HIV Treatment as Prevention: The Utility and Limitations of Ecological Observation

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Results from several observational studies of HIV-discordant couples and a randomized controlled trial (HIV Prevention Trials Network 052) show that antiretroviral therapy (ART) can greatly reduce heterosexual HIV transmission in stable HIV-discordant couples. However, such data do not prove that ART will reduce HIV incidence at the population level. Observational investigations using ecological measures have been used to support the implementation of HIV treatment for the specific purpose of preventing transmission at the population level. Many of these studies note ecological associations between measures of increased ART uptake and decreased HIV transmission. Given the urgency of implementing HIV prevention measures, ecological studies must de facto be used to inform current strategies. However, the hypothesis that widespread ART can eliminate HIV infection may have raised expectations beyond what we may be able to achieve. Here we review and discuss the construct of the exposure and outcome measures and analysis methods used in ecological studies. By examining the strengths and weaknesses of ecological analyses, we aim to aid understanding of the findings from these studies to inform future policy decisions regarding the use of ART for HIV prevention.

Vyšlo v časopise: HIV Treatment as Prevention: The Utility and Limitations of Ecological Observation. PLoS Med 9(7): e32767. doi:10.1371/journal.pmed.1001260
Kategorie: Review
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1001260

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1. RothmanKJGreenlandSLashTL 2008 Modern epidemiology Philadelphia Lippincott Williams & Wilkins

2. PiantadosiSByarDPGreenSB 1988 The ecological fallacy. Am J Epidemiol 127 893 904

3. HallettTBWhitePJGarnettGP 2007 Appropriate evaluation of HIV prevention interventions: from experiment to full-scale implementation. Sex Transm Infect 83 Suppl 1 i55 i60 doi:10.1136/sti.2006.023663

4. MorgensternH 1995 Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health 16 61 81 doi:10.1146/annurev.pu.16.050195.000425.bv

5. GreenlandSRobinsJ 1994 Invited commentary: ecologic studies—biases, misconceptions, and counterexamples. Am J Epidemiol 139 747 760

6. SchwartzS 1994 The fallacy of the ecological fallacy: the potential misuse of a concept and the consequences. Am J Public Health 84 819 824 doi:10.2105/AJPH.84.5.819

7. RobinsonW 1950 Ecological correlations and the behavior of individuals. Am Sociol Rev 15 351 357 doi:10.1093/ije/dyn357

8. DurrheimDOgunbanjoG 2004 Making sense of statistics for the family practitioner: “what are ecological studies?” S Afr Fam Pract 46 48

9. MosesSBradleyJENagelkerkeNJRonaldARNdinya-AcholaJO 1990 Geographical patterns of male circumcision practices in Africa: association with HIV seroprevalence. Int J Epidemiol 19 693 697

10. BongaartsJReiningPWayPConantF 1989 The relationship between male circumcision and HIV infection in African populations. AIDS 3 373 377

11. CaldwellJCCaldwellP 1996 The African AIDS epidemic. Sci Am 274 62-63, 66-68

12. WeissHAQuigleyMAHayesRJ 2000 Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 14 2361 2370

13. SiegfriedNMullerMDeeksJVolminkJEggerM 2005 HIV and male circumcision—a systematic review with assessment of the quality of studies. Lancet Infect Dis 5 165 173 doi:10.1016/S1473-3099(05)01309-5

14. BaileyRCPlummerFAMosesS 2001 Male circumcision and HIV prevention: current knowledge and future research directions. Lancet Infect Dis 1 223 231 doi:10.1016/S1473-3099(01)00117-7

15. GrayRHKigoziGSerwaddaDMakumbiFWatyaS 2007 Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 369 657 666 doi:10.1016/S0140-6736(07)60313-4

16. SiegfriedNMullerMDeeksJJVolminkJ 2009 Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev 2009 CD003362 doi:10.1002/14651858.CD003362.pub2

17. HenryKChinnockBJQuinnRPFletcherCVde MirandaP 1988 Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex. JAMA 259 3023 3026

18. DumondJBYehRFPattersonKBCorbettAHJungBH 2007 Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS 21 1899 1907 doi:10.1097/QAD.0b013e328270385a

19. NicolMRKashubaADM 2010 Pharmacologic opportunities for HIV prevention. Clin Pharmacol Ther 88 598 609 doi:10.1038/clpt.2010.189

20. PereiraASKashubaADFiscusSAHallJETidwellRR 1999 Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden. J Infect Dis 180 2039 2043 doi:10.1086/315149

21. KashubaADDyerJRKramerLMRaaschRHEronJJ 1999 Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1. Antimicrob Agents Chemother 43 1817 1826

