JAIDS Journal of Acquired Immune Deficiency Syndromes:
The Future of HIV Prevention
Padian, Nancy S. MS, MPH, PhD*,†; Isbell, Michael T. JD‡; Russell, Elizabeth S. PhD§; Essex, M. DVM, PhD§
*Office of the Global AIDS Coordinator (OGAC), US President's Emergency Plan for AIDS Relief, Washington, DC
†University of California, Berkeley, School of Public Health, Berkeley, CA
‡Independent Health Policy Consultant, New York, NY
§Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA.
Correspondence to: M. Essex, DVM, PhD, Harvard School of Public Health AIDS Initiative, FXB 402, 651 Huntington Avenue, Boston, MA 02115 (e-mail: email@example.com).
The authors have no funding or conflicts of interest to disclose.
Abstract: In the decades since the emergence of HIV, numerous approaches to prevent transmission have been tested with varying degrees of success. Because a highly effective vaccine will not be available within the next decade, it is increasingly clear that preventing new HIV infections will require successful implementation of promising behavioral and biomedical interventions in combination. These prevention packages must be sufficiently flexible to include a variety of evidence-based interventions that serve each dynamic population they target, particularly those who are most vulnerable. To optimize the impact of combination intervention packages, well-designed implementation science studies are vital. Efficacy in a clinical trial does not necessarily translate to effectiveness at the population-level, and prioritized research studies should investigate programmatic implementation and operations scale-up and new methods to monitor and evaluate these processes both for organization and cost-effectiveness. With an estimated 2.7 million people becoming newly infected with HIV in 2010, the prevention of HIV remains an urgent global health priority. Since the emergence of HIV/AIDS more than 30 years ago, the evidence base for HIV prevention has expanded and evolved. Here we explore the status of evidence-based HIV prevention, describing both the continuing challenges and the emerging opportunities to reduce HIV incidence.
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.
1. Connor EM, Sperling RS, Gelber R, et al.. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331:1173–1180.
3. De Walque D, Dow WH, Nathan R, et al.. Incentivising safe sex: a randomised trial of conditional cash transfers for HIV and sexually transmitted infection prevention in rural Tanzania. BMJ Open. 2012;2:e000747.
4. Baird S, Chirwa E, McIntosh C, et al.. The short-term impacts of a schooling conditional cash transfer program on the sexual behavior of young women. Health Econ. 2010;19(suppl):55–68.
5. Baird SJ, Garfein RS, McIntosh CT, et al.. Effect of a cash transfer programme for schooling on prevalence of HIV and herpes simplex type 2 in Malawi: a cluster randomised trial. Lancet. 2012;379:1320–1329.
6. Kohler HP, Thornton RL. Conditional cash transfers and HIV/AIDS prevention: unconditionally promising? World Bank Econ Rev. 2012; 26:165–190.
7. Shapiro RL, Hughes MD, Ogwu A, et al.. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362:2282–2294.
8. Cohen MS, Chen YQ, McCauley M, et al.. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505.
9. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al.. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168–1174.
10. Grant RM, Lama JR, Anderson PL, et al.. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–2599.
11. Baeten J, Celum C. Antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study [MOAX0106]. Paper presented at: 6th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 17–20, 2011; Rome, Italy.
12. Thigpen M, Kebaabetswe P, Smith D, et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study [WELBC01]. Paper presented at: 6th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 17–20, 2011; Rome, Italy.
13. Kashuba AD, Patterson KB, Dumond JB, et al.. Pre-exposure prophylaxis for HIV prevention: how to predict success. Lancet. 2011; [published online ahead of print, DOI: 10.1016/S0140-6736(11)61852-7].
14. van der Straten A, van Damme L, Haberer J, et al.. How well does PREP work? Unraveling the divergent results of PrEP trials for HIV prevention. AIDS. 2012;26:F13–19.
15. Auvert B, Taljaard D, Lagarde E, et al.. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med. 2005;2:e298.
16. Bailey RC, Moses S, Parker CB, et al.. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007;369:643–656.
17. Gray RH, Kigozi G, Serwadda D, et al.. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369:657–666.
18. Novitsky V, Ndung'u T, Wang R, et al.. Extended high viremics: a substantial fraction of individuals maintain high plasma viral RNA levels after acute HIV-1 subtype C infection. AIDS. 2011;25:1515–1522.
19. Quinn TC, Wawer MJ, Sewankambo N, et al.. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000;342:921–929.
20. Truong HH, Kellogg TA, McFarland W, et al.. Sentinel surveillance of HIV-1 transmitted drug resistance, acute infection and recent infection. PLoS One. 2011;6:e25281.
21. Lockman S, Shapiro RL, Smeaton LM, et al.. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007;356:135–147.
23. Jewkes RK, Dunkle K, Nduna M, et al.. Intimate partner violence, relationship power inequity, and incidence of HIV infection in young women in South Africa: a cohort study. Lancet. 2010;376:41–48.
