HIV: Modeling the experiment & the problem of evolution

I just noticed a small article in the ScienceNOW Daily News on using microbicide gels to decrease the risk of contracting HIV. Give it a read!

So why did this article (and this more detailed information from the NIH) catch my attention?

Right now, as I type this, over 9,400 women in Africa are participating in a second, even larger clinical trial - the subject of some other interesting research I'll get into below. The results of that study will in large part determine whether or not this product makes it to market. Being my usual critical self, I immediately have two questions come to mind: "Will it be effective?" and "Is it safe?"

This first question will get a strong answer via this study - after all, 'effective' is relatively straight forward thing to describe and measure. But what do we mean by "safe"?? This brings me to the other big reason this article grabbed my attention: Dr. Sally Blower.

This past fall I had the pleasure of meeting Dr. Sally Blower, a mathematical biologist at UCLA, while I was visiting Ohio State's Mathematical Biosciences Institute during a workshop. She presented some of her research taking a critical look at the second study mentioned in the ScienceNOW article. Her technical paper on the matter can be found on her website.

To briefly summarize the work she presented, she and her colleagues were interested in addressing the possible risk of drug resistant strains arising from the use of these microbicide gels. HIV has a relatively high mutation rate (leading to lots of genetic variation in a viral population) and anyone already infected with HIV who is exposed to anti-retroviral drugs (ARVs) could unknowingly be facilitating natural selection on the virus, leading to drug resistant strains of HIV. Unfortunately, this is a very real problem in the fight against HIV/AIDS, and to let a high-risk product pass clinical testing could come at a price in the long run.

So to understand how well the experiment could assess this risk, as well as the efficiency of the microbicide gels as a means of protection against HIV infection, she and her colleagues created a computer model of the experiment. They began by simulating a population of women and men in which HIV was being transmitted.

As the omniscient creators of this virtual world, they were able to include and manipulate many key factors in the transmission process, including other means of protection (e.g. condoms), the efficacy of the gels, and so on. They were able to "parameterize [the] transmission model using epidemiological, clinical, and behavioral data to predict the consequences of widescale usage of high-risk microbicides" in the population. They then collected data from a number of simulations, following the same type of protocol as the real study, which they could then compare to the actual transmission process in the simulated population.

This clever use of mechanistic models and real world data accomplished two things. First, the computer model allowed them to assess the limitations of the real world experimental protocol, which helps researchers in their interpretation of the real-world experimental results. Second, because they were free to vary the model parameters and run the simulated experiment repeatedly, they could explore the simulated transmission process under different scenarios and describe how the factors included in the model contribute to the eventual outcome.

So did we learn anything from all of this? Among their results, they found that the "planned trial designs could mask resistance risks and therefore enable high-risk microbicides to pass clinical testing" - unfortunate news. On the other hand, their findings suggest that "even if ARV-based microbicides are high-risk and only moderately efficacious, they could reduce HIV incidence."

I can't say what the future holds for these microbicide gels, although I certainly hope they prove to be another means to battle against HIV worldwide. If you'd like more information on HIV/AIDS, check out the 2008 report on the global AIDS epidemic (I'd recommend browsing the "Media kit") from the United Nations Programme on HIV/AIDS.