22. MusiccoMLazzarinANicolosiAGaspariniMCostigliolaP 1994 Antiretroviral treatment of men infected with human immunodeficiency virus type 1 reduces the incidence of heterosexual transmission. Italian Study Group on HIV Heterosexual Transmission. Arch Intern Med 154 1971 1976

23. SiegfriedNvan der MerweLBrocklehurstPSintTT 2011 Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev 2011 CD003510 doi:10.1002/14651858.CD003510.pub3

24. CohenMSMcCauleyMGambleTR 2012 HIV treatment as prevention and HPTN 052. Curr Opin HIV AIDS 7 99 105 doi:10.1097/COH.0b013e32834f5cf2

25. DonnellDBaetenJMKiarieJThomasKKStevensW 2010 Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet 375 2092 2098 doi:10.1016/S0140-6736(10)60705-2

26. BunnellREkwaruJPSolbergPWamaiNBikaako-KajuraW 2006 Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. AIDS 20 85 92

27. SullivanPKayitenkoreKChombaEKaritaEMwananyandaL 2010 Reduction of HIV transmission risk while prescribed anti-retroviral therapy (ARVT): Misclassification of ARVT status as a methodological issue [abstract]. AIDS Vaccine 2010; 28 Sept–1 Oct 2010; Atlanta, Georgia, US. AIDS Res Hum Retroviruses 26 A-1 A-184 doi:10.1089/aid.2010.9998

28. Del RomeroJCastillaJHernandoVRodriguezCGarciaS 2010 Combined antiretroviral treatment and heterosexual transmission of HIV-1: cross sectional and prospective cohort study. BMJ 340 c2205 c2205 doi:10.1136/bmj.c2205

29. WangLGeZLuoJShanDGaoX 2010 HIV transmission risk among serodiscordant couples: a retrospective study of former plasma donors in Henan, China. J Acquir Immune Defic Syndr 55 232 238 doi:10.1097/QAI.0b013e3181e9b6b7

30. GayCLCohenMS 2008 Antiretrovirals to prevent HIV infection: pre- and postexposure prophylaxis. Curr Infect Dis Rep 10 323 331

31. GranichRMGilksCFDyeCDe CockKMWilliamsBG 2009 Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 373 48 57 doi:10.1016/S0140-6736(08)61697-9

32. EatonJWJohnsonLFSalomonJABärnighausenTBendavidE 2012 HIV treatment as prevention: systematic comparison of mathematical models of the potential impact of antiretroviral therapy on HIV incidence in South Africa. PLoS Med 9 e1001245 doi:10.1371/journal.pmed.1001245

33. MontanerJSLimaVDBarriosRYipBWoodE 2010 Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet 376 532 539 doi:10.1016/S0140-6736(10)60936-1

34. DasMChuPLSantosG-MScheerSVittinghoffE 2010 Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. PLoS ONE 5 e11068 doi:10.1371/journal.pone.0011068

35. FangC-THsuH-MTwuS-JChenM-YChangY-Y 2004 Decreased HIV transmission after a policy of providing free access to highly active antiretroviral therapy in Taiwan. J Infect Dis 190 879 885 doi:10.1086/422601

36. WoodEKerrTMarshallBDLLiKZhangR 2009 Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 among injecting drug users: prospective cohort study. BMJ 338 b1649 doi:10.1136/bmj.b1649

37. LawMGWoolleyITempletonDJRothNChuahJ 2011 Trends in detectable viral load by calendar year in the Australian HIV observational database. J Int AIDS Soc 14 10 doi:10.1186/1758-2652-14-10

38. PorcoTCMartinJNPage-ShaferKAChengACharleboisE 2004 Decline in HIV infectivity following the introduction of highly active antiretroviral therapy. AIDS 18 81 88

39. CastelADBefusMWillisSGriffinAWestT 2011 Use of the community viral load as a population-based biomarker of HIV burden, Washington, DC. AIDS 26 345 353 doi:10.1097/QAD.0b013e32834de5fe

40. KatzMHSchwarczSKKelloggTAKlausnerJDDilleyJW 2002 Impact of highly active antiretroviral treatment on HIV seroincidence among men who have sex with men: San Francisco. Am J Public Health 92 388 394

41. CohenMSChenYQMcCauleyMGambleTHosseinipourMC 2011 Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 365 493 505 doi:10.1056/NEJMoa1105243

42. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention Conference Programme 2011 Fauci: looking to Rome, with optimism. Available: http://blog.ias2011.org/post/2011/07/10/Looking-to-Rome-with-Optimism.aspx. Accessed 26 December 2011

