By 2007, as the trials reached completion or were stopped early for reasons of harm or futility, negative sentiments about HIV prevention science started to emerge. This situation was most notable in the vaccine and microbicide fields. Just months after a 2008 Science  article that discussed some of the current failures in the microbicide field and questioned the future of the microbicides, a promising microbicide result for PRO 2000 (0.5%) gel (discussed later) was presented at the 16th Conference on Retroviruses and Opportunistic Infections [41•]. This good news notwithstanding, most recent prevention trials (with the important exception of the male circumcision trials) have not demonstrated efficacy in preventing HIV infection [27••,29,30,33,42].
The number of recently completed but unsuccessful prevention trials mask important progress in the efforts to reduce HIV infection. Building on observations in couples from Quinn et al.  and Fideli et al.  on the close correlation between viral load and HIV transmission, new opportunities for HIV prevention have emerged through expanding access to testing and knowledge of HIV status, linked to antiretroviral therapy (ART) for infected persons. This ‘test and treat’ concept has potential as an intervention for decreasing viral load in communities and thus reducing the probability of transmission at a population level. The use of ART as a prevention tool has already proven effective in prevention of mother-to-child HIV transmission (PMTCT) – women who are given ART during pregnancy and postpartum have a significantly decreased risk for transmission of virus to their newborn [45–47]. However, use of ART, as a prevention tool requires patients to know their HIV-positive status, have access to care, and to adhere to medications necessary to lower viral loads and minimize antiviral drug resistance. With six drug classes now in use (http://www.fda.gov/oashi/aids/virals.html, accessed 30 March 2009), several of which are in affordable generic formulations, advances in the field of antiviral chemotherapy have made effective viral load reduction even more feasible.
The ‘Step’ study of the MRK Ad5 gag/pol/nef HIV-1 vaccine did not indicate vaccine benefit in adenovirus-seronegative persons and showed higher HIV seroconversion in adenovirus-seropositive persons [37••]. Deep tissue HIV invasion may occur in just 2 weeks or less, demonstrating how hard it will be to use a human immunologic barrier to block HIV, given the current state of knowledge .
Although the effectiveness of male condoms is exceedingly well documented despite the lack of a RCT , condom usage rates are still low in most high-risk persons globally. The Zimbabwean MIRA trial did not suggest the female diaphragm to be more successful in preventing HIV compared with condom use alone . Efficacy of female condoms remains unknown and unstudied in clinical trials; effectiveness data are also sparse.
Cellulose sulfate gel, 1.0% C31G (SAVVY), Carraguard, and Buffer-gel products failed to prevent HIV transmission in prevention RCTs [32–36,41•,50]. However, PRO 2000 (0.5%) gel, a nonspecific entry/fusion inhibitor, was 30% effective (0.05 < P ≤ 0.10 against placebo gel or no gel groups, P < 0.05 against placebo and no gel groups combined) in reducing HIV incidence [41•]. Microbicide trials with antiretroviral active agents (e.g., tenofovir) are in progress .
Animal data suggest that ART can be given before HIV exposure and continued for several weeks after exposure to reduce risk of HIV transmission [52–55]. Preexposure prophylaxis (PrEP), some with postexposure (PEP) components are in progress worldwide in both men who have sex with men (MSM) and at-risk heterosexuals. Perhaps the most promising product (as of this 2009 writing) is tenofovir combined with emtricitabine (TDF/FTC or Truvada) due to its lower likelihood of emerging drug resistance, high genital tract concentrations, and long half-life [56,57]. If effective, implementation will be challenging, especially in more resource-limited settings where even HIV-infected persons are underserved with antiretroviral services. Nonetheless, if drug prices fall, decision analysis models suggest it could be a cost-effective intervention .
Randomized clinical trials in South Africa, Uganda, and Kenya demonstrated approximately 50% seroincidence decline in circumcised heterosexual men [23–25]. This has galvanized an effort to expand such services in high prevalence venues, given their high cost efficiency [59–61]. As scale-up occurs, mitigation of harm from suboptimal surgery will be a challenge [62–64]. Benefits of circumcision to MSM are unknown, and would only be expected to benefit men who are exclusively (or almost exclusively) insertive in their sexual acts [65,66].
