Evidence builds that HIV mutates to resist HAART
The good news: Mutations are consistent
While reports that patients may be cured of HIV after years of highly active antiretroviral therapy (HAART) are circulating, clinicians need to be aware of a recent study clearly demonstrating that the virus in patients treated by these therapies still can mutate.
A study recently published in Molecular Biology and Evolution finds evidence that HIV can evolve and become drug-resistant even while a patient’s combination drug therapy reduces viral load to undetectable levels.1
The study also shows a certain predictability in the mutations, which is good news for drug companies that want to create chemical barriers to stop the virus from evolving into a drug-resistant form.
"The basic idea is, you have this virus evolving down a road, and the drug therapy puts up a roadblock, and then the virus will go someplace else," says Keith A. Crandall, PhD, an evolutionary biologist in the department of zoology of Brigham Young University in Provo, UT.
The research demonstrates that it’s possible to predict which way the virus will evolve. "So drug companies take this information and build a new roadblock," he says.
Crandall and his colleagues’ research suggests HIV drug resistance will continue to spread, making it increasingly difficult to select drug therapies that work.
"We’re going to see the exact same thing as we did with antibiotics, except that HIV mutates faster," he adds.
HIV’s evolution rate depends on factors such as whether a patient has had prior exposure to monotherapy. HAART’s ability to suppress the virus may not last as long in patients who were previously treated with one of the antiretroviral drugs, Crandall says.
Suppress HIV before viral load is high
"Also, when do you initiate drug therapy in the patient’s progression?" he says. "If you begin it at the peak of the viral load, then the viral population has a much better chance of evolving resistance because its population is so high."
However, if clinicians wait to start HAART, there’s a higher probability of the HIV population already having resistant mutations.
The best scenario would be to catch the virus before the viral load has exploded. Alternatively, if a clinician sees a patient after the viral load has had its first burst of activity, it would be better to wait and start HAART after the patient’s own immune system kicks in and brings the viral load down, Crandall suggests.
"I’m sure you have patients whose immune systems are compromised for other reasons, and in those patients you want to intervene as soon as you can," he says. Otherwise, it’s better to wait until the viral load has come down.
The study also highlights the importance of focusing on drug compliance and emphasizing to patients that drug therapy is not a cure.
"If your patient has been on drug therapy for two years and still shows undetectable levels of virus, that is not the time to take the patient off of drug therapy," Crandall says. "That will just make it easier for the virus to come back up and rebound."
Researchers analyzed HIV in patients who had been on triple-drug therapy for more than two years. Although the patients’ viral loads were less than 50 copies/mL, investigators still found signs of HIV evolution. The evolutionary patterns were similar in different patients, suggesting parallel evolution, Crandall says.
Parallel evolution is what happened when fish and dolphins developed fins, for example. Parallel changes are those that occur in independent lines that share a common ancestral character state. Convergent evolution, by contrast, refers to natural selection, when an entity changes in order to adapt to its environment.
Some scientists have doubted that parallel evolution exists at the molecular level, but this study seems to indicate that it does.
Same mutations occur in different patients
"You have independent patients evolving the same mutations to escape drug therapy, which suggests there are a limited number of ways for HIV to escape," Crandall says.
"The fact that they’re all evolving in a similar evolutionary pathway means that if you design a drug to affect that pathway, it will affect a lot of patients," he adds.
Crandall became involved in the research a couple of years ago when a colleague at the National Cancer Institute asked him to analyze some HIV sequences. They began a collaboration to see whether HIV was evolving, even when it was suppressed to undetectable levels in patients on triple-drug therapy.
The researchers explored the relationship between genetic variation and disease progression and measured genetic diversity at two time points in samples from eight patients.1 In five patients, the HIV had evolved, with identical changes occurring in each person.
The researchers concluded that either very small populations of virus are being activated and then are replicating and evolving, or that latent reservoirs are activated.
The next step is to study the viral reservoirs in patients on triple-drug regimens to see if the virus is coming out of these reservoirs to replicate and evolve, Crandall says, adding that he hopes to become involved in such a project within the next six months.
If the virus is coming out of the reservoirs and depletes the reservoirs, this could mean there is an end-point when drug therapy has cured some patients. But if the virus outside the reservoirs becomes activated and replenishes the reservoirs, there will never be a drug therapy cure, he adds.
"It’s an evolutionary question," Crandall explains. "You take samples of the virus from the reservoir early on, and then you take samples from the reservoirs four years down the road and see if there has been an evolution. If there has been, then they are being replenished."
Reference
1. Crandall KA, Kelsey CR, Imamichi H, et al. Parallel evolution of drug resistance in HIV: Failure of nonsynonymous/synonymous substitution rate ratio to detect selection. Mol Biol Evol 1999; 16:372-382.
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