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HIV drugs for treatment, and for prevention Editorial
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The Lancet, Early Online Publication, 27 May 2010
Francois Dabis a, Marie-Louise Newell b, Bernard Hirschel c
a INSERM U897, Institut de Sante Publique, Epidemiologie et Developpement (ISPED), Universite Victor Segalen, 33076 Bordeaux Cedex, France
b Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Somkhele, KwaZulu-Natal, South Africa
c Unite VIH/SIDA, Hopitaux Universitaires, Geneva, Switzerland
Vaccines remain a distant hope in HIV prevention, vaginal microbicides have been ineffective so far, and treatment of sexually transmitted diseases does not reduce HIV transmission in most settings. Only condoms, male circumcision, abstinence, or delaying onset of sexual debut are effective, but with current patterns of behaviour none of these reduce risks sufficiently to halt the pandemic in sub-Saharan Africa. Innovative HIV prevention approaches are needed.1
Without antiretroviral therapy, HIV RNA viral load drives sexual2 and mother-to-child3 transmission. Antiretrovirals lower viral load in all body compartments. In a systematic review of cohort studies of serodiscordant couples in whom routine use of condoms was encouraged, transmission risk depended substantially on whether HIV-infected index patients were on antiretrovirals (0·46 cases of HIV acquisition per 100 person-years, five transmission events) or not (5·64 per 100 person-years, 456 events).4 There were no transmissions when the index patient had a viral load below 400 copies per mL.
Granich and colleagues5 developed a statistical model predicting that universal HIV testing of all sexually active adults and immediate antiretroviral therapy (regardless of CD4 cell count) could have a major effect on severe generalised HIV epidemics. However, in a subsequent model, Dodd and colleagues6 showed that the effect of immediate antiretroviral therapy probably depends on characteristics of the sexual-partner network (such as heterogeneity, and concurrency and mixing), and could indeed, under certain assumptions, be negative.
In The Lancet today, Deborah Donnell and co-workers (the Partners in Prevention HSV/HIV Transmission Study Team)7 report the results of a study nested within a placebo-controlled trial, which showed no effect of HSV-2 treatment on HIV transmission in nearly 3400 African serodiscordant heterosexual couples.8 As one in ten participants started on antiretrovirals during the trial, the investigators were able to compare HIV transmission before and after starting treatment. HIV incidence was 2·24 per 100 person-years before starting antiretrovirals (102 transmission events) and 0·37 per 100 person-years after starting antiretrovirals (one event, which probably occurred before full suppression of viral load in the index partner), yielding an adjusted incidence rate ratio of 0·08, a 12-fold reduction in transmission. Most transmissions occurred at high viral loads (≥50 000 copies per mL). The investigators conclude that high viral load might be one reason to treat even at high CD4 cell counts. Although these findings are observational and subject to bias, the consistency of the published reports and the strength of the observed associations favour such a conclusion.
Similar observational data accrued for 20 years for male circumcision before the results of randomised trials led to the writing of public health guidelines. Will we have to wait as long before international recommendations can be formulated on the contribution of antiretrovirals to HIV prevention? The HPTN 052 trial, by the National Institute of Allergy and Infectious Diseases9 has randomised couples in whom the infected partner has a CD4 cell count of 250Ñ550 cells per µL to either start antiretrovirals immediately or wait until the CD4 cell count drops below 250 cells per µL; results are expected in 2014. This trial will provide useful data on long-term measures of efficacy of ART among HIV discordant couples, adherence when ART is initiated earlier, incidence of drug resistance, and potential risk compensation. Meanwhile, worldwide, indications for starting antiretroviral therapy expand to higher CD4 cell counts.
No HIV test, no treatment, no transmission prevention: the concept of treatment-as-prevention implies changes in screening and testing for HIV. Motivations for testing vary, but many people test to obtain treatment today when they feel unwell.10 Restricting antiretrovirals to those with advanced HIV disease is a barrier to the uptake of HIV testing.11 Voluntary HIV counselling and testing, common policy in most countries, does not result in enough people testing regularly enough to affect onward HIV spread. Radically different strategies are now being proposed, as exemplified by the recent launch of the massive HIV prevention and treatment campaign in South Africa.12
During the hour or so it takes to read this Comment and linked Article, 300 new HIV infections will have occurred in Africa. We should not wait for the results of further models, observational studies, or the ongoing couple-based prevention trial before engaging in population-based trials of test-and-treat. Prevention of new infections would be the main goal but individual-level benefits can also be expected; to be evaluated against initially increased costs to the health-care system. Indeed, today's results argue powerfully for a new generation of research on HIV prevention at the population level with the best possible scientific methodology, including cluster-randomised trials.
We declare that we have no conflicts of interest.
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