Being almost compliant with antiretroviral therapy was associated with a sharp increase in the risk that HIV-infected patients would develop resistance to one or more of the drugs, P. Richard Harrigan, Ph.D., reported at an American Medical Association press briefing.
In a prospective cohort study of 1,191 HIV-infected patients, those who picked up 80%-90% of their prescription refills, and those who occasionally had low serum drug levels even if they picked up 95% of their medication, had more than a fourfold increase in the risk of developing drug-resistant mutations, said Dr. Harrigan, director of the British Columbia Center for Excellence in HIV Research Labs, Vancouver, B.C.
He joined other HIV experts in stressing the importance of antiretroviral therapy adherence. Inconsistent drug levels allow viral loads to increase and also put pressure on the virus to adapt. Patients who consistently take all their medication suppress viral reproduction so well that mutations are unlikely, and those with poor adherence don't have enough drugs in their system to stimulate mutations.
“Physicians should get this message to patients: Be fully, completely adherent as much as humanly possible,” he said.
In the study of patients in British Columbia, the median age was 37 years, the median CD4 cell count was 280 cells/μL, and the median viral load was 120,000 copies/mL. All patients began antiretroviral therapy during 1996-1999; 26 drug combinations were used. Viral load, drug levels, and resistance genotyping were assessed at baseline, after 1 month of therapy, and then quarterly (J. Infect. Dis. 2005;191:339-47).
After an average follow-up of 2.5 years, 25% of the cohort had developed resistance to one or more drugs. Among this group, 68.5% were resistant to lamivudine (3TC), 40% to nonnucleoside reverse transcriptase inhibitors, 33% to nucleoside reverse transcriptase inhibitors, and 23% to protease inhibitors.
The highest risk of resistance mutations occurred in those who picked up 80%-90% of their prescription refills. This group was 4.15 times more likely to develop resistance mutations than were those who picked up 0%-20% of their refills.
An 80%-90% refill rate is “pretty reasonable for some diseases, but not for this. It's not like in horseshoes, where close is good enough. Here, close is a bad thing,” Dr. Harrigan said.
Patients with one or two abnormally low drug concentrations in their first two posttherapy plasma samples were 1.45 times more likely to develop mutations than were those with normal drug levels.
But some patients who picked up more than 95% of their medication still weren't taking it consistently, and they, too, were at a high risk of developing resistance mutations. Among this group, those who had two abnormally low drug plasma levels were 4.57 times more likely to develop mutations than were those with normal drug plasma levels.
As long-term survival increases drug resistance is becoming more of a problem, Dr. Harrigan said. In recent studies, up to 50% of the U.S. population being treated for HIV infection had some degree of resistance.
The 25% resistance rate among the study patients reflects free access to antiretroviral drugs, provided by Canada's nationalized health system. Still, even with free access to medication, only 30% of the study group was fully adherent.
The complexities of antiretroviral dosing interfere significantly with adherence, said Kathleen Squires, M.D., of the University of Southern California, Los Angeles. The risk of nonadherence increases as patients move beyond initially prescribed regimens, which usually are the most manageable.