COMBINATION THERAPY WITH STAVUDINE AND DIDANOSINE IN CHILDREN WITH ADVANCED HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - PHARMACOKINETIC PROPERTIES, SAFETY, AND IMMUNOLOGICAL AND VIROLOGICAL EFFECTS

Objectives. To obtain preliminary information on the pharmacokinetic p roperties, tolerance, safety, and antiviral activity of combination th erapy with stavudine and didanosine in children with advanced human im munodeficiency virus (HIV) infection. Methods. Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (med ian CD4+ lymphocyte count at baseline, 42 cells/mu L; range, 8 to 553 cells/mu L) were treated with stavudine (2 mg/kg per day in two divide d doses) and didanosine (180 mg/m(2) per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. A ll children had received stavudine alone for 19 to 33 months before th e addition of didanosine to the treatment regimen. Children were asses sed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter. Results. Analysis of stavudine and didanosine plasma half-life values, clearan ces, and area under the plasma concentration-versus-time curves reveal ed no obvious clinical pharmacokinetic interaction between the drugs t hrough study week 12. Combination therapy was well tolerated, and ther e were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three ch ildren with baseline CD4+ lymphocyte counts greater than 50 cells/mu L had greater than 20% increases in their counts within the first 12 we eks of therapy; CD4+ lymphocyte count increases were not observed in t he other children. Plasma HIV RNA concentrations showed median decline s of 0.88 log(10) (range, -3.41 log(10) to 0.31 log(10)) and 0.30 log( 10) (range, -0.63 log(10) to 0.89 log(10)) at study weeks 12 and 24, r espectively. Conclusions. Combination therapy with stavudine and didan osine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be c onfirmed, and the regimen's clinical efficacy should be examined, in c ontrolled studies of HIT-infected children with less-advanced disease.