This proposed research has several strengths. First, having an open-label rather than a placebo-controlled study allows for relevant data to be collected about the general MSM population on issues important to the success of an HIV prevention clinic. These things include the efficacy of PrEP and changes in sexual behavior of individuals on PrEP. Secondly, placebo-controlled studies may underestimate real-world adherence due to the fact that there is less incentive to take a pill that may be a placebo. This study will give a more realistic perspective on medication compliance. Thirdly, having participants in the study for 3 years will increase the longitudinal data on adherence and risk
compensation with a rich data set. Lastly, this study has been designed to have low type 1 and type 2 errors. This means it is unlikely that a null hypothesis will be rejected when it is actually true and is unlikely that the study will fail to reject a null hypothesis when the alternative hypothesis is true.
One weakness of this study is the close observation of the participants. Adding too many interventions beyond regular outpatient visits to the PrEP clinic may influence the behaviors of the individuals in the study. Participants may want to improve the dynamics with their PrEP provider and be dishonest with their surveys regarding risk compensation. The hope is that this will not happen.
Some obstacles are anticipated. It may be difficult to procure the funding required to start a PrEP clinic. Some funding will come from research grants to support the study, but additional financial support will be needed from BMC to make this a reality. This
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may delay when the project can begin. It is also uncertain if the demand exists to have a stand-alone PrEP clinic, which may result in an insufficient number of participants for the research study. PrEP administration may be better handled by primary care providers in an outpatient clinic setting.
The Boston area provides an immense amount of diversity, so this study will be generalizable to MSM populations throughout the United States. Because this study only looks at the MSM population, it is unlikely to be generalizable to heterosexual
individuals or IVDUs. Summary
HIV affects over 1.2 million people in the United States. This viral infection leads to decreased CD4+ T cells, increased susceptibility to OIs, and eventually AIDS and death.80 Viral loads can be decreased to undetectable levels with the use of cART. Every
year 50,000 individuals become newly infected with HIV in the U.S.,23 this may be
reduced in the future due to the FDA approval of Truvada for the indication of PrEP. When detectable levels of drug are present in the blood stream of patients, there is up to a 92% relative risk reduction of HIV infection compared to placebo.3
Because PrEP treatment has only been approved since 2012, there are many perceived barriers to administration of PrEP to patients. Side effects, PrEP adherence, development of resistant virus, and risk compensation are several of the ongoing concerns that providers cite as reasons against prescribing PrEP to at-risk populations.2
Most publications on PrEP have been randomized placebo trials in the research setting that focused on adherence-based efficacy3 and risk compensation behaviors.3,4
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Now that Truvada is widely available, researchers are starting to elucidate patients’ sexual habits on PrEP in the everyday outpatient settings.5 However, there is a need for
more research regarding how the general population will utilize PrEP, specifically to determine if risk compensation occurs and what it looks like over extended periods of time. There is also a need for the implementation of a PrEP clinic as there are none in the Boston area despite the large number of at-risk individuals in Massachusetts.
This study initiates a PrEP clinic at BMC to follow patients for 3 years in an open-label randomized controlled trial of eligible MSM patients who either start PrEP immediately or are delayed by one year. The aim is to determine if risk compensation occurs in these patients by following condom usage, development of STIs, sexual partner numbers, and sexual encounter numbers/types. Secondary outcomes will include
measurements of medication adherence. The resulting information will help the medical field better understand the longitudinal risks and benefits of PrEP and what they can do to improve compliance and risk-reduction behaviors.
Clinical and/or Public Health Significance
PrEP is covered by Medicaid and often covered by private insurers, so the remaining barriers to accessing PrEP are three-fold. Patients may be unaware of PrEP or their eligibility, there may be nowhere to obtain it, or providers are uncomfortable prescribing it. Every doctor before entering the healthcare system takes the Hippocratic Oath, which includes commitment to do no harm. From the surveys it seems that
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benefits to be able to make an informed decision for their patients, who rely on them to do so.
This study addresses at least two of these barriers. Initiating a clinic gives at-risk people a place to go to receive PrEP. It also supplies the providers with a wealth of information about adherence and risk compensation over an extended period of time to help them with medical decision making. Indirectly, starting a PrEP clinic may increase the awareness of PrEP as individuals start to visit and information spreads by word of mouth.
