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Abstract

Highly active antiretroviral therapy (HAART) nonadherence is related to negative health outcomes and is well-documented in adolescents and young adults (AYAs) with behaviorally acquired HIV. Few studies describe methods to improve adherence in this population. This retrospective study describes placebo pill trial use (ie, pills with inert substance prescribed to practice taking HAART) in AYAs initiating HAART and its relation to disease outcomes. Sixty-two AYAs initiated HAART during the review period. Disease outcomes during the first year of standard clinical care were abstracted from medical records. In all, 72.6% of participants received ≥1 pill trial and 27.4% received ≥2 trials. Placebo trial use was not independently related to adherence post-HAART initiation. “Prescription” of a second trial was related to less optimal disease status over the first 6 months of treatment. Placebo trials have the potential to inform clinical care, aid in identifying AYAs at risk for nonadherence, and may provide a novel intervention strategy before/after HAART initiation.

Keywords

adherence adolescent and young adult intervention

Human immunodeficiency virus (HIV) infection can be effectively treated but effective management^1,2 requires strict adherence to the treatment regimen.³ Unfortunately, nonadherence to highly active antiretroviral therapy (HAART) regimens is well-documented. This is especially true for youth (ie, adolescents and young adults [AYAs]), where rates of adherence range from 20% to 100%.^4

–7 Nonadherence has significant implications for the individual, including subsequent treatment response and health outcomes,^4

–8 such as poor virologic response, development of drug resistance, and mortality.^8
–10 Given the association of infection transmissibility with a patient’s HIV viral load (VL), HAART nonadherence also has significant public health implications.

Unfortunately, few efficacious interventions are currently described in extant literature to promote adherence behaviors in youth with HIV.^11,12 This paucity is striking, especially given this population may be more likely to engage in risky health behaviors. Although the Panel on Antiretroviral Guidelines for Adults and Adolescents states that interventions to improve HAART adherence are needed both before and after HAART initiation,¹³ available interventions (eg, behavioral family therapy¹⁴) are limited by cost, high patient demands, and/or lack of applicability to existing clinical care settings. Brief, individualized interventions designed for direct integration into standard clinical care are needed to optimize HAART adherence and health outcomes.

Researchers in adult HIV settings have provided preliminary data supporting the efficacy of brief, behaviorally focused interventions to support adherence-related behaviors,^15
–17 and the application of individualized, behavioral interventions has shown promise across other pediatric chronic illness groups.¹⁸ One such intervention implements a placebo pill trial; pills with inert substance designed to mimic the HAART regimen and prescribed to practice taking HAART and identify possible barriers to adherence. Formerly used in clinical trials to exclude nonadherent participants¹⁹ and increase empathy and adherence-related knowledge of medical students,^20
–22 the placebo trial has also more recently been used as an intervention to improve medication adherence in adults with HIV.²³

Wagner and colleagues provided preliminary data supporting placebo trial use to increase HAART adherence.^15,23,24 For example, 87% (n = 20) of adult men who achieved at least 90% adherence to the placebo trial and initiated HAART also achieved at least 90% HAART adherence during the first month of therapy.²⁴ Similarly, Wagner found that adherence to the placebo trial was the most robust predictor of later HAART adherence in adults (n = 201) with a history of substance abuse.¹⁵ Despite this initial support, no studies have examined placebo trial use among youth with HIV. Given the unique developmental challenges and treatment barriers faced during the AYA period,^25,26 further examination of its value in this population is needed. As such, the current retrospective study utilized systematic medical chart review to: (1) describe the use of a placebo trial in youth with behaviorally acquired HIV initiating HAART within a clinical care setting, (2) compare clinical outcomes between youth receiving a placebo trial to those who did not receive a placebo trial prior to HAART initiation, and (3) compare clinical outcomes between youth receiving 1 placebo trial to those receiving 2 or more trials prior to HAART initiation. We hypothesized that youth receiving a placebo trial prior to HAART initiation and youth requiring only 1 trial would have more optimal disease outcomes, as suggested by lower VL and higher CD4 count, following treatment initiation.

Methods

Participants and Procedures

Youth diagnosed with HIV and initiating HAART during a 3-year period (August 2007 to August 2010) were eligible for enrollment in this retrospective study. Inclusion criteria required that youth: (1) were aged 13 to 24 at the time of treatment or placebo trial initiation; (2) received a confirmed diagnosis of HIV via serum assay; (3) received a behaviorally acquired HIV diagnosis, confirmed via medical chart review; (4) were followed in the institution’s HIV clinic; and (5) initiated HAART. Youth were excluded if they had previously documented HAART exposure or were a pregnant female.

