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12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
BACKGROUND: Tipranavir (TPV), the first non-peptidic protease inhibitor (NPPI), has demonstrated robust antiviral activity against multiple protease inhibitor (PI)-resistant HIV-1, both in vitro and in clinical studies. A large Phase IIB study of TPV/r has allowed characterization of the impact of genotype, phenotype and inhibitory quotient (IQ) on antiviral activity of TPV in highly treatment-experienced (HTE) patients.
METHODS: BI 1182.52 was a multicentre, international, randomized, blinded trial of three twice-daily doses of TPV/r (500 mg/100 mg, 500 mg/200 mg and 750 mg/200 mg). Entry criteria included experience with the three main classes of antiretroviral, including at least two PIs and ≥1 primary PI mutation. The primary end-points were viral load (VL) reduction after 2 weeks functional monotherapy and safety at 4 weeks. Genotype was measured using the Visible Genetics Trugene. 4.0 assay; and phenotype was measured using the VIRCO Antivirogram. assay. IQ was calculated using the trough plasma TPV concentration at 14 days, divided by the protein-adjusted viral IC50 for each patient (protein adjustment factor was 3.75).
RESULTS: Two-hundred-and-sixteen patients were randomized and evenly distributed across arms with regard to baseline viral load, CD4 cell count, demographics and prior treatment experience. The median fold-change in susceptibility relative to wild-type (WT) for TPV and available PIs at baseline was 1.1, 76.5, 8.7, 7.0, 12.2, 36.8 and 94.2 for TPV, lopinavir, amprenavir, saquinavir, indinavir, nelfinavir and ritonavir, respectively. This study has identified four universal PI-associated mutations (UPAMs; mutations at codons 33, 82, 84 and 90) that are associated with class cross resistance. Three of these mutations (33, 82 and 84) are in the protease active site, such that 16 to 20 compensatory mutations may be required for ≥2 UPAMs to coexist. Patients with 0–2 UPAMs had a –0.97 to –1.32 log10 change in VL, compared with –0.32 log10 in patients with 3 UPAMs. The relationship of UPAMs to phenotypic susceptibility was evaluated. In the presence of 0–2 UPAMs, the median fold-change in TPV IC50 was 0.9, 1.0 and 1.3, compared with 2.2- fold in patients with 3 UPAMs. Across all three arms of the study, patients whose isolates had ≤1 and >one- to two-fold change in TPV IC50 relative to WT demonstrated a –1.23 and –1.24 log10 change in VL, respectively, at 2 weeks. A –0.21 log10 response was seen in patients whose isolates had >two- to fourfold change in TPV IC50, suggesting a phenotypic cut off of approximately twofold WT IC50 (VIRCO assay). Similarly, the median VL responses after 2 weeks for IQs ≤5, >5–25, >25–50, >50–100, >100–150 and >150 were –0.19, –0.35, –0.82, –1.31, –0.96 and –1.23 log10, respectively. This result suggests that there is an apparent IQ breakpoint of roughly 50 in HTE patients, below which there is a decrease in antiviral response.
CONCLUSIONS: This analysis has determined that a good response to TPV is maintained in the presence of <3 UPAMs, IC50 <twofold WT, and IQ >50. Importantly, over two-thirds of patients, even in this HTE population, met these criteria. Considering that most HIV-1 isolates remain fully susceptible to TPV until a large number of protease gene mutations (>15) are present, this high IQ suggests that TPV/r will provide an important option for the majority of HTE HIV-1-positive patients.
PRESENTING AUTHOR: S McCallister
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2003-07-08
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