HIV is a significant public health issue around the world which kills over 1 million people every year. The ability to prevent this viral infection from occurring can prevent millions of premature deaths. PrEP offers one significant platform to achieve this public health intervention, and may serve as a great tool in the fight against HIV.
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LIST OF JOURNAL ABBREVIATIONS
AIS Association of Interdisciplinary Studies
AM J Public Health American Journal of Public Health
Ann Behav Med Annals of behavioral medicine : a publication of the Society of Behavioral Medicine
Antimicrob Agents Chemother Antimicrobial Agents and Chemotherapy
BMC British Medical Journal
Clin Infect Dis Clinical Infectious Diseases
Cold Spring Harb Perspective Biol Cold Spring Harbor Perspective in Biology
CROI Conference on Retroviruses and Opportunistic
Infections
Curr Opin HIV AIDS Current Opinion in HIV & AIDS
Curr Top Microbiol Immuno Current Topics in Microbiology and Immunology
EMBO J EMBO Journal
Int J Biochem Mol Biol International Journal of Biochemistry and Molecular Biology
Int J Cancer International Journal of Cancer J Infect Dis Journal of Infectious Diseases
J Int Assoc Physicians AIDS Care Journal of the International Association of Physicians In AIDS Care
59
J Virol Journal of Viriology
Lancet Infect Dis The Lancet Infectious Diseases
MMWR Morb Mortality Wkly Rep Morbidity and Mortality Weekly Report N Engl J Med New England Journal of Medicine Nat Rev Dis Prim Nature Reviews Disease Primers Nat Rev Micro Nature Reviews Microbiology Nat Struct Biol Nature Structural Biology
PLoS Med PLOS Medicine
Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America
Sci Transl Med Science Translational Medicine
Top HIV Med Topics in HIV medicine : a publication of the International AIDS Society
60
REFERENCES
1. WHO | HIV/AIDS http://www.who.int/mediacentre/factsheets/fs360/en/. Accessed 1/2/2016, 2016.
2. Karris MY, Beekmann SE, Mehta SR, Anderson CM, Polgreen PM. Are we prepped for preexposure prophylaxis (PrEP)? provider opinions on the real-world use of PrEP in the united states and canada. Clin Infect Dis. 2014;58(5):704-712.
http://cid.oxfordjournals.org/content/58/5/704.abstract.
3. 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(27):2587-2599.
http://dx.doi.org/10.1056/NEJMoa1011205. doi: 10.1056/NEJMoa1011205.
4. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410.
http://dx.doi.org/10.1056/NEJMoa1108524. doi: 10.1056/NEJMoa1108524.
5. Volk JE, Marcus JL, Phengrasamy T, et al. No new HIV infections with increasing use of HIV preexposure prophylaxis in a clinical pracice setting. Clinical Infectious Disease. 2015.
6. Movement advancement project | LGBT populations http://www.lgbtmap.org/equality-
maps/lgbt_populations. Accessed 4/14/2016, 2016.
7. Fee E, Brown TM. Michael S. gottlieb and the identification of AIDS. Am J Public
Health. 2006;96(6):982-983. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470620/. doi: 10.2105/AJPH.2006.088435.
8. Centers for Disease Control. Pneumocystis pneumonia -- los angeles MMWR Morb
Mortal Wkly Rep. 1981;30(21):250. Accessed 12/11/2015.
9. Centers for Disease Control. Kaposi's sarcoma and pneumocystis pneumonia among homosexual men--new york city and california. MMWR Morb Mortal Wkly Rep. ;30(25):305.
10. Curran JW, Jaffe HW. AIDS: The early years and CDC's response
http://www.cdc.gov/mmwr/preview/mmwrhtml/su6004a11.htm. Accessed 12/11/2015, 2015.
11. Epidemiologic aspects of the current outbreak of kaposi's sarcoma and opportunistic infections. N Engl J Med. 1982;306(4):248-252.
61
12. Giraldo G, Beth E, Huang E-. Kaposi's sarcoma and its relationship to
cytomegalovirus (CMV) III. CMV DNA and CMV early antigens in kaposi's sarcoma.
Int J Cancer. 1980;26(1):23-29. doi: 10.1002/ijc.2910260105.