The suppression of herpes simplex virus type-2 infection with chronic acyclovir did not reduce HIV seroconversions in either MSM in the Americas or with high-risk heterosexual women in Africa [21••,22•]. This was disappointing given the very strong correlation of HSV-2 infection with risk of HIV acquisition reported in observational studies; many in the field expected HSV-2 suppression to mimic adult male circumcision successes . In addition to these more recent trials, previous community-RCTs have examined the effect of improved STI treatment on HIV transmission [18–20,26]. The results of these studies were mixed suggesting that treatment of bacterial STI may be more effective in preventing HIV infection in settings with low-to-emerging HIV epidemics or mature epidemics with high incidence and where there is a high background prevalence of bacterial STI [68–71].
Structural interventions are policy changes that encourage risk reduction. Raising cigarette taxes to discourage youth from smoking and banning smoking in public indoors areas are two familiar examples. The Microfinance for AIDS and Gender Equity (IMAGE) study combined a microfinance program with training in sex–power relationships and HIV-risk reduction in rural South Africa. Reductions in levels of intimate-partner violence were significant in the intervention arm along with reductions in HIV-risk behaviors , but HIV rates did not differ . Although HIV results were disappointing, the RCT illustrates how multicomponent interventions will be used to try to break the cycle of HIV transmission.
In summary, 28 years into the pandemic only five randomized controlled trials have demonstrated a decrease in HIV-incidence rates. The Mwanza trial demonstrated a 42% reduction in HIV seroincidence in persons living in communities with immediate availability of syndromic management of bacterial sexually transmitted diseases (STDs) . This promising finding was not observed in the context of three subsequent phase III RCTS of STD intervention studies in the Rakai, Masaka, Manicaland regions [18,19,26]. A microbicide has shown promise in the HPTN035 study of PRO 2000 0.5% gel [41•]. The protective effect of medical male circumcision in preventing female–male transmission of HIV has been confirmed consistently in three independently conducted phase III RCTs [23–25]. The translation of these impressive finding has been limited by political, cultural/social and programmatic challenges [59,61,62,76–81]. This leaves us with a limited arsenal of proven HIV-prevention strategies, though circumstantial evidence of male condom efficacy and salutary benefits of delayed sexual debut and partner reduction remain compelling.
Notwithstanding the scientific challenges in preventing HIV infection, the conduct of RCTs in HIV prevention has numerous additional challenges in design, selecting appropriate outcome measures for both efficacy and effectiveness studies including the lack of proxy markers for protection [82•,83]. A key factor contributing to small effect size of interventions is the ethical obligation to provide risk reduction education in comparison or control populations, even in settings where there remains limited access to prevention in the real world. For example in the MIRA RCT, female diaphragms and condoms were compared against condoms alone . Although women using diaphragms had the same transmission rates as those whose partners used condoms, it was interpreted widely that diaphragms were ineffective. A more correct interpretation was that they might have been equally efficacious as condoms, as condom use in the diaphragm group was uncommon, despite encouragements for their use.
The prevention community has also been slow to embrace combination prevention efficacy trials despite what we have learned from therapeutic trials or strategies in the PMTCT field about the importance of using more comprehensive intervention strategies targeting all potential routes of viral entry and/or replication. Instead, HIV-prevention efforts have adopted the approach of incremental/attributable risk reduction. Although these unitary strategies for HIV prevention are alluring in theory (lower cost, ease of implementation); research investments (from the USA National Institute of Allergy and Infectious Diseases, the United Kingdom Medical Research Council, and the Bill and Melinda Gates Foundation, for example) have disproportionately emphasized ‘magic bullets’ for HIV prevention (i.e., prophylactic vaccines, PrEP, and microbicides) compared with more complex multicomponent interventions. The latter could have epidemic impact of more immediacy and effectiveness [37••,40,84]. The authors of this review believe that future trials must combine interventions, each with small effects but with the potential for synergy if combined. Prevention science strategies and trial conduct needs to take into account the myriad of biological, behavioral, and structural factors that increase a person's risk for infection at multiple levels. Rarely does an individual at risk of getting infected with HIV have a single intrinsic factor that might lead to infection.
