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UCLA study may
explain pitfalls of drug holidays

UCLA study may
explain pitfalls of drug holidays

Researchers say natural body cycles may lead to viral rebound during drug holidays.

Researchers have been puzzled over why HIV-positive patients who have periodic interruptions in their drug therapy reach a point where the therapy no longer reduces their HIV viral loads, even in the absence of any evidence of acquired drug resistance. Now two researchers at the University of California, Los Angeles's AIDS Institute have devised a novel hypothesis based upon mathematical modeling linked to the physical phenomenon known as "resonance."

Based on the assumption that viral dynamics have a cycle that varies from patient to patient, the researchers suggest that these forces interact with treatment interruptions in a way that causes high fluctuations in the patient's viral load and, ultimately, virologic failure. At that point, the drugs can no longer reduce the levels of virus in the patient's blood.

Therefore, the UCLA researchers feel there may not be a single, structured treatment-interruption therapy that will be effective for all HIV patients.

"This is important to keep in mind when developing therapies for HIV-patients," Sally Blower, professor of biomathematics and coauthor of the study with postdoctoral researcher Romulus Breban, says in a press statement, "Our research shows that mathematical models can be extremely useful as tools for generating hypotheses."

Resonance is the oscillation that results when a system with natural cycles is affected by an external force that is itself moving at an appropriate frequency, resulting in a strong fluctuation. A swing pushed in the same direction in which it is already moving, for instance, will swing higher as a result of that force placed upon it at a frequency that corresponds to the natural periodicity of the swing.

In the same way, the periodic interruptions in HIV antiretroviral therapy might contribute toward pushing the viral load higher when those interruptions occur at a specific time during the viral load's cycle, the researchers suggest. Resonance is observed when the antiretroviral drugs cannot reduce the viral load.

"Resonance is a very general phenomenon that has been long known in physics and engineering," Breban says in a press statement. "We are the first to apply it to virology."

"At the beginning of treatment, the patient's viral load is quickly suppressed," Breban continues. "But the therapy interruptions combined with the viral dynamics, which can vary widely from person to person, can lead to treatment failure."

While small initial pilot studies into treatment interruptions showed no virologic failure in the test subjects, a large-scale clinical trial in 2003 was prematurely terminated due to a 53% virologic failure rate. And the disappointing findings have continued, prompting authorities to cancel another treatment-interruption study. On January 18, the National Institute of Allergy and Infectious Diseases halted enrollment into an international HIV/AIDS trial known as Strategies for Management of Anti-Retroviral Therapy, which compared continuous antiretroviral therapy with episodic drug treatments, after researchers determined that patients on episodic treatment faced more than double the risk of disease progression than the other patients.

If the resonance hypothesis to treatment interruptions is correct, then the results of the Blower-Breban study have important implications for the treatment of patients, clinical trial design, and public health.

The National Institutes of Health/National Institute of Allergy and Infectious Disease funded the study, which appears in the April 15 issue of the medical journal The Lancet. (The Advocate)

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