In none of these trials did the control group receive a dilute version of the intervention being tested (i.e., no overlap). Male circumcision, nonoxynol-9 gel, and vaccine were not provided in any form to controls, and no additional STI training, drugs, or supervisory or educational visits were provided to the control communities in the Mwanza trial. However, in all of the interventions with the exception of the STI treatment trial , the control group received an enhanced or exceptional prevention package beyond the local standard of care.
All seven behavioral interventions yielded flat results; however, in the Masaka, Uganda community randomized trial, significant protective effects were found in a subgroup analysis among sexually active women in analyses at the individual level (IRR = 0.41, 95% CI 0.19–0.89) [19,67]. Of the four studies that reported both projected and observed HIV incidence in the control arm, all but one observed incidence rates that were substantially lower than original projections. Only in Project EXPLORE did the projected HIV incidence in the control arm accurately reflect that observed in the trial . Thus, overall, limited power may have limited the ability to detect an effect.
A central issue common to six of these seven trials is that some form of the intervention overlaps with that provided to the control group, though in more dilute form. With one exception (Regai Dzive Shiri) [26,63], each of these studies offered some combination of risk-reduction counseling, condom promotion, and referral and treatment for STIs that exceeded the local standard of care. The effects of so-doing are apparent in the four trials that measured changes in risk behaviors, with all four noting declines in both arms [19,29,38,59].
The Regai Dzive Shiri youth intervention was a CRCT (see text under ‘Literature search’); no prevention services were offered to the comparison communities and uptake of the intervention was low (41%) among survey participants . Adherence was also poor in the Stepping Stones trial, with 44% of participants reporting attendance at 75% or more of the Stepping Stones sessions [26,38]. Adherence ranged between 70 and 75% for the other two trials for which adherence data were reported, Project Explore , and the Zimbabwean workplace intervention .
To date, there has only been one microfinance RCT that has examined HIV endpoints and there was no effect on HIV incidence in study communities . This may be due, in part, to the indirect nature of the intervention, which was directly offered to women microfinancers, whereas the effect on HIV was expected to diffuse to younger women in the populations, which might take years to manifest . The observed HIV incidence was greater than that projected, adherence was moderate (65%), and there was no change in behavior in either study arm .
Eleven of the 12 trials of microbicides and the latex diaphragm trial demonstrated flat results. However, of note, 0.5% PRO 2000/5 gel demonstrated a 33% reduction in incidence compared to placebo gel (hazard ratio = 0.7, 95% CI 0.5, 1.1, P = 0.10) in the intent-to-treat analysis and a 36% reduction compared to no gel (P = 0.04) in the per protocol analysis . However, in a larger study, PRO 2000 gel had no effect on HIV incidence . Although the overall estimates for the cellulose sulfate  and SAVVY (C31G) gel  trials were nonsignificant, subgroup analyses revealed significant adverse results in the interim and per protocol analyses of the cellulose sulfate trial and among women in the SAVVY trial with greater than median coital frequency and greater than median frequency of gel use.
Reduced power to detect an effect resulting from a lower than expected incidence of new infections was apparent in six of the seven flat microbicide trials that reported this information. Adherence ranged between 73 and 96% among those studies for which adherence was reported (the lower bound reported in the diaphragm trial), with only two achieving rates of at least 85% in the intervention arm [33,55]. In addition, results from the diaphragm trial indicated differential condom use over the course of the trial with an average of 53% in the intervention arm and 85% in the control . Although none of these studies offered a dilute, overlapping version of the intervention to controls, all of the studies offered exceptional prevention interventions to both arms. With one exception, risk-taking behavior decreased in both study arms in all of the trials that reported these data .
Only one trial of PrEP using antiretrovirals (ARVs) for HIV prevention has been completed . The observed annual HIV incidence was roughly half of what was anticipated, and premature closure of the trial markedly reduced study power. Adherence rates shy of 70% were observed in both arms . Enhanced prevention services were provided to controls and risk behavior was reduced in both study arms throughout the trial.
A fourth circumcision trial examined HIV transmission to female partners of HIV-infected men who were enrolled in the circumcision RCT in Rakai, Uganda . Overall, no significant reduction in HIV incidence was observed, but HIV acquisition was increased in the subgroup of female partners of men who resumed sexual activity early before complete wound healing compared to those who delayed resumption of sexual activity (relative risk = 2.92, 95% CI 1.02–8.46, P = 0.06) .