13. Giraldo G, Beth E, Haguenau F. Herpes-type virus-particles in tissue-culture of kaposis sarcoma from different geographic regions. J Natl Cancer I. ;49(6):1509-1526. 14. Masur H, Michelis MA, Greene JB, et al. An outbreak of community-acquired pneumocystis carinii pneumonia. N Engl J Med. 1981;305(24):1431-1438.
http://dx.doi.org/10.1056/NEJM198112103052402. doi: 10.1056/NEJM198112103052402.
15. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men. N Engl J Med.
1981;305(24):1425-1431. http://dx.doi.org/10.1056/NEJM198112103052401. doi: 10.1056/NEJM198112103052401.
16. Centers for Disease Control. Current trends update on acquired immune deficiency syndrome (AIDS) --united states http://www.cdc.gov/mmwr/preview/mmwrhtml/00001163.htm. Accessed 12/15/2015, 2015.
17. Pincock S. Françoise barré-sinoussi: Shares nobel prize for discovery of HIV. The
Lancet. 2008;372(9647):1377. doi: http://dx.doi.org/10.1016/S0140-6736(08)61575-5.
18. Centers for Disease Control. Epidemiologic notes and reports persistent, generalized lymphadenopathy among homosexual males
http://www.cdc.gov/mmwr/preview/mmwrhtml/00001096.htm. Accessed 12/15/2015, 2015.
19. Barré-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science.
1983;220(4599):868-871. http://www.jstor.org.ezproxy.bu.edu/stable/1690359.
20. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS
Science. 1984;224(4648):500-503.
21. Coffin J, Haase A, Levy JA, et al. Human immunodeficiency viruses Science. 1986;232(4751):697.
22. Lever AML, Berkhout B. 2008 nobel prize in medicine for discoverers of HIV.
Retrovirology. 2008;5:91-91.
http://search.ebscohost.com/login.aspx?direct=true&db=mdc&AN=18854052&site=ehost-live. doi:
62
23. Centers for Disease Control and Prevention. Statistics overview | statistics center | HIV/AIDS | CDC http://www.cdc.gov/hiv/statistics/overview/index.html. Accessed 12/6/2015, 2015.
24. Prevalence and awareness of HIV infection among men who have sex with men --- 21 cities, united states, 2008
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5937a2.htm?s_cid=mm5937a2_w. Accessed
12/15/2015, 2015.
25. HIV transmission | HIV basics | HIV/AIDS | CDC
http://www.cdc.gov/hiv/basics/transmission.html. Accessed 1/2/2016, 2016.
26. Murphy K, Travers P, Walport M, Janeway C. Acquired immune deficiency syndrome. In: Immunobiology. ; 2012:543-570.
27. Briggs JAG, Wilk T, Welker R, Krsusslich H, Fuller SD. Structural organization of authentic, mature HIV-1 virions and cores. EMBO J. 2003;22(7):1707-1715.
http://emboj.embopress.org/content/22/7/1707.abstract.
28. Landmarks of the HIV genome
http://www.hiv.lanl.gov/content/sequence/HIV/MAP/landmark.html. Accessed 1/2/2016, 2016.
29. Laskey SB, Siliciano RF. A mechanistic theory to explain the efficacy of antiretroviral therapy. Nat Rev Micro. 2014;12(11):772-780.
http://dx.doi.org/10.1038/nrmicro3351.
30. Dalgleish AG, Beverley PCL, Clapham PR, Crawford DH, Greaves MF, Weiss RA. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus.
Nature. 1984;312(5996):763-767. http://dx.doi.org/10.1038/312763a0.
31. Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nature Reviews
Disease Primers. 2015:15035. http://dx.doi.org/10.1038/nrdp.2015.35.
32. Liu J, Bartesaghi A, Borgnia MJ, Sapiro G, Subramaniam S. Molecular architecture of native HIV-1 gp120 trimers. Nature. 2008;455(7209):109-113.
http://dx.doi.org/10.1038/nature07159.