Although not provided to all youth initiating HAART (due to differences in disease acuity, refusal, etc), a percentage of youth received a 1- or 2-week placebo trial prior to HAART initiation. A 2-week placebo pill trial was typical; however, shorter trial periods were completed secondary to (1) patient request or (2) clinical status and urgency to start treatment soon. Although not standardized, similar education (ie, trials were prescribed in order to enable practice of a medication regimen, identify possible barriers to medication adherence, and provide anticipatory guidance/education regarding HAART and health behaviors) was completed by all providers. In the case of multiple placebo pill trials, trials were typically prescribed in immediate succession. Patients and/or providers requested multiple trials to provide additional exposure and facilitate greater competence with managing a daily medication regimen; however, HAART prescription was not contingent on placebo trial performance. The placebo regimen included the same dosing frequency, pill size, and number of pills as the anticipated HAART medication regimen. Placebo pills contain lactose sugar (or microcrystalline powder for lactose-intolerant youth) and are commercially available in various sizes. Per standard clinical care, youth were prescribed HAART and then followed on an outpatient basis at specified intervals (ie, HAART initiation; 2-week follow-up; and 1-, 3-, 6-, 9-, and 12-month follow-ups).

Demographic information (eg, participant gender, age, and race), disease-related information (eg, medical regimen), and placebo trial characteristics (eg, length of trial, number of trials) were abstracted from participants’ electronic medical record. Per standard clinical care, disease marker data, including CD4 count, CD4%, and VL, were obtained at each routine clinic visit and results abstracted from participants’ electronic medical record. Previous research confirms CD4 count and CD4% are related to disease progression and survival, and decreased VL is related to better clinical outcomes.^10,27,28

Statistical Analyses

Descriptive statistics (ie, measures of central tendency, frequencies) were used to describe demographic and disease-related characteristics and to determine the number of youth receiving a placebo trial prior to initiating HAART. Hierarchical linear regression analysis, controlling for disease markers at baseline (step 1), was used to determine the differences between those receiving a pill trial and those who did not receive a trial (step 2) in disease markers at 1, 3, 6, 9, and 12 months post-HAART initiation. Disease markers at baseline were controlled for in order to account for those patients who may have had more advanced disease and, thus, not eligible for a trial. Given the number of analyses performed and to decrease the likelihood of type 1 error, P < .01 was utilized for statistical significance. Hierarchical linear regression analysis, controlling for disease markers at baseline, was also used to determine differences in disease markers between those receiving 1 pill trial and those receiving 2 or more trials prior to initiating HAART at 1, 3, 6, 9, and 12 months post-HAART initiations.

Results

Sixty-two youth (67.7% male, 96.8% African American, 19.4% private insurance) were diagnosed with HIV, mean (standard deviation [SD]) 19.0 (1.6) years, initiated HAART, 19.5 (1.6) years, and met other inclusion criteria during the 3-year study period. Of the total sample, 72.6% received at least 1 placebo trial, 27.4% received a second trial, and 8.1% received a third trial prior to HAART initiation (see Figure 1). Of those receiving 1 placebo trial, 68% completed a 1 pill/d regimen, 26% completed a 3 pill/d regimen, and 5% completed an individualized regimen. Disease outcomes across the first 12 months of treatment are included in Table 1.

Figure 1.

Trajectory of placebo trial use and HAART initiation.

Table 1.

Disease Marker Data.

Disease Marker	Visit	Total Sample, Mean (SD)	Placebo Trial, Mean (SD)	No Trial Mean (SD)
CD4	Baseline	343.5 (143.4)	356.4 (125.9)	302.3 (188.9)
	1-Month	443.1 (180.7)	448.3 (183.1)	422.5 (181.0)
	3-Month	456.4 (148.6)	463.5 (135.7)	433.3 (191.9)
	6-Month	532.3 (212.1)	529.5 (210.7)	540.0 (225.4)
	9-Month	526.9 (248.4)	514.6 (227.0)	558.2 (306.3)
	12-Month	563.5 (243.0)	561.3 (239.2)	570.0 (270.8)
CD4%	Baseline	21.3 (9.7)	22.7 (9.3)	17.0 (10.1)
	1-Month	26.2 (10.3)	26.2 (10.6)	26.0 (9.5)
	3-Month	28.3 (10.3)	28.5 (9.4)	27.4 (13.4)
	6-Month	32.3 (9.8)	31.6 (8.0)	34.3 (13.9)
	9-Month	31.7 (10.0)	31.3 (8.3)	32.7 (14.0)
	12-Month	39.1 (27.5)	41.1 (30.6)	33.0 (14.5)
VL	Baseline	80986.1 (156472.2)	59858.7 (119819.0)	144368.4 (228738.0)
	1-Month	396.5 (843.2)	267.4 (543.0)	884.0 (1475.8)
	3-Month	4609.7 (21923.9)	5919.3 (24838.9)	98.8 (150.1)
	6-Month	3427.9 (16346.9)	4666.6 (19013.1)	21.6 (27.2)
	9-Month	5037.2 (27238.5)	827.9 (3034.6)	17244.3 (53677.7)
	12-Month	86.3 (395.7)	26.1 (48.9)	253.4 (772.1)