A diverse biomedical and biobehavioral portfolio of research is essential for us to make progress in HIV control. Building on the tools provided by basic, clinical, and social sciences, we need to move new products and strategies into rigorous field testing. Implementation of single modality interventions will not solve the problem. History has taught us through PEPFAR and the Global Fund to Fight AIDS, tuberculosis and malaria that ‘where there is a will there is a way’. These therapeutic implementation successes have also highlighted the numerous challenges in the context of failing healthcare delivery systems, inadequate infrastructure and limited human resources to attain access, coverage and acceptability levels needed to make a difference to current epidemic trajectories [85,86,87•].
Vaccines and microbicides are still seen as the holy grails of prevention as reflected in budgetary allocations. Although these approaches will remain an important part of our medium-to long-term strategy, we must invest in strategies with impact in the shorter term. Combinations of interventions based on existing tools such as the delaying sexual debut, partner fidelity, use of condom barriers (the abstinence, be faithful, correct condom use ‘ABC’ mantra), and male circumcision will be needed to complement whatever biomedical interventions are made available and are used by the target communities. We believe that the lessons learned suggest that multicomponent, multilevel interventions with careful monitoring and evaluation in implementation will be more likely to succeed than unitary biomedical approaches.
Our review research was supported by the HIV Prevention Trials Network (HPTN), sponsored by the National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the National Institutes of Health, the United States Department of Health and Human Services (U01 AI068619).
2 UNAIDS. AIDS epidemic update: December 2007. Geneva: UNAIDS; 2007.
3 UNAIDS. 2008 Report on the global AIDS epidemic. Geneva: UNAIDS; 2008.
4 WHO, UNAIDS, UNICEF: Towards Universal Access: scaling up priority HIV/AIDS interventions in the health sector. Progress Report 2008. Geneva, Switzerland: WHO, UNAIDS, UNICEF; 2008.
5 WHO, UNAIDS, UNICEF: Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector. Geneva: WHO; 2008.
6 Celentano DD, Nelson KE, Lyles CM, et al
. Decreasing incidence of HIV and sexually transmitted diseases in young Thai men: evidence for success of the HIV/AIDS control and prevention program. AIDS 1998; 12:F29–F36.
7 Hallett TB, Aberle-Grasse J, Bello G, et al.
Declines in HIV prevalence can be associated with changing sexual behaviour in Uganda, urban Kenya, Zimbabwe, and urban Haiti. Sex Transm Infect 2006, 82 Suppl 1:i1–i8.
8 Kilian AH, Gregson S, Ndyanabangi B, et al
. Reductions in risk behaviour provide the most consistent explanation for declining HIV-1 prevalence in Uganda. AIDS 1999; 13:391–398.
9 Nelson KE, Celentano DD, Eiumtrakol S, et al
. Changes in sexual behavior and a decline in HIV infection among young men in Thailand. N Engl J Med 1996; 335:297–303.
10 Rojanapithayakorn W, Hanenberg R. The 100% condom program in Thailand. AIDS 1996; 10:1–7.
11 Dunkle KL, Jewkes RK, Brown HC, et al
. Gender-based violence, relationship power, and risk of HIV infection in women attending antenatal clinics in South Africa. Lancet 2004; 363:1415–1421.
12 Fenton L. Preventing HIV/AIDS through poverty reduction: the only sustainable solution? Lancet 2004; 364:1186–1187.
13 Gupta GR. How men's power over women fuels the HIV epidemic. BMJ 2002; 324:183–184.
14 Parker RG, Easton D, Klein CH. Structural barriers and facilitators in HIV prevention: a review of international research. AIDS 2000; 14(Suppl 1):S22–S32.
