Combining prevention interventions is a familiar approach for public health interventions in low- and middle-income countries (LMIC). Control of tuberculosis (TB), for example, is recommended through the combination of case finding, contact tracing, isoniazid preventive therapy, optimized therapy, often directly observed, and environmental risk reduction to improve fresh air exchange in airplanes, housing, prisons, or health care settings.1–6 The public health challenge is how to implement what we know works to reduce TB transmission. Another example is malaria control that relies on the use of insecticide-treated bednets, environmental control of mosquito breeding sites, indoor residual spraying, seasonal malaria chemoprophylaxis, improved diagnosis and therapy (eg, artemisinin combination therapy) in the context of expanded primary care access, community education and engagement, and use of mosquito repellents.7,8 A malaria vaccine may join this list of intervention tools within a decade.9 Similar to TB and malaria, HIV now has a sound public health evidence base from both clinical trials10 and from observational studies to suggest appropriate elements of a strong combination prevention package suitable to target the generalized epidemic of sub-Saharan Africa (Table 1).
There is mixed evidence supporting the benefits of other biomedical interventions (ie, those not listed in Table 1). A tenofovir-containing vaginal microbicide worked to reduce short-term risk in the CAPRISA 004 trial, as did tenofovir–emtricitabine oral pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM in the iPrEx trial) and discordant couples in Africa (Partners PrEP and TDF-2 trials), whereas other clinical trials have been disappointing.49–54 Adherence levels have not yet been high enough to take full advantage of the biological potential of the topical or oral PrEP concept. Similarly, tools like the control of sexually transmitted infections (STI)15,55–58 and diagnosis/treatment of coinfections59–66 have demonstrated inconsistent evidence for their utility in HIV control, although they are valuable contributions to the health of individuals and the well-being of the community and may be justified as components of combination prevention in certain epidemic settings. Hence, both STI and TB programmatic improvements are being included in the PopART intervention but oral/topical PrEP are not.
As evidence accumulates in the future, other prevention approaches may be considered in combination prevention. HIV vaccines are an obvious choice if products prove efficacious, safe, and are licensed and produced for use.67,68 Future trials may prove both topical and oral PrEP to be more consistently efficacious if adherence can be improved. For example, 2 dapivirine vaginal ring microbicide efficacy trials are underway, one called The Ring Study, sponsored by the International Partnership for Microbicides,69 and a sister trial sponsored by the Microbicides Trials Network, called ASPIRE (MTN-020).70,71 The dapivirine microbicide ring delivers drug with only a monthly ring change needed, to potentially mitigate the adherence barrier of event-driven or daily use of oral or topical products.72–74
RATIONALE FOR THE HPTN 071 TRIAL
In the context of growing evidence of the efficacy of multiple modalities for HIV prevention, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) leadership determined the need to conduct research to determine the effectiveness of a combination of prevention interventions on HIV incidence at a population level. With support from PEPFAR, the National Institute of Allergy and Infectious Disease, the National Institute of Mental Health, the National Institute on Drug Abuse, and the Bill and Melinda Gates Foundation, the HPTN 071 (PopART) study [Population Effects of Antiretroviral Therapy (ART) to Reduce HIV Transmission] was designed to answer this important question. The implementation of the study interventions in South Africa and Zambia is supported through PEPFAR supplements to implementing partners through the United States Centers for Disease Control and Prevention and the U.S. Agency for International Development.
Covering greater numbers of persons with such interventions as testing and enhanced linkage to expanded care and voluntary medical male circumcision (VMMC) would both help reduce morbidity and mortality among HIV-infected persons receiving combination antiretroviral therapy (cART) and also reduce transmission risk to others. Although there are encouraging data from ecological and observational studies supporting the potential for HIV treatment to help with HIV prevention,29–31 none to date have tested the acceptability and operational challenges of delivering a combination universal test and treat and prevention intervention package in sub-Saharan Africa (SSA).