24. Maman S, Mbwambo JK, Hogan NM, et al.. HIV-positive women report more lifetime partner violence: findings from a voluntary counseling and testing clinic in Dar es Salaam, Tanzania. Am J Public Health. 2002;92:1331–1337.
25. Van der Straten A, King R, Grinstead O, et al.. Sexual coercion, physical violence, and HIV infection among women in steady relationships in Kigali, Rwanda. AIDS Behav. 1998;2:61–73.
26. Macaluso M, Blackwell R, Jamieson DJ, et al.. Efficacy of the male latex condom and of the female polyurethane condom as barriers to semen during intercourse: a randomized clinical trial. Am J Epidemiol. 2007;166:88–96.
27. Schwartz JL, Barnhart K, Creinin MD, et al.. Comparative crossover study of the PATH Woman's Condom and the FC Female Condom. Contraception. 2008;78:465–473.
28. Stein ZA. HIV prevention: the need for methods women can use. Am J Public Health. 1990;80:460–462.
29. Pettifor A, McCoy SI, Padian N. Paying to prevent HIV infection in young women? Lancet. 2012. E-pub ahead of print.
30. Padian NS, McCoy SI, Karim SS, et al.. HIV prevention transformed: the new prevention research agenda. Lancet. 2011;378:269–278.
31. Padian NS, McCoy SI, Balkus JE, et al.. Weighing the gold in the gold standard: challenges in HIV prevention research. AIDS. 2010;24:621–635.
32. Padian NS, Buve A, Balkus J, et al.. Biomedical interventions to prevent HIV infection: evidence, challenges, and way forward. Lancet. 2008;372:585–599.
34. Merson M, Padian N, Coates TJ, et al.. Combination HIV prevention. Lancet. 2008;372:1805–1806.
35. Piot P, Bartos M, Larson H, et al.. Coming to terms with complexity: a call to action for HIV prevention. Lancet. 2008;372:845–859.
36. Padian NS, Holmes CB, McCoy SI, et al.. Implementation science for the US President's Emergency Plan for AIDS Relief (PEPFAR). J Acquir Immune Defic Syndr. 2011;56:199–203.
37. Padian NS, McCoy SI, Manian S, et al.. Evaluation of large-scale combination HIV prevention programs: essential issues. J Acquir Immune Defic Syndr. 2011;58:E23–E28.
38. The United States President's Emergency Plan for AIDS Relief: Five-Year Strategy. December 2009. Available at: http://www.pepfar.gov/
. Accessed February 15, 2012.
39. PEPFAR Scientific Advisory Board. Recommendations for the Office of the US Global AIDS Coordinator: Implications of HPTN 052 for PEPFAR's Treatment Programs. Washington, DC: PEPFAR; 2011. Available at: www.pepfar.gov/documents/organization/177126.pdf
. Accessed February 15, 2012.
40. PEPFAR. Prevention of Mother-to-Child Transmission of HIV: Expert Panel Report and Recommendations to the U.S. Congress and U.S. Global AIDS Coordinator. Washington, DC: PEPFAR; 2010. Available at: http://www.pepfar.gov/progress/pmtctpanel/index.htm
. Accessed February 15, 2012.
41. Rosen S, Fox MP. Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review. PLoS Med. 2011;8:e1001056.
42. Stringer EM, Chi BH, Chintu N, et al.. Monitoring effectiveness of programmes to prevent mother-to-child HIV transmission in lower-income countries. Bull World Health Organ. 2008;86:57–62.
43. Monitoring and Evaluation to Assess and Use Results Demographic and Health Surveys (MEASURE DHS) Project. HIV/AIDS Survey Indicators Database [database online]. Calverton, MD: MEASURE DHS; 2011.
44. Bateganya MH, Abdulwadud OA, Kiene SM. Home-based HIV voluntary counseling and testing in developing countries. Cochrane Database Syst Rev. 2007:CD006493.
45. Sweat M, Morin S, Celentano D, et al.. Community-based intervention to increase HIV testing and case detection in people aged 16-32 years in Tanzania, Zimbabwe, and Thailand (NIMH Project Accept, HPTN 043): a randomised study. Lancet Infect Dis. 2011;11:525–532.
46. Guay LA, Musoke P, Fleming T, et al.. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999;354:795–802.
48. Katzenstein D, Koulla-Shiro S, Laga M, et al.. Learning and doing: operational research and access to HIV treatment in Africa. AIDS. 2010;24(suppl 1):S1–S4.
50. Schwartlander B, Stover J, Hallett T, et al.. Towards an improved investment approach for an effective response to HIV/AIDS. Lancet. 2011;377:2031–2041.
51. Galarraga O, Colchero MA, Wamai RG, et al.. HIV prevention cost-effectiveness: a systematic review. BMC Public Health. 2009;9(suppl 1):S5.
prevention; adherence; microbicides; antiretrovirals; behavioral interventions; biomedical interventions
© 2012 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read