Abstracts (first author)

Talk 

The role of antiretroviral dynamics in the evolution of drug resistance in HIV

Author(s): Hill AL, Rosenbloom DIS, Rabi AS, Georgette N, Siliciano RF, Nowak MA

Summary:

Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically among drug classes. We developed an evolutionary model that explains these observations and predicts treatment outcomes. Our model incorporates drug pharmacokinetics and pharmacodynamics, fitness differences between susceptible and resistant strains, mutations and patient adherence measures. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time during which resistance can be selected for. We find that poor adherence to such drugs causes treatment failure via growth of susceptible virus, explaining puzzling clinical observations. We examine both monotherapy and combination therapy, demonstrating how the concept of the ‘mutant selection window’ can help explain HIV resistance. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance, even in the case of imperfect adherence and “drug holidays. We use our results to prioritize a wide range of dual- and triple- therapies based on expected clinical outcomes. Our approach represents a first step for simulating clinical trials of untested anti-HIV regimens and may help in the selection of new drug regimens for investigation. More generally, we show how fluctuating drug concentrations exacerbate the problem of resistance compared to constant doses with the same time averaged concentration or inhibition level, especially when multiple mutations are needed for resistance.


Video


Abstracts (coauthor)

Summary:

The emergence of resistance in combination therapy can be facilitated by treatment regimes where only one drug is active at certain periods of time, resulting in temporal effective monotherapy (e.g. structured treatment interruptions). This occurs because resistance mutations can arise in a stepwise instead of a concurrent manner when only one drug reaches an effective concentration. We propose that effective monotherapy can also occur at a spatial level because of discordant penetration of drugs into compartments of the body. Here, we present a mathematical model for the evolution of drug resistance in combination therapy when there is differential drug penetration. Our model shows that the presence of body compartments where only one drug in a combination regime penetrates to a therapeutic concentration strongly speeds up the evolution of multi-drug resistance. Resistance mutations are acquired in a stepwise manner through colonization of body compartments where the pathogen can survive without being resistant to all the drugs in the regime. These results offer a possible explanation for the evolution of single-drug resistance in the course of combination therapy. We compare our model results to clinical trials for antiretrovirals and antibiotics to identify cases where stepwise acquisition of mutations can be facilitated by differential drug penetration. Overall, our results suggest that the use of drugs with similar penetration profiles in combination therapy may prevent the evolution of multi-drug resistance.

Contacts

Chairman: Octávio S. Paulo
Tel: 00 351 217500614 direct
Tel: 00 351 217500000 ext22359
Fax: 00 351 217500028
email: mail@eseb2013.com

Address

XIV Congress of the European Society for Evolutionary Biology

Organization Team
Department of Animal Biology (DBA)
Faculty of Sciences of the University of Lisbon
P-1749-016 Lisbon
Portugal

Website

Computational Biology & Population Genomics Group 
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