15th International AIDS Conference Bangkok, Thailand - July 11-16, 2004

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrB1236)

Walmsley S, Leith J, Katlama C, Arasteh K, Pierone G, Blick G, Lazzarin A, Johnson M, Samuels C, Jones P, Chaves R, Quinson A, Kohlbrenner V, McCallister S, Mayers D, Curry K
University of Toronto, Toronto, Canada

BACKGROUND: TPV is a novel non-peptidic protease inhibitor with activity against multiple-PI-resistant HIV-1. BI1182.51 was a 24-week, open-label, safety and pharmacokinetic (PK) study of TPV/r alone or in combination with a second boosted PI, in highly treatment-experienced patients who were genotypic screen failures from the RESIST trials.

METHODS: Patients with ≥3 protease mutations at codons 33, 82, 84, and 90 were randomized to: 1) TPV/r (500mg/200mg) control, 2) TPV/SQV/r (500mg/1000mg/200mg), 3) TPV/APV/r (500mg/600mg/200mg) or 4) TPV/LPV/r (500mg/400mg/100mg), all BID. All patients received a preselected investigator-defined optimized background regimen. For the first 2 weeks, all patients received an RTV-boosted single PI regimen. After 2 weeks of treatment, TPV was added to the dual-boosted PI arms. This planned interim analysis focused on primary safety and PK endpoints.

RESULTS: Data was derived from 296 of 315 randomized patients who reached week 4 by the interim report cutoff date. Plasma C[min] in 173 patients were compared at weeks 1 and 2 (single-boosted PI) versus weeks 3 and 4 (dual-boosted PI); AUC and C[max] in 134 patients were compared at weeks 2 and 4. Co-administration of TPV/r and the other PIs was associated with decreases in PK parameters: SQV (AUC [down arrow]70%, C[max] [down arrow]66%, C[min] [down arrow]81%), APV (AUC [down arrow]45%, C[max] [down arrow]40%, C[min] [down arrow]56%), LPV (AUC [down arrow]49%, C[max] [down arrow]43%, C[min] [down arrow]55%). All combinations were well tolerated during the 4-week time period, and the frequency of AEs was similar between all 4 arms at both weeks 2 and 4. The incidence of laboratory abnormalities was also similar in all 4 arms; triglyceride elevations were the most frequent abnormality.

CONCLUSIONS: This analysis demonstrates short-term safety of TPV/r alone or with APV, SQV, or LPV. Reductions in plasma PK parameters of SQV, APV, and LPV were observed when co-administered with TPV/r, though the clini cal relevance of these reductions is not established.

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WeOrB1236

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