December 1, 2011
The concept of antiretroviral therapy (ART) as prevention is now almost cliché, but it was not long ago that the thought of treating HIV as a means of preventing transmission of the virus could justly be considered avant-garde. Certainly, there were tantalizing data supporting a role for ART in reducing infectiousness. Counting virus in semen and cervical fluid clearly showed that levels of HIV in these compartments fell with the initiation of HIV therapy, reducing inoculum. Observational studies conducted in areas where HIV is endemic found reductions in HIV transmission with the introduction of ART. But, a glass-half-empty skepticism regarding ART as a means to prevent the spread of HIV was common, given concerns about cost, viral resistance and drug toxicity. Then came the HIV Prevention Trials Network (HPTN) study 052.1
With a Jon-Stewart-worthy "Bam!," the results of this trial snapped us to attention and we all became believers. The trial, long in the planning, was straightforward. Take a large number of couples across the developing world where one partner was HIV positive and the other was not. When the HIV-positive partner's CD4+ cell count was higher than the threshold for ART initiation (greater than 250 cells/µL and below 550 cells/µL), he or she would be randomized to start ART immediately or wait until his or her count dropped below 250 cells/µL (or when clinically indicated). The rate of transmission to the uninfected partner would then be assessed over time. All couples received prevention counseling and ample supplies of condoms. Overall, 1,763 couples were enrolled, more than half from Africa and almost all were heterosexual dyads. Of the HIV-positive participants, half were women and the median CD4+ cell count was just over 400 cells/µL.
At a mean follow-up time of 1.7 years, the study's Data and Safety Monitoring Board (DSMB) determined that the trial results should be made public. There were 39 transmissions to uninfected partners, 28 of which were virologically linked to the HIV-positive partner in the couple. Of these, only one occurred in a couple assigned to immediate ART for the HIV-positive partner. Subsequently, it was found that this one man transmitted HIV very soon after initiating ART. This translates into a relative reduction of 96 percent in the number of linked transmission events with the use of ART for the prevention of HIV to an uninfected partner.
Importantly, the study also addresses the when-to-start-ART question and, in examining clinical outcomes among the HIV-positive participants, found a 41-percent reduction in risk of HIV-related clinical events -- mostly extrapulmonary tuberculosis -- for HIV-positive participants who were assigned to start HIV therapy early. The study follow-up was too short to meaningfully detect differences in survival among HIV-positive participants in each of the study arms.
The HPTN 052 study is one of the top HIV stories of the decade, if not ever. This trial demonstrated resoundingly that ART not only lowers the concentration of virus in genital secretions, but that this translates into a reduction in actual infectiousness. Coupled with models describing the potential benefits of the early use of ART on transmission dynamics across a population, this study provides a strong rationale for ART for all HIV-positive persons.
Critics may point to limitations in the study, such as the capping of the entry CD4+ cell count at 550 cells/µL. However, there is little cause to suspect that the effects of ART on transmission would be less at high counts. More important, the HPTN 052 data do not speak to transmission via men having sex with men -- specifically anal sex. Likewise, this was not a study of ART to reduce transmission by needle sharing. These are limitations and extrapolation to anything other than penile-vaginal sexual transmission of HIV would be just that, extrapolation.
Further, there remain concerns about the limitations of ART itself, especially among HIV treatment providers who know well that the ART sword is double-edged. As the prescription of medication is not without its own risks, is it justified to treat an individual with the intention to protect others? This is an important question that could also be asked of other measures undertaken with the benefit of the public health in mind (e.g., vaccinations to provide herd immunity). For many who have drunk the Kool-Aid on ART as prevention, however, the lines between personal and public health are becoming blurred as accumulating data suggest the positive personal health effects of ART even at high CD4+ cell counts (see below).
The ART-as-prevention genie is out of the bottle and as ART continues to improve in terms of tolerability, affordability and convenience, its application for personal and public health is inevitable.
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