Anti-HIV drug simulation offers 'realistic' tool to predict drug resistance and viral mutation
Computer model should help develop better anti-HIV drug combination therapies
2-Sep-2012 - Pooling data from thousands of tests of the antiviral activity of more than 20 commonly used
anti-HIV drugs, AIDS experts at Johns Hopkins and Harvard universities have developed what they say is the first accurate computer
simulation to explain drug effects. Already, the model clarifies how and why some treatment regimens fail in some patients who
lack evidence of drug resistance. Researchers say their model is based on specific drugs, precise doses prescribed, and
on "real-world variation" in how well patients follow prescribing instructions.
Johns Hopkins co-senior study investigator and infectious disease specialist Robert Siliciano, M.D., Ph.D., says the
mathematical model can also be used to predict how well a patient is likely to do on a specific regimen, based on their
prescription adherence. In addition, the model factors in each drug's ability to suppress viral replication and the
likelihood that such suppression will spur development of drug-resistant, mutant HIV strains.
"With the help of our simulation, we can now tell with a fair degree of certainty what level of viral suppression is being
achieved - how hard it is for the virus to grow and replicate - for a particular drug combination, at a specific dosage and drug
concentration in the blood, even when a dose is missed," says Siliciano, a professor at the Johns Hopkins University School
of Medicine and a Howard Hughes Medical Institute investigator. This information, he predicts, will remove "a lot of the
current trial and error, or guesswork, involved in testing new drug combination therapies."
Siliciano says the study findings, to be reported in the journal Nature Medicine online Sept. 2, should help scientists
streamline development and clinical trials of future combination therapies, by ruling out combinations unlikely to work.
One application of the model could be further development of drug combinations that can be contained in a single pill
taken once a day. That could lower the chance of resistance, even if adherence is not perfect. Such future drug regimens, he says,
will ideally strike a balance between optimizing viral suppression and minimizing risk of drug resistance.
Researchers next plan to expand their modeling beyond blood levels of virus to other parts of the body, such as the brain,
where antiretroviral drug concentrations can be different from those measured in the blood. They also plan to expand their analysis to
include multiple-drug-resistant strains of HIV.
Besides Siliciano, Johns Hopkins joint medical-doctoral student Alireza Rabi was a co-investigator in this study. Other
study investigators included doctoral candidates Daniel Rosenbloom, M.S.; Alison Hill, M.S.; and co-senior study investigator Martin
Nowak, Ph.D. - all at Harvard University.
Funding support for this study, which took two years to complete, was provided by the National Institutes of Health,
with corresponding grant numbers R01-MH54907, R01-AI081600, R01-GM078986; the Bill and Melinda Gates Foundation; the Cancer
Research Institute; the National Science Foundation; the Howard Hughes Medical Institute; Natural Sciences and Engineering
Research Council of Canada; the John Templeton Foundation; and J. Epstein.
Currently, an estimated 8 million of the more than 34 million people in the world living with HIV are taking antiretroviral
therapy to keep their disease in check. An estimated 1,178,000 in the United States are infected, including 23,000 in the state of Maryland.
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For additional information, go to:
http://www.hopkinsmedicine.org/pharmacology_molecular_sciences
/faculty/bios/siliciano.html
http://www.hhmi.org/research/investigators/siliciano_bio.html
http://www.nature.com/nm/index.html
Source:
http://www.eurekalert.org/pub_releases/2012-09/jhm-ads083012.php
Contact:
David March
dmarch1@jhmi.edu
410-955-1534
Johns Hopkins Medicine
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