The field of biomedical HIV prevention has undergone remarkable changes over the past 5 years. Clinical trials have demonstrated efficacy with interventions such as voluntary medical male circumcision (VMMC),1–3 a topical vaginal microbicide,4 daily oral preexposure prophylaxis (PrEP),5–7 and the use of antiretroviral treatment (ART) to reduce the risk of HIV transmission in HIV-serodiscordant heterosexual exposure.8 AIDS vaccine research has been complex and challenging, but it is at its most promising point in decades.9
These advances have expanded conceptions of what belongs in the prevention “toolbox,” particularly for infection via sexual transmission. They have also added complexity to previous theoretical conversations about plans for introduction and access to these interventions. Finally, scientific developments in biomedical prevention have activated a prevention-focused advocacy movement working at the grassroots, national, and global levels. This advocacy, backed by epidemiological models,10,11 seeks to use existing tools to begin to end the AIDS epidemic while maintaining a prevention research agenda focused on developing additional tools to eventually end the epidemic.
Together, all these advances have helped create a new environment. But these new prevention approaches are not created equal. They may be preferentially suited to certain populations or for certain periods of an individual's life. Furthermore, there are fundamental differences in outcomes. For example, ARV-based prevention using ART for HIV-positive people to reduce risk of transmission may also deliver a clinical benefit for those taking the medications,12 whereas VMMC has primary population-level and individual-level benefits for HIV-negative men and secondary benefits for women by decreasing the number of HIV-positive men.13 Daily oral tenofovir-based PrEP may be most appropriate in HIV-negative individuals during periods of high risk of HIV exposure. Epidemiological models predict different levels of impact of various strategies when used alone or in combination.11 There are also major differences in the next steps warranted for each strategy: from follow-on trials to build on the modest positive results from the Thai RV144 AIDS vaccine trial9 and CAPRISA 004 microbicide trial4; to demonstration projects for use of oral PrEP14; to ambitious “catch-up” campaigns targeting millions of adult men for VMMC15; and to trials that demonstrate the effectiveness of ART for prevention at community level.16
The challenge for prevention advocacy today is to fashion a coherent and focused agenda that sets and tracks priorities for strategies that can be implemented and scaled-up now; those that need further study and implementation in the near- and mid-term; and those that need to be developed through iterative investigations including basic science and clinical trials. Addressing this challenge is of the utmost importance; key priorities and specific barriers are addressed below.
DEFINING COMBINATION PREVENTION
Terms such as “high-impact prevention” and “combination prevention” are widely used by researchers, public health professionals, and by funding entities such as the US President's Emergency Response for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), and normative agencies like UNAIDS.17–19 Yet, there is a pervasive lack of clarity and specificity about definitions. Combination prevention must be tailored to specific contexts—but this reality should not justify maintaining nebulous definitions and avoiding difficult conversations about what strategies should be included or excluded from high-impact packages. Available modeling suggests that in epidemics driven by heterosexual transmission, core components of high-impact prevention would include expanded testing, VMMC, ART to maximize the benefits of treatment as prevention, and PMTCT programs.11,20 The use of such interventions will need to be complemented by ongoing male and female condom promotion and safe syringe access, and prevention focused on key populations including gay men and other men who have sex with men, transgender women, sex workers, adolescents, people who inject drugs, and others. At a minimum, this language—and the development of implementation strategies—should be clear and consistent across PEPFAR, GFATM, and UNAIDS documentation and activities. There should, in addition, be the development of models that provide country programs with information regarding the relative impact of each strategy and match investments to the scale-up needs required to achieve coverage for maximum impact.