43. del RioC 2011 Treatment is prevention: the results of HPTN 052. Journal Watch. Available: http://aids-clinical-care.jwatch.org/cgi/content/full/2011/719/1. Accessed 25 November 2011

44. SquiresKEHughesJM 2011 [Letter to the President of the United States on behalf of the Infectious Diseases Society of America and the HIV Medicine Association.] Available: http://www.hivma.org/uploadedFiles/HIVMA/Policy_and_Advocacy/Policy_Priorities/Evidence_Based_Prevention/Comments/HPTN_052_Letter.pdf#search=%22squireshughes%22. Accessed 3 June 2012

45. MaughTH2nd 2011 May 13 Anti-HIV drugs prove highly effective in preventing transmission of virus. Los Angeles Times Available: http://articles.latimes.com/2011/may/13/health/la-he-aids-prevention-20110513. Accessed 29 May 2012

46. Panel on Antiretroviral Guidelines for Adults and Adolescents 2012 Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. US Department of Health and Human Services Available: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed 29 May 2012

47. World Health Organization 2011 The strategic use of antiretrovirals for treatment and prevention of HIV Geneva World Health Organization Available: http://www.who.int/hiv/pub/meetingreports/consultation_20111116/en/index.html. Accessed 29 May 2012

48. EpsteinHMorrisM 2011 HPTN 052 and the future of HIV treatment and prevention. Lancet 378 225 doi:10.1016/S0140-6736(11)61117-3

49. CatesW 2011 HPTN 052 and the future of HIV treatment and prevention. Lancet 378 224 225 doi:10.1016/S0140-6736(11)61116-1

50. AnglemyerARutherfordGWEggerMSiegfriedN 2011 Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. Cochrane Database Syst Rev 2011 CD009153 doi:10.1002/14651858.CD009153

51. SchwartländerBStoverJHallettTAtunRAvilaC 2011 Towards an improved investment approach for an effective response to HIV/AIDS. Lancet 377 2031 2041 doi:10.1016/S0140-6736(11)60702-2

52. GeffenN 2011 When to start antiretroviral therapy in adults: the results of HPTN 052 move us closer to a “test-and-treat” policy. South Afr J HIV Med 12 9 11 Available: http://sajhivmed.org.za/index.php/sajhivmed/article/view/733/586. Accessed 29 May 2012

53. MontanerJSG 2011 Treatment as prevention—a double hat-trick. Lancet 378 208 209 doi:10.1016/S0140-6736(11)60821-0

54. 2011 HIV treatment as prevention—it works. Lancet 377 1719 doi:10.1016/S0140-6736(11)60713-7

55. SealeALazarusJVGrubbIFakoyaAAtunR 2011 HPTN 052 and the future of HIV treatment and prevention. Lancet 378 226 225 doi:10.1016/S0140-6736(11)61118-5

56. LawMGPrestageGGrulichAVan de VenPKippaxS 2001 Modelling the effect of combination antiretroviral treatments on HIV incidence. AIDS 15 1287 1294

57. BlowerSBodineEKahnJMcFarlandW 2005 The antiretroviral rollout and drug-resistant HIV in Africa: insights from empirical data and theoretical models. AIDS 19 1 14

58. LimaVDJohnstonKHoggRSLevyARHarriganPR 2008 Expanded access to highly active antiretroviral therapy: a potentially powerful strategy to curb the growth of the HIV epidemic. J Infect Dis 198 59 67 doi:10.1086/588673

59. Meyer-RathGOverM 2012 HIV treatment as prevention: modelling the cost of antiretroviral treatment—state of the art and future directions. PLoS Med 9 e1001247 doi:10.1371/journal.pmed.1001247

60. CohenMSGayCL 2010 Treatment to prevent transmission of HIV-1. Clin Infect Dis 50 S85 S95 doi:10.1086/651478

61. GardnerEMMcLeesMPSteinerJFdel RioCBurmanWJ 2011 The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis 52 793 800 doi:10.1093/cid/ciq243

62. BurnsDNDieffenbachCWVermundSH 2010 Rethinking prevention of HIV type 1 infection. Clin Infect Dis 51 725 731 doi:10.1086/655889

63. US Centers for Disease Control and Prevention 2011 Nov 29 Only one quarter of Americans with HIV have virus under control. Available: http://www.cdc.gov/nchhstp/newsroom/WAD2011PressRelease.html. Accessed 29 May 2012

64. KatzITEssienTMarindaETGrayGEBangsbergDR 2011 Antiretroviral therapy refusal among newly diagnosed HIV-infected adults. AIDS 25 2177 2181 doi:10.1097/QAD.0b013e32834b6464

