Protease Inhibitors

The U.S. Food and Drug Administration (FDA) recently approved the protease inhibitors indinavir, ritonavir, saquinavir, and nelfinavir.30-32 These compounds act as competitive inhibitors of the HIV protease, which cleaves the Gag and Pol polyproteins into individual functional proteins. Recent studies in adults demonstrate decreases in plasma viral RNA, improvements in CD4 counts, and lower AIDS-related mortality with protease inhibitor monotherapy.30 Protease inhibitors in combination with NRTIs have a significant impact on the level of plasma HIV RNA and in clinical outcome in adults.8

2.3.1. Ritonauir

A recent Phase 1/11 study assessed the safety, tolerability, pharmaco-kinetic profile, and antiviral and clinical effects of the oral solution ritonavir in HIV-infected children. HIV-infected children between the age of 6 months and 18 years were eligible; a total of 48 children were included in the analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in the discontinuation of ritonavir in 7 children (14.5%). Ritonavir was well absorbed at all dose levels, and plasma concentration reached a peak at 2-4 h after dose. CD4 cell counts increased by a median 79 cells/mm3 following 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 -2 logio copies/ml within 4-8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m2 for the 24-week period. Palatability is a problem with ritonavir liquid formulation. A list of administration suggestions has been compiled by the AIDS Clinical Trials Group (see Appendix).

2.3.2. Indinavir

Indinavir was studied in a similar fashion as above. Fifty-four HIV-infected children were first treated with indinavir monotherapy and then with combination antiretroviral therapy. Indinavir dry-filled capsules were relatively well tolerated, but the liquid formulation was found not to be consistently bioavailable between patients or within a patient. Hematuria and renal calculi complicated therapy in some individuals. Currently, a combination trial of stavudine and lamivudine is on-going utilizing indi-navir capsules in older children.33

2.3.3. Nelfnavir Mesylate (Viracept®)

Nelfinavir is an inhibitor of HIV protease which is available in 250-mg tablets and 50 mg/gm strength in a powder. In combination with reverse transcriptase inhibitors, nelfinavir demonstrated additive (didanosine or stavudine) to synergistic (zidovudine, lamivudine, or zalcitibine) antiviral activity in vitro without enhanced cytotoxicity. Adverse effects in adults are primarily gastrointestinal, with abdominal cramping or diarrhea occurring in 8-12% of recipients. Nelfinavir was studied in one open-label, uncontrolled trial in 38 pediatric patients ranging in age from 2 to 13 years with a goal of achieving plasma concentrations which approximate those observed in adults. The most frequent reported adverse event among patients receiving nelfinavir was diarrhea.

Nineteen HIV-infected children were administered combination anti-retroviral regimens, including nelfinavir. The mean age of this group of experienced, protease-naive children was 8.37 years. Through 48 weeks, the participants treated with nelfinavir-containing regimens had positive CD4+

responses despite viral RNA concentrations which were close to baseline. The apparent "disconnection" between viral failure and immunologic success may last at least 48 weeks.34 The mechanisms of this disparity are unknown.

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