TREATMENT AS PREVENTION: NARROW GAPS IN THE TREATMENT CASCADE
The most widely embraced element of high-impact prevention is the expanded use of ART to reduce the risk of HIV transmission. This “treatment as prevention” strategy was confirmed in serodiscordant heterosexual couples in the HPTN 052 trial and is now subject to much debate, normative policy guidance, and further investigation to understand the potential population-level benefit on prevention. The potential multiple benefits of expanding access to ART for prevention will only be realized if there is a concerted effort to define and address gaps at every stage of what is now popularly known as the treatment cascade: the flow from testing HIV positive, to linkage to care, to initiation of ART to ongoing follow-up that results in effective viral suppression.21 Research is needed on optimal solutions to address gaps in this cascade. In addition, these steps (and gaps) often exist in areas where drugs and services are available to those who wish to access it, but there are even larger gaps in the cascade where there is no or quite limited access to health care and where availability of drugs is inconsistent.22 Clinical trials evaluating the effectiveness of ART for prevention at the population (or community) level are being developed, with some already in the field. In many other instances, implementation of key interventions, such as community-based service provision, can be effective if scaled up.23
COORDINATION ON VMMC
In the 5 years since the World Health Organization (WHO) and UNAIDS issued a recommendation for VMMC as a prevention tool in specific African countries,24 there has been some progress in implementation, including development and rollout of high-efficiency service delivery models, increasing country-level ownership and effective campaigns that have met or exceeded targets in short time frames in some countries.25 However, there is limited coordination and clarity about what is needed in terms of demand creation, advocacy, and communication coordination. Despite notable past and ongoing efforts to define effective strategies for demand creation, there are still major gaps in the understanding of how to efficiently promote VMMC for maximum uptake by the target population.26 These demand creation efforts are distinct from advocacy, which is urgently needed to ensure that VMMC is recognized as a core component of combination prevention both by the civil society groups that are effectively organizing around scale-up of treatment as prevention and by public health leadership at national and global levels. As one example, the 2012 Declaration of Commitment issued by the International AIDS Society at the International AIDS Conference in Washington, DC, did not specifically mention VMMC as being integral to an effective global response.27
From a civil society perspective, it seems that increased coordination is needed on the part of normative agencies, major funders, and implementers of VMMC to segment and define issues related to demand creation, advocacy, and communication and prepare for decision making regarding newer circumcision methods such as nonsurgical devices.28 Prevention advocates have a critical role to play in making the case for VMMC as part of a comprehensive global response. Advocacy groups emphasizing that treatment is prevention, but not yet incorporating VMMC as core to long-term success in reducing incidence, need to become allies in promoting a broader message that prevention is prevention—with ART and VMMC as 2 fundamental pillars.
GATHERING DATA TO SETTLE UNCERTAINTY ON PREP
VMMC and treatment as prevention are interventions that have been validated in clinical trials and embraced as appropriate for implementation and scale-up. An equally important but far murkier area for civil society advocacy relates to strategies that have shown some proof of concept but that are yet to be confirmed in other studies or those for which demonstration projects are needed. The main example in the latter category is the area of PrEP and specifically the use of daily oral tenofovir-based PrEP. It has been nearly 2 years since data from 2 PrEP trials of the daily oral combination pill tenofovir/emtricitabine (TDF/FTC) in heterosexual men and women6,7 were released to complement data from the iPrEx trial in gay men and transgender women5—all of which demonstrated efficacy of daily oral TDF/FTC. In that time period, the US Food and Drug Administration (FDA) approved daily oral TDF/FTC for HIV prevention in HIV-negative adults,29 and the WHO issued guidance on PrEP demonstration projects targeting low-income and lower- to middle-income countries.30 A range of other guidance documents and position statements have also been issued by various professional associations.31–34 The situation is complicated by the results of 2 recent studies in young heterosexual women (FEM-PrEP and VOICE) that did not demonstrate efficacy of daily oral TDF/FTC for PrEP because of participant's lack of adherence to the study drug.35,36 This has led to a lack of clarity about whether such an intervention is efficacious in such women and whether it can be effective in real-world settings, where young women may not take the drugs regularly as prescribed. A core set of pilot or demonstration projects needs to be implemented to evaluate the feasibility, acceptability, and potential effectiveness of this new strategy. It is acknowledged that the use of daily oral TDF/FTC for PrEP will have implementation challenges37 because it requires regular HIV testing to ensure that those receiving PrEP are HIV negative and receive adherence support and monitoring for potential seroconversion, long-term side effects, and toxicities. But, it remains unclear how to weigh these challenges against the demonstrated efficacy of this intervention in specific populations that could benefit most from this new option, such as in serodiscordant couples, where the negative partner with pregnancy intentions may benefit from PrEP during those periods or where the HIV-infected partner may not be able or willing to take ART. In the absence of a strategic suite of projects designed to answer this and other questions, there will remain unfortunate gaps in understanding of how to translate clinical trial efficacy into public health effectiveness.