65. QuinnTCWawerMJSewankamboNSerwaddaDLiC 2000 Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 342 921 929 doi:10.1056/NEJM200003303421303

66. BaetenJMKahleELingappaJRCoombsRWDelany-MoretlweS 2011 Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci Transl Med 3 77ra29 doi:10.1126/scitranslmed.3001888

67. PowersKAGhaniACMillerWCHoffmanIFPettiforAE 2011 The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study. Lancet 378 256 268 doi:10.1016/S0140-6736(11)60842-8

68. BrennerBGRogerMRoutyJPMoisiDNtemgwaM 2007 High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 195 951 959 doi:10.1086/512088

69. Lopez-QuinteroCShtarkshallRNeumarkYD 2005 Barriers to HIV-testing among Hispanics in the United States: analysis of the National Health Interview Survey, 2000. AIDS Patient Care STDS 19 672 683 doi:10.1089/apc.2005.19.672

70. SpielbergFBransonBMGoldbaumGMLockhartDKurthA 2003 Overcoming barriers to HIV testing: preferences for new strategies among clients of a needle exchange, a sexually transmitted disease clinic, and sex venues for men who have sex with men. J Acquir Immune Defic Syndr 32 318 327

71. SheltonJDCohenMBarnhartMHallettT 2010 Is antiretroviral therapy modifying the HIV epidemic? Lancet 376 1824 1825 doi:10.1016/S0140-6736(10)62163-0

72. WandHWilsonDYanPGonnermannAMcDonaldA 2009 Characterizing trends in HIV infection among men who have sex with men in Australia by birth cohorts: results from a modified back-projection method. J Int AIDS Soc 12 19 doi:10.1186/1758-2652-12-19

73. NovitskyVWangRBussmannHLockmanSBaumM 2010 HIV-1 subtype C-infected individuals maintaining high viral load as potential targets for the “test-and-treat” approach to reduce HIV transmission. PLoS ONE 5 e10148 doi:10.1371/journal.pone.0010148

74. WolbersMBabikerASabinCYoungJDorrucciM 2010 Pretreatment CD4 cell slope and progression to AIDS or death in HIV-infected patients initiating antiretroviral therapy—the CASCADE collaboration: a collaboration of 23 cohort studies. PLoS Med 7 e1000239 doi:10.1371/journal.pmed.1000239

75. JanssenRSSattenGAStramerSLRawalBDO'BrienTR 1998 New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. JAMA 280 42 48

76. Le VuSPillonelJSemailleCBernillonPLe StratY 2008 Principles and uses of HIV incidence estimation from recent infection testing—a review. Euro Surveill 13 18969

77. BuschMPPilcherCDMastroTDKaldorJVercauterenG 2010 Beyond detuning: 10 years of progress and new challenges in the development and application of assays for HIV incidence estimation. AIDS 24 2763 2771 doi:10.1097/QAD.0b013e32833f1142

78. Joint United Nations Programme on HIV/AIDS 2010 Methods for estimating HIV incidence. Epi Alert, UNAIDS Quarterly Update on HIV Epidemiology Available: http://www.unaids.org/en/media/unaids/contentassets/documents/dataanalysis/epi_alert_2010Q1_en.pdf. Accessed 3 June 2012

79. SheltonJDHalperinDTWilsonD 2006 Has global HIV incidence peaked? Lancet 367 1120 1122 doi:10.1016/S0140-6736(06)68436-5

80. GrulichAEWilsonDP 2010 Is antiretroviral therapy modifying the HIV epidemic? Lancet 376 1824 doi:10.1016/S0140-6736(10)62162-9

81. KerrTSmallWBuchnerCZhangRLiK 2010 Syringe sharing and HIV incidence among injection drug users and increased access to sterile syringes. Am J Public Health 100 1449 1453 doi:10.2105/AJPH.2009.178467

82. StoltzJ-AWoodESmallWLiKTyndallM 2007 Changes in injecting practices associated with the use of a medically supervised safer injection facility. J Public Health (Oxf) 29 35 39 doi:10.1093/pubmed/fdl090

83. WoodEMontanerJSGYipBTyndallMWSchechterMT 2003 Adherence and plasma HIV RNA responses to highly active antiretroviral therapy among HIV-1 infected injection drug users. CMAJ 169 656 661

84. MurrayJMPrestageGGriersonJMiddletonMMcDonaldA 2011 Increasing HIV diagnoses in Australia among men who have sex with men correlated with the growing number not taking antiretroviral therapy. Sex Health 8 304 310 doi:10.1071/SH10114

