Special Report on Drug Resistance

HIV-resistance evolution requires new strategies

Mutation risk higher if HIV RNA increases

A new study finds that 60% of HIV patients on stable therapy with detectable viral replication have a rate of new HIV mutations of about 1.5 mutations per year.1

"We mostly were interested in documenting the evolution of resistance while patients were on stable antiretroviral therapy," says Sonia Napravnik, PhD, epidemiologist with the division of infectious diseases at the University of North Carolina School of Medicine in Chapel Hill.

"A lot of times, therapy patients are not able to suppress viral replication to below detectable levels; some will always have some detectable virus level while on therapy," she notes.

"Clinically, it’s challenging to know what to do in that situation."

The options generally include the following:

  • Switch the patient’s therapy to introduce new drug agents and see if this reduces viral replication and whether it creates new mutations and toxicities, Napravnik says.
  • Maintain the patient on therapy, even if the patient has some replicating virus.

"The question is, if you keep patients on this therapy, what is their likelihood of acquiring additional mutations that will confer drug resistance?" she adds. "That’s a concern if you keep a patient on the same therapy."

This observational, prospective clinical study involved patients who had been on stable therapy for a minimum of 30 days before their first genotype test, Napravnik says.

After having a genotype test, the patients remained on the same therapy until a second genotype test was conducted, with a median time between genotypes of nine months, she explains.

All of the patients were selected because they had detectable viral load, Napravnik adds.

"We wanted to see what proportion of patients acquired a new mutation that conferred drug resistance in that interval of being on stable therapy; and overall, 60% of patients acquired at least one new mutation conferring drug resistance in that interval."

The most important factor that proved predictive of at least one mutation was if the HIV RNA slope increased across that interval of time, she says. "It wasn’t the baseline HIV RNA or the first genotype, it was what was happening across the interval of time.

"The other factor that indicated an increased risk of developing a new mutation was if the patient did not have any mutations at the first genotype test, Napravnik says.

"The mutations we saw emerge were relatively consistent with what we would come to expect. The mutations that were apparent at the first genotype and the frequency of those mutations were what we saw at the second genotype also; certain mutations would arise in a relatively predictable manner."

Basically, the research indicates clinicians will risk additional mutations if a patient is kept on stable therapy, and there will be ongoing viral replication, she says.

The best predictors of who will develop mutations vs. those who will not are the change in HIV RNA over time and the type of mutations the patient currently has, Napravnik adds.

"If the HIV RNA is staying stable or going down, even though the patient is on the same therapy, then the risk of developing a new mutation is much lower than if it’s steadily creeping up," she notes. "That’s something to watch for."

Also, it’s important for health care providers to continue to refine and better understand how to properly use the genotypic information they receive, Napravnik continues.

"We’ll probably see a lot of important new breakthroughs in HIV to help us use information we get from genotype or phenotype tests in guiding clinical care decisions," she says.

"Figuring out how to use the [resistance] information and interpret it from research and a clinical perspective is the next important step," Napravnik adds.


1. Edwards D, Stalzer B, Napravnik S, et al. HIV resistance evolution in the setting of stable antiretroviral therapy. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; November 2004. Poster H-176.