15 Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet 2008; 372:669–684.
16 Gupta GR, Parkhurst JO, Ogden JA, et al
. Structural approaches to HIV prevention. Lancet 2008; 372:764–775.
17 Padian NS, Buvé A, Balkus J, et al
. Biomedical interventions to prevent HIV infection: evidence, challenges, and way forward. Lancet 2008; 372:585–599.
18 Wawer MJ, Sewankambo NK, Serwadda D, et al
. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Rakai Project Study Group. Lancet 1999; 353:525–535.
19 Kamali A, Quigley M, Nakiyingi J, et al
. Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial. Lancet 2003; 361:645–652.
20 Grosskurth H, Mosha F, Todd J, et al
. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet 1995; 346:530–536.
21•• Celum C, Wald A, Hughes J, et al
. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371:2109–2119.
22• Watson-Jones D, Weiss HA, Rusizoka M, et al
. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008; 358:1560–1571. This smaller study also demonstrated no benefit of HSV-2 suppression in prevention HIV infection.
23 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–e1298.
24 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.
25 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.
26 Gregson S, Adamson S, Papaya S, et al
. Impact and process evaluation of integrated community and clinic-based HIV-1 control: a cluster-randomised trial in eastern Zimbabwe. PLoS Med 2007; 4:e102–e1102.
27•• Jewkes R, Nduna M, Levin J, et al
. Impact of Stepping Stones on incidence of HIV and HSV-2 and sexual behaviour in rural South Africa: cluster randomised controlled trial. BMJ 2008; 337:a506–a1506.
28 Latkin CA, Donnell D, Metzger D, et al
. The efficacy of a network intervention to reduce HIV risk behaviors among drug users and risk partners in Chiang Mai, Thailand and Philadelphia, USA. Soc Sci Med 2009; 68:740–748.
29 Cowan FM, Pascoe SJ, Langhaug LF, et al
. The Regai Dzive Shiri Project: a cluster randomised controlled trial to determine the effectiveness of a multicomponent community-based HIV prevention intervention for rural youth in Zimbabwe: study design and baseline results. Trop Med Int Health 2008; 13:1235–1244.
30 Pronyk PM, Hargreaves JR, Kim JC, et al
. Effect of a structural intervention for the prevention of intimate-partner violence and HIV in rural South Africa: a cluster randomized trial. Lancet 2006; 368:1973–1983.
31 Padian NS, van der Straten A, Ramjee G, et al
. Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomised controlled trial. Lancet 2007; 370:251–261.
32 Halpern V, Ogunsola F, Obunge O, et al
. Effectiveness of cellulose sulfate vaginal gel for the prevention of HIV infection: results of a Phase III trial in Nigeria. PLoS ONE 2008; 3:e3784.
33 Feldblum PJ, Adeiga A, Bakare R, et al
. SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS ONE 2008; 3:e1474.
34 Peterson L, Nanda K, Opoku BK, et al
. SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana. PLoS ONE 2007; 2:e1312.
35 Skoler-Karpoff S, Ramjee G, Ahmed K, et al
. Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372:1977–1987.
36 Van Damme L, Govinden R, Mirembe FM, et al
. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 2008; 359:463–472.
37•• Buchbinder SP, Mehrotra DV, Duerr A, et al
. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372:1881–1893.
38 Flynn NM, Forthal DN, Harro CD, et al
. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 2005; 191:654–665.
39 Pitisuttithum P, Gilbert P, Gurwith M, et al
. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 2006; 194:1661–1671.
40 Grant RM, Hamer D, Hope T, et al
. Whither or wither microbicides? Science 2008; 321:532–534.
41• Abdool Karim S, Coletti A, Richardson B, et al.
Safety and effectiveness of vaginal microbicides buffer gel and 0.5% PRO 2000/5 gel for the prevention of HIV infection in women: results of the HPTN 035 Trial. In: CROI. Montreal, Canada; 2009. This is the first evidence of effectiveness of vaginal microbicide to prevention HIV transmission. The full manuscript will be published in 2009.