Testing expansion as an intervention in and of itself was assessed in the National Institute of Mental Health Project ACCEPT (HPTN 043) study which found that although expanded HIV testing was well accepted,20 it did not confer a significant reduction in population-level HIV incidence.19 One might speculate that the lack of a substantial impact on HIV transmission from expanded testing alone was the consequence of limited posttesting behavioral change and suboptimal linkage to ART-based care for those found to be HIV infected. In addition, the balance of benefits versus risks associated with very early and longer-term therapy (currently under study in the START trial),75 and particularly in LMIC settings, is unknown. LMIC with limited health care resources and minimal access to viral load testing might experience a high risk of the emergence of viral resistance from suboptimal adherence in asymptomatic persons, for example.76–79 At a population level, the need for controlled clinical trials in real-world field settings is underscored by the challenges of behavioral disinhibition (also termed risk compensation) for persons on cART who may sometimes perceive themselves healthier and/or less infectious to others.80–85 Finally, we do not know the logistical feasibility and cost-effectiveness of implementing expanded HIV detection and cART coverage within health care systems struggling to manage high overall disease burdens.86,87
HPTN 071 (PopART) Study Design Synopsis
Of the 21 communities participating in the HPTN 071 (PopART) study, 14 previously participated in the Zambia-South Africa TB and AIDS Reduction (ZAMSTAR) study, conducted by some of the investigators involved in this study.88–93 Thus, the HPTN 071 (PopART) study builds on strong relationships established between the investigators and the communities including the presence of active community advisory groups. Continuous consultative feedback from both communities and from government health officials has been essential in forging the details of the trial. The Ministries of Health of South Africa and Zambia and the relevant state, provincial, and district health authorities have been engaged fully in ethical vetting, implementation, and planning for the dissemination of study results.
The 21 communities of HPTN 071 (PopART) include 9 in the Western Cape Province of South Africa and 12 communities in Zambia and arranged in 7 matched triplets, with 4 triplets in Zambia and 3 in South Africa. Within each country, communities were matched based on the best available estimates of HIV prevalence and on geographical location and implementing partner for HIV services, with the aim of minimizing the between-community variance in baseline HIV incidence within matched triplets. Restricted randomization was used to ensure overall balance in cluster size, ART uptake and mean HIV prevalence across the study arms.94 In a public randomization ceremony in February 2013, 1 community from each triplet was randomly assigned to each of the 3 study arms (Fig. 1).
Arm A will receive the full PopART combination prevention program consisting of the following:
Offering voluntary HIV counseling and testing annually to every household (ie, home-based testing18 and couples counseling) with expanded HIV testing in health facilities.
Linking those with HIV infection to care at the local health facility.
Offering immediate cART to all HIV-infected persons regardless of CD4+ cell count or viral load.
Initiating cART for those HIV-infected persons already in care.
Promoting VMMC for men who test HIV seronegative.
Promoting prevention of mother-to-child HIV transmission services to HIV-infected pregnant women.
Improving the diagnosis and treatment of STI.
Providing risk reduction education and condoms in the community and in the health facilities.
Arm B will receive all the HIV prevention strategies in the PopART combination prevention program, except that cART will not be universal but will be offered to those who are eligible according to prevailing national guidelines, typically at a threshold of ≤350 CD4+ cells per microliter.95
Arm C will receive the current standard of care. However, special attention will be paid to ensure that there are no drug and laboratory reagent shortages or stock-outs in any of the 21 communities, ie, in all 3 study arms.
The full population in all 21 communities is estimated to be about 1.2 million persons. To measure the impact of the strategy, a population cohort will be selected from the general population consisting of a random sample of 2500 adults (one per household) aged 18–44 years from each community. Thus, the population cohort will have 52,500 persons recruited from the 21 communities (all 3 study arms; Fig. 1). A baseline survey of the cohort will be carried out at the time the intervention is initiated to assess the comparability of the 3 study arms. Follow-up surveys of the cohort will be carried out at 12, 24, and 36 months to measure HIV incidence, success in coverage of the interventions in the communities, and other outcomes.
The primary study outcome will be HIV incidence over 3 years in members of the population cohort who are HIV negative at baseline and will be compared in the intervention and control clusters to measure the population-level effectiveness of the PopART intervention. HPTN 071 (PopART) is very well powered to detect an effect of more than 35% in Arm A or Arm B compared with Arm C and is moderately well powered to detect an effect of 30%. To compare Arms A and B, the study is well powered to detect a difference between effects of 60% and 30%, 55% and 25%, and 50% and 20%. Assumptions are that there is a baseline HIV prevalence of 15% and that there will be losses to follow-up of 25% over 3 years in the population cohort.
