February 6, 2008

TDM-Guided PI Dose Increases of Limited Benefit

Using therapeutic drug monitoring (TDM) to guide protease inhibitor (PI) dosing in treatment-experienced patients was generally considered to be ineffective, according to data from an AIDS Clinical Trials Group (ACTG) study presented this week at the 15th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. However, the study did show a potential TDM-guided dose-increase benefit in some populations of HIV-positive patients, including blacks and Hispanics, as well as those with less resistance to the PI they used during the trial.

ACTG study 5146, reported at CROI by Lisa Demeter, MD, of the University of Rochester School of Medicine, and her colleagues set out to explore whether increasing blood concentrations of PIs, using TDM to guide dosing, could improve treatment responses in people experiencing treatment failure while taking a PI-containing regimen.

A total of 411 volunteers were enrolled, all of whom had viral loads of at least 1,000 copies while on their most recent drug regimen and a history of treatment failure while on a PI-based treatment regimen.

At the start of the study, all patients began treatment with a new combination of drugs that including a PI. Two weeks later, the amount of the PI in patients’ blood was measured, using TDM.

TDM, a relatively popular laboratory test used in the care of HIV-positive patients in Europe, measures the amount, or concentration, of many antiretrovirals, including PIs, in the bloodstream. Drug concentrations that are too low may not be effective against HIV and can increase the risk of resistance. TDM is not widely employed in the United States, as there are lingering questions regarding its usefulness in making important HIV treatment decisions.

The ratio of the patients’ PI concentration, in relation to the drug’s 50 percent inhibitory concentration (IC50)—the drug concentration needed to reduce drug-sensitive and drug-resistant HIV replication by 50 percent—is called the inhibitory quotient (IQ). A normalized IQ (NIQ) is the ratio of a patient’s IQ to the IQs of patients who had good responses to the same PI, with a NIQ of greater than 1 meaning that a patient’s PI concentration is considered high enough to treat his or her HIV. This NIQ, Dr. Demeter explained, was used to decide who would get an increased dose of their PI, with the suggestion that people with NIQs of less than or equal to 1 would have lower viral loads if they received higher than usual doses of their PI.

In this study, the ACTG researchers randomized 183 patients who had NIQs of 1 or less to receive “standard of care” (SOC)—the use of approved, Norvir (ritonavir)-boosted PI doses—or to use TDM to increase their PI dose, more than once if necessary, in an effort to raise their NIQs. Patients with NIQs of greater than 1 and were assigned to an observational arm—continued on their treatment as usual—or discontinued the study after four weeks.

The primary goal of the study was to compare viral load changes in the TDM and SOC groups after 20 weeks in the study. Approximately 51 percent of TDM and SOC patients were people of color and 10 percent were women.

According to Dr. Demeter, there were no significant differences between the TDM and SOC arms in either CD4 count or viral load responses to treatment after 20 weeks. In other words, using TDM to increase the dose of PIs in people with low NIQs did not improve their response to treatment. While increasing the dose of the PI generally led to increased blood concentrations of the drug—interestingly, blood concentrations of Lexiva (fosamprenavir) were largely unresponsive to increased dosing of the drug—this did not translate into greater treatment benefits.

As for patients in the observational group, viral load responses to treatment while enrolled in this study were generally better. Dr. Demeter offered that these patients’ NIQs were likely better to begin with—and were more likely to respond favorably to treatment—because they had less treatment experience than those with lower NIQs in the TDM and SOC groups.

Dr. Demeter explained that treatment responses were better among some groups in the TDM arm of the study, compared with those in the SOC arm. Looking back on the data, the ACTG researchers showed that patients with less drug resistance to the PI being used were more likely to benefit from increasing the dose of the drug.

They also found that black and Hispanic patients may have responded better to increasing the PI dose than white patients. Dr. Demeter said that the reason for this has not been established, but could be due to genetic differences in how drugs are absorbed or broken down by people of different races or ethnic groups.

When looking at groups of participants based on both their HIV drug resistance and race or ethnic group, the study team found that black patients with less HIV drug resistance to their protease inhibitor did better on the TDM than the SOC arm. However, white patients with HIV that was highly resistant to the PI they were taking did worse on the TDM arm compared with the SOC arm. Hispanic patients appeared to have outcomes similar to black patients, but the results were not as statistically significant as for black patients.

Overall, Dr. Demeter said in her concluding remarks, participants with low NIQs did not benefit from using TDM to increase their PI dose. However, she also noted that increased PI dosing was well-tolerated and there were no safety differences between the TDM and SOC arms. She also reiterated that patients with less PI resistance might benefit from TDM-guided PI dose increases.

As for the observed racial and ethnic differences, Dr. Demeter said that that ACTG is planning studies to evaluate whether genetic factors could possibly explain the differences between white, black and Hispanic participants.

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