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HIV Drug Resistance Set to Rise? Publication Pdf attached
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MedPage Today
Published: January 14, 2010
"Regression analysis determined the degree of increase in NNRTI resistance will depend (p < 0.05) on the proportion of patients (who are infected with wild-type strains and being treated with a regimen of two NRTIs and one NNRTI) who achieve viral suppression (Fig. 2B). This proportion depends on the efficacy of the regimen and adherence to it; thus, if only 70% are virally suppressed, NNRTI-resistance could increase by more than 30% (Fig. 2B). This increase is predicted to be mainly due to transmission from untreated individuals infected with NNRTI-resistant strains who are in either the acute or chronic stage of infection."
After leveling off for several years, resistance to HIV drugs is likely to rise again, if the conclusions of a new mathematical model turn out to be accurate.
The model suggests that about 60% of the resistant HIV strains now circulating in San Francisco are capable of starting their own mini-epidemics, according to Sally Blower, PhD, of UCLA, and colleagues.
In an online article in Science, the researchers warn that a new wave of drug-resistant HIV strains could interrupt progress toward controlling the pandemic around the world.
Early modeling by her group -- later borne out by data -- suggested that HIV resistance would emerge among patients on treatment and then plateau, Blower told MedPage Today.
But the new model suggests that some resistant strains are now being transmitted among people who have never been treated. "Essentially, it's like the beginning of the HIV epidemic all over again," Blower said.
Action Points
* Explain to interested patients that this study suggests that HIV drug resistance will soon start to increase.
* Caution that the finding is based on a sophisticated mathematical model and may not take into account all of the relevant factors.
The study drew a mixed reaction from HIV/AIDS specialists.
Resistance expert Mark Wainberg, PhD, of McGill University in Montreal, one of the discoverers of the HIV drug 3TC, called the article "very important."
In an e-mail to MedPage Today, Wainberg, one of the discoverers of the HIV drug 3TC, said, "The fact that transmission of drug resistance represents a major concern for the future ... is terribly disconcerting."
But not everyone is disconcerted. The fears raised by the study are "hype," according to John Mellors, MD, of the University of Pittsburgh, because the researchers assume that HIV therapy is unchanging.
"In fact, therapy is continually changing and is become more effective and generating less resistance," Mellors wrote in an e-mail. "So the sky is not falling."
Blower and colleagues noted in Science that many models of resistance only track the effects of single strains, but the new model is capable of analyzing multiple strains with different levels and types of resistance -- including single-, double-, and triple-class resistance to the three major HIV drug classes.
When tested retrospectively, they said, the model reproduced the resistance dynamics that were seen in San Francisco as treatment developed from monotherapy, through dual therapy, to the early triple-drug cocktails and to the modern era.
Notably, the model estimates the current proportion of resistant strains to be 14% -- close to empirically-derived estimates of 13% to 16%, the researchers said.
In the next five years, the model predicts, resistance to two classes of drugs -- protease inhibitors and nucleoside reverse transcriptase inhibitors -- will remain relatively low.
But resistance to the third major class -- the non-nucleoside reverse transcriptase inhibitors -- will increase, the model suggests.
The conventional wisdom, Blower said, has been that resistant strains are less fit than wild-type virus and thus less able to infect new patients.
But currently, Blower said, about 60% of resistant strains circulating in San Francisco are sufficiently fit that they could be transmitted to more than one person.
And about three-quarters of those are resistant to the non-nucleoside reverse transcriptase inhibitors, the researchers said.
"The strains that are resistant to the non-nukes are actually pretty fit," Blower said, "almost as fit as wild-type strains."
One implication, she said, is that therapy in the developing world -- where the non-nucleoside reverse transcriptase inhibitors are mainstays -- may lead to a new wave of resistance that could cripple efforts to slow the pandemic.
Robert Schooley, MD, of the University of California San Diego, said drug resistance "is the inevitable result of antimicrobial agents."
Schooley said in an e-mail that there's no reason not to treat people who need care, but "it is critical to use drugs when the benefits (for the individual or the population) outweigh the risks."
Specifically, he said, it's important to monitor viral load to ensure that the virus is adequately suppressed and that resistance is not developing.
The researchers had support from the National Institute of Allergy and Infectious Diseases, the Natural Sciences and Engineering Research Council of Canada, MITACS, the John Simon Guggenheim Foundation, the National Academies Keck Foundation, and the Semel Institute for Neuroscience & Human Behavior. The researchers did not report any conflicts.
This article was developed in collaboration with ABC News.
Primary source: Science
Source reference:
Smith RJ, et al "Evolutionary dynamics of complex networks of HIV drug-resistant strains: the case of San Francisco" Science 2010; DOI: 10.1126/science.1180556.
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