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.
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."
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.