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Purpose:
A high IQ—the ratio of trough plasma drug concentration to the
protein-adjusted viral IC50—is a useful indicator of the
potential therapeutic margin of antiretroviral (AR) drugs. The IQ data for
most AR drugs was obtained in studies of treatment naïve patients (pts). TPV
is a non-peptidic protease inhibitor (NPPI) that has demonstrated sustained
viral-load (VL) response during up to 80 weeks of treatment in
multiple-protease inhibitor (PI)–experienced pts. The BI 1182.52 phase II
study allowed evaluation of the IQ breakpoint for successful viral
suppression using TPV in highly treatment experienced (HTE) pts.
Methods:
BI 1182.52 was an international, randomized, double-blinded trial of three
doses (500 mg/100 mg; 500 mg/200 mg; and 750 mg/200 mg) of TPV/r given BID
in HIV + pts. Pts were triple–class-experienced, and had detectable plasma
virus on their > second PI-based regimen. IQ was calculated using the
trough plasma TPV concentration at 14 days after starting TPV/r, divided by
the protein-adjusted viral IC50. The protein adjustment factor
was 3.75. TPV IQ was related to the change in VL during two weeks of
functional monotherapy with TPV/r in these HTE patients.
Results:
216 HIV +
patients with a median baseline VL of 4.5 log10
copies/mL and CD4+ cell counts of 153 cells/mm3 were enrolled. 157 pts from
all 3 study arms were included in the IQ analysis. The median VL responses
after 2 weeks of functional TPV/r monotherapy 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 respectively. This result suggests
that there is an apparent IQ breakpoint of roughly 50 in HTE pts below which
there is a decrease in antiviral response. 67% of patients in this study
reached this IQ threshold >50.
Conclusions:
The IQ of TPV observed in this trial of HTE triple class experienced pts
compares favorably IQ data for other PIs obtained from treatment-naive pts.
This high IQ, coupled with the need for multiple protease gene mutations in
most HIV isolates that show decreased susceptibility to TPV, suggests that
TPV/r may provide antiviral activity in the majority of HTE HIV + patients. |