85. TruongHMKelloggTKlausnerJDKatzMHDilleyJ 2006 Increases in sexually transmitted infections and sexual risk behavior without a concurrent increase in HIV incidence among men who have sex with men in San Francisco: a suggestion of HIV serosorting? Sex Transm Infect 82 461 466 doi:10.1136/sti.2006.019950

86. British Columbia Centre for Disease Control 2011 HIV and sexually transmitted infections 2010. Available: http://www.bccdc.ca/NR/rdonlyres/2035512C-DBEC-495B-A332-C410EE9520C7/0/CPS_Report_STI_HIV_2010_annual_report_FINAL_20111122.pdf. Accessed 29 May 2012

87. GuyRJMcDonaldAMBartlettMJMurrayJCGieleCM 2007 HIV diagnoses in Australia: diverging epidemics within a low-prevalence country. Med J Aust 187 437 440

88. GrulichAEKaldorJM 2008 Trends in HIV incidence in homosexual men in developed countries. Sex Health 5 113 118 doi:10.1071/SH07075

89. DukersNHSpaargarenJGeskusRBBeijnenJCoutinhoRA 2002 HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: using a novel approach for detecting recent infections. AIDS 16 F19 F24

90. DouganSElfordJChadbornTRBrownAERoyK 2006 Does the recent increase in HIV diagnoses among men who have sex with men in the UK reflect a rise in HIV incidence or increased uptake of HIV testing? Sex Transm Infect 83 120 125 doi:10.1136/sti.2006.021428

91. DuncanKCReadingCBorweinAMMurrayMCPalmerA 2011 HIV incidence and prevalence among aboriginal peoples in Canada. AIDS Behav 15 214 227 doi:10.1007/s10461-010-9792-y

92. SpittalPMCraibKJPWoodELalibertéNLiK 2002 Risk factors for elevated HIV incidence rates among female injection drug users in Vancouver. CMAJ 166 894 899

93. MillerCLWoodESpittalPMLiKFrankishJC 2004 The future face of coinfection: prevalence and incidence of HIV and hepatitis C virus coinfection among young injection drug users. J Acquir Immune Defic Syndr 36 743 749

94. BruneauJDanielMAbrahamowiczMZangGLamotheF 2011 Trends in human immunodeficiency virus incidence and risk behavior among injection drug users in montreal, Canada: a 16-year longitudinal study. Am J Epidemiol 173 1049 1058 doi:10.1093/aje/kwq479

95. GranichRGuptaSSutharABSmythCHoosD 2011 Antiretroviral therapy in prevention of HIV and TB: update on current research efforts. Curr HIV Res 9 446 469

96. BoilyMCBuvéABaggaleyRF 2010 HIV transmission in serodiscordant heterosexual couples. BMJ 340 c2449 doi:10.1136/bmj.c2449

97. FisherMPaoDBrownAESudarshiDGillON 2010 Determinants of HIV-1 transmission in men who have sex with men: a combined clinical, epidemiological and phylogenetic approach. AIDS 24 1739 1747 doi:10.1097/QAD.0b013e32833ac9e6

98. BoilyMCMâsseBAlsallaqRPadianNSEatonJW 2012 HIV treatment as prevention: considerations in the design, conduct, and analysis of cluster randomized controlled trials of combination HIV prevention. PLoS Med 9 e1001250 doi:10.1371/journal.pmed.1001250

99. Imperial College London Faculty of Medicine 2011 About PopART. Available: http://www1.imperial.ac.uk/medicine/research/researchthemes/infection/infectious_diseases/hiv_trials/hiv_prevention_technologies/popart/about/. Accessed 3 June 2012

100. 2011 Jun 2 The end of AIDS? The Economist Available: http://www.economist.com/node/18774722. Accessed 29 May 2012

101. CrepazNLylesCMWolitskiRJPassinWFRamaSM 2006 Do prevention interventions reduce HIV risk behaviors among people living with HIV? A meta-analytic review of controlled trials. AIDS 20 143 157 doi:10.1097/01.aids.0000196166.48518.a0

102. HasseBLedergerberBHirschelBVernazzaPGlassTR 2010 Frequency and determinants of unprotected sex among HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis 51 1314 1322 doi:10.1086/656809

103. CohenMS 2010 HIV treatment as prevention and “the Swiss statement”: in for a dime, in for a dollar? Clin Infect Dis 51 1323 1324 doi:10.1086/656810

104. CoatesTJRichterLCaceresC 2008 Behavioral strategies to reduce HIV transmission: how to make them work better. Lancet 372 669 684 doi:10.1016/S0140-6736(08)60886-7