People infected with HIV (search) who take their medications most but not all of the time may be up to four times more likely to develop drug resistance.

Drug resistance renders even the most effective HIV drugs helpless at controlling the virus.

A major new Canadian study shows that consistent yet imperfect use of a combination of three HIV drugs known ashighly active antiretroviral therapy (search) (HAART) more than quadrupled the risk of developing resistance to one or more of the drugs.

“It’s pretty good adherence to be picking up 70 percent, 80 percent, or 90 percent of your prescriptions, but doing that is actually putting you at the highest risk of picking up drug resistance,” says researcher P. Richard Harrigan, PhD, director of the British Columbia Centre for Excellence in HIV Research Labs in Vancouver, Canada.

“It’s not like in horseshoes where close is good enough. Close is probably a bad thing in terms of drug resistance,” says Harrigan.

In contrast, people who took their HAART medications as directed 95 percent or more of the time had a much lower risk developing drug resistance and were more likely to have very low blood levels of HIV.

Harrigan presented the results of his study today at an American Medical Association briefing in New York City on the epidemic of HIV drug resistance.

Drug Resistance, the Latest Challenge in HIV Therapy

HAART has drastically reduced the death rate due to HIV/AIDS in the last 10 years, but researchers say resistance to one or more of the drugs used in the three-drug cocktail is an increasingly common problem. Drug resistance now affects more than 50 percent of people treated for HIV in the U.S.

HIV drug resistance (search) occurs when the virus mutates and decreases the ability of a drug or combination of drugs to prevent replication of the virus in the body.

About 20 drugs from three different classes are currently used in HAART in a variety of combinations, which allows doctors to change the treatment if resistance to one of the drugs occurs.

But resistance to one drug can also decrease the effectiveness of other drugs in the same class and reduce the overall effectiveness of the treatment in the long-term by allowing HIV levels to increase.

HIV Drug Adherence Predicts Resistance

In the study, researchers followed more than 1,100 men and women who began treatment for HIV infection in Alberta, Canada, from 1996-1999 for 2.5 years.

To determine how well the participants followed their prescribed HAART therapy, researchers analyzed prescription refill records as well as checked blood samples to see if the patient had the desired levels of drugs in their system.

During the 2.5-year follow-up period, the study showed that one in four participants developed resistance to one or more of their HIV medications. Among those that developed HIV drug resistance, the average time before drug resistance developed was about eight months.

The two biggest factors associated with drug resistance were inconsistent medication use and a high HIV level in the blood at the start of the study, which is the result of starting treatment later in the course of the disease.

Researchers found that HIV patients who took 80 percent of their medications were four times more likely to develop drug resistance than those who rarely picked up their HAART prescriptions.

“If you don’t pick up any of your prescriptions, you’re not very likely to pick up drug resistance,” says Harrigan. “But that’s not where you want to be in terms of your health because patients with lower adherence had a lower likelihood of actually surviving.”

The study showed that the risk of developing drug resistance was highest among people who took their drugs as prescribed 70-90 percent of the time.

Those who were near perfect in refilling their prescriptions (greater than 95 percent refill rate) and actually took them as directed according to blood tests had a fourfold lower risk of developing drug resistance compared to inconsistent HAART users.

Researchers say this group likely avoided drug resistance by effectively suppressing HIV to nearly undetectable levels, which dramatically reduces the risk of the virus mutating and becoming resistant to medication.

However, only about 30 percent of the HIV patients in the study fit into this “near-perfect drug user” category, and researchers point out that this is among a group of Canadian citizens who received their medications and health care free of charge.

Helping HIV Patients Take Their Medications

In the U.S., researchers say nearly 50 percent of HIV patients have detectible levels of the virus in their blood, an indicator that they may not be taking their HAART medications as prescribed.

Experts say failure to take HAART as prescribed is a major factor behind treatment failure and progression to AIDS. Although nonadherence is a common problem in many diseases, researchers say the issue is particularly dangerous in HIV treatment.

“Nonadherence is nonforgiving with HIV infection,” says John G. Bartlett, MD, chief of the division of infectious disease at the Johns Hopkins University School of Medicine in Baltimore, Md. “If you don’t take your blood pressure medication, your blood pressure goes up for that day and then goes back down again. But with HIV medication, you don’t get the chance of them being active or effective later.”

The antiretroviral drugs used in HAART work by preventing the virus from replicating. But when a dose of the drugs is missed, the levels of the virus in the blood can rise rapidly and begin to mutate, which increases the likelihood of resistance.

One of the reasons it has consistently been difficult for HIV patients to take their medications as prescribed is that the treatment regimen often required taking as many as 14 pills at different times or with different food restrictions.

But researchers say the number of pills required for HAART is now as low as two or three pills once a day and is predicted to drop to one pill per day within the next year.

In the meantime, a team effort is required to help HIV patients stick to their drug schedule, according to Kathleen Squires, MD, associate professor of medicine at the University of Southern California, who also attended the briefing.

That team approach often includes:

--Assigning a case manager who sits down with the patient and helps them visualize how they will fit taking HAART into their lifestyle.

--Offering directly observed therapy in which a health care worker goes to the patient’s home to deliver treatment, or the patient comes to the clinic to get medication.

--Group or individual counseling at a variety of locations, including clinics, community organizations, or the patient’s home.

Bartlett says researchers also have to keep ahead of drug resistance by developing new drugs that are active against new targets or those strains of HIV that are currently resistant. But finding ways to help people with HIV reap the biggest benefits of HAART remains a major hurdle in HIV treatment.

“We have to figure out better ways to help patients to remember to take medications as prescribed,” says Bartlett.

By Jennifer Warner, reviewed by Michael W. Smith, MD

SOURCES: Harrigan, R. The Journal of Infectious Diseases, Feb. 1, 2005; vol 191: pp 339-347. Richard Harrigan, PhD, director, British Columbia Centre for Excellence in HIV Research Labs, St. Paul’s Hospital, Vancouver, Canada. John G. Bartlett, MD, Stanhope Baynes Jones Professor of Medicine; chief, division of infectious disease, The Johns Hopkins University School of Medicine. Kathleen Squires, MD, associate professor of medicine, University of Southern California.