To confront this dilemma, one line of argument emphasizes the potentially greater acceptability and potential efficacy of next-generation strategies such as a long-acting injectable antiretrovirals or an antiretroviral-containing vaginal ring used for PrEP. Another emphasizes the risk of setting aside a strategy that has been shown to work—particularly one that does not need to be used at the time of sex or with explicit partner consent. The reality is that both arguments have merit and that the debate cannot be settled without a suite of well-designed and well-coordinated demonstration projects answering critical questions. Public health agencies, and funders, should work with implementation partners to swiftly fill this gap—before the 1-year anniversary of FDA approval and WHO's publication of the rapid guidance on PrEP demonstration projects.
SUSTAINING SUPPORT FOR RESEARCH OVER THE LONG TERM
Perhaps, the greatest challenge facing biomedical prevention research advocacy is balancing activism around delivery of existing tools and developing new ones. It is important to capitalize on the momentum of the movement to begin to end AIDS and to use existing tools more efficiently and for maximum impact—while also sustaining support for operations research to understand how to integrate and deliver interventions effectively and efficiently and for ongoing trials of emerging strategies including PrEP, microbicides, and vaccines (see Fig. 1).
Why is there the need to develop new tools if the available tools today can begin to end the epidemic? How to sustain support for research when there are long timelines for follow-on trials: the next AIDS vaccine trial of a strategy related to the one evaluated in RV144 may not begin until 2016.38 Other strategies, such as passive immunization using potent broadly neutralizing antibodies or a vaccine that induces similar immune defenses, could be even further off.39 Cure research is also in relatively early conceptual stages, with long timelines for clinical evaluation of specific interventions.40
In the context of constrained resources for all aspects of the global AIDS response, it is a particular challenge to advocate for sustained investment that will not show dividends—in terms of new efficacious interventions—for many years. Yet, this sustained financial and community-level support for further biomedical prevention research is essential. Successful implementation of currently available strategies in high-impact combination packages could dramatically reduce rates of new HIV infections, morbidity and mortality.41 Such action will also reduce the cost of the global AIDS response over the long term. But it will not eliminate new HIV infections or reduce the need for simpler highly effective prevention tools such as a vaccine that can sustain the gains made with more resource-intensive prevention packages.11
Prevention advocates are working to convey the message that implementing today's available prevention interventions provides a bridge to long-term additional solutions. In addition, advocates are working to define expectations about when various strategies—including improved ART, for example, a new drug or formulation that might only require quarterly or monthly dosing for effective viral control—might be available. This effort should be matched by trial sponsors and scientists developing interventions providing transparent communication of timelines and proactive engagement on trial design issues and by sustained research funding from governments and other donors.
In resource-limited countries, some of the most passionate advocacy regarding the “why invest in research” question has come from individuals and communities who have historically been underserved by existing prevention strategies. Paradoxically, or perhaps inevitably, communities that have received limited attention from HIV prevention programming and/or have been unable to use the strategies that have been offered to them have become passionate advocates for emerging technologies. For example, gay men and other men who have sex with men, along with transgender women, have become outspoken PrEP and rectal microbicide advocates—even as they affirm and eloquently describe the structural barriers of criminalizing legislation and rampant homophobia, along with the lack of basic prevention: lubricant, condoms, stigma-free clinics and service providers.42
Women, including women living with HIV, also remain mobilized around the need for sustained research. There is a vibrant history of grassroots awareness raising and advocacy for women-controlled HIV prevention focused primarily on female condoms and microbicides.43 More recently, both PrEP and treatment as prevention have been configured as potentially female-controlled prevention strategies, with HIV-positive women stating the need for PrEP for both men and women.44 As one participant at a community consultation said, “I want PrEP because I am HIV-positive, and I don't want the burden of prevention to be on me as an HIV-positive woman.”45
The audacious vision of an end to the HIV epidemic is years from coming to fruition. But the creative tensions and frictions at play in the world of biomedical prevention research today are the growing pains of a movement seeking to ensure that this goal is reached.
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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 2011; Rome, Italy.
7. Thigpen MC, Kebaabetswe PM, Paxton LA, et al.. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423–434.
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. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al.. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209–2220.
10. The HIV Modelling Consortium Treatment as Prevention Editorial Writing Group. Coordinating research activities in mathematical modelling. Paper presented at: HIV Modeling Consortium, 2011. Stellenbosch, South Africa. Available at: http://www.hivmodelling.org
. Accessed March 14, 2013.
11. Schwartländer B, Stover J, Hallett T, et al.. Towards an improved investment approach for an effective response to HIV/AIDS. Lancet. 2011;377:2031–2041.