42 Ross DA, Changalucha J, Obasi AI, et al
. Biological and behavioural impact of an adolescent sexual health intervention in Tanzania: a community-randomized trial. AIDS 2007; 21:1943–1955.
43 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.
44 Fideli US, Allen SA, Musonda R, et al
. Virologic and immunologic determinants of heterosexual transmission of human immunodeficiency virus type 1 in Africa. AIDS Res Hum Retroviruses 2001; 17:901–910.
45 Garcia PM, Kalish LA, Pitt J, et al
. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med 1999; 341:394–402.
46 Mayaux MJ, Dussaix E, Isopet J, et al
. Maternal virus load during pregnancy and mother-to-child transmission of human immunodeficiency virus type 1: the French perinatal cohort studies. SEROGEST Cohort Group. J Infect Dis 1997; 175:172–175.
47 Mofenson LM, Lambert JS, Stiehm ER, et al
. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 1999; 341:385–393.
48 Robb ML. Failure of the Merck HIV vaccine: an uncertain step forward. Lancet 2008; 372:1857–1858.
49 Holmes KK, Levine R, Weaver M. Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ 2004; 82:454–461.
50 Cates W, Feldblum P. HIV prevention research: the ecstasy and the agony. Lancet 2008; 372:1932–1933.
51 Balzarini J, Van Damme L. Microbicide drug candidates to prevent HIV infection. Lancet 2007; 369:787–797.
52 Cranage M, Sharpe S, Herrera C, et al
. Prevention of SIV rectal transmission and priming of T cell responses in macaques after local preexposure application of tenofovir gel. PLoS Med 2008; 5:e157, discussion e157.
53 Denton PW, Estes JD, Sun Z, et al
. Antiretroviral preexposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 2008; 5:e16.
54 Garcia-Lerma JG, Otten RA, Qari SH, et al
. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 2008; 5:e28.
55 Subbarao S, Otten RA, Ramos A, et al
. Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges. J Infect Dis 2006; 194:904–911.
56 Dumond JB, Yeh RF, Patterson KB, et al
. Antiretroviral drug exposure in the female genital tract: implications for oral pre and postexposure prophylaxis. AIDS 2007; 21:1899–1907.
57 Paxton LA, Hope T, Jaffe HW. Preexposure prophylaxis for HIV infection: what if it works? Lancet 2007; 370:89–93.
58 Paltiel AD, Freedberg KA, Scott CA, et al
. HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis 2009; 48:806–815.
59 Auvert B, Marseille E, Korenromp EL, et al
. Estimating the resources needed and savings anticipated from roll-out of adult male circumcision in Sub-Saharan Africa. PLoS ONE 2008; 3:e2679.
60 Kahn JG, Marseille E, Auvert B. Cost-effectiveness of male circumcision for HIV prevention in a South African setting. PLoS Med 2006; 3:e517.
61 Williams BG, Lloyd-Smith JO, Gouws E, et al
. The potential impact of male circumcision on HIV in Sub-Saharan Africa. PLoS Med 2006; 3:e262.
62 Bailey RC, Egesah O, Rosenberg S. Male circumcision for HIV prevention: a prospective study of complications in clinical and traditional settings in Bungoma, Kenya. Bull World Health Organ 2008; 86:669–677.
63 Bailey RC, Plummer FA, Moses S. Male circumcision and HIV prevention: current knowledge and future research directions. Lancet Infect Dis 2001; 1:223–231.
64 Mattson CL, Muga R, Poulussen R, et al
. Feasibility of medical male circumcision in Nyanza Province, Kenya. East Afr Med J 2004; 81:230–235.
65 Millett GA, Flores SA, Marks G, et al
. Circumcision status and risk of HIV and sexually transmitted infections among men who have sex with men: a meta-analysis. JAMA 2008; 300:1674–1684.
