Early testing can predict effects of drugs on kids
Results could spare months of wasted therapy
By giving four tests to children immediately after they begin therapy with HIV drugs, it is possible to know within a week how well they will respond to the treatment, says a team of researchers from the National Cancer Institute in Bethesda, MD.1
As part of a phase I/II study of the antiviral drug ritonavir involving 41 HIV-positive children, scientists found that by performing a combination of tests earlier than is now standard practice, they were able to predict correctly in 36 of the children if the drug would be effective in controlling the virus.
The findings could save children from months of wasted suboptimal treatment, says Brigitta Mueller, MD, a researcher now at Children’s Hospital in Boston, who led the study.
Doctors usually base long-term prognosis on two tests—CD4 cell counts and amount of HIV present in blood—taken several months after therapy has begun. However, if therapy is not optimal, the virus can develop resistance to the drug, which narrows long-term treatment possibilities.
"When viral load starts to increase, the virus starts multiplying, develops mutations, and becomes resistant," says Mueller. "Often, if you become resistant to one drug, you become resistant to the whole class of drugs."
The trial, which began in 1995, was designed to assess the safety and tolerability of ritonavir, and to establish dosing guidelines in children.2 The HIV and AIDS Malignancy Branch of the National Cancer Institute performed the trial, in collaboration with the University of Florida and the University of South Florida/All Children’s Hospital. HIV-infected children between six months and 18 years of age were eligible.
Mueller and her team simply maximized the "wealth of information that came from that trial," she says. They established a substudy to determine whether early testing could be an accurate predictor of a child’s response to HIV drugs.
The 41 children were divided into groups and given different doses of ritonavir: 250, 300, 350, or 400 mg/m2. Ritonavir was administered as monotherapy during the first 12 weeks every 12 hours, after which zidovudine and/or didanosine were added.
To predict long-term virological responses, Mueller and her team began monitoring CD4 counts and viral load levels immediately before treatment began and on days one, two, three, four, seven, 14, and 28, as well as on day seven of weeks 12 and 24. At the end of the first week of therapy, they also measured plasma drug concentration and the rate of viral elimination from the blood.
A retrospective analysis after 12 weeks of treatment showed researchers that specific viral load levels or CD4 levels seemed to indicate children who were "good responders" or "poor responders" to the drug.
When Mueller’s team analyzed tests performed on each child during the first week of the study, they discovered a number of similarities in the good responders. Each had consistently higher rates of viral clearance and higher plasma concentrations of ritonavir, indications that the drugs stayed in their systems longer. The children also had a lower viral-load count and higher CD4 counts, signs of low levels of virus replication and better immune function.
Those parameters were then incorporated into a mathematical prediction method. The team found they could accurately predict the long-term response of 36 of 41 children. They also noted that for three other children in the study, they were unable to make a prediction based on the analysis. Mueller admits that while the results are extremely encouraging, they represent a first step and need further testing in more patients in other settings.
One important implication of these results, says Mueller, is the possibility for early identification of patients who were given suboptimal or failing therapy. To prevent the emergence of drug-resistant virus, physicians could either switch patients to another drug regimen or increase the drug dose, rather than expose the child to weeks of a drug that only is increasing resistance.
Early monitoring works with protease inhibi tors, explains Mueller, because those drugs act quickly to lower viral load. "Only in the last three or four years have we really begun to understand how quickly they act," she notes. AZT and older drugs aren’t as strong as protease inhibitors, so more treatment time is required before a decrease is evident.
While Mueller’s team studied a monotherapy, she suspects that results of combination therapies could be detected in just the second or third day of treatment. "We don’t know that yet, but it is certainly worth studying." She cautions that the ritonavir findings are not based on a real-life scenario because they involve a monotherapy. HIV has surprised researchers so many times that nothing can be assumed, she reminds. However, she says, with more study her findings could lead to a recommendation to clinic physicians.
She adds that the results could be applied to adults as well. "There are obviously major differences between children and adults," says Mueller. "But our results showed some similarities between children and adults in the rate of virus clearance, one of the key parameters of the analysis."
References
1. Mueller B, Zeichner S, Kuznetsov V. Individual prognoses of long-term responses to antiretroviral treatment based on virological, immunological and pharmacological parameters measured during the first week under therapy. AIDS 1998; 15:F191-196.
2. Mueller B, Nelson Jr. R, Sleasman J. A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection. Pediatrics 1998; 101:335-343.
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