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DURHAM, N.C. – The longest-running study of a common HIV combination-drug treatment shows development of drug resistance is extremely uncommon, even in people who experienced viral rebound during the study.

Finding a drug that fights HIV for the long-term is important because about half the HIV-infected people in the U.S. have some level of resistance to anti-HIV drugs, said Charles Hicks, M.D., lead author of the study and an associate professor of medicine in the division of infectious diseases at Duke University Medical Center. The research was presented July 14, 2004, at the International AIDS Conference in Bangkok, Thailand.

One of the key drugs administered in the study, a fixed-dose combination of lopinavir and ritonavir (LPV/r), is among the most frequently prescribed protease inhibitors in the U.S., Hicks said. Protease inhibitors prevent HIV from making viable copies of itself by blocking the protease enzyme, which HIV needs to replicate. Protease inhibitors can significantly reduce virus levels by stopping HIV replication. However, as with antibiotics, if patients do not take the drugs at the prescribed time and manner, the virus can develop drug resistance.

To determine whether HIV developed resistance to the drugs, Hicks analyzed more than five years of data from 100 patients participating in Study 720, a randomized, blinded, multi-center trial of LPV/r. The study was funded by Abbott Laboratories. Hicks is a paid consultant for Abbott Laboratories.

No patient in the study developed resistance to the LPV/r protease inhibitor, Hicks found. "Even in people whose virus came back, there doesn't appear to be any resistance. That suggests it might be possible to use this treatment over relatively long periods of time," he said.

The rapid rate at which HIV replicates itself makes the virus particularly difficult to combat. Drug resistance develops more quickly in HIV than other infectious diseases, such as those caused by bacteria, because HIV's quick replication cycle gives the virus many more opportunities to evolve resistance to drugs.

If patients do not take the drugs correctly, the level of drug in their blood can drop low enough for the virus to grow, Hicks said. "With repeated exposure to low drug levels, the virus develops resistance to the drugs," he said.

Properly following HIV drug therapy can be difficult for patients, who often must take three or more drugs more than once per day. Some drugs perform best when taken on an empty stomach; others must be taken with food. A few also require refrigeration. Side effects may discourage people from strictly following a particular drug regimen.

In Study 720, which began in 1998, 100 HIV-infected patients began treatment with LPV/r, stavudine (d4T) and lamivudine (3TC). None had previously received antiretroviral therapy. After 252 weeks of follow-up, 64 percent had undetectable levels of HIV in their blood. A total of 27 patients had experienced low-level viral rebound during the five year period – the virus rose to detectable amounts in their blood. Samples for genetic testing of HIV drug resistance were available from 17 of those patients.

The researchers found none of the 17 patients had HIV with resistance to lopinavir. Nor did the virus develop resistance to stavudine, another drug administered during the study. Resistance to the final component of the regimen, lamivudine, was also uncommon. Both stavudine and lamivudine are nucleoside reverse transcriptase inhibitors, which stop HIV from replicating.

Other medical centers participating in the study include the University of Colorado; Pacific Oaks Research; Weill Medical College of Cornell University; Baylor College of Medicine; Northwestern University; Rush University Medical College; Harvard University; the AIDS Research Consortium of Atlanta; and the University of North Carolina at Chapel Hill.