High antiretroviral drug adherence key in effort to avoid drug resistance 

New study highlights its importance

A new study confirms the findings of previous research that antiretroviral drug adherence is a strong predictor of whether drug resistance occurs in HIV patients.

Investigators at the British Columbia Centre for Excellence Research Labs in Vancouver looked for signs of HIV drug resistance among 1,200 HIV patients. They collected more than 3,000 resistance tests for an average of two tests per patient and up to 13 tests on some patients, says P. Richard Harrigan, PhD, director.

Harrigan released data from a new study about HIV antiretroviral adherence at an HIV antiretroviral drug resistance media briefing held by the American Medical Association (AMA) in New York City Jan. 13, 2005.

"Three hundred patients of the 1,200 patients who started had evidence of detectable resistance, and this mostly was to a drug called 3TC," he says. "This is not too surprising because 3TC was the most commonly used drug in triple combination therapy."

Two hundred patients had resistance to 3TC, also called lamivudine (Epivir) over the study’s 2½ years; 100 patients had evidence of resistance to other nucleoside reverse transcriptase inhibitors (NRTIs), and 120 patients had resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), Harrigan explains.

"As time goes on, there’s a gradual selection and accumulation of resistance to each of our categories," he says. "Although the average person did not pick up any resistance, for those who did, the average time was 8.3 months to pick it up."

Researchers analyzed patients’ accumulation of multiple mutations, baseline parameters that might predict development of resistance, amount of virus in bloodstream, CD4 t-cell counts, demographics, type of antiretroviral therapy, history of injection drug use, and two potential measurements of adherence, Harrigan continues.

Patients who had a history of injection drug use were slightly more likely to pick up drug resistance, but that probably was based more on their activity and behavior and disordered lives than a drug interaction, he notes.

"One thing what was not significant as a predictor was the type of triple therapy you started with," Harrigan says. "It didn’t matter if it was based on protease inhibitors, NNRTIs, or NRTIs, because this was not a significant predictor of getting drug resistance, and neither was a person’s gender or baseline diagnosis of whether the person had AIDS or not."

However, adherence was a significant predictor.

HIV patients who adhere to their medication regimen 70% to 80% of the time place themselves at the highest risk of developing drug-resistant virus, he says. "That’s pretty good adherence to pick up 70% to 80% of medications, but doing that puts you at highest risk of picking up resistance," Harrigan adds. "Close enough is a bad thing."

Since the wild virus is stronger and more durable than the mutated HIV, resistance doesn’t become an issue when the wild virus is unsuppressed by drugs.

It might seem logical to think that if a patient doesn’t take 50% of the drug then the patient obviously will have resistance, but that’s incorrect, says John G. Bartlett, MD, founding director of the Johns Hopkins HIV Care Program at the Johns Hopkins University School of Medicine in Baltimore. Bartlett, who is a member of the AIDS Alert editorial advisory board, also spoke at the AMA briefing.

"If a patient takes 50% of the drug, it won’t kill the virus, so they’ll get no benefit, but they probably won’t have enough pressure to have drug-resistance form," he says. "For [maximum] effect, take as much of the drug as you can, and for resistance also take the full load, but a little lapse may be the worst thing you can do."

The problem occurs when an HIV patient’s level of antiretroviral drug in plasma falls below the level needed to maintain viral suppression. These trough concentrations permit a mutant window of opportunity for viral growth, says Kathleen Squires, MD, associate professor of medicine at Keck School of Medicine, University of Southern California in Los Angeles.

Squires is the medical director of the Rand Schrader Clinic in Los Angeles, and she also spoke at the AMA media briefing on HIV/AIDS.

Researchers and clinicians have worked hard over the past decade to develop drug regimens in which the HIV patient’s drug levels never fall into that trough if the drugs are taken as prescribed.

However, all it takes is for a patient to miss the occasional dose to create an environment in which HIV can mutate into a drug-resistant form, Squires says.

Various tracking methods used

Researchers used two methods to measure adherence, including looking at prescription refill records and measuring the plasma samples to see if there were detectable concentrations of antiretroviral drugs, Harrigan says.

While the first method is not a direct measure of adherence, it is a way to see if people are using the drugs because they are unlikely to pick up a refill if they haven’t already finished the medication they already have, he says.

The second method is based on the theory that plasma samples are unlikely to have detectable drug levels if patients aren’t taking the drugs as they should, Harrigan adds.

By using these measures, investigators found that the patients who were the least adherent, meaning they had the fewest number of prescription refills, did not have much antiretroviral drug resistance, he says.

"If you don’t pick up any of your HIV prescriptions, you don’t pick up drug resistance, but that’s not where you want to be in terms of health because the lower the adherence to picking up the drugs, the lower the likelihood of surviving," Harrigan explains.

Also, the patients who picked up 100% of their medication refills were the least likely patients to develop drug resistance, and this finding also was logical, he says.

Investigators studying HIV drug adherence also have used electronic MEMS caps, which generate data showing how many times a patient has opened a pill bottle, which makes it a pretty good measure of adherence to a drug regimen, Squires says.

While MEMS caps have been used to improve medication adherence, other research has looked at how frequently virologic failure occurs in HIV patients, based on MEMS cap/adherence data.1,2

For example, one study of 161 HIV-infected women found that virologic failure occurred in 71% of those who adhered to their drug regimens 12% of the time or less; 43% had virologic failure at an adherence rate of 13% to 44%; 28% had virologic failure at an adherence rate of 45% to 87%, and 17% had virologic failure at an adherence of 88% or greater.2

The research consistently shows a direct correlation between adherence and the ability to achieve the necessary drug plasma levels and the ability or capacity to achieve virological success, Squires adds.

However, the big question investigators wanted to answer was, "At what level of adherence did the most drug resistance develop?"

They found that when patients picked up their medication refills on time, between 60% and 90% of the time they were at increased risk for HIV drug resistance, but the highest risk was among those who picked up their medications about 80% of the time, says Harrigan.

"We found in this longitudinal study that at least 25% of subjects developed resistance in a 2½-year time period," he explains. "We found that adherence to patient’s drug regimens really stands out as an important issue."

Also, investigators found that only 30% of patients actually had picked up all of their medications on time and also consistently had detectable drug levels in their bloodstreams, Harrigan says.

"As time goes on, it becomes a bit more of a challenge for patients to take their medications; and the medications we’re developing are becoming easier to deal with, so there’s some balance there," he notes.

"Some predictors of drug resistance were associated with high levels of baseline viral load and inconsistent use of antiretroviral therapy," adds Harrigan.

"But the worst thing is to take 70% to 90% of your prescription — that’s the worst place to be in terms of developing drug resistance," he notes.

"The final point is resistance mutations last forever," Bartlett says. "We may not measure them because they may be hidden."

Resistance strains may be small in number, but they don’t go away, he adds.

References

1. Rosen MI, Rigsby MO, Salahi JT, et al. Electronic monitoring and counseling to improve medication adherence. Behav Res Ther 2004; 42:409-422.

2. Howard AA, Arnsten JH, Lo Y, et al. A prospective study of adherence and viral load in a large multi-center cohort of HIV-infected women. AIDS 2002; 16:2,175-2,182.