EDITORIALS
Preventing HIV transmission with antiretrovirals
Kevin M De Cock; Siobhan P Crowley*; Ying-Ru Lo; Reuben M Granich; Brian G Williams
Department of HIV/AIDS, World Health Organization, 20 avenue Appia, 1211 Geneva 27, Switzerland
Three of the most extraordinary events in global health over the past 30 years have been the emergence of the pandemic of HIV/AIDS, the development of antiretroviral therapy (ART) capable of arresting HIV progression and reducing mortality, and scale-up of therapy in low- and middle-income countries. By the end of 2007, approximately 3 million people were accessing ART in resource-constrained settings,1 an unimaginable achievement a few years previously, yet one whose expansion and sustainability are threatened by resource constraints and competing priorities. Adding complexity are scientific uncertainties - where is the pandemic going, what is the best way to use ART for individual health and what role can ART play in HIV prevention?
By the end of 2007, an estimated 33 million persons were living with HIV and 2.7 million had become newly infected that year.2 Sub-Saharan Africa has 67% of all estimated infections. At the risk of oversimplification, two broad patterns have emerged globally: HIV affects the general population in sub-Saharan Africa but elsewhere is largely concentrated in specific groups at risk. Eight countries in southern Africa have an adult HIV prevalence of 15% or above.
Although the annual incidence of HIV infections globally peaked around the mid-1990s,3 the absolute number of people living with HIV in Africa continues to increase as a result of persistent high incidence and population growth rate. Universal access remains a remote aspiration unless HIV transmission is substantially and rapidly reduced.
While treatment and prevention seem different concerns, recent research suggests earlier initiation of therapy may provide individual as well as public health benefit. Industrialized country guidelines mostly advocate starting ART in asymptomatic individuals when the CD4+ count falls below 350/µl.4 WHO's 2006 guidelines are permissive in this regard but are often interpreted as more conservative, and understood to advise initiation at CD4+ counts below 200/µl.5 Two observations are that, irrespective of guidelines, the majority of persons with HIV are diagnosed late with advanced disease; and that the optimal time to start has never been definitively established through randomized controlled trials.
Recent observational studies showed improved survival in persons starting ART earlier compared to those deferring treatment (the thresholds examined against higher CD4 counts were < 350 CD4+ cells/µl; and < 500/µl).6,7 Experience in South Africa showed a greatly increased risk of death with increased time lived at CD4+ counts below 200/µl,8 and increasing tuberculosis incidence with time lived below 500/µl.9 WHO will be reviewing evidence and revising guidance on ART use, including when to start, for adults and children later this year, but there are many advocates for earlier therapy.
There is little doubt that ART has preventive effects; what is uncertain is how best to apply it and combine it with other evidence-based prevention interventions for maximal synergy and benefit. For HIV-negative persons, guidelines already exist concerning use of ART for post-exposure prophylaxis,10 and results of randomized controlled trials of pre-exposure prophylaxis will soon become available. It is the treatment of persons who are already infected, however, that may have the widest impact. The rationale seems simple: transmission only occurs from infected persons who are numerically far fewer than HIV-negative susceptible persons; viral load is the greatest risk factor for all modes of transmission; ART lowers viral load; prevention of mother-to-child transmission offers proof of concept; and there is observational evidence of reduced transmission from discordant heterosexual couples when the index partner is on ART.11,12
Several papers have proposed expanded use of ART as a means of limiting HIV spread13,14 and further impetus to this discussion was given by a mathematical model published by WHO scientists in late 2008.15 Their paper reported that in an HIV/AIDS epidemic of southern African severity, universal voluntary HIV testing on an annual basis followed by immediate ART could reduce HIV incidence by about 95% within a decade, with cost-saving over the medium term. Formidable challenges to such an approach include conducting the necessary research; operational and financial feasibility; ethical and human rights challenges, acceptability; and the potential for drug resistance and toxicity.
