New options might be around the corner for those challenged by failing
regimens & resistance
by Chael Needle
LifeGuide
[Treatment Horizons]
What treatment options might become available for someone who is HAART-experienced, drug resistant, and can no longer suppress viral loads to undetectable levels? Researchers at University of California, San Francisco, led by Dr. Steven C. Deeks, have approached this question not by trying to treat drug-resistant viruses, but rather studying how HIV develops in relation to various drug classes in order to discover “workarounds” in order to maintain an immunological response.
Deeks, who along with his team published the results of a recent study in the November 1 issue of The Journal of Infectious Diseases, says: “About five years ago, we observed that, when individuals who had drug resistance stopped all their drugs, their viral load went up pretty quickly and their T cells dropped dramatically.” The researchers, in other words, had expected little or no change: If the virus was drug-resistant, there shouldn’t be a fluctuation on or off the medications, right? The researchers considered two possibilities: that the drugs that were stopped were still partially active against HIV despite the presence of multidrug resistance, and that the resistant strain of the virus was less “fit”—and thus more vulnerable to anti-HIV medications—than the wild-type strain.
Researchers interrupted each drug class, one at a time; seventeen subjects discontinued all protease inhibitor treatment and six subjects discontinued all reverse transcriptase inhibitor treatment. Interrupting each class separately, and in a controlled way, allowed the researchers to compare a participant’s steady state on his or her current regimen with changes in viral load and T-cell counts in relation to the absence of one of the drug classes.
The research team’s major (and surprising) finding “was that nucleoside analogues—AZT, and so forth—have substantial residual activity [against HIV], even in the presence of lots of resistance mutations. The drugs still work,” says Deeks, who cautions that, though these observations have subsequently been confirmed by other researchers, the small study does not warrant hasty revisions of regimens until larger studies confirm the results. “With this information, when we construct new regimens for individuals with drug resistance, we focus on getting as many of these nucleoside analogues [in the regimen] as possible, regardless of what the resistance tests show.
Whereas mutations once only meant a resistance-related decrease in activity against HIV, now they might also translate into improved or maintained immunological function. How? “The second major area of this research is the concept of fitness. Here, the answer is still not that clear, but the preliminary data suggests that 3TC resistance as well as protease-inhibitor resistance are both important in terms of reducing the fitness and perhaps the virulence of the virus. These are a fundamentally different way that these drugs have benefit: They are not necessarily pushing the virus down but altering the virus.” Some drugs are selecting out mutations that reduce replication capacity, weakening the strain’s ability to reproduce itself. The risk-benefit ratio of maintaining a less “fit” strain of HIV is better than allowing the virus that is most vulnerable to anti-HIV drugs—wild-type HIV—but also the most powerful, or the most “fit,” to reemerge.
“Probably both [PIs and NRTIs] are important, particularly in individuals with advanced disease,” notes Dr. Deeks. “With earlier-stage disease you can imagine approaches in which just one drug class is used to maintain some benefit, with the idea of stopping, for example, the protease inhibitors, thereby reducing the amount of toxicity and more importantly reducing the rate at which the virus continues to evolve. Data would suggest that that is probably only a reasonable approach in someone with high CD4 T-cell counts who can afford to lose some of the residual benefits that are occurring with these drugs.”
Deeks believes that this developing knowledge could be a boon to large, randomized clinical trials designed to figure out who needs which drug when. For example, his team has since found that “non-nucleoside reverse transcriptase inhibitors really have no role in the presence of resistance. They neither have residual antiviral activity nor select for a virus which is less fit. Now we are looking at T20 and the preliminary data suggests that, although T20 no longer has any residual antiviral activity against the resistant virus, it appears to select for a virus with decreased fitness.”
Chael Needle wrote about HIV’s effect on the brain for the November 2005 issue.
January 2006
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