12. Grinsztein B, Hosseinipour M, Swindells S. Effect of early versus delayed initiation of antiretroviral therapy (ART) on clinical outcomes in the HPTN 052 randomized clinical trial. [THLBB05]. Paper presented at: Program and abstracts of the XIX International AIDS Conference; July 2012; Washington, DC.
13. Hankins C, Forsythe S, Njeuhmeli E. Voluntary medical male circumcision
: an introduction to the cost, impact, and challenges of accelerated scaling up. PLoS Med. 2011;8:e1001127.
15. WHO, UNAIDS and PEPFAR. Joint strategic action framework to accelerate the scale-up of voluntary medical male circumcision
for HIV prevention
in Eastern and Southern Africa. Paper presented at: WHO, UNAIDS, PEPFAR, December 5, 2011. Available at: http://www.pepfar.gov/documents/organization/178294.pdf
. Accessed March 14, 2013.
16. Tanser F, Bärnighausen T, Grapsa E, et al.. High coverage of ART associated with decline in risk of HIV acquisition in Rural KwaZulu-Natal, South Africa. Science. 2013:966–971.
20. Alsallaq R, Baeten J, Hughes J, et al.. Modelling the effectiveness of combination prevention from a house-to-house HIV testing platform in KwaZulu Natal, South Africa. Sex Transm Infections. 2011;87:A36.
21. Gardner EM, McLees MP, Steiner JF, et al.. The Spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. 2011;52:793–800.
22. Cohn J, Baker B. Obstacles and opportunities to improve antiretroviral regimen access in low-income countries. Curr HIV/AIDS Rep. 2010;7:161–167.
24. WHO and UNAIDS. New Data on Male Circumcision and HIV Prevention
: Policy and Programme Implications. Montreux, Switzerland: WHO; 2007:5–8.
25. UNAIDS and PEPFAR. Voluntary medical male circumcision
for HIV prevention
: the cost, impact, and challenges of accelerated scale-up in Southern and Eastern Africa. PLoS Collection. UNAIDS and PEPFAR, November 2011. Available at: http://www.ploscollections.org/VMMC2011
. Accessed March 14, 2013.
26. Mwandi Z, Murphy A, Reed J, et al.. Voluntary medical male circumcision
: translating research into the rapid expansion of services in Kenya, 2008–2011. PLoS Med. 2011;8:e1001130.
28. Bitega JP, Muyenzi Leon N, Theobald H, et al.. Safety and efficacy of the PrePex device for rapid scale-up of male circumcision for HIV prevention
in resource-limited settings. J Acquir Immune Defic Syndr. 2011;58:127–134.
31. CDC. Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. CDC Morb Mortal Wkly Rep. 2012;61:586–589.
32. CDC. Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. CDC Morb Mortal Wkly Rep. 2011;60:65–68.
33. McCormack S, Fidler S, Fisher M. The British HIV association/British association for sexual health and HIV position statement on pre-exposure prophylaxis in the UK. Int J STD AIDS. 2012;23:1–4.
34. Bekker LG, Rebe K, Brown B, et al.; on behalf of the Southern African HIV Clinicians Society Consensus Committee. Southern African guidelines for the safe use of pre-exposure prophylaxis in men who have sex with men who are at risk for HIV infection. South Afr J HIV Med. 2012;13:40–55.
35. Marrazzo J, Ramjee G, Nair G, et al.. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). Paper presented at: 20th Conference on Retroviruses and Opportunistic infections; March 2013; Atlanta, GA.
36. Van Damme L, Corneli A, Ahmed K, et al.. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411–422.
37. Smith DK, Dearing JW, Sanchez T, et al.. Introducing wicked issues for HIV pre-exposure prophylaxis implementation in the U.S. Am J Prev Med. 2013;44(1 suppl 2):S59–S62.
38. Steenhuysen J. Scientists see AIDS vaccine
within reach after decades. Reuters. 2012;15.
39. Kwong P, Mascola J, Nabel G. Rational design of vaccines to Elicit broadly neutralizing antibodies to HIV-1. Cold Spring Harb Perspect Med. 2011;1:a007278.
40. Deeks S, Autran B, Berkhout B, et al.. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012;12:607–614.
41. Blandford J. Global Webinar: The Impact of Treatment as Prevention—Models to Guide Ending the Epidemic. Paper presented at: the AVAC; January 26, 2012. New York, NY. Available at: http://www.avac.org/ht/d/ContentDetails/i/41812
. Accessed March 14, 2013.