BACKGROUND: THE EVOLVING EVIDENCE BASE FOR PREVENTION
Soon after it was recognized that the HIV virus was transmitted by sexual contact and injection of blood, antibody tests were able to permit diagnosis of HIV infection, screening of blood supplies, and monitoring of epidemiological. About a decade later, highly active antiretroviral therapy (ART) was available to treat HIV/AIDS effectively in developed countries. The demonstration that timely use of antiretroviral drugs (ARVs) also reduced mother-to-child transmission reinforced emerging optimism in the response to HIV.1 The significant cost of the drugs narrowed their availability, and another decade would pass before ART programs expanded into developing countries, albeit only partially.
Expiration of drug patents, competition from generic manufacturers, and negotiated price reductions eventually offered the possibility of extensive prolongation of life even in regions, such as sub-Saharan Africa, with limited health care resources and the world's highest prevalence and incidence of HIV/AIDS. During the late 2000s, however, efforts to expand ART confronted “donor fatigue” and the global economic recession, raising concerns as to the sustainability of treatment programs. Although HIV incidence declined in many countries over the last 10–15 years, the number of people surviving for years after testing positive for HIV also increased as effective treatments became more widely available.
The paradox of falling incidence in the presence of increasing numbers of people who are surviving after HIV diagnosis as a result of treatment successes focused renewed emphasis on prevention strategies. In 2010, twice as many people were newly infected as initiated ART.2 Although vaccine development and other efforts to develop new prevention tools have been disappointing, other prevention interventions, such as male circumcision and the use of ARVs as prevention, have proven more encouraging.
TYPES OF PREVENTION INTERVENTIONS
Prevention strategies have traditionally been categorized as either behavioral or biomedical. Behavioral strategies include condom promotion and education to reduce number of sexual partners, especially multiple concurrent partners. More innovative indirect behavioral interventions are now being piloted with some success, including cash transfers to keep young women in school or to encourage them to choose partners close to their own age.3–5 Programs to directly incentivize remaining HIV negative in general populations have had lesser impact6 and highlight the need to understand why an intervention was successful and to limit scale-up to settings with similar populations and motivating factors.
Biomedical prevention strategies include the use of ARVs and vaccines (if and when available). In addition to prevention of mother-to-child transmission (PMTCT),7 treatment of the index case in discordant couples also confers a substantial prevention benefit, regardless of the patient's clinical status.8 ARVs have shown some promise in other uses—for example, as microbicides and pre-exposure prophylaxis9–12—but so far, efficacy has been unpredictable, likely due in part to different demographics in the study populations.13,14
Other promising interventions combine behavioral and biomedical elements, including treatment of concurrent sexually transmitted infections (with mixed results) and male circumcision, which has been repeatedly shown to reduce transmission.15–17 In reality, however, even strategies often considered strictly biomedical (such as ART) also have important behavioral elements, such as client motivation for early diagnosis, retention in care, and adherence to prescribed regimens.
In addition to the behavioral–biomedical categorization, prevention strategies have been characterized according to whether they reduce an uninfected individual's risk of infection (primary prevention) or reduce the amount of virus transmitted from an infected individual (secondary transmission). Male circumcision, behavior change, and pre-exposure prophylaxis fall within the former category, whereas PMTCT or ART taken by an infected person in an HIV-discordant couple fall into the latter. The remarkable success of ART to demonstrate the possibility of near elimination of secondary transmission in these settings has energized the prevention community and sparked extensive research into expanding the use of ART for prevention.
BIOLOGICAL CHALLENGES WITH ARV-BASED PREVENTION
Despite the growing evidence that ARVs play a significant role in preventing new infections, important challenges remain. With the notable exception of PMTCT, little experience exists on which to base predictions as to prevention interventions' population-level effectiveness. For example, a disproportionate number of new infections may stem from transmission by individuals with acute or early infections,18,19 which may not be readily detectable by standard antibody tests or which may not be captured by “test and treat” programs that annually sample the population.
Another potential challenge to the effectiveness of ARV-based prevention is the transmission of drug-resistant variants of HIV, which has been described in up to 15% of men who have sex with men in San Francisco, where a large fraction of HIV-infected men are on ARVs.20 The use of the same drugs for both disease therapy and chemoprophylaxis raises additional concerns, as up to half of HIV-1C–infected women given nevirapine for PMTCT may develop drug resistance, as has been noted for even larger proportions of infants who became infected despite the use of PMTCT regimens by their mothers.21
As ARVs are increasingly incorporated into prevention strategies, it will be important to determine whether individuals prescribed drugs primarily to prevent transmission will show the same commitment as ART patients to adherence. The motivation to take ARVs to prevent one's death and preserve health may considerably differ from the motivation to take ARVs to keep from infecting sexual partners, which may be dependent on the nature of the relationships.
Long-term use of ARVs for HIV prevention, combined with their already substantial and increasing long-term use among people living with HIV, could potentially increase the incidence of chronic diseases, such as cancer, heart disease, and stroke. Epidemiological studies designed to evaluate such outcomes in patients on long-term ARV regimens will become increasingly important.
Although recent years have witnessed an encouraging expansion of prevention strategies, critical gaps continue to undermine our ability to intervene to prevent new infections.
Prevention Strategies for Young Women
In much of the world, especially sub-Saharan Africa, HIV disproportionately affects women and girls.22 Compared with men, physiological susceptibility to HIV is heightened in women, and entrenched gender norms often disempower them from controlling their choice of sexual partners or the circumstances in which sex occurs.23–25 Even female condoms (whose efficacy has not been unequivocally proven)26,27 require male acceptance. Accordingly, development of prevention methods that women can initiate and control remains an urgent priority.28 ARV-based prevention potentially addresses this gap, although studies are warranted to assess women's equal capacity to access and adhere to such regimens.