Abbreviations: SD, standard deviation; VL, viral load.

Controlling for disease markers at baseline, hierarchical linear regression analysis revealed no significant differences (P > .01) between those receiving a placebo trial and those who did not receive a trial across any disease marker during the first 12 months of treatment. Examining only those AYAs receiving a pill trial and controlling for disease markers at baseline, hierarchical linear regression analysis revealed that AYAs receiving multiple trials were more likely to have lower CD4% at 1 month (ΔR ² =.07, R ² =.81), 3 months (trend; ΔR ² = .08, R ² = .56), 6 months (ΔR ² =.19, R ² = .66), and 9 months (ΔR ² = .18, R ² = .61) post-HAART initiation than those who completed only 1 trial (see Table 2).

Table 2.

Regression Analysis Summary for Use of Multiple Trials Predicting CD4% at 1-, 3-, 6-, and 9-Month Follow-up.

Model	B	SEB	β	P Value
1-Month follow-up
Baseline CD4%	1.01	.09	.91	<.001
Multiple trial	−5.76	1.80	−.26	.003
3-Month follow-up
Baseline CD4%	.71	.14	.68	<.001
Multiple trial	−5.42	2.47	−.29	.037
6-Month follow-up
Baseline CD4%	.67	.10	.72	<.001
Multiple trial	−6.98	1.72	−.43	<.001
9-Month follow-up
Baseline CD4%	.63	.12	.64	<.001
Multiple trial	−7.08	2.08	−.43	.002

Discussion

We did not detect significant differences in disease markers between those who received a placebo pill trial and those who did not, and our hypothesis that individuals able to first practice a HAART regimen would have better disease outcomes following HAART initiation was not supported. Due to limited data regarding trial adherence (unstandardized assessment via self-report and/or pill count), participants who received a pill trial were grouped together regardless of whether they achieved ≥90% adherence, which may have contributed to our lack of significant results. Research suggests 20% to 40% of participants achieve ≥90% adherence to HAART, regardless of their participation in adherence-promotion programs.^3,29,30 In other words, a subset of individuals is able to achieve satisfactory disease outcomes independently, without any additional intervention. Certainly, our inability to stratify or control for initial trial adherence may have limited our ability to find significant differences between groups.

Current data did not support a relationship between multiple trial use and CD4 or VL and is a direction for future research; however, we did find that AYAs receiving multiple trials were more likely to have lower CD4% post-HAART initiation. Although the use of a placebo trial in itself may not result in improved clinical outcomes over time, this finding suggests that placebo trials may provide 1 novel and clinically relevant method to inform clinical care and aid clinicians in identifying those at risk for less optimal disease outcomes following treatment initiation. Although pill trial performance was not a criterion for HAART initiation, it is likely the patient and/or provider opted to complete a second or third trial with the intention to provide additional practice and problem solving around adherence-related concerns. Researchers providing care to adults with HIV and a history of drug use have withheld HAART contingent on pill trial adherence¹⁵; however, we view pill trials as 1 promising strategy to identify AYAs at risk for nonadherence and to provide appropriate education and preventative care.

Prior research consistently concluded that providers frequently misclassify patients as having poor or good adherence and perform only at chance when predicting a patient’s adherence compared to more objective adherence measures.^3,31,32 Prescription of more than 1 placebo trial may serve as a proxy for other risk markers for less optimal disease outcomes and thus assist providers in identifying those for whom additional intervention may be needed. Although objective adherence data for the placebo trial is not available, qualitatively, we know participants received 2 or more trials for reasons including less than perfect adherence on the first trial and/or participant desire for further practice. In contrast, prior prospective intervention studies with adults prescribed HAART only when ≥90% adherence on placebo trials was achieved.^15,17,24,25 In these studies, rates of ≥90% antiretroviral adherence by participants who achieved ≥90% adherence during the placebo pill trials ranged from 39% to 87%.^15,24 Interestingly, Wagner and colleagues found 100% of participants requiring a single-pill trial achieved ≥90% adherence to HAART compared to 67% of participants requiring 2 or more trials.²⁴ Our finding, that participants requiring only 1 trial achieved more optimal disease outcomes than those requiring multiple trials, is consistent with Wagner and colleagues’ findings. In a time of increased health-care costs, identification of those most at risk for less optimal disease outcomes is critical. Placebo trials may offer an innovative method to identify those most ready for treatment and those in need of additional intervention prior to medication initiation. Prospective investigation is warranted; subsequent, targeted interventions for this high-risk group may decrease treatment-related barriers and prevent the decline in adherence behaviors frequently observed over time.