The secondary outcomes will be measured in the population cohort to assess the effect of the intervention on a number of additional factors, including HIV incidence during each year of follow-up, reported sexual risk behavior, ART adherence and toxicity, HIV-related stigma, HIV disease progression, community viral load, ART drug resistance, herpes simplex virus-2 incidence, and TB case notification rates.
Process variables to be measured in the intervention clusters will include the following: acceptance of HIV testing and retesting; uptake of male circumcision among men testing HIV negative; proportion started on cART within 3 months of HIV diagnosis; and uptake of prevention of mother-to-child HIV transmission services. In addition, case–control studies will be conducted to examine factors related to the following: uptake of HIV testing during the first round of home-based testing in Arms A and B; uptake of immediate treatment in Arm A; and uptake of HIV testing in the second round of home-based testing in Arms A and B.
To inform the intervention before it is deployed in the communities, social science research has been undertaken to better understand the communities, their previous and current HIV landscape, and attitudes toward different prevention approaches. In addition, further social science research will be carried out throughout the study period to examine the acceptability of the PopART intervention and to document the effects of the interventions on a number of factors, including risk behaviors, social networks, HIV identity, and community-level HIV associated stigma. At the end of the testing campaign in each community, random samples of individuals who accept or decline testing will be interviewed to explore the reason for their decision. In addition, interviews will be carried out with randomly selected patients with good or poor adherence to ART.
Economic Evaluations and Modeling
Economic studies are planned to measure the incremental cost of the intervention packages, to estimate their cost-effectiveness, and to measure the burden on local health facilities of implementing the intervention. Hence, we are recording costs of all implementation efforts for such activities as testing, linkage, care, VMMC, expanded laboratory and ART costs, and community-level educational efforts. Mathematical modeling will use these data to assess the magnitude of the expected impact, given the process inputs, as the trial progresses.
OTHER POPULATION-LEVEL COMBINATION PREVENTION STUDIES
A large population-based combination prevention study is also planned in Botswana with funding from PEPFAR and sponsorship of the CDC.96–99 The study builds on work from an ongoing study of the Botswana-Harvard AIDS Institute Partnership in Mochudi, a community of 40,000 persons in Botswana.100–105 PEPFAR and the Bill and Melinda Gates Foundation have subsequently sponsored a harmonization effort between the HPTN 071 (PopART) study and the Botswana Combination Prevention Project that shares similar goals as those of HPTN 071 (PopART) but has a different study design. Laboratory, questionnaire, cost/economic assessments, and design/analytic issues have all been addressed to facilitate future meta-analysis opportunities. Another large combination prevention study is planned by the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS in France) with the Africa Centre for Health and Population Studies in KwaZulu Natal Province, South Africa.30,106–108 Initial work of the Africa Centre is promising in suggesting the potential impact of increases in cART coverage in patients with advanced HIV disease on HIV incidence.30,109 The findings from the latter study in rural South Africa are encouraging as it provides more rigorous ecological data than hitherto available.31,32,110,111 Other studies addressing treatment as prevention and/or combination prevention for HIV have been reviewed elsewhere.106
The opportunity to combine known efficacious interventions for HIV prevention into combination packages allows the examination of potential synergies that may be achieved in control of HIV transmission.10,15,16,112–115 Challenges are daunting given the need to have a high degree of coverage and efficiency in testing coverage, linkage to care, and high adherence in the context of expanded cART coverage.86,87,116,117 The extent to which efforts are successful in deploying needed interventions to the field at the levels needed to interrupt transmission cycles is the critical unknown at present. The engagement of national health authorities and local communities is essential for conduct of the study, dissemination of results, and future scale-up of successful approaches that are discovered. Combining known efficacious prevention approaches is complex to design and test, but their use in a synergistic strategy may open the door to substantial reductions in HIV incidence in some of the world's most afflicted nations.
