451-W.
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Pilot Study of Saquinavir-SGC (Fortovase, SQV) 1000 mg Twice Daily and Lopinavir/Ritonavir (Kaletra, LPV/r) in Protease Inhibitor-Experienced HIV+ Individuals: Dose Escalation and Combined Normalized Inhibitory Quotient (cNIQ)
J. Hellinger*1, A. B. Morris1, S. Piscitelli2, D. Gordon1, K. Foy1, L. Jackson-Pope1, D. Cordeiro1, M. Peeters2, R. Hoetelmans2, P. J. de Caprariis3, and C. Cohen1
1Comm. Res. Initiative, Boston and Springfield, MA; 2Virco, Rockville, MD, and Mechelen, Belgium; and 3Roche Labs., Nutley, NJ
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Background: High levels of protease inhibitors (Pis) may be critical for treatment of HIV+ patients with multiclass drug resistance.
Methods: This is an open-label, single-arm, 48-week study of safety and antiviral activity of SQV + LPV/r in PI experienced, LPV-naïve subjects. NRTI choices guided by virtual phenotype (vPT). Tenofovir was allowed. All initiated with SQV 1000-mg BID. NIQ relates the patient's C-trough/fold change in resistance to a reference trough/cutoff fold change to correct for protein binding and standardize the IQ target value. cNIQ is the sum of the week 12 NIQ for LPV and for SQV. Logistic regression was performed to evaluate predictors of 12-week viral load below 50 c/mL. The study is fully accrued with 24-week data available February 2002.
Results: 28 enrolled: female 29%, male 71%; Risk factors: Het 25%, IDU 18%, MSM 57%; Age: mean 40 years. Log median baseline plasma HIV-RNA 4.96; 92,087c/mL; CD4=218 cells/muL. Prior PI use: mean 2.9, 70% SQV experienced. vPT-predicted resistance to SQV in 31% and LPV in 42%. 53% were off antivirals at the time of resistance testing. 14 (50%) required initial SQV dose reduction to 600 mg primarily due to gastrointestinal intolerance, and then dose escalated to 1000-mg. 3 discontinued prematurely for adverse events. CD4+ cell counts increased a mean 94 cells/muL at week 12. 65% <50 copies/mL at week 12 (ITT); 72% <50 (AT). Log viral load decline was 2.3 at week 12 AT. Median trough SQV concentration was 1.1 mug/mL at week 4; 0.82 mug/mL at week 12. Median trough LPV concentration was 7.1 mug/mL at week 4; 6.9 mug/mL at week 12. In 10 patients with drug levels, vPT, and 12-week outcome, neither drug levels alone nor vPT alone correlated with virologic response. The cNIQ of LPV and SQV was predictive of achieving viral load < 50 c/mL at week 12 p=0.007).
Conclusions: SQV 1000 mg BID with LPV/r + nucleosides achieves high Ctrough levels of both SQV and LPV, active against highly PI resistant virus. In 50% of subjects, SQV required dose escalation Data suggest the cNIQ was predictive of 12-week viral suppression outcome for this regimen.
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