Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
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10 Alternative Designs
10 Alternative Designs
Pages 204-224
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From page 204... ...
This argues for studies that can identify improved ways of improving adherence and/or reducing high-risk behavior, or tailor an individual's intervention to provide the maximal amount of protection against HIV infection that is available with current interventions. Similarly, although investigators conducting late-stage biomedical HIV prevention trials are ethically required to provide all participants with 204
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From page 205... ...
And further, when feasible, there can be important advantages to designs that enroll HIV-discordant couples to assess the protective effectiveness of interventions in settings where the main, and sometimes sole, HIV exposure of the uninfected partner is known. The committee believes that these considerations suggest the need for investigators to explore alternative study designs that test multiple preventive interventions, including multiple behavioral risk-reduction interventions and strategies to improve product adherence.
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From page 206... ...
, while B could entail offering some participants a more intense behavioral risk-reduction intervention and offer others standard risk-reduction counseling, in which case subjects would be unblinded with respect to both their biological and behavioral interventions. Or, in A, some participants may receive a biomedical intervention while others receive a placebo of this intervention, as in the original example, while some subjects in B might receive either a new behavioral risk-reduction intervention while others receive standard risk-reduction counseling.
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From page 207... ...
Thus, while the two intervention strategies could modify risk behavior and thus HIV infection risk in different ways, the "better" behavioral riskreduction intervention strategy would not depend on whether a subject is receiving A or its placebo. If the biomedical intervention were efficacious, one would expect it to be effective, though possibly by different amounts, in subjects receiving either of the behavioral risk-reduction interventions.
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From page 208... ...
. Then a 2 × 2 factorial design aiming to assess the benefits of the microbicide as well as the type of behavioral risk-reduction intervention would have the following arms: Arm 1: Microbicide gel plus standard risk-reduction counseling Arm 2: Microbicide gel plus enhanced behavioral risk-reduction intervention Arm 3: Placebo gel plus standard risk-reduction counseling Arm 4: Placebo gel plus enhanced behavioral risk-reduction intervention This is a partially blinded design because subjects would know if they are receiving an enhanced behavioral risk-reduction intervention versus standard risk-reduction counseling, but they would not know whether they are receiving the microbicide or placebo gel.
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From page 209... ...
If there is a quantitative interaction, the trial would have about the same power as an equally sized trial comparing microbicide to placebo in subjects receiving a single type of counseling whose effect is, loosely speaking, equal to the average effect of the two types of behavioral risk-reduction interventions in the factorial design. When investigators analyze a factorial trial, the first step is to assess whether the assumption of no interaction or a quantitative interaction is consistent with the data.
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From page 210... ...
However, when an alternative endpoint cannot be reliably used, the behavioral interventions should be based on the endpoint of HIV infection, which implies that the number of distinct behavioral interventions would typically be the same as the number of biomedical intervention arms. Incomplete Factorial Designs In settings where investigators plan to assess more than one intervention, but all combinations of the interventions are not of interest, they can realize economies of scale by using a single trial with a common control group.
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From page 211... ...
DISCORDANT COUPLE DESIGNS Most late-stage HIV prevention trials of biomedical interventions have used designs which enroll at-risk subjects and follow them for HIV infection, without direct knowledge of their exposures to HIV. An implicit assumption in such studies is that the types and frequencies of HIV exposures of participants may vary, but that the randomized intervention groups have similar distributions ("mixes")
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From page 212... ...
As with traditional designs, the results of such a study can be analyzed by comparing the cumulative incidence rates of HIV infection in the different intervention arms. Despite offering counseling on HIV prevention, trials enrolling such couples have recorded HIV infection rates as high as 8–12 per 100 person-years (Quinn et al., 2000; Hugonnet et al., 2002; Allen et al., 2003; Coldiron et al., 2007)
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From page 213... ...
Thus, in light of the potential advantages of using discordant couples in late-stage HIV prevention trials of biomedical interventions, the committee believes that their feasibility should be assessed in the early stages of the planning of such trials. Recommendation 10-2: When feasible and consistent with the scientific goals of a late-stage HIV prevention trial, investigators are encour
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From page 214... ...
Suppose that what actually happened in this trial is that women assigned to the intervention felt that it offered an effective alternative to condoms in protecting against HIV infection, and that they preferred the alternative because they could avoid confrontations with their sexual partners over condom use. In that case, another view of the trial results is that an alternative strategy to condom use -- namely, "use condoms where possible, but if that is inconvenient, use the diaphragm plus lubricant" -- may be equally effective in preventing HIV infection as a simple recommendation that women use condoms.
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From page 215... ...
For a phase 3 microbicide trial, one strategy could be to define clusters as communities served by different health centers, and randomize all the women in a given community to receive either the microbicide gel or the placebo. Investigators have used cluster randomization most often to evaluate interventions normally delivered to groups or communities, such as controls on sexually transmitted diseases (Grosskurth et al., 1995; Wawer et
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From page 216... ...
However, migration can be high in many regions, including areas in Africa, and communities receiving the control strategy would need to provide it to individuals who move into their area from intervention communities, and vice versa. A potential advantage of cluster randomization is that it can allow investigators to estimate individual plus community-level protection against infectious disease.
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From page 217... ...
Trials involving microbicides and PrEP could be individually or cluster randomized, and in some cases could mix features of each approach. For a trial evaluating a microbicide, with HIV incidence among women as the primary endpoint, a microbicide would need to protect women to reduce HIV infections in men in the community.
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From page 218... ...
Estimates of the intraclass coefficient in large HIV-prevention trials evaluating controls on sexually transmitted disease have varied widely (Grosskurth et al., 1995; Wawer et al., 1999; Kamali et al., 2003; Todd et al., 2003)
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From page 219... ...
If HIV incidence drops noticeably in intervention communities and not in control communities, it could become evident which group is receiving the treatment. Overall, cluster randomization has a potentially useful role in HIV prevention studies, especially where some interventions, such as certain counseling or educational interventions, are easier to give to groups rather than individuals.
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From page 220... ...
As an alternative to this practice, investigators could accept that women in this age range are likely to become pregnant, especially when the trial has a long follow-up period, and regard the dynamic intervention as a total package. If the best course of action for pregnant women is unclear, investigators could take the opportunity to learn how best to protect pregnant women from HIV infection, and randomize them at that point over a set of prevention options such as remaining on product versus discontinuing product and initiating intense counseling for ways of preventing HIV infection during pregnancy versus discontinuing product without initiating any additional form of preventive intervention.
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From page 221... ...
1995. Impact of improved treatment of sexu ally transmitted diseases on HIV infection in rural Tanzania: Randomised controlled trial.
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From page 222... ...
2002. Incidence of HIV infection in stable sexual partnerships: A retro spective cohort study of 1802 couples in Mwanza region, Tanzania.
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From page 223... ...
formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: A randomized trial: The Mashi study. Journal of the American Medical Association 296(7)
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