Widespread early therapy for HIV is intellectually compelling because it targets viral load, the major biological risk factor for transmission and disease progression. Delaying treatment until HIV has inflicted severe damage on the immune system and further transmission occurs is a different practice to the approach of other infectious diseases such as tuberculosis. Earlier diagnosis and treatment offer opportunity for "positive prevention" emphasizing other health interventions, as well as enhancement of sexual and reproductive health and rights of persons living with HIV.16 Nonetheless, the world requires evidence before policy development on ART for HIV prevention can be envisaged.
WHO will organize a consultation in late 2009 to examine research priorities, operational considerations and ethical and human rights concerns around the use of ART for HIV prevention. Additional questions other than impact in generalized epidemic settings include relevance to concentrated epidemics, impact on tuberculosis incidence, prevention of mother-to-child transmission and cost implications.
At a time when other avenues of HIV prevention research, including vaccine evaluations, have given discouraging results, how to use ART for the greatest simultaneous therapeutic and prevention benefit is perhaps the most pressing question in HIV research. 
References
Available at: http://www.who.int/bulletin/volumes/87/7/09-067330/en/index.html
References
1. World Health Organization, UNAIDS, UNICEF. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Geneva: World Health Organization; 2008. Available from: http://www.who.int/hiv/pub/towards_universal_access_report_2008.pdf [accessed on 2 June 2009] .
2. 2008 report on the global AIDS epidemic. Geneva; UNAIDS; 2008.
3. Bongaarts J, Buettner T, Heilig G, Pelletier F. Has the HIV epidemic peaked? Popul Dev Rev 2008;34:199-224. doi:10.1111/j.1728-4457.2008.00217.x
4. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Rockville, MD: Department of Health and Human Services; 2009. Available from: http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 [accessed on 2 June 2009] .
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6. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1815-26. PMID:19339714 doi:10.1056/NEJMoa0807252
7. When To Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-63. PMID:19361855 doi:10.1016/S0140- 6736(09)60612-7
8. Lawn S, Little F, Bekker L-G, Kaplan R, Campbel E,Orrell C et al. Changing mortality risk associated with CD4 cell response to long-term ART: sub-Saharan Africa [abstract 140]. In: 16th Conference on Retroviruses and Opportunistic Infections, Montreal, 8-11 February 2009.
9. Lawn S, Myer L, Edwards D, Wood R. Short and long term risk of TB associated with CD4 cell response to ART in South Africa [abstract 788]. In: 16th Conference on Retroviruses and Opportunistic Infections, Montreal, 8-11 February 2009.
10. Post-exposure prophylaxis to prevent HIV infection. Joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. Geneva: World Health Organization; 2008. Available from: http://whqlibdoc.who.int/publications/2007/9789241596374_eng.pdf [accessed on 2 June 2009] .
11. Castilla J, Del Romero J, Hernando V, Marincovich B, Garcia S, Rodriguez C, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005; 40:96-101. PMID:16123689 doi:10.1097/01.qai.0000157389.78374.45
12. Reynolds R, Makumbi F, Kagaayi J, Nakigozi G, Galiwongo R, Quinn T, et al. ART reduced the rate of sexual transmission of HIV among HIV-discordant couples in rural Rakai, Uganda [abstract 52a]. In: 16th Conference on Retroviruses and Opportunistic Infections, Montreal, 8-11 February 2009.
13. Janssen RS, Holtgrave DR, Valdiserri RO, Shepherd M, Gayle HD, De Cock KM. The serostatus approach to fighting the HIV epidemic: prevention strategies for infected individuals. Am J Public Health 2001;91:1019-24. PMID:11441723 doi:10.2105/AJPH.91.7.1019
14. Montaner JS, Hogg R, Wood E, Kerr T, Tyndall M, Levy AR, et al. The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic. Lancet 2006;368:531-6. PMID:16890841 doi:10.1016/ S0140-6736(06)69162-9
15. Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2009;373:48-57. PMID:19038438 doi:10.1016/S0140-6736(08)61697-9
16. Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva: World Health Organization; 2008. Available from: http://www.who.int/hiv/pub/prev_care/OMS_EPP_AFF_en.pdf [accessed on 2 June 2009] .
* Correspondence to Siobhan P Crowley (e-mail: crowleys@who.int).