PrEP and drug resistance mutations

15 Jan 2015, by Erick

There has been a lot of interest and excitement about the application of pre-exposure prophylaxis (PrEP) for HIV, which means giving people uninfected people HIV drugs in order to keep them from being infected with HIV. This works very well when people adhere to the regimen, and in fact was Science’s 2011 breakthrough of the year after the “Partners in PrEP” study. FTC/TDF, sold under the trademark name Truvada, is the first drug approved by the FDA for PrEP. However, HIV is notorious for becoming drug resistant, and so large-scale deployment of HIV drugs for uninfected people leads to the obvious question: won’t that lead to increased drug resistance? In HIV treatment, for example, traditionally patients are not administered drug during the “acute” phase of infection because drug resistance mutations are more likely to arise when replication rates are high. If you give people the drug ahead of time, won’t that be even worse?

A while back Connor and I were invited by Dara Lehman to collaborate on a project concerning drug resistance on samples from the original Partners PrEP study. The original study did look at drug resistance, but only with techniques that allowed them to see drug resistance if it was present at > 10% of viruses sequenced. For this new study we would use deep sequencing to get higher sensitivity. To gloss over lots of details, sequencing error has different likelihood and impacts based on the viral genetic background, and we had to be careful and design a strategy leveraging inline controls.

The results came out recently in a paper [PDF] in the Journal of Infectious Diseases, along with a nice commentary [PDF] that puts the results into perspective. We did see additional drug resistance mutations. Overall, some of the drug resistance mutations were transmitted and some appeared to have arisen in the study participants, some happened when people started PrEP medication with undetected HIV, and more rarely some came from PrEP itself. This doesn’t mean that we shouldn’t use PrEP, but we should realize that there is a balance to be struck between keeping people HIV-free and the appearance of drug-resistance mutations (see the thoughtful commentary piece for more). I’m very grateful to Dara and the other authors for having the opportunity to work on this study.

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