By Michael Smith, North American Correspondent, MedPage Today
Published: February 19, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
Any HIV therapy that reduces the risk of an immune cell being infected by a factor of at least 100,000 is enough to keep the virus in check, researchers reported.
The finding, from a detailed mathematical model of antiviral activity, suggests why some drugs and drug combinations do better than others, according to Robert Siliciano, MD, PhD, of Johns Hopkins University in Baltimore and colleagues.
And the model also demonstrated that the complexity and cost of HIV treatment might be reduced -- and access to treatment improved -- by choosing drugs based on their ability to inhibit infection, Siliciano and colleagues reported online in Nature Medicine.
In principle, it might even be possible to move to dual therapy or even monotherapy, if the inhibition remained high enough, Siliciano told MedPage Today. "There are trials of (protease inhibitor) monotherapy already, with reasonably good results," he wrote in an email.
The key to the model, the researcher said, is understanding how well individual drugs block the infection of immune cells in a single round of replication and then calculating what happens to the inhibition when drugs are combined.
In some combinations, the individual effects are nearly independent of each other, increasing the power of the regimen as a whole, the researchers reported.
In others, the drugs share a common target and their effects add up, but not as much as might be expected, they found.
For this analysis, the researchers calculated the instantaneous inhibitory potential (IIP) of a range of commonly used drugs and combinations. IIP is a useful and intuitive measure of antiviral activity, the authors explained.
They defined the IIP as the log reduction in infected cells caused by a drug or combination.
Among the surprises, Siliciano said, was the fact that the IIP varied widely among drugs.
For instance, one of the earliest anti-retrovirals -- the nucleoside analogue reverse transcriptase inhibitor stavudine (or d4T) -- had an IIP of less than one log.
In contrast, the boosted protease inhibitor darunavir (Prezista) had an IIP of about 10 logs by itself, while the combination of darunavir and efavirenz (Sustiva), had an IIP of about 12 logs.
Overall, the researchers reported, a drug or regimen can be effective if its IIP is between five and eight logs.
But of 31 regimens evaluated, only one with an IIP of less than eight was able to reduce the viral load to undetectable in 70% of patients after 48 weeks.
"Overall, the results fit well with clinical results," Siliciano said.
The work could help refine anti-HIV strategy, which for years has focused in attacking different aspects of the viral life cycle. In most cases, the approach worked but it wasn't clear why come combinations worked and others did not.
"What this work does is explain why some combinations work and others don't," Siliciano said.
There no immediate clinical application of the work, but it will help in "shaping future clinical research questions," Siliciano said.
The study was supported by the NIH and the Howard Hughes Medical Institute.
The journal said the authors declared no competing financial interests.
Primary source: Nature Medicine
Source reference:
Jilek BJ, et al. "A quantitative basis for antiretroviral therapy for HIV-1 infection" Nature Medicine 2012; DOI: 10.1038/nm.2649.
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