Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
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5 Design Considerations: Adherence
5 Design Considerations: Adherence
Pages 119-147
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From page 119... ...
To properly interpret the results of a clinical trial that failed to show a protective effect, investigators need to distinguish the extent to which the product was not biologically efficacious, participants did not use it as directed, or they engaged in more risky behavior because they thought the product was protecting them. Regardless of whether a trial demonstrates an effect, understanding when and why participants did not adhere to the product regimen can provide valuable insights into the design and delivery of future HIV prevention interventions.
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From page 120... ...
. Although underutilized in the HIV field, qualitative research methods can be particularly useful to understanding the multiple factors that influence adherence and risk behavior patterns and developing suitable adherence measurements and improvement strategies (Friedland, 2006; Sankar et al., 2006)
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From page 121... ...
Pers. Daily Intake 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Dosing Date Dosing Date 2 doses V VVVV VVVVV 1 dose V 03:00 03:00 24:00 0 doses 24:00 18:00 18:00 12:00 12:00 Dosing Time Dosing Time 06:00 06:00 03:00 03:00 Comp Comp Start V1 V2 V3 End Start V1 V2 V3 End fdur fdur Pers.
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From page 122... ...
Even though each patient was "79 percent adherent," the clinical consequences of those four patterns could be very different, and the actions needed to improve adherence would differ for the four participants. As Figure 5-1 shows, product adherence is a complex concept.
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From page 123... ...
5-2 should develop and use adherence measures that can capture different adherence patterns over time. Measuring Adherence, Sexual Behavior, and Condom Use Investigators can gather information on product adherence and risk behavior through a variety of indirect and direct measures.
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From page 124... ...
Given the limited published empirical evidence on adherence measures for nonvaccine biomedical HIV prevention interventions, the committee draws heavily on the fields of ART adherence and sexual risk behavior assessment in making its assessment and recommendations. Indirect Measurement Methods Self-Reports of Product Adherence and Risk Behavior Self-report of product adherence and risk behavior is widely used in research and clinical settings because it is relatively inexpensive, easy to administer, allows for probing about nonadherence, and has low participant burden (Berg and Arnsten, 2006)
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From page 125... ...
. In contrast, studies comparing self-reports of sexual behavior with biomarkers of semen exposure indicate that individuals may underreport sensitive or stigmatized risk behavior (see, for example, Gallo et al., 2007)
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From page 126... ...
. Pill and Applicator Counts Many clinical trials rely on less specific but possibly more objective measures of product adherence, such as pill counts.
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From page 127... ...
However, in the trial setting, access to the product usually is limited to the study pharmacy and study population, though product sharing among trial participants has been raised as a concern in some studies. Given that distribution of the study product is more tightly controlled, the use of pharmacy refill records may have greater applicability for measuring adherence in the trial setting than in the clinical setting.
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From page 128... ...
has been suggested as a potential biomarker for unprotected sexual behavior, trans
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From page 129... ...
. Such biomarkers have been used primarily to evaluate the effectiveness of contraceptives, but they may have a role in validating self-reports of sexual activity in HIV/STI prevention trials (Mauck and Doncel, 2007)
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From page 130... ...
Since no adherence measurement tool is perfect, several studies have found that using multiple measures to "triangulate" adherence levels and risk behaviors is helpful in reducing the error introduced by any particular method (Liu et al., 2001; Pool et al., 2006)
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From page 131... ...
Studies of ART adherence interventions may have particular relevance for medication-based HIV prevention strategies, such as PrEP or acyclovir for HSV-2 suppression. Although some aspects of adherence undoubtedly differ between the two arenas, they have important similarities: biomedical HIV prevention trials target products to uninfected individuals, and HIV-infected individuals often start ART while they are still asymptomatic.
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From page 132... ...
conducted a meta-analysis of 19 randomized, controlled trials of strategies to improve ART adherence, measuring their impact on reported adherence and participants' HIV-1 RNA viral load. They found that participants receiving adherence strategies were about 1.5 times as likely (95% CI: 1.16–1.94)
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From page 133... ...