Finally, our study differed from previous research in that disease markers rather than objective electronic monitors and/or self-reported adherence data were used. However, as medication adherence and virologic response are associated in a dose–response manner, disease markers may be considered adequate proxy measures of adherence.³³ That said, it may be that disease markers are not sensitive enough to detect subtle, but clinically significant, differences in behaviors related to adherence. A similar conclusion was suggested in a review of behavioral intervention studies in adults, which found stronger effect sizes for studies measuring adherence behaviors opposed to VL as the study outcome.³⁴

Of course, the retrospective nature of this systematic medical record review and small sample size restricts the conclusions that can be drawn. First, the quality and quantity of variables available for inclusion in the current study were constrained to the information found within the existing medical record. For example, future research should use objective measures of pill trial adherence (eg, pill count). Also, while education regarding adherence is routinely provided, participants did not receive systematic adherence interventions as part of standard clinical care, and information regarding possible adherence strategies offered by the care team was not available for abstraction. Future research recruiting a larger sample should also examine the contribution of other demographic and individual characteristics (eg, age, living situation, employment status, disclosure status) and their potential relationship to trial use and disease outcomes. Second, participants were not randomly assigned to receive the pill trial. Clinicians decided who to offer the placebo trial to; the offering of the placebo trial was not protocolized and variability of practice in this regard cannot be ruled out. This likely created groups that differed in important ways that influenced later treatment adherence. For example, previous studies found factors, including age,³⁵ socioeconomic status (SES),³⁶ family features,³⁷ and negative mood states,³⁸ influence adherence. Future studies are needed that randomly assign participants stratifying by these correlates. Third, the involved nature of standard clinical care when initiating HAART treatment paired with the high-risk nature of our population (ie, largely urban and low SES) is likely responsible for missing data despite generous windows to define acceptable clinic attendance. Finally, although a relatively large sample size when compared to the general rates of youth with HIV in the United States and comparable to similar intervention studies with adults having HIV, the limited sample size restricted the analyses that could be performed.

Despite these limitations, results still offer several important implications and directions for future research in this high-risk population. Although future, prospective studies will determine placebo trial efficacy in improving later HAART adherence, placebo trials currently offer an innovative and cost-effective method to assess patient readiness for treatment and may offer a complementary strategy for incorporation into larger behavioral interventions.^39,40 Of note, the use of a placebo trial while awaiting genotype results provides a unique opportunity for constructive dialog between providers and youth regarding ease of medication management, diagnostic disclosure concerns, and barriers to adherence behaviors without delaying HAART initiation. And in contrast to active medications, the current cost for a 2-week placebo trial and pill box ranges from US$5.09 (1 pill/d placebo regimen) to US$13.49 (3 pills/d placebo regimen), providing an affordable option for many clinic settings.

In summary, this is the first study to evaluate the use of a placebo trial with youth, where developmental factors (eg, decreased privacy and mobility) predispose this age-group to an increased risk of suboptimal HAART adherence.^7,41 Thus, the likelihood of negative consequences (ie, progression to AIDS, development of drug resistance,⁴² and poor medical outcomes)³¹ is increased. Prior research demonstrates later persistence to the HAART regimen is best predicted by adherence at the outset of treatment.⁴³ As such, the use of a placebo trial is a feasible method to evaluate readiness to initiate treatment and provides health-care providers a rare opportunity to work with patients to problem solve barriers to adherence before active treatment is initiated.¹⁷ Consistent with recent US Department of Health and Human Services Panel Guideline recommendations to promote HAART adherence both before and after HAART initiation, the placebo trial is uniquely suited to be seamlessly incorporated into other interventions that target adherence following HAART initiation. For example, brief, individualized interventions designed for direct integration into clinical care may benefit from the utilization of placebo trials as 1 intervention component to help optimize later adherence and health outcomes.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Use of Placebo Pills Before Treatment Initiation in Youth with HIV: Are They Ready?

Abstract

Keywords

Methods

Participants and Procedures

Statistical Analyses

Results

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

References