Despite the stabilisation or fall in HIV prevalence seen in some countries in recent years, the HIV pandemic continues to be one of the profoundest threats to global health. Even in countries such as Uganda, which have seen a substantial fall in prevalence, the incidence of new infections continues at an unacceptably high level and in parts of Southern Africa incidence is still extremely high with the lifetime probability of infection exceeding 50% in some populations.
While the roll-out of ART represents a substantial achievement in HIV/AIDS control, and has given new hope to millions of HIV-infected individuals, it has made the need to reduce the incidence of new infections even more pressing. If incidence cannot be reduced substantially, it will become increasingly difficult – logistically and financially – to provide effective care for the ever-expanding number of HIV-infected patients who need it. Given the high cost of ART, effective HIV prevention measures represent an even more cost-effective investment than previously because of the high treatment costs averted.
These observations, combined with the dearth of preventive interventions of proven effectiveness in rigorously conducted trials, point to the continuing importance of HIV prevention research. The large number of flat HIV prevention trials has led some to question the value of continuing investment in this area. We would respond to this with three comments.
First, the HIV prevention score-card, shown in , is as notable for the small number of published studies as for the high proportion of flat results. Given that we are now 30 years into the global epidemic, and that the severity of the epidemic as a global health emergency has been understood for at least 25 years, it is perhaps surprising that there have been only 39 published trials across all seven intervention categories for prevention of sexual transmission [14
]. Commentators have pointed to the high cost of some of these trials, but compared with the global expenditure on HIV control programmes the resources channelled to prevention science have been very limited.
There is little doubt that an expanded evidence-base on HIV prevention methods and a broader array of interventions with rigorous evidence of effectiveness would improve the chances that available resources would be better used for prevention. An important question for investigators and sponsors is whether some trials have incorporated levels of data collection, monitoring and documentation that are a requirement for trials supporting licensing of new products, but which may be excessive for non-regulatory trials.
Second, we have argued in this paper that there are disparate reasons for the flat results seen in HIV prevention trials. In some cases, there are limitations in the design or conduct of the trials that have precluded a useful estimate of effectiveness. In these cases, the solution is not to abandon the intervention, but to ensure that future trials take these considerations into account. In other cases, the trials have given a convincing negative conclusion and these results point to a need to abandon or modify the intervention, or increase the stringency of the selection criteria for future candidates. In some cases, flat results together with carefully collected process data have pointed to new ways of delivering interventions that might be more effective.
Third, there has been a growing tendency to question the role of RCTs in HIV prevention science, particularly for complex prevention approaches involving behavioural or structural interventions. Some interventions, particularly those such as mass media programmes or legal or fiscal measures, may require implementation on such a large scale that randomisation of discrete geographical units is not feasible. Others may act over such a long time-scale and through such an extended causal pathway that evaluation in an RCT may be challenging. Nevertheless, many such interventions can, in principle, be subjected to this type of study using either an individually-randomised or CRT design. The large number of flat results should not be used as an argument for abandoning a well-established research method. Rather, as we have argued above, it should lead us to look either at improvements in the design and conduct of these trials or improvements in the design and implementation of interventions. A well-conducted trial demonstrating lack of effectiveness of an intervention represents a valuable contribution to prevention science, even though the findings may be disappointing. Such trials remain the cornerstone of the evidence needed to support implementation of HIV prevention programmes.
In those cases in which RCTs are not feasible, we must rely on examination of the evidence from rigorously-conducted observational studies, such as large-scale quasi-experimental studies involving comparison of intervention and control areas with careful documentation of relevant baseline data, trends over time and comprehensive process data. Such studies must be carefully designed to maximise their validity [23
]. Just as HIV prevention may require combinations of synergistic interventions, HIV prevention research requires the strategic use of a combination of RCTs addressing the design issues highlighted in this supplement and, when RCTs are not feasible, expanded use of rigorous observational study designs.
We hope that this series of papers provides a useful review of past and ongoing HIV prevention research, and offers new insights into directions for future research. The HIV pandemic is likely to remain one of the major threats to global health, robbing millions around the world of the chance to lead healthy, productive lives. High-quality research is essential to assure a robust evidence-base to help national programmes select the most effective preventive interventions and implement them most strategically in appropriate populations.