. Applying ART Adherence Improvement Strategies to HIV Prevention The findings from studies and meta-analyses of strategies to improve ART use suggest ways to improve adherence to biomedical HIV prevention interventions. However, important knowledge gaps remain: • As noted in a recent meta-analysis (Amico et al., 2006)
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From page 134... ...
. Investigators designing clinical trials of biomedical HIV prevention interventions may need to adapt and combine various strategies to maximize adherence (Haynes et al., 2005)
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From page 135... ...
Such analyses also yield information on the acceptability and feasibility of the intervention, and the extent to which the trial results will apply to the target population. Analyzing the association between exposure or adherence patterns and HIV incidence can help investigators estimate the causal effect of different interventions and reveal whether the primary intention-to-treat analysis is estimating efficacy or some particular form of effectiveness, given the observed dosing schedule.
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From page 136... ...
However, even if reported adherence levels in a trial are high, doubt may remain about true adherence levels, and thus about the product's efficacy and value in the community. Comparing Adherence Between Study Arms Differences in adherence between the intervention and control arms in a randomized trial imply that different products have different side-effect profiles, or otherwise affect participants differently.
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From page 137... ...
Analyze differences The measured levels of This might indicate that in product exposure, product adherence and the active product versus adherence, and risk sexual behavior differ placebo produce different side behavior between study between study arms. effects, prompting subjects to arms.a comply differently with the assignment.b Analyze differences People within study arms Some subpopulations might be in product exposure, differ greatly in how better suited to another type adherence, and risk they use the product, and of protection than the one behavior between subjects possibly also in their risk- under study.
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From page 138... ...
other hand, if a product is protective and HIV incidence differs between arms, the least-protected participants would tend to drop out sooner. Effect of Measurement Error Investigators would have no reason to expect measurement error to differ between study arms in a blinded randomized trial.
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From page 139... ...
Investigators need to address these differences in their analyses, rather than reporting only the percentage of people who comply with the regimen in each arm. Effect of Measurement Error If subjects within a study arm differ significantly in their reported exposure to the product, adherence to the product regimen, and sexual behavior, investigators will need to consider whether the differences reflect true differences, errors in measurement, or a combination of both.
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From page 140... ...
For instance, if a product is associated with more sexually transmitted diseases, some women may start to use it less often, and hence different subpopulations may have similar use levels in both trial arms. However, when the study arms are blinded and investigators observe similar distributions of adherence between them, they can be more confident in the exchangeability of subpopulations with similar compliance levels among study arms.
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From page 141... ...
Statisticians have developed sophisticated causal models that attempt to address questions such as: "What would have occurred if exposure had been different? " One such model links potential responses to different levels of treatment and risk behavior, and allows estimation of the model's parameters based on the randomization used to assign patients to study arms.
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From page 142... ...
Recommendation 5-6: Investigators should provide data on product adherence and risk behavior results to the data monitoring committee, as this information may influence the committee's views of the relative efficacy and safety of the study arms, and the feasibility of the study. Recommendation 5-7: Investigators should analyze adherence and behavior as both outcomes in an HIV prevention trial and modifiers of the effect of the biomedical intervention on HIV infection risk.
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From page 143... ...
2001. Compar ing objective measures of adherence to HIV antiretroviral therapy: Electronic medication monitors and unannounced pill counts.
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From page 144... ...
2007. Biomarkers of semen in the vagina: Applications in clinical trials of contraception and prevention of sexually transmitted pathogens includ ing HIV.
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From page 145... ...
Presentation at the first public meeting for the Committee on Methodological Challenges in HIV Prevention Trials, Washington, DC. Rueda, S., L
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From page 146... ...
A meta-analytic review of randomized controlled trials. Journal of Acquired Immune Deficiency Syndromes 43(Suppl 1)
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From page 147... ...
2006. Home visits to improve adherence to highly active antiretroviral therapy: A ran domized controlled trial.
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