66 Vermund SH, Qian HZ. Circumcision and HIV prevention among men who have sex with men: no final word. JAMA 2008; 300:1698–1700.
67 Abu-Raddad LJ, Magaret AS, Celum C, et al
. Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa. PLoS ONE 2008; 3:e2230.
68 Freeman EE, Orroth KK, White RG, et al
. Proportion of new HIV infections attributable to herpes simplex 2 increases over time: simulations of the changing role of sexually transmitted infections in sub-Saharan African HIV epidemics. Sex Transm Infect 2007; 83(Suppl 1):i17–i24.
69 Grosskurth H, Gray R, Hayes R, et al
. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet 2000; 355:1981–1987.
70 White RG, Orroth KK, Glynn JR, et al
. Treating curable sexually transmitted infections to prevent HIV in Africa: still an effective control strategy? J Acquir Immune Defic Syndr 2008; 47:346–353.
71 White RG, Orroth KK, Korenromp EL, et al
. Can population differences explain the contrasting results of the Mwanza, Rakai, and Masaka HIV/sexually transmitted disease intervention trials? A modeling study. J Acquir Immune Defic Syndr 2004; 37:1500–1513.
72 Underhill K, Montgomery P, Operario D. Sexual abstinence only programmes to prevent HIV infection in high income countries: systematic review. BMJ 2007; 335:248.
73 Underhill K, Montgomery P, Operario D. Abstinence-plus programs for HIV infection prevention in high-income countries. Cochrane Database Syst Rev 2008:CD007006.
74 Underhill K, Operario D, Montgomery P. Abstinence-only programs for HIV infection prevention in high-income countries. Cochrane Database Syst Rev 2007:CD005421.
75 Pronyk PM, Kim JC, Abramsky T, et al
. A combined microfinance and training intervention can reduce HIV risk behaviour in young female participants. AIDS 2008; 22:1659–1665.
76 Gray RH, Li X, Kigozi G, et al
. The impact of male circumcision on HIV incidence and cost per infection prevented: a stochastic simulation model from Rakai, Uganda. AIDS 2007; 21:845–850.
77 Gray RH, Wawer MJ, Polis CB, et al
. Male circumcision and prevention of HIV and sexually transmitted infections. Curr Infect Dis Rep 2008; 10:121–127.
78 Kigozi G, Gray RH, Wawer MJ, et al
. The safety of adult male circumcision in HIV-infected and uninfected men in Rakai, Uganda. PLoS Med 2008; 5:e116.
79 Krieger JN, Bailey RC, Opeya J, et al
. Adult male circumcision: results of a standardized procedure in Kisumu District, Kenya. BJU Int 2005; 96:1109–1113.
80 Shaffer DN, Bautista CT, Sateren WB, et al
. The protective effect of circumcision on HIV incidence in rural low-risk men circumcised predominantly by traditional circumcisers in Kenya: two-year follow-up of the Kericho HIV Cohort Study. J Acquir Immune Defic Syndr 2007; 45:371–379.
81 Siegfried N, Muller M, Volmink J, Deeks J, Egger M, Low N, Weiss H, Walker S, Williamson P. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev 2003:CD003362.
82• Lagakos SW, Gable AR. Challenges to HIV prevention: seeking effective measures in the absence of a vaccine. N Engl J Med 2008; 358:1543–1545. A helpful review of key prevention trials challenges, emphasizing PrEP and microbicide trials.
83 Lagakos SW, Gable AR. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, D.C.: National Academies Press; 2008.
84 Corey L, McElrath MJ, Kublin JG. Poststep modifications for research on HIV vaccines. AIDS 2009; 23:3–8.
85 De Cock KM, Gilks CF, Lo YR, Guerma T. Can antiretroviral therapy eliminate HIV transmission? Lancet 2009; 373:7–9.
86 Garnett GP, Baggaley RF. Treating our way out of the HIV pandemic: could we, would we, should we? Lancet 2009; 373:9–11.
87• Granich RM, Gilks CF, Dye C, et al
. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2009; 373:48–57.