Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
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This underscores the need for late-stage clinical trials of biomedical interventions that can detect and quantify modest intervention effects on HIV infection, and adequately evaluate product safety. The committee's key recommendations for pretrial research and planning include the following.
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Finally, in order to enable more efficient evaluations of biomedical interventions, the committee recommends that researchers give priority to developing biomarkers of recent HIV infection which can be used in cross-sectional samples to estimate HIV incidence rates, identifying surrogate markers for HIV infection and product activity that investigators can reliably use as intermediate trial endpoints, and exploring alternative trial designs that might answer important research questions more efficiently than the traditional two-arm superiority design. I n the more than 25 years of the human immunodeficiency (HIV)
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randomized, controlled trials found that male circumcision reduced the risk of heterosexually acquired HIV infection among men (Auvert et al., 2005; Bailey et al., 2007; Gray et al., 2007)
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. This report recommends a number of ways to improve the design, monitoring, and analysis of late-stage randomized clinical trials that evaluate nonvaccine biomedical interventions to prevent HIV infection.
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For HIV prevention trials, in which investigators can only partially control participants' adherence to the product regimen and risk-taking behavior, this distinction between efficacy and effectiveness can be substantial (Chapter 2)
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, even in areas with high HIV incidence rates, short-term HIV prevention efficacy trials often need to enroll large numbers of subjects, just as longer-term effectiveness trials do. Late-stage effectiveness trials that evaluate HIV infection offer the opportunity to evaluate potential surrogate markers for HIV infection, and the committee believes that this is a worthwhile secondary goal for these studies.
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However, the use of a blinded control group in late-stage HIV prevention trials of a biomedical intervention can be disadvantageous if a participant's knowledge of his/her intervention would affect that person's risk-taking behavior. In that case, the relative effectiveness observed in the trial might not reflect that seen when the intervention is introduced into the community.
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Finally, although some behavioral risk-reduction interventions have been shown to decrease self-reported risk behaviors, and a few have shown decreases in STIs, none to date have been shown to significantly reduce HIV infection rates. Effective behavioral interventions increase the effectiveness of biomedical interventions and are valuable in their own right.
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If a trial will adapt specific interventions shown to be effective in other settings, investigators should field-test the strategies during the planning of the trial, to ensure that they can be implemented as envisioned. PREGNANCY Many late-stage biomedical HIV prevention trials are conducted among sexually active women of reproductive age in areas with high fertility rates.
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The study protocol should specify how investigators will collect and monitor information on pregnancy outcomes during the trial, and indicate activities that they will undertake if the trial demonstrates that the product is effective in preventing HIV infection (Chapter 4)
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or modified DOT could be very useful for proof-of-concept trials, investigators should not use these approaches in effectiveness trials if that approach will not work in real-world practice because the trial results may be poor predictors of the effectiveness of an intervention.
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RECRUITMENT AND RETENTION Late-stage biomedical HIV prevention trials typically require investigators to enroll 1,000–4,000 participants at one or multiple sites, and to follow them for several years. A lower-than-expected rate of enrollment can result in an underpowered trial that fails to reveal an effective intervention, or delay the public health impact of a positive trial.
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When developing the research protocol for a late-stage trial, and when selecting and preparing a trial site, external investigators should develop equal partnerships with local investigators and to involve community representatives in developing the protocol and throughout the trial. Investigators also may need to conduct extensive pretrial research at the study sites, with populations similar to those that the main trial will enroll, to ensure that the interventions are culturally relevant, and to estimate the anticipated rates of HIV infection, attrition, pregnancy, and adherence for the trial site.
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Because studies are powered based on the number of HIV infections investigators expect to occur among participants during the trial, modest overestimates of HIV incidence can substantially reduce the power of a trial to detect an important intervention effect. Overestimates of HIV incidence have led to premature closure of several recent trials.
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The committee discusses methods used to analyze the results of prevention trials using HIV infection as the primary efficacy endpoint, along with their limitations. A complication in such trials results from the fact that HIV infection is a silent event: at best, investigators can determine only a time interval in which an individual's infection occurred.
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. In sum, the committee concludes that alternative trial designs, more extensive site preparation, and careful monitoring and analysis of trial results are key to evaluating prevention interventions and determining which of them can exert the greatest possible long-term impact on the HIV epidemic.
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identified, investigators should use modified trial designs that can provide information on both the short- and long-term benefits of an intervention. Recommendation 2-3: Sponsors, investigators, and regulatory agencies should consider using both blinded and unblinded control groups in future trials to more fully understand the effects of the intervention on HIV infection risk and behavior.
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• Investigators should continue to follow all women who become pregnant for HIV infection, regardless of whether they discontinue the study product. Recommendation 4-2: Although the current policy of excluding pregnant women from biomedical HIV prevention and other trials stems from an historically protec tionist orientation adopted by regulators, the principles of research ethics neither mandate nor preclude use of the product by pregnant women.
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or modified DOT could be very useful in proof-of-concept trials, investigators should not use these methods in effectiveness trials if that approach will not be used in real-world practice, because the trial results may then be poor predictors of the effectiveness of the interventions. Recommendation 5-4: Donors should fund and investigators should undertake empirical evaluations of strategies to increase adherence to biomedical HIV pre vention products during and after a clinical trial.
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Recommendation 5-7: Investigators should analyze adherence and behavior as both outcomes in an HIV prevention trial and modifiers of the effect of the biomedi cal intervention on HIV infection risk. Recommendation 5-8: Investigators should analyze the potential impact of adher ence by doing the following: • Perform a stratified analysis when adherence appears similar between study arms.
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Chapter 8 Estimating HIV Incidence Recommendation 8-1: Investigators should base their estimate of HIV incidence on at least one source of data from the direct longitudinal follow-up of individuals in the trial setting. Given the importance of accurate estimates and the inherent uncertainties of any single approach, the direct estimate of HIV incidence should be corroborated by at least one other source.
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Recommendation 9-2: The data monitoring committees for HIV prevention trials should always have the option of unblinding interim results if they believe that doing so might lead them to recommend that the trial be modified or terminated, or lead to other actions that are in the best interests of the trial participants. In particular, when the efficacy data show nonsignificant trends favoring one of the blinded arms, a DMC should unblind itself as this might reflect an intervention that may be harming patients.
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Recommendation 10-2: When feasible and consistent with the scientific goals of a late-stage HIV prevention trial, investigators are encouraged to consider discor dant couple designs because of their advantages over designs in which the actual HIV exposures of participants are unknown. Recommendation 10-3: Investigators should consider the potential merits of using noninferiority, cluster randomization, and dynamic designs in future biomedical HIV prevention trials.
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2007. Preventing HIV infection among injecting drug users in high-risk countries: An assessment of the evidence.
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2007a. Tenofovir disoproxil fumarate for prevention of HIV infection in women: A phase 2, double-blind, randomized, placebo controlled trial.
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