Eight of the nine trials of STI treatment for HIV prevention delivered flat results, though one study found a significant effect on HIV incidence in a subgroup of men who attended program meetings (adjusted IRR = 0.48, 95% CI 0.24–0.98, P = 0.04) . Five RCTs evaluated various approaches to improved management of curable STIs, including two of syndromic STI management in the general population (both CRCTs) [19,42], two of periodic presumptive therapy (one a CRCT in the general population  and the other an individual RCT in FSWs ), and one individual RCT of intensive, microscopy-assisted STI screening in FSWs . The remaining three RCTs tested acyclovir suppressive therapy in both high-risk and low-risk populations [28,30,53].
Several factors probably contributed to the striking contrast between the positive results of the Mwanza STI treatment trial and the five flat RCTs that targeted curable STIs. Although low power, poor adherence, overlapping interventions, or other enhanced prevention services in the comparison communities did not appear to be problems in the Mwanza trial, at least one of these issues arose in each of the five flat trials. In addition, observed HIV incidence fell short of that projected in all four of the RCTs that reported this information [19,41,42,52] and adherence was a moderate 81% in the fifth trial . Perhaps more importantly, like the behavioral interventions, all of these trials offered enhanced or exceptional prevention services to controls, including improved STI services (constituting overlap with the primary intervention being tested) in three of the five RCTs [41,51,52]. Indeed, these control arm interventions were reflected in decreases in risk behaviors in both arms of all five RCTs. Finally, the Mwanza trial was implemented in an earlier phase HIV epidemic than was the case for the five flat trials of treatment of curable STIs, all of which were conducted in late-phase, generalized epidemics when genital herpes had largely replaced curable etiologies of genital ulcers, while rates of other curable STIs had fallen substantially in the general population.
Although epidemic phase was not a concern in the three acyclovir suppression trials, adherence was a challenge, with the proportion of participants reporting taking at least 90% of pills ranging from 51 to 73% in two of the three RCTs. In addition, exceptional HIV prevention services were available to controls with attendant reductions in risk behaviors in all trial arms [28,30,53]. However, growing data suggest that in these trials, it is likely that the 400 mg twice daily (b.i.d.) acyclovir regimen tested was not capable of extinguishing persistent immune activation or other biological mechanisms triggered by herpes simplex virus (HSV) infection, which could increase susceptibility to HIV [68,69].
HIV prevention can work, as demonstrated by successes in Thailand and Uganda and now the promise of male circumcision [56–58,71,72]. Yet in the face of what continues to be one of the most devastating pandemics, we have ever known, new, evidence-based approaches are urgently needed. In this context, the fact that almost 90% of RCTs of interventions for prevention of sexual transmission of HIV have delivered flat results demands careful analysis. This review revealed that the majority of flat RCTs are attributable, at least in part, to issues related to trial design and/or implementation. These issues must be addressed in future intervention research.
A key issue in evaluating RCTs is the nature of the control group, and in particular, the intensity of prevention services offered to both study arms [73–76]. Enhanced or exceptional HIV prevention programs in the control arm that exceed the community standard of care (and may even include a diluted version of the primary intervention) are rarely sustainable after trial completion, and their intensity may dramatically reduce the ability to detect the effect of a new and effective intervention. Furthermore, in these cases, the results have little external validity because the comparison does not represent the effect of the intervention compared to the condition actually experienced by individuals in the community who could not avail themselves of the services offered to the control group.
Trials in which investigators or institutional review boards often feel obligated to provide controls with enhancements that are dilute versions of the intervention being tested (such as RCTs of behavioral or STI treatment interventions) are particularly vulnerable to flat results. In contrast, RCTs of new biomedical interventions such as vaccines, microbicides, or male circumcision rarely offer dilute forms of the intervention in the comparison group. This makes distinguishing an ineffective intervention from design issues more straightforward. Indeed, in all the trials that had a significant effect (positive or adverse), the control group did not receive a prevention package that resembled the main intervention.
The ethical issues of offering enhanced HIV prevention services in the comparison arm must be weighed against the ethical issues of lengthy and expensive prevention trials that provide the control group with an unsustainable level of prevention services that does not reflect community standards. Further, such trials may jeopardize our ability to identify and offer participants and at-risk individuals around the world additional effective HIV prevention options. Stepped-wedge designs are one approach that, when appropriate, may help address this ethical dilemma . Similarly, a reliable incidence assay might obviate the need for prospective follow-up of a control group, and thus render decisions about what to provide them over the course of the study irrelevant.