33. Chan DC, Fass D, Berger JM, Kim PS. Core structure of gp41 from the HIV envelope glycoprotein. Cell. 1997;89(2):263-273. doi: http://dx.doi.org/10.1016/S0092-8674(00)80205-6. 34. Miller MD, Farnet CM, Bushman FD. Human immunodeficiency virus type 1 preintegration complexes: Studies of organization and composition.. J Virol. 1997;71(7):5382.
63
35. Fassati A, Goff SP. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J Virol. 2001;75(8):3626-3635.
36. Jayappa KD, Ao Z, Yao X. The HIV-1 passage from cytoplasm to nucleus: The process involving a complex exchange between the components of HIV-1 and cellular machinery to access nucleus and successful integration. Int J Biochem Mol Biol. 2012;3(1):70-85. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325773/.
37. Craigie R, Bushman FD. HIV DNA integration. Cold Spring Harb Perspect Biol. 2012;2(7):a006890. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385939/. doi:
10.1101/cshperspect.a006890.
38. Engelman A, Cherepanov P. The structural biology of HIV-1: Mechanistic and therapeutic insights. Nat Rev Micro. 2012;10(4):279-290.
http://dx.doi.org/10.1038/nrmicro2747.
39. Oroszlan S, Luftig RB. Retroviral proteinases. Curr Top Microbiol Immunol. 1990;157:153-185.
40. Pantaleo G, Graziosi C, Fauci AS. The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993;328(5):327-335.
http://dx.doi.org/10.1056/NEJM199302043280508. doi: 10.1056/NEJM199302043280508.
41. Bartlett J. The natural history and clinical features of HIV infection in adults and adolescents. In: Hirsch M, ed. UpToDate. ; 2016. Accessed 4/6/2016.
42. Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents
Chemother. 2005;49(11):4721-4732. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280117/.
doi: 10.1128/AAC.49.11.4721-4732.2005.
43. Wild CT, Shugars DC, Greenwell TK, McDanal CB, Matthews TJ. Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci U S A.
1994;91(21):9770-9774.
44. Esnouf R, Ren J, Ross C, Jones Y, Stammers D, Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat Struct Biol. 1995;2(4):303- 308.
45. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science. 2000;287(5453):646-650. doi: 10.1126/science.287.5453.646.
64
46. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350(10):1023-1035.
http://www.nejm.org/doi/abs/10.1056/NEJMra025195. doi: 10.1056/NEJMra025195.
47. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med. 1994;331(18):1173-1180. http://dx.doi.org/10.1056/NEJM199411033311801. doi:
10.1056/NEJM199411033311801.
48. Cardo DM, Culver DH, Ciesielski CA, et al. A Case–Control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med. 1997;337(21):1485-1490. http://dx.doi.org/10.1056/NEJM199711203372101. doi:
10.1056/NEJM199711203372101.
49. Notice to readers update: Provisional public health service recommendations for chemoprophylaxis after occupational exposure to HIV.
http://www.cdc.gov.ezproxy.bu.edu/mmwr/preview/mmwrhtml/00042200.htm. Accessed 12/20/2015,
2015.
50. Youle M, Wainberg MA. Could chemoprophylaxis be used as an HIV prevention strategy while we wait for an effective vaccine? AIDS. 2003;17(6):937-938.
51. Tsai C, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9- (2-phosphonylmethoxypropyl)adenine. Science. 1995;270(5239):1197-1199.
http://www.jstor.org.ezproxy.bu.edu/stable/2889224.
52. Youle M, Wainberg MA. Pre-exposure chemoprophylaxis (PREP) as an HIV prevention strategy. J Int Assoc Physicians AIDS Care. 2003;2(3):102-105.
53. Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK,. Antiretroviral pre- exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice.
PLoS Med. 2008;5(1).
54. 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(7):904-911.
55. García-Lerma JG, Otten RA, Qari SH. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS
Med. 2008;5(2):e28. doi: 10.1371/journal.pmed.0050028.
56. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in botswana. N Engl J Med.
65
2012;367(5):423-434. http://dx.doi.org/10.1056/NEJMoa1110711. doi: 10.1056/NEJMoa1110711.
57. Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in bangkok, thailand (the bangkok tenofovir study): A randomised, double-blind, placebo-controlled phase 3 trial. The Lancet.
2013;381(9883):2083-2090. doi: http://dx.doi.org/10.1016/S0140-6736(13)61127-7.