The authors thank Dr. Wafaa El-Sadr, Ms. Megan Valentine, and Ms. Megan Pask for their help with the manuscript. The study is made possible with the support of the regional and national Ministries of Health of Zambia and South Africa. HPTN 071 Protocol Team members: Helen Ayles, Megan Baldwin, Nulda Beyers, Peter Bock, Virginia Bond, David Burns, Nathaniel Chishinga, Deborah Donnell, Lynda Emel, Susan Eshleman, Sarah Fidler, Sian Floyd, Christophe Fraser, Peter Godfrey-Faussett, Sam Griffith, James Hargreaves, Katharina Hauck, Richard Hayes, Tanette Headen, Lyn Horn, Corey Kelly, Peter Kim, Estelle Piwowar-Manning, Ayana Moore, Kalpana Sabapathy, Ab Schaap, Kwame Shanaube, Peter C. Smith, Sten H. Vermund, Deborah Watson-Jones, Rhonda White.
1. Reid SE, Reid CA, Vermund SH. Antiretroviral therapy in sub-Saharan Africa: adherence lessons from tuberculosis and leprosy. Int J STD AIDS. 2004;15:713–716.
2. Raviglione M, Marais B, Floyd K, et al.. Scaling up interventions to achieve global tuberculosis control: progress and new developments. Lancet. 2012;379:1902–1913.
3. Lienhardt C, Glaziou P, Uplekar M, et al.. Global tuberculosis control: lessons learnt and future prospects. Nat Rev Microbiol. 2012;10:407–416.
4. Pai NP, Pai M. Point-of-care diagnostics for HIV and tuberculosis: landscape, pipeline, and unmet needs. Discov Med. 2012;13:35–45.
5. Uyei J, Coetzee D, Macinko J, et al.. Integrated delivery of HIV and tuberculosis services in sub-Saharan Africa: a systematic review. Lancet Infect Dis. 2011;11:855–867.
6. Legido-Quigley H, Montgomery CM, Khan P, et al.. Integrating tuberculosis and HIV services in low- and middle-income countries: a systematic review. Trop Med Int Health. 2013;18:199–211.
7. Breman JG, Brandling-Bennett AD. The challenge of malaria eradication in the twenty-first century: research linked to operations is the key. Vaccine. 2011;29(suppl 4):D97–D103.
8. malERA Consultative Group on Health Systems and Operational Research. A research agenda for malaria eradication: health systems and operational research. PLoS Med. 2011;8:e1000397.
9. Moorthy V, Newman R, Duclos P, et al.. Assessment of the RTS, S/AS01 malaria vaccine. Lancet Infect Dis. 2013;13:319–327.
10. Padian NS, McCoy SI, Karim SS, et al.. HIV prevention transformed: the new prevention research agenda. Lancet. 2011;378:269–278.
11. 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.
12. 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.
13. 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.
14. Smith MK, Powers KA, Muessig KE, et al.. HIV treatment as prevention: the utility and limitations of ecological observation. PLoS Med. 2012;9:e1001260.
15. Vermund SH, Hayes RJ. Combination prevention: new hope for stopping the epidemic. Curr HIV/AIDS Rep. 2013;10:169–186.
16. Kurth AE, Celum C, Baeten JM, et al.. Combination HIV prevention: significance, challenges, and opportunities. Curr HIV/AIDS Rep. 2011;8:62–72.
17. Jurgensen M, Sandoy IF, Michelo C, et al.. Effects of home-based voluntary counselling and testing on HIV-related stigma: findings from a cluster-randomized trial in Zambia. Soc Sci Med. 2013;81:18–25.
18. Sabapathy K, Van den Bergh R, Fidler S, et al.. Uptake of home-based voluntary HIV testing in sub-Saharan Africa: a systematic review and meta-analysis. PLoS Med. 2012;9:e1001351.
19. Coates T, Eshleman S, Chariyalertsak S, et al.. Community-level reductions in estimated HIV incidence: HIV prevention trials network 043, project accept. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; March 4, 2013; Atlanta, GA.
20. 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.
21. Safren SA, O'Cleirigh C, Skeer MR, et al.. Demonstration and evaluation of a peer-delivered, individually-tailored, HIV prevention intervention for HIV-infected MSM in their primary care setting. AIDS Behav. 2011;15:949–958.
