Thirty years into the global HIV pandemic, there is a critical need for effective prevention strategies that can be implemented with high levels of coverage in populations with high incidence of new infections. Worldwide, nearly 3 million new HIV infections were estimated to have occurred in 2008 [1
]. No single, stand-alone HIV prevention intervention offers a “magic bullet.” It is unlikely that a single deployed intervention, even a vaccine [2
], will halt the pandemic. However, a growing number of behavioral [3
] and biomedical [9
] HIV prevention strategies appear promising in providing some protection against infection, and the efficacy of several is supported by randomized controlled trials (RCTs) [17
]. Indeed, combining several partially protective strategies might have additive or synergistic effects in reducing HIV incidence on a population level. Analogous to the need for combination antiretroviral therapy (ART) for treatment, there is growing recognition that combination HIV prevention strategies might optimize HIV prevention impact [18••
], potentially enough to reduce transmission below the reproductive rate necessary to sustain HIV epidemics around the globe [19
UNAIDS (2010) provides the following definition of combination HIV prevention
“The strategic, simultaneous use of different classes of prevention activities (biomedical, behavioral, social/structural) that operate on multiple levels (individual, relationship, community, societal), to respond to the specific needs of particular audiences and modes of HIV transmission, and to make efficient use of resources through prioritizing, partnership, and engagement of affected communities” [20
Multicomponent packages of evidence-based biomedical, behavioral, and structural interventions must be assembled to be appropriate, acceptable, and deliverable to populations with high levels of coverage and adherence. These prevention packages must address risk factors at the individual, dyadic, sexual or needle sharing network, and community levels, while taking into account the epidemiologic context (). Determining what constitutes a sufficient level of evidence for inclusion in any given combination package is a critical step. Levels of intervention efficacy (often demonstrated in single studies in only one subpopulation or setting) vary. Since some HIV prevention interventions cannot pragmatically or ethically be randomized, decisions about evidence may need to be drawn from quasi-experimental and programmatic data, in addition to RCTs. Methodologic challenges include deciding what level of experimental or observational evidence is sufficient to warrant inclusion of an intervention in a prevention “package.” Guidelines developed by the US Preventive Services Task Force, the Centers for Disease Control and Prevention, and others often include ratings of the strength of evidence to address this dilemma (see http://www.ahrq.gov/clinic/uspstf07/ratingsv2.htm
). However, it is important to anticipate and recognize that interventions found to be efficacious in one setting may not readily transfer and may require cultural adaptation. Standardized approaches for translating interventions have been developed including the ADAPT-ITT [21
] and RE-AIM models [22
], among others.
HIV risk target levels to consider for combination HIV prevention packages
To our knowledge, no major multicomponent package of interventions has been launched in a full-scale, community-level randomized trial to assess impact on HIV seroincidence. The challenges inherent in assembling the optimal HIV prevention package, scaling it up for delivery, and empirically assessing the combined, rather than single-intervention effect are considerable. Recognizing this, in 2009, the National Institutes of Health (NIH) launched a research initiative called the Methods of Prevention Package Program (MP3) to fund combination HIV prevention studies. The purpose of these grants is to devise optimal HIV prevention packages for specific populations, and to design evaluation strategies to rigorously examine the acceptability, safety, and efficacy of those packages. The research teams for these studies have brought together multidisciplinary collaborators with expertise in behavioral and biomedical methods of HIV prevention, epidemiology, mathematical modeling, and clinical trial design and implementation [23
]. The resulting MP3 grants illustrate a range of potential prevention approaches that may be required for heterogeneous HIV epidemics in different geographic regions and populations (). A second round of awards focused on populations other than those targeted in the first MP3 studies will begin in 2011. Previously completed and ongoing clinical trials of novel HIV prevention strategies, such as those conducted by the NIH’s HIV Prevention Trials Network (HPTN), the Microbicide Trials Network (MTN), the HIV Vaccine Trials Network (HVTN), the Medical Research Council Clinical Trials Network (MRC), and other organizations, have tended to focus on testing single interventions. Such RCTs provide a critical foundation for the development and rigorous evaluation of evidence-based combination prevention packages.
First round of NIH-funded combination HIV prevention studies
A core tenet of the MP3 program is that understanding the patterns and risks for HIV transmission at a population level (be that national or local) guides the compilation of an optimal package of prevention interventions. This “know your epidemic” approach [24
] involves understanding determinants of local HIV prevalence (and ideally incidence) to identify population targets with the highest rate of recent HIV infections, and to maximize the prevention benefits achieved. However, the need to know one’s epidemic should not be taken as an imperative that impedes action, when local epidemiologic data are not available at finest levels of completeness, granularity, or timeliness.
Combination ART reduces HIV replication by attacking the virus at multiple points of its life cycle, leading to multiple therapeutic targets for treatment, and yielding dramatic clinical benefits. Similarly, combination HIV prevention is likely to be most effective when different points in the “transmission cycle” are impeded [25
], combining strategies to reduce infectiousness
of HIV-positive persons with strategies that reduce HIV susceptibility
in the uninfected. Most early HIV prevention policies focused heavily on HIV-negative, at-risk persons (eg, using behavior change communication campaigns). However, seronegative persons represent a very large pool to target for high coverage. In 30 years, only such nations as Uganda and Thailand have actually managed to reverse HIV epidemics using prevention strategies focused on HIV-seronegative persons [26
]. Strategies to reduce the infectiousness of HIV-positive individuals by reducing secondary HIV transmission are now being assessed (eg, HPTN 052 and HPTN 065) [22
]. Theoretically, if a high proportion of people living with HIV/AIDS (PLWHA) learned their HIV serostatus and adopted interventions such as ART to reduce their infectiousness coupled with behavioral risk reduction, this could have a significant impact on HIV transmission [27
]. Optimizing HIV prevention for PLWHA in a community also targets significantly more people who may be motivated to seek care for their own health needs, than risk-reduction programs aimed at healthy, HIV-negative persons. Given the need to minimize both infectiousness (ART, condoms, STI treatment for positives) and susceptibility (multiple interventions for negatives), combination prevention incorporating complementary strategies aimed at both infected and uninfected persons offers the most promising way forward.