58. Consumer updates > FDA approves first medication to reduce HIV risk.
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm311821.htm. Accessed 1/3/2016, 2016.
59. Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV infection in the united states - 2014 - prepguidelines2014.
http://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf. Accessed 12/23/2015, 2015.
60. Jacobs D. A PrEP user's perspective. Vancouver, British Coulmbia: AIS 2015; 2015. 61. Koester K, Amico R, Liu A, et al. Sex on PrEP: Qualitative findings from the iPrEx open label extension (OLE) in the US. AIDS 2014. 2014.
62. Gilmore H, Koester K, Liu A., et al. To take or not to take PrEP; perspectives from participants enrolled in the iPrEx open label extension (OLE) in the united states. J Int
Assoc Physicians AIDS Care. 2014.
63. Solomon MM, Lama JR, Glidden DV, et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS. 2014;28(6):851-859.
64. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in san francisco. PLoS ONE. 2011;6(8):e23688.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163584/. doi: 10.1371/journal.pone.0023688.
65. Liegler T, Abdel-Mohsen M, Bentley LG, et al. HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial. J Infect Dis. 2014;210(8):1217-1227.
http://jid.oxfordjournals.org/content/210/8/1217.abstract.
66. HIV & AIDS information :: At least 25,000 people in the US may now be using PrEP
http://www.aidsmap.com/At-least-25000-people-in-the-US-may-now-be-using-PrEP/page/3006288/.
Accessed 4/13/2016, 2016.
67. HIV-1 infection with multiclass resistance despite preexposure prophylaxis (PrEP) | CROI conference http://www.croiconference.org/sessions/hiv-1-infection-multiclass-resistance-despite-
66
68. Vital signs: HIV diagnosis, care, and treatment among persons living with HIV — united states, 2011.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6347a5.htm?s_cid=mm6347a5_w. Accessed
4/13/2016, 2016.
69. del Rio C. Current concepts in antiretroviral therapy failure. Top HIV Med. 2006;14(3):102-106.
70. Parikh UM, Mellors JW. HIV-1 drug resistance resulting from antiretroviral therapy far exceeds that from pre-exposure prophylaxis. J Infect Dis. 2012;55(2):303-304.
http://cid.oxfordjournals.org/content/55/2/303.short.
71. CDC stacks | laboratory testing for the diagnosis of HIV infection : Updated recommendations - 23447 | guidelines and recommendations
http://stacks.cdc.gov/view/cdc/23447. Accessed 4/14/2016, 2016.
72. Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4(151):151ra125-151ra125. http://stm.sciencemag.org/content/4/151/151ra125.abstract. 73. Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: A cohort study. Lancet Infect Dis. 2014;14(9):820-829. doi:
http://dx.doi.org.ezproxy.bu.edu/10.1016/S1473-3099(14)70847-3.
74. Amico KR. Adherence to preexposure chemoprophylaxis: The behavioral bridge from efficacy to effectiveness. Curr Opin HIV AIDS. 2012;7(6):542-548.
75. Cassell MM, Halperin DT, Shelton J, Stanton D. Risk compensation: The achilles' heel of innovations in HIV prevention? BMJ. 2006;332(7541):605-607.
76. Gamarel K, Golub S. Intimacy motivations and pre-exposure prophylaxis (PrEP) adoption intentions among HIV-negative men who have sex with men (MSM) in romantic relationships. Ann Behav Med. 2015;49(2):177-186.
http://dx.doi.org/10.1007/s12160-014-9646-3. doi: 10.1007/s12160-014-9646-3.
77. Calabrese SK, Underhill K. How stigma surrounding the use of HIV preexposure prophylaxis undermines prevention and pleasure: A call to destigmatize “Truvada whores”. Am J Public Health. (10):1960. doi: 10.2105/AJPH.2015.302816. 78. Duran D. Truvada whores? HuffPost Gay Voices. 2012.
79. McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): Effectiveness results from the pilot phase of a
67
pragmatic open-label randomised trial. The Lancet. 2016;387(10013):53-60. doi:
http://dx.doi.org.ezproxy.bu.edu/10.1016/S0140-6736(15)00056-2.
80. Janeway CAJ, Travers P, Walport M, et al. Immunobiology: The immune system in