22. Cohen MS, McCauley M, Gamble TR. HIV treatment as prevention and HPTN 052. Curr Opin HIV AIDS. 2012;7:99–105.
23. McNairy ML, Cohen M, El-Sadr WM. Antiretroviral therapy for prevention is a combination strategy. Current HIV/AIDS Rep. 2013;10:152–158.
24. Chen YQ, Masse B, Wang L, et al.. Statistical considerations for the HPTN 052 Study to evaluate the effectiveness of early versus delayed antiretroviral strategies to prevent the sexual transmission of HIV-1 in serodiscordant couples. Contemp Clin Trials. 2012;33:1280–1286.
25. Cohen MS, McCauley M, Sugarman J. Establishing HIV treatment as prevention in the HIV Prevention Trials Network 052 randomized trial: an ethical odyssey. Clin Trials. 2012;9:340–347.
26. Eshleman SH, Hudelson SE, Redd AD, et al.. Analysis of genetic linkage of HIV from couples enrolled in the HIV Prevention Trials Network 052 trial. J Infect Dis. 2011;204:1918–1926.
27. 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.
28. Donnell D, Baeten JM, Kiarie J, et al.. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;375:2092–2098.
29. Jia Z, Ruan Y, Li Q, et al.. Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003-11): a national observational cohort study. Lancet. 2012. DOI: 10.1016/S0140-6736(12)61898-4.
30. Tanser F, Barnighausen 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;339:966–971.
31. Das M, Chu PL, Santos GM, et al.. Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. PloS One. 2010;5:e11068.
32. Montaner JS. Treatment as prevention—a double hat-trick. Lancet. 2011;378:208–209.
33. Chi BH, Adler MR, Bolu O, et al.. Progress, challenges, and new opportunities for the prevention of mother-to-child transmission of HIV under the US President's Emergency Plan for AIDS Relief. J Acquir Immune Defic Syndr. 2012;60(suppl 3):S78–S87.
34. Bertagnolio S, Penazzato M, Jordan MR, et al.. World Health Organization generic protocol to assess drug-resistant HIV among children <18 months of age and newly diagnosed with HIV in resource-limited countries. Clin Infect Dis. 2012;54(suppl 4):S254–S260.
35. Holmes KK, Levine R, Weaver M. Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ. 2004;82:454–461.
36. Sweat MD, Denison J, Kennedy C, et al.. Effects of condom social marketing on condom use in developing countries: a systematic review and meta-analysis, 1990-2010. Bull World Health Organ. 2012;90:613–622A.
37. Beksinska ME, Smit JA, Mantell JE. Progress and challenges to male and female condom use in South Africa. Sex Health. 2012;9:51–58.
38. Gallo MF, Kilbourne-Brook M, Coffey PS. A review of the effectiveness and acceptability of the female condom for dual protection. Sex Health. 2012;9:18–26.
39. Stoneburner RL, Low-Beer D. Population-level HIV declines and behavioral risk avoidance in Uganda. Science. 2004;304:714–718.
40. Marum E, Taegtmeyer M, Parekh B, et al.. What took you so long? the impact of PEPFAR on the expansion of HIV testing and counseling services in Africa. J Acquir Immune Defic Syndr. 2012;60(suppl 3):S63–S69.
41. Allen S, Serufilira A, Bogaerts J, et al.. Confidential HIV testing and condom promotion in Africa. Impact on HIV and gonorrhea rates. JAMA. 1992;268:3338–3343.
42. Needle R, Fu J, Beyrer C, et al.. PEPFAR's evolving HIV prevention approaches for key populations—people who inject drugs, men who have sex with men, and sex workers: progress, challenges, and opportunities. J Acquir Immune Defic Syndr. 2012;60(suppl 3):S145–S151.
43. Dutta A, Wirtz AL, Baral S, et al.. Key harm reduction interventions and their impact on the reduction of risky behavior and HIV incidence among people who inject drugs in low-income and middle-income countries. Curr Opin HIV AIDS. 2012;7:362–368.
44. van Hulst M, de Wolf JT, Staginnus U, et al.. Pharmaco-economics of blood transfusion safety: review of the available evidence. Vox Sang. 2002;83:146–155.
