Antiretroviral chemoprophylaxis: PROUD and pragmatism
Authors: Kenneth H Mayer, Chris Beyrer
Journal: The Lancet (2015)

About 20 years ago, very shortly after antiretroviral drugs were first shown to inhibit HIV replication and improve clinical outcomes, studies of animals showed that pre-exposure and post-exposure antiretroviral treatment could protect against retroviral challenges.1Tsai CC Follis KE Sabo A et al.Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine.Science. 1995; 270: 1197-1199Crossref PubMed Scopus (503) Google Scholar The first use of antiviral drugs for chemoprophylaxis in human beings was that of zidovudine in HIV-infected pregnant women to prevent transmission to their children.2Connor 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: 1173-1180Crossref PubMed Scopus (3328) Google Scholar Subsequently, seven efficacy trials of antiretroviral primary prevention have shown that tenofovir-based regimens can prevent HIV acquisition in African male and female heterosexuals, men and transgender women who have sex with men in Asia, Africa, Europe, and the Americas, and men and women in Thailand who inject drugs.3Abdool 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: 1168-1174Crossref PubMed Scopus (2030) Google Scholar, 4Grant 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: 2587-2599Crossref PubMed Scopus (3645) Google Scholar, 5Baeten JM Donnell D Ndase P et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.N Engl J Med. 2012; 367: 399-410Crossref PubMed Scopus (2252) Google Scholar, 6Thigpen MC Kebaabetswe PM Paxton LA et al.Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.N Engl J Med. 2012; 367: 423-434Crossref PubMed Scopus (1478) Google Scholar, 7Choopanya 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.Lancet. 2013; 381: 2083-2090Summary Full Text Full Text PDF PubMed Scopus (994) Google Scholar, 8McCormack S Dunn DT Deasi M et al.Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.Lancet. 2015; (published online Sept 10.)http://dx.doi.org/10.1016/S0140-6736(15)00056-2Google Scholar, 9Molina J-M, Capitant C, Spire B. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS Ipergay trial. Conference on Retroviruses and Opportunistic Infections 2015; Feb 23–26, 2015; Seattle, WA, USA. Abstract 23LB.Google Scholar Protection was directly correlated with adherence to treatment. Individuals who were highly adherent achieved levels of protection that exceeded those associated with consistent condom use.10Anderson 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: 151ra125Crossref PubMed Scopus (680) Google Scholar Despite early studies showing the efficacy of antiretroviral pre-exposure prophylaxis (PrEP), widespread uptake has not been immediate. Because the safety threshold for the use of drug treatments by otherwise healthy people must be high, concerns were raised about the potential for tenofovir–emtricitabine to cause symptoms, to be nephrotoxic, or to deplete bone mineral density, although initial studies3Abdool 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: 1168-1174Crossref PubMed Scopus (2030) Google Scholar, 4Grant 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: 2587-2599Crossref PubMed Scopus (3645) Google Scholar, 5Baeten JM Donnell D Ndase P et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.N Engl J Med. 2012; 367: 399-410Crossref PubMed Scopus (2252) Google Scholar, 6Thigpen MC Kebaabetswe PM Paxton LA et al.Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.N Engl J Med. 2012; 367: 423-434Crossref PubMed Scopus (1478) Google Scholar, 7Choopanya 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.Lancet. 2013; 381: 2083-2090Summary Full Text Full Text PDF PubMed Scopus (994) Google Scholar, 8McCormack S Dunn DT Deasi M et al.Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.Lancet. 2015; (published online Sept 10.)http://dx.doi.org/10.1016/S0140-6736(15)00056-2Google Scholar, 9Molina J-M, Capitant C, Spire B. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS Ipergay trial. Conference on Retroviruses and Opportunistic Infections 2015; Feb 23–26, 2015; Seattle, WA, USA. Abstract 23LB.Google Scholar of thousands of participants showed that, with routine monitoring, adverse events were few, and were readily manageable. Some commentators suggested that irregular use of antiretroviral drugs could lead to selection for drug-resistant strains, but few PrEP-related resistant infections have been recorded, primarily because most individuals who became infected were non-adherent, limiting selection pressure.11van de Vijver DA Nichols BE Abbas UL et al.Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models.AIDS. 2013; 27: 2943-2951Crossref PubMed Scopus (55) Google Scholar Because tenofovir–emtricitabine is expensive in many countries (up to US$15 000 per year), some questioned whether PrEP could be cost effective. However, in high-incidence settings, access to PrEP by people at greatest risk for infection could save money, since PrEP use can be limited to a period of risk, whereas, if HIV infection occurs, treatment with more expensive triple antiretroviral combination treatment is lifelong.12Walensky RP Park JE Wood R et al.The cost-effectiveness of pre-exposure prophylaxis for HIV infection in South African women.Clin Infect Dis. 2012; 54: 1504-1513Crossref PubMed Scopus (77) Google Scholar The most contentious concerns about PrEP involve risk compensation: the fear that increased access to PrEP would lead people to abandon condom use. This hypothesis reflects an odd mix of naivety and moralism. If condoms were being consistently used, the rates of new HIV infections would not remain at 2 million new infections per year.13UNAIDSAIDS info.http://aidsinfo.unaids.org/Google Scholar Rates of new HIV infections remain alarmingly high in several key populations (ie, young women in Africa, men who have sex with men and transgender women in most countries, sex workers, and people who inject drugs in countries that were part of the former Soviet Union,13UNAIDSAIDS info.http://aidsinfo.unaids.org/Google Scholar where access to effective prevention methods, such as clean syringes and opiate substitution treatment, have been supplanted by punitive laws and mass incarceration). The existence of coercive policies affecting vulnerable populations has led some advocates to question whether PrEP implementation could increase stigma and coercion by medicalising HIV risk, enabling authorities to avoid dealing with social drivers of HIV spread. Others have questioned whether PrEP could be readily implemented outside the controlled environment of a clinical trial and remain sufficiently effective to warrant wider use. According to Sheena McCormack and colleagues' PROUD study8McCormack S Dunn DT Deasi M et al.Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.Lancet. 2015; (published online Sept 10.)http://dx.doi.org/10.1016/S0140-6736(15)00056-2Google Scholar published in The Lancet, the answer is a resounding yes. The investigators enrolled 544 men who have sex with men who were seeking services at English sexual health clinics, and randomly assigned them to immediate PrEP (n=275) or deferred PrEP (n=269), to begin after 1 year. The deferred group had to be ended early, because of the 86% efficacy (90% CI 64–96) in the immediate group. There was a worrying 9% yearly HIV incidence rate in the deferred PrEP group, who received counselling, condoms, and post-exposure prophylaxis on demand, compared with a rate of 1·2% in the immediate PrEP group. The number needed to treat to prevent one new HIV infection per year was 13. This number compares favourably with most public heath preventive interventions (eg, statins to prevent cardiovascular or cerebrovascular events); and in 2017, this fixed drug combination's patent will expire, lowering costs worldwide. So, where do we go from here? The results from PROUD suggest that pragmatic deployment of PrEP must be part of any relevant primary HIV prevention strategy. Identifying and offering treatment to all people with HIV must also be a priority for their personal health, and to decrease HIV transmission.14Cohen MS Chen YQ McCauley M et al.Prevention of HIV-1 infection with early antiretroviral therapy.N Engl J Med. 2011; 365: 493-505Crossref PubMed Scopus (5387) Google Scholar But, given that more than 20 million people with HIV are not yet taking antiretroviral drugs,13UNAIDSAIDS info.http://aidsinfo.unaids.org/Google Scholar and many are unaware that they are infected, universal treatment will take time and might be insufficient to control HIV spread in high incidence networks. In such settings, first generation oral PrEP can be deployed to arrest further spread. Further refinements of PrEP could involve intermittent or coitally dependent dosing, intravaginal rings, injectable chemoprophylaxis, or immunoprophylaxis.15AIDS Vaccine Advocacy CoalitionAVAC report 2013: research & reality.www.avac.org/report2013Google Scholar However, the PROUD results show that PrEP should be part of the range of services offered by any clinical programme that focuses on sexual health. The time for cautionary speculation is over: HIV prevention services should be expanded worldwide by offering PrEP routinely to those who could benefit. KHM has received unrestricted research support from Gilead Sciences. CB declares no competing interests. CB is President of the International AIDS Society; KHM is a member of the International AIDS Society Governing Council. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trialIn this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Full-Text PDF Open Access