Investigators of the Pediatric AIDS Clinical Trials Group (PACTG), a network of trial sites supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development (NICHD), have announced results of an interim analysis of the first pediatric study of efavirenz, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that can be taken once daily. The purpose of the study, known as PACTG 382, is to determine the safety, dosing and antiviral effect of efavirenz in combination with antiretrovirals in HIV-infected children. Efavirenz, when used in combination with nelfinavir and other antiretrovirals, suppressed HIV replication over a 20-week period in most children.
"This study demonstrates that efavirenz used in combination with other antiretrovirals can have potent antiviral effects in children," comments Anthony S. Fauci, M.D., NIAID director. "It offers another choice for treating HIV-infected children who currently have fewer treatment options than adults." At present, 12 drugs are approved for treating HIV disease in adults, compared to seven, including efavirenz, approved for children. Efavirenz is the second drug in the NNRTI class of antivirals to be approved for use in children.
The study directly contributed to accelerated Food and Drug Administration approval earlier this month of efavirenz as a treatment option for HIV-infected children. Study Chair Stuart Starr, M.D., of the Children’s Hospital of Philadelphia, says, "Timely collaboration between PACTG investigators and pharmaceutical companies made it possible for efavirenz to be approved for HIV-infected children at the same time that it was approved for adults."
PACTG 382 is a Phase I/II multicentered study evaluating a combination therapy consisting of efavirenz, the protease inhibitor nelfinavir and nucleoside reverse transcriptase inhibitors (NRTIs). As a safeguard, this highly intensive study was designed to closely monitor blood levels of efavirenz and nelfinavir. Drug doses were adjusted as needed.
A total of 57 children were enrolled in the study. Participants were younger than 16 years, had not been previously treated with protease inhibitors or NNRTIs, and were able to swallow capsules. The median age of the children was 8.0 years; the median CD4+ T cell count was 699 cells/mm3, and the median viral load was 10,000 copies HIV RNA/ml. NRTIs were continued or changed at entry as clinically indicated. Pharmacokinetic studies were carried out at weeks two and six. Efavirenz was given at a starting dose of 600 mg/m2 once a day in combination with nelfinavir at the currently approved dose of 20-30 mg/kg three times per day. To date, this combination has been well tolerated by most subjects.
The most common side effects were: rash (28.1 percent), which was seen more commonly in children than in adults; diarrhea (15.8 percent); and abnormally low levels of neutrophils (8.8 percent), a type of white blood cell. The percentage of participants whose HIV RNA was less than 400 copies/ml was 3.5 percent at baseline, 51.9 percent at the second week, 60.0 percent by the fourth week, 75.0 percent by the fifth week, 78.4 percent by week 12 and 66.7 percent at week 20. This antiviral effect is comparable or superior to that observed with previously tested combinations of antiretrovirals in this patient population. Furthermore, once-a-day administration of efavirenz may make it easier for patients or caregivers to adhere to therapy. Additional follow-up through the full 48-week course of the study will be important to determine if the drop in viral load is long-lasting and if the regimen will be well tolerated in children over time.
The study co-chair is Courtney Fletcher, Pharm.D., University of Minnesota, Minneapolis. Dr. Fletcher and Richard Brundage, Pharm.D., Ph.D., also of the University of Minnesota, are the protocol pharmacologists. Stephen Spector, M.D., University of California San Diego, is the protocol virologist. Dr. James McNamara and Dr. Lynne Mofenson are the NIAID and NICHD protocol medical officers.
Pharmaceutical support for this study was provided by DuPont Pharmaceuticals Company (efavirenz) and Agouron Pharmaceuticals Inc. (nelfinavir).
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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