45. Persaud D, Gay H, Ziemniak C, et al.. Functional HIV cure after very early ART of an infected infant. 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 4, 2013; Atlanta, GA.
46. Cohen MS, Muessig KE, Smith MK, et al.. Antiviral agents and HIV prevention: controversies, conflicts, and consensus. AIDS. 2012;26:1585–1598.
47. Rey D. Post-exposure prophylaxis for HIV infection. Expert Rev Anti-Infective Ther. 2011;9:431–442.
48. Saez-Cirion A, Bacchus C, Hocqueloux L, et al.. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. PLoS Pathog. 2013;9:e1003211.
49. 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.
50. Baeten JM, Donnell D, Ndase P, et al.. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399–410.
51. 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.
52. 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.
53. Marrazzo J, Ramjee G, Palanee T, et al.. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 3–6, 2013, 2013; Atlanta, GA.
54. 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.
55. 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.
56. 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.
57. Korenromp EL, White RG, Orroth KK, et al.. Determinants of the impact of sexually transmitted infection treatment on prevention of HIV infection: a synthesis of evidence from the Mwanza, Rakai, and Masaka intervention trials. J Infect Dis. 2005;191(suppl 1):S168–S178.
58. Hayes R, Watson-Jones D, Celum C, et al.. Treatment of sexually transmitted infections for HIV prevention: end of the road or new beginning? AIDS. 2010;24(suppl 4):S15–S26.
59. Walson J, Singa B, Sangare L, et al.. Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): a multi-site, randomised trial. Lancet Infect Dis. 2012;12:925–932.
60. Walson JL, Sangare LR, Singa BO, et al.. Evaluation of impact of long-lasting insecticide-treated bed nets and point-of-use water filters on HIV-1 disease progression in Kenya. AIDS. 2013;27:1493–1501.
61. Modjarrad K, Vermund SH. Effect of treating co-infections on HIV-1 viral load: a systematic review. Lancet Infect Dis. 2010;10:455–463.
62. Modjarrad K, Chamot E, Vermund SH. Impact of small reductions in plasma HIV RNA levels on the risk of heterosexual transmission and disease progression. AIDS. 2008;22:2179–2185.
63. Webb EL, Kyosiimire-Lugemwa J, Kizito D, et al.. The effect of anthelmintic treatment during pregnancy on HIV plasma viral load: results from a randomized, double-blind, placebo-controlled trial in Uganda. J Acquir Immune Defic Syndr. 2012;60:307–313.
64. Webb EL, Mawa PA, Ndibazza J, et al.. Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377:52–62.
65. Ndibazza J, Muhangi L, Akishule D, et al.. Effects of deworming during pregnancy on maternal and perinatal outcomes in Entebbe, Uganda: a randomized controlled trial. Clin Infect Dis. 2010;50:531–540.
66. Walson JL, Otieno PA, Mbuchi M, et al.. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS. 2008;22:1601–1609.
67. McMichael AJ, Haynes BF. Lessons learned from HIV-1 vaccine trials: new priorities and directions. Nat Immunol. 2013;14:413.
68. Liao HX, Lynch R, Zhou T, et al.. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013;496:469–476.
72. Fetherston SM, Malcolm RK, Woolfson AD. Controlled-release vaginal ring drug-delivery systems: a key strategy for the development of effective HIV microbicides. Ther Deliv. 2010;1:785–802.
73. Malcolm RK, Fetherston SM, McCoy CF, et al.. Vaginal rings for delivery of HIV microbicides. Int J Womens Health 2012;4:595–605.
74. Geonnotti AR, Katz DF. Compartmental transport model of microbicide delivery by an intravaginal ring. J Pharm Sci. 2010;99:3514–3521.
75. Lifson AR, Group IERCW, Belloso WH, et al.. Development of diagnostic criteria for serious non-AIDS events in HIV clinical trials. HIV Clin Trials. 2010;11:205–219.
76. Manasa J, Katzenstein D, Cassol S, et al.. Primary drug resistance in South Africa: data from 10 years of surveys. AIDS Res Hum Retroviruses. 2012;28:558–565.