We also examined changes in risk behavior over the course of the trial in the intervention and control arms and found that in most cases, risk-taking behavior was reduced in both. Some of this change may be attributable to enhanced prevention services offered in the trial. A ‘Hawthorne effect’, in which simply participating in the study and being followed produces a positive result, might also have contributed. For example, in a prospective cohort study of FSWs in Kenya, HIV-1 incidence declined 10-fold during 3 years of follow-up . This phenomenon further attenuates the ability to detect the marginal benefit of the new intervention, especially if it is postulated to have only a modest effect.
It is clear from results of recent trials that, in the near-term, there will be no single ‘magic bullet’ for HIV prevention. Instead, the emphasis in prevention research is shifting to evaluation of combination prevention packages in which synergies among interventions with modest levels of effect might lead to substantial efficacy overall [82,83]. What types of evidence for potential efficacy should be used to select interventions for inclusion in these packages? In addition to approaches such as male circumcision with robust RCT evidence for significant effects, we might consider interventions that demonstrate efficacy among specific, relevant subgroups (e.g., men who attended program meetings in the STI intervention in Zimbabwe ). Interventions with significant secondary outcomes in RCTs (e.g., other STDs [3,84]) might also be candidates for evaluation in combination packages if we assume that these outcomes lie on the causal pathway to HIV infection .
Should we also consider interventions for which evidence from RCTs is mixed or absent, but for which observational data or modeling strongly suggest that both the underlying concept and the specific intervention are likely to deliver substantial protection? Most HIV prevention programs and policies are not currently based on RCT evidence. Public health agencies such as the Centers for Disease Control and Prevention (CDC), the Agency for Healthcare Research and Quality, the World Health Organization, and UNAIDS have long recognized the dilemma posed by relying solely on RCT data. Therefore, many develop guidelines [as established, for example, by the US Preventive Services Task Force (USPSTF)] that are based not only on RCTs, but also on observational data from well designed nonrandomized trials; cohort, case–control, or multiple time series studies; mathematical modeling; dramatic results from uncontrolled experiments or even expert opinion by explicitly using a systematic approach to rating the evidence from these different methods . Similarly, epidemiologists and public health practitioners rarely rely only on the evidence from controlled trials to infer causality between an exposure and an outcome. For example, when reviewing evidence from multiple sources to establish whether smoking was associated with lung cancer, Sir Bradford Hill  suggested that experimental evidence was only one of several considerations for causal inference. Other criteria included parameters that characterized the nature of the association between the independent and dependent variable, including the magnitude of the effect, consistency, temporality, specificity, and the biological plausibility of the association.
That said, a critical issue is that most RCTs reviewed here are highly managed, labor-intensive, and expensive, meeting the standards of regulatory bodies such as the US Food and Drug Administration (FDA). As alluded to above, before abandoning randomization, it is important to consider the entire universe of RCTs, including stepped-wedge designs, large simple trials, or trials in which intervention communities are compared to either what currently exists or wherein incidence comparisons are made with nonparticipants as determined by reliable assays (should they be developed). The need for a counterfactual to infer causality cannot be denied and may be especially important when such combination programs are rolled out and evaluated at-scale, particularly if they are designed based on uncertain efficacy.
RCTs will undoubtedly remain our gold standard in defining the evidence base for prevention programs and policies. However, to assess the purity of this gold standard, the HIV prevention science community must not only examine evidence from RCTs with significant outcomes (including from subgroups and secondary outcomes), but must also examine flat trials and address the design and implementation issues discussed above. In addition, we must acknowledge and explicitly define the role of other types of evidence in the development of HIV prevention recommendations.
Pure gold is a thing of great beauty and value, but lacks the strength and affordability that make alloys like steel so useful and durable. Similarly, well designed and executed RCTs are magnificent and invaluable cornerstones of HIV prevention policies and programs. However, before abandoning entire classes of potentially beneficial interventions, we must forge ‘alloys’ of data from RCTs, observational studies, and other lines of evidence, cautiously and explicitly titrating the use of less rigorous sources, and recognize that these ‘alloys’ are likely to offer the best guide to decide what to include in prevention packages, what to scale up, and wherein further research is warranted.
We begin by acknowledging the numerous investigators responsible for these studies. Each one we were able to contact, willingly shared data and opinions that contributed greatly.
N.S.P. was supported by a grant from the Bill and Melinda Gates Foundation (No. 21082) and J.N.W. was supported by a grant from the National Institute of Allergy and Infectious Diseases (RO1 AI083034).
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