Protease Inhibitors and Clinical Response

Three Phase 1/11 clinical studies of protease inhibitors ritonavir, indi-navir, and nelfinavir have been carried out in children. In addition to evaluation of safety and pharmacokinetics, these studies indicated that protease inhibitors can control virus replication and restore CD4 T cell counts. Consequently, the Public Health Service recommends that all HIV-1-infected children should be treated with combination antiretroviral therapy, which includes protease inhibitors.16

2.2.1. Ritonavir

A liquid formulation of ritonavir administered as monotherapy and in combination with RT inhibitors was evaluated in a Phase 1/11 study involving 48 children, who ranged in age from 0.5 to 14.4 years (median age, 7.7 years).17 Over the course of the 24-week study, 7 (15.9%) children responded with a reduction in plasma virus to undetectable levels that was

TABLEI

Response of Pediatric Cohort Following 24 Weeks of PR Inhibitor Therapy"

TABLEI

Response of Pediatric Cohort Following 24 Weeks of PR Inhibitor Therapy"

Percentage of patients

CD4 T cell reconstitution'

Decrease in plasma virusc

59

2- to 100-fold

>1.7 log,0

26

1- to 100-fold

-0.5 log,0

15

<2-fold

<0.5 log,0

aData are summarized from a study of 44 children treated with ritonavir plus zidovudine and didanosine.19

^Children who were CDC immune stage 1 displayed median 2- to 4-fold increases in CD4 T cells, which generally restored CD4 T cells to values that were normal for age. Children who were immune stage 3 could display median increases as great at 100-fold in CD4 T cell numbers. ^Decreases greater than 3 logs to undetectable plasmalevelswere displayedby some children.

aData are summarized from a study of 44 children treated with ritonavir plus zidovudine and didanosine.19

^Children who were CDC immune stage 1 displayed median 2- to 4-fold increases in CD4 T cells, which generally restored CD4 T cells to values that were normal for age. Children who were immune stage 3 could display median increases as great at 100-fold in CD4 T cell numbers. ^Decreases greater than 3 logs to undetectable plasmalevelswere displayedby some children.

sustained for at least 8 weeks. About 60% of the total study group experienced greater than a 1.7 log™ decrease in virus RNA and a concomitant increase of 2- to 100-fold in CD4 T cells (Table I). Approximately 16% of the children failed to demonstrate a sustained decrease in plasma virus or more than a transient increase in CD4 T cells. Almost 25% of the children displayed an unexpected response, in that CD4 T cells increased dramatically, whereas virus RNA was suppressed only transiently and rebounded to baseline levels. Recent reports identify a similar response in the adult population.18 One explanation for these results is that viruses which emerge during combination therapy may have diminished pathogenic potential relative to pretherapy viruses.

2.2.2. Indinavir

Clinical evaluation of indinavir alone or in combination with RT inhibitors in 54 HIV-1-infected children (ages 3.1-18.9 years) revealed that the free-base suspension was less bioavailable than the capsule formulation.19 Even with the limitations of the initial study and the relatively high plasma virus levels (4.76 logw) at entry in the cohort, 16 of 35 patients achieved a sustained decrease of at least 1 logw viral RNA copies/ml of plasma, while undetectable virus levels were achieved in 3 children. A sustained increase in absolute CD4 T cells occurred in all patients, with a median increase of 60 cells/mm3 after 16 weeks of therapy. No significant difference in baseline CD4 values between children who did or did not respond at 16 weeks was detected. In a pilot study of combination indinavir in capsule form plus RT inhibitors in 12 children, median plasma HIV RNA concentrations declined by 1.3 log,, copies/ml after 24 weeks, while median CD4 T cell counts increased by 294 cells/mm3 during the same period.20 Based on these studies, Phase 1/11 studies ofa new formulation ofindinavir were initiated in 1998 within the Pediatric AlDS Clinical Trial Group (PACTG). Similar studies of combination therapy with saquinavir and RT inhibitors in children are in the planning stages through the PACTG.

2.2.3. Nelfinavir

A third large-scale Phase 1/11 pediatric study evaluated nelfinavir powder and tablet formulations in combination with one or two nucleoside RT inhibitors in a cohort of 62 HIV-1-infected children (ages 3 months to 13 years).21 The two formulations displayed similar pharmacokinetics and oral bioavailability with limited toxicity. Baseline median plasma HIV RNA levels for 55 subjects were approximately 4.5 logw, which decreased by a median 0.7 log10, copies/ml. Viral RNA declined in 36% (15/55) of the children to undetectable levels that were sustained for a median time of 42 weeks. CD4

T lymphocytes increased by as much as 7-8% at week 26 of therapy, although the increase in CD4 T cells was more pronounced in patients who sustained plasma virus at undetectable levels.

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