77. Nichols BE, Boucher CA, van de Vijver DA. HIV testing and antiretroviral treatment strategies for prevention of HIV infection: impact on antiretroviral drug resistance. J Intern Med. 2011;270:532–549.
78. Sigaloff KC, Calis JC, Geelen SP, et al.. HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: a systematic review. Lancet Infect Dis. 2011;11:769–779.
79. Obiako OR, Murktar HM, Ogoina D. Antiretroviral drug resistance—implications for HIV/AIDS reduction in sub-Saharan Africa and other developing countries. Niger J Med. 2010;19:352–360.
80. DiClemente RJ, Funkhouser E, Wingood G, et al.. Protease inhibitor combination therapy and decreased condom use among gay men. South Med J. 2002;95:421–425.
81. Ostrow DE, Fox KJ, Chmiel JS, et al.. Attitudes towards highly active antiretroviral therapy are associated with sexual risk taking among HIV-infected and uninfected homosexual men. AIDS. 2002;16:775–780.
82. Stolte IG, Dukers NH, Geskus RB, et al.. Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active antiretroviral therapy: a longitudinal study. AIDS. 2004;18:303–309.
83. Dukers NH, Goudsmit J, de Wit JB, et al.. Sexual risk behaviour relates to the virological and immunological improvements during highly active antiretroviral therapy in HIV-1 infection. AIDS. 2001;15:369–378.
84. Tun W, Celentano DD, Vlahov D, et al.. Attitudes toward HIV treatments influence unsafe sexual and injection practices among injecting drug users. AIDS. 2003;17:1953–1962.
85. MacKellar DA, Hou SI, Whalen CC, et al.. HIV/AIDS complacency and HIV infection among young men who have sex with men, and the race-specific influence of underlying HAART beliefs. Sex Transm Dis. 2011;38:755–763.
86. Vermund SH, Sidat M, Weil LF, et al.. Transitioning HIV care and treatment programs in southern Africa to full local management. AIDS. 2012;26:1303–1310.
87. Shelton JD. HIV/AIDS. ARVs as HIV prevention: a tough road to wide impact. Science. 2011;334:1645–1646.
88. Ayles H, Schaap A, Nota A, et al.. Prevalence of tuberculosis, HIV and respiratory symptoms in two Zambian communities: implications for tuberculosis control in the era of HIV. PloS One. 2009;4:e5602.
89. Ayles HM, Sismanidis C, Beyers N, et al.. ZAMSTAR, The Zambia South Africa TB and HIV Reduction Study: design of a 2 x 2 factorial community randomized trial. Trials. 2008;9:63.
90. Shanaube K, Sismanidis C, Ayles H, et al.. Annual risk of tuberculous infection using different methods in communities with a high prevalence of TB and HIV in Zambia and South Africa. PloS One. 2009;4:e7749.
91. Sismanidis C, Moulton LH, Ayles H, et al.. Restricted randomization of ZAMSTAR: a 2 x 2 factorial cluster randomized trial. Clin Trials. 2008;5:316–327.
92. Zachary D, Mwenge L, Muyoyeta M, et al.. Field comparison of OraQuick ADVANCE Rapid HIV-1/2 antibody test and two blood-based rapid HIV antibody tests in Zambia. BMC Infect Dis. 2012;12:183.
93. O'Brien J. Using radio to create awareness and educate the community about tuberculosis and HIV in Zambia. Int J Tuberc Lung Dis. 2011;15(11 suppl 3):S37.
94. Hayes R, Sabapathy K, Fidler S. Universal testing and treatment as an HIV prevention strategy: research questions and methods. Curr HIV Res. 2011;9:429–445.
95. WHO. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2010 revision. In: WHO, ed. HIV/AIDS Programme: Strengthening Health Services to Fight HIV/AIDS. Vol. 2010 Revision. Geneva, Switzerland: World Health Organization; 2010:1–156.
96. Jayeoba O, Dryden-Peterson S, Okui L, et al.. Acceptability of male circumcision among adolescent boys and their parents, Botswana. AIDS Behav. 2012;16:340–349.
97. Andersson N, Cockcroft A. Male circumcision, attitudes to HIV prevention and HIV status: a cross-sectional study in Botswana, Namibia and Swaziland. AIDS Care. 2012;24:301–309.