In the quest to expand prevention options for women, new research findings5,29 are noteworthy. In a randomized controlled trial in rural Malawi, Baird et al5 found that young women who received monthly cash payments (either without conditions or conditioned on their staying in school) were significantly less likely than girls who did not receive payments to be infected with HIV. The promising results strongly suggest that other economic interventions should be evaluated.
Although major clinical trials are ongoing, no stand-alone behavioral intervention to date has proven successful in reducing HIV incidence.30–32 Although the decline in new infections in many countries has undisputedly been driven by behavior change,33 how best to motivate behavior change remains unclear. Regardless, behavioral issues will remain central to the future of HIV prevention. A critical focus of implementation science (discussed below) is to build the evidence base as to how best to increase demand, uptake, retention, and adherence and prevent potential behavioral disinhibition (or risk compensation) as a result of emerging prevention methods.
Although ARV-based prevention methods will undoubtedly serve as a cornerstone of future HIV prevention efforts, such strategies cannot be implemented in isolation from other essential prevention interventions.31,32 Prevention science is increasingly focusing on evaluations of combination prevention packages. Under this paradigm, biomedical, behavioral, and structural interventions are implemented concurrently, with the aim of enhancing overall effectiveness by achieving synergies among multiple interventions.34,35
The United States President's Emergency Plan for AIDS Relief has pledged to intensify efforts to measure combination prevention packages in large randomized controlled trials, employing flexible methods to evaluate effectiveness, and including program impact pathways and monitoring and evaluation strategies in prevention programs in the field. In moving forward, an important priority is to assess large, complex, heterogeneous prevention programs comprising individual components of often-uncertain efficacy. Rigorous methods of evaluating impact will be required for such trials, underscoring the prominence of implementation science in future HIV-related research.36–38
Although data on the efficacy of treatment for prevention in discordant-couple trials may be unequivocal, the same cannot be said for the effectiveness of treatment for prevention at the population level. To build the evidence base for effective prevention strategies, the focus of prevention science has shifted from basic and clinical research (ie, what to do) to implementation science (ie, how to do it).30,36,39 To optimize program implementation, each step in the implementation cascade, from testing to care and retention, must be delineated and evidence-based strategies that are cost-effective, efficient, and effective need to be identified for each step.40–42 Due to persistent stigma and discrimination, special approaches must be considered among key high-risk populations.
HIV testing is the entry point for all prevention and care programs. Stigma associated with HIV and low rates of testing and counseling continue to impede prevention and care efforts. Testing coverage remains low, with a median 17% of women and 14% of men surveyed between 2005 and 2009 in generalized epidemics in sub-Saharan Africa ever having been tested and learned their results.43 To maximize impact, testing must be repeated with some regularity for uninfected people, requiring not only expanded services but also increased demand for knowledge of one's serostatus. The stigma associated with positive test results must be minimized, and new social norms must be forged, with knowledge of one's serostatus as the standard. Home-based, door-to-door testing, on-site rapid testing, and provider-initiated testing are all promising models.44,45
Rigorous evaluations must assess service delivery models that optimize linkage to care and treatment although protecting patient rights and confidentiality and ensuring retention in care and strong treatment adherence. In particular, implementation research needs to focus not only on ways to retain patients but also on ways to improve methods to measure retention and adherence.
Experience with HIV prevention programs in the field highlights why the research focus on implementation has increased. Several years after clinical trials found that voluntary medical male circumcision (VMMC) reduces the risk of female-to-male sexual HIV transmission by roughly 60%,15–17 the 14 countries prioritized for scale-up of VMMC have progressed only about 5% of the way toward the goal of 80% coverage.1 Likewise, more than a decade after a major international study demonstrated that single-dose nevirapine significantly lowers the odds of mother-to-child HIV transmission,46 more than half of all HIV-positive pregnant women still do not receive antiretroviral prophylaxis, even though the intervention builds on existing service systems and may be integrated into standard neonatal settings.
Effective programmatic implementation and scale-up involves considerations that are seldom addressed in efficacy trials. In the case of VMMC, for example, rollout pace and success are affected by such factors as commodity procurement and supply management, recruitment and organization of human resources, organization of clinical settings, choice of service delivery strategies, and generation of robust demand for services.47 Well-designed implementation research can enable program implementers to learn by doing, linking specific programmatic strategies with improved health outcomes.48
Particular efforts are needed to build the evidence base for ways to optimize programmatic efficiency. In the case of VMMC, efficiency-enhancing practices—for example, task-shifting and task-sharing in VMMC settings, faster surgical techniques, and organizing clinical settings to increase client flow and minimize health workers' idle time—increase by several orders of magnitude the number of VMMC clients that can be served by a single site in 1 day.49
At the broader systemic level, new analytic tools are needed to enhance the public health impact of limited prevention resources. Although national program planners are urged to allocate resources toward basic programmatic strategies that offer the greatest likelihood of long-term impact,50 a shortage of relevant data on the effectiveness and cost-effectiveness of standard HIV prevention interventions impedes national efforts to allocate resources most strategically.51 Moreover, with respect to the handful of largely biomedical prevention methods for which cost-effectiveness data are available, methodological approaches used to assess cost-effectiveness are not easily comparable, undermining national efforts to use limited resources most effectively.51 Intensified research and analysis on relative cost-effectiveness are needed to equip decision makers with the means to maximize programmatic results.
Although recent prevention science advances have generated optimism in the response to HIV, substantial challenges remain. Most notable is the challenge of translating evidence of efficacy into effective sustainable prevention programs. With the aim of expanding the evidence base for scale-up and cost-effectiveness, more implementation science studies are needed.
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