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Purpose:
Tipranavir (TPV) is the first non-peptidic protease inhibitor (NPPI). TPV-based
therapy has demonstrated sustained viral-load response for up to 80 weeks of
treatment in single and multiple PI–experienced patients with up to 20
protease gene mutations.
BI 1182.52 allows for the relationship between genotypic resistance and
antiviral activity to be characterized.
Methods:
BI 1182.52 was an international, randomized, double-blinded trial of 3
twice-daily TPV/r doses (500 mg/100 mg; 500 mg/200 mg; and 750 mg/200 mg) in
HIV-1+ patients. Patients were triple-class–experienced with detectable
viremia on at least their second PI-based regimen. Screening genotype
included at least 1 primary PI mutation (from 30N, 46I/L, 48V, 50V,
82A/F/L/T, 84V, or 90M), with not more than 1 of 82L/T, 84V, or 90M. The
change in viral load was determined after 2 weeks of functional monotherapy.
Genotype was measured using the Visible Genetics Trugene® 4.0
assay.
Results:
216 patients with a median baseline viral load of 4.5 log10
copies/mL and CD4+ cell count of 153 cells/mm3 were randomized.
The median viral load response at 2 weeks was –0.91, –0.96, and –1.19 log10
in the 500/100, 500/200, and 750/200 arms, respectively. Overall, 7%, 29%,
48%, and 16% had 6–10, 11–15, 16–20, and >20 protease gene mutations at
baseline, respectively. A reduced median virologic response of –0.16 log10
was observed in patients in the 500/100 group with >20 mutations, compared
with –0.99 to –1.26 log10 in the other arms. A dose response was
also seen for the number of baseline universal protease inhibitor-associated
mutations (UPAMs), L33I/V/F, V82A/F/L/T, I84V, and L90M. In most isolates,
the presence of 1 or 2 UPAMs was associated with reduced susceptibility to
currently available PIs. A decreased median viral load response was observed
for 500/100 in isolates with 2 UPAMs (–0.77 log10), and for
500/200 and 750/200 for virus with 3 UPAMs (–0.33 log10 and –0.54
log10, respectively).
Conclusions:
In this highly treatment-experienced population, the 500/200 dose of TPV/r—selected
for Phase III trials—demonstrated a robust viral load response in patients
with up to 20 protease gene mutations and <3 baseline UPAMs. These results
suggest that TPV is active against the majority of viruses that would be
expected to be resistant to all currently marketed PIs. |
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