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New strategy to rapidly assess efficacy of AIDS drugs in children

Researchers accurately predicted long-term response to ritonavir treatment in 36 of 41 pediatric patients.

[Triple combinations] [Current testing]

[Your turn]

November 1998

BETHESDA, Md. - Parents of HIV-positive children want to know soon after their child begins a new treatment whether or not it is controlling the virus. But, getting that answer now requires several weeks of testing - and waiting.

A team of scientists report taking an important first step toward speeding up the process. In a study of the antiviral drug ritonavir (Norvir, Abbott) involving 41 HIV-positive children, the scientists found that by performing a combination of tests earlier than is now standard, they could reliably predict within a week of starting therapy whether or not the drug would be effective. Their prediction was correct in nearly nine out of 10 children.

"The essence of our analysis is that only a combination of multiple parameters reflecting the function of the immune system, level of viral replication, and drug pharmacology contains sufficient information to robustly [predict] long-term treatment efficacy from short-term measurements," said Dimiter Dimitrov, PhD, a scientist with the National Cancer Institute (NCI) and senior author of the study.

Triple combinations

According to the study's lead author Brigitta Mueller, MD, formerly an NCI scientist and currently at Harvard Medical School, the analysis should be applicable for combinations of drugs, even though the study evaluated initial therapy with a single drug. In fact, when 39 children from the study later began a triple-drug combination of ritonavir, zidovudine (AZT, Retrovir, Glaxo Wellcome) and didanosine (ddI, Videx, Bristol-Myers Squibb), Mueller and colleagues used the model to predict correctly the treatment outcome of 80% of the children.

Mueller added that the analysis also could potentially have implications for HIV-positive adults. "There obviously are major differences between children and adults," said Mueller of the study, which involved a collaboration of scientists from NCI and Abbott Laboratories in Abbott Park, Ill. "But our results showed some similarities between children and adults in the rate of virus clearance, one of the key parameters of the analysis."

Current testing

Currently, doctors evaluate a person's long-term prognosis based on two tests: CD4 counts and viral loads. Previous studies have suggested that changes in the concentration of the virus several months after the start of therapy can be predictive of a person's long-term risk of developing AIDS. However, if the therapy is suboptimal, the children are unnecessarily exposed to drug toxicity, and the virus can develop resistance to the drug.

The analysis that Mueller's group developed goes one step further. By using four parameters - the pretreatment levels of CD4 cells and HIV RNA in the blood, the plasma drug concentration at the end of the first week of therapy, and the rate of virus elimination from the blood - the scientists could predict the HIV blood concentration three months after the initiation of therapy, a measure that is related to the risk of developing AIDS and death.

During a phase 1 clinical trial, the scientists found that after 12 weeks of treatment it was possible to divide the children, based on changes in their plasma HIV concentrations, into two broad categories of good or poor responders to the drug. They also discovered that about half of the children who fell into the "poor responder" group remained there even after receiving the highest possible dose of the drug, while several children in the "good responder" category benefited from relatively small amounts of ritonavir. This indicated that factors other than how much drug a patient receives had to be at work in determining the effectiveness of the treatment.

To tease out these factors, the scientists went back and analyzed tests that they had performed for each child during the first week of the study. The scientists discovered a number of similarities in the good responders. They had consistently higher rates of viral clearance, coupled with higher plasma concentrations of ritonavir, an indication that the drug stayed in their systems longer than the poor responders. The good responders also had a lower viral load count and higher CD4 cell.

"These findings suggested that it might be possible to use these data from the first week of treatment to predict a child's chances of being a long-term responder to the drug," said Steven Zeichner, MD, PhD, an NCI scientist and author of the study.

The scientists plugged these parameters into a mathematical prediction method for each child in the study. Based on this analysis, they found that they had accurately predicted the long-term response of 36 out of 41 children. They also noted that for three other children in the study, they were unable to make a prediction one way or the other based on the analysis.

"These results are extremely encouraging," said Dimitrov. "But they represent a first step, and they do need to be tested further in more patients and other settings."

For your information:

• Mueller BU, Zeichner SL, Kuznetsov VA, et al. Individual prognoses of long-term responses to antiretroviral treatment based on virological parameters measured during the first week under therapy. AIDS 1998:10.

Your turn

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Copyright 2000, SLACK Incorporated. Revised 15 September 2000.