioral interventions that have been developed for use (outside of clinical trials) often involve multiple, relatively time-intensive sessions.63 It will be important to develop behavioral interventions that can be adapted to the structure and time frame of biomedical clinical trials, perhaps entailing more frequent but shorter interventions. One promising approach involves the use of cell phones or Personal digital assistants (PDAs) to deliver follow-up risk reduction messages to enhance initial in-person interventions. The messages could also serve to address, in an on-going fashion, preventive misconception issues. personal digital assistants (PDAs) and cell phones have undergone initial evaluations for feasibility and acceptability among adolescents and adults as methods for increasing antiretroviral medication adherence and for encouraging risk reduction.64-68 Text messaging via cell phones is a very common mode of communication for adolescents, suggesting that this would be an acceptable and effective way to deliver information and interventions to adolescent participants in biomedical HIV prevention research.
It is essential that adolescents be included in HIV prevention clinical trials. Behaviorally, adolescents and young adults are at risk for HIV infection and continue to represent a substantial proportion of infections. Moreover, due to the unique psychosocial, cognitive, physiological, and neurological developmental issues associated with adolescence and emerging adulthood, it cannot be assumed that results of adult HIV prevention clinical trials will fully apply to this younger age group. As noted by Short et al,69 inclusion of adolescents in clinical trials is consistent with the concept of justice outlined in the Belmont report70 on ethical conduct of research.
However, the very issues that make inclusion of adolescents in HIV prevention clinical trials necessary from scientific and ethical perspectives also demand that particularly intensive efforts be made to protect participating adolescents from harm that could accrue from a clinical trial. Preventive misconception, the tendency to overestimate probability of assignment to the experimental condition and to assume that the experimental intervention is efficacious, could lead to increased sexual risk behavior (ie, risk compensation) in the context of a prevention clinical trial. It will therefore be important to develop interventions to target the two components of preventive misconception and to directly focus on minimization of risky sexual behavior. These interventions will need to be adapted to fit in within the time frame and context of biomedical HIV prevention trials and rigorously evaluated.
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