Ryan Zurakowski, Assistant Professor
HIV Evolution During Dynamic Therapy
National Institute of Health (pending)
Office: Evans 313
The development of multi-drug regimens for HIV therapy has resulted in HIV infection becoming a chronic, manageable disease in first world countries. The widespread use of three-drug regimens, usually consisting of two nucleoside/nucleotide analog reverse-transcriptase inhibitors (nRTIs) and either a non-nucleotide/nucleoside analog reverse-transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) usually provides adequate viral suppression and mutational barrier to maintain viral load at or below the measurement threshold indefinitely. While these three-drug regimens, known as highly active antiretroviral therapy, or HAART, are highly effective at suppressing the virus in the long term, some patients nevertheless experience viral load rebound, driven by the emergence of a viral mutant resistant to all three components of their HAART regimen.
When a resistant mutant emerges, it becomes necessary to switch to a new three-drug regimen, whose components exhibit no cross-resistance with the failed three-drug regimen. There are a limited number of independent drug combinations. A patient who has developed viral strains resistant to all such combinations is called Multi-Drug Resistant or MDR, and such patients are left with few viable treatment options. It is critical, therefore, to preserve the remaining pool of independent HAART regimens, especially for patients who have experienced virological failure on more than one previous regimen.
We are developing model-based approaches to therapy switching for HIV which minimize the risk of subsequent treatment failures by simultaneously considering the contributions of viral and proviral genetic makeup and the total viral load to this risk. This approach differs from the previous approaches in several important ways. It focuses on therapy switches in patients who have not yet developed multi-drug resistant virus, for whom potentially successful antiviral regimens still exist. It incorporates into its calculation of risk not only the known incidences of cross-resistance between antiviral drugs, but also the knowledge of genetic distance between dominant resistant strains, based on the patient's history of antiviral use. To develop these approaches, we will specifically study models of HIV quasispecies dynamics and models of resistance emergence, and use these models to suggest laboratory and clinical experiments to implement these techniques.
Treatment interruptions to decrease risk of resistance emerging during therapy switching in HIV treatment. R. Zurakowski and D. Wodarz. "Proc. 46th IEEE Conference on Decision and Control" (to appear).
Decreasing the risk of resistance emerging during therapy switching in HIV infection with long-lived reservoirs. R. Luo and R. Zurakowski. "Proc. American Control Conference 2008" (submitted).
Resistance Risk Management in HIV Therapy Switching with Explicit Quiescent T-Cell Modeling. R. Luo and R. Zurakowski. "Proc. Conf. International Federation of Automatic Control 2008" (submitted).