98. Njeuhmeli E, Forsythe S, Reed J, et al.. Voluntary medical male circumcision: modeling the impact and cost of expanding male circumcision for HIV prevention in eastern and southern Africa. PLoS Med. 2011;8:e1001132.
99. Plank RM, Ndubuka NO, Wirth KE, et al.. A Randomized Trial of Mogen Clamp versus Plastibell for Neonatal Male Circumcision in Botswana. J Acqui Immune Defic Syndr. 2013;62:e131–e137.
100. McDonald B, Moyo S, Gabaitiri L, et al.. Significant elevations in interleukin-6 levels as a predictor of all-cause mortality among adults receiving cART in Botswana: results from a clinical trial (Paper #780). 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 5, 2013; Atlanta, GA.
101. Plank R, Wirth K, Ndubuka NK, et al.. Uptake of neonatal male circumcision as part of HIV prevention efforts in Botswana: maternal motivators and barriers (Paper #1011). 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 4, 2013; Atlanta, GA.
102. Davis R, Dzoro S, Moyo S, et al.. Optimizing a dried blood spot-based pooled RT-PCR technique for identification of acute HIV infections in Mochudi, Botswana (TUPDBO203). XIX International AIDS Conference; July 24, 2012; Washington, DC, USA.
103. Rossenkhan R, Novitsky V, Sebunya TK, et al.. Viral diversity and diversification of major non-structural genes vif, vpr, vpu, tat exon 1 and rev exon 1 during primary HIV-1 subtype C infection. PloS One. 2012;7:e35491.
104. Novitsky V, Smith UR, Gilbert P, et al.. Human immunodeficiency virus type 1 subtype C molecular phylogeny: consensus sequence for an AIDS vaccine design? J Virol. 2002;76:5435–5451.
105. Novitsky VA, Montano MA, McLane MF, et al.. Molecular cloning and phylogenetic analysis of human immunodeficiency virus type 1 subtype C: a set of 23 full-length clones from Botswana. J Virol. 1999;73:4427–4432.
106. Granich R, Gupta S, Suthar AB, et al.. Antiretroviral therapy in prevention of HIV and TB: update on current research efforts. Curr HIV Res. 2011;9:446–469.
107. Barnighausen T, Tanser F, Dabis F, et al.. Interventions to improve the performance of HIV health systems for treatment-as-prevention in sub-Saharan Africa: the experimental evidence. Curr Opin HIV AIDS. 2012;7:140–150.
108. Dabis F, Newell ML, Hirschel B. HIV drugs for treatment, and for prevention. Lancet. 2010;375:2056–2057.
109. Bor J, Herbst AJ, Newell ML, et al.. Increases in adult life expectancy in rural South Africa: valuing the scale-up of HIV treatment. Science. 2013;339:961–965.
110. Montaner JS, Lima VD, Barrios R, et al.. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet. 2010;376:532–539.
111. Granich R, Williams B, Montaner J. Fifteen million people on antiretroviral treatment by 2015: treatment as prevention. Curr Opin HIV AIDS. 2013;8:41–49.
112. Chang LW, Serwadda D, Quinn TC, et al.. Combination implementation for HIV prevention: moving from clinical trial evidence to population-level effects. Lancet Infect Dis. 2013;13:65–76.
113. Estill J, Egger M, Blaser N, et al.. Cost-effectiveness of point-of-care viral load monitoring of ART in resource-limited settings: mathematical modelling study. AIDS. 2013;27:1483–1492.
114. Estill J, Egger M, Johnson LF, et al.. Monitoring of antiretroviral therapy and mortality in HIV programmes in Malawi, South Africa and Zambia: mathematical modelling study. PloS One. 2013;8:e57611.
115. 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.
116. Smith K, Powers KA, Kashuba AD, et al.. HIV-1 treatment as prevention: the good, the bad, and the challenges. Curr Opin HIV AIDS. 2011;6:315–325.
117. Mills EJ, Nachega JB, Ford N. Can we stop AIDS with antiretroviral-based treatment as prevention. Glob Health Sci Pract. 2013;1:29–34.