Figure 4.
Correlation of IIP with clinical outcome. (a) Predicted decay of IIP if subsequent doses are missed. IIP is plotted as a function of time after Cmax from the last dose. We calculated IIP using measured m and IC50 values (Supplementary Table online) and published t1/2 values. For NRTIs, we used t1/2 values for the active intracellular triphosphate forms18. Drug levels are assumed to decay exponentially. The initial IIP decay rate is proportional to m/t1/2 (Supplementary Notes online). For drugs with high m values and short t1/2 such as indinavir and saquinavir, IIP drops dramatically if one or two doses are missed, whereas for drugs with long t1/2 such as EFV and DRV, IIP is maintained at a high level even if doses are missed. (b) Relationship between IIP24 values and recommended “Column A” drugs. Recommended initial HAART regimens consist of two NRTIs plus one highly active “Column A” drug. The IIP24 values for the preferred “Column A drugs” (dark shading) tend to be higher than those of the alternate “Column A” drugs (light shading) or non-“Column A” drugs. Data from unboosted PIs are indicated by symbols with a black border. (c) Relationship between IIP24 values and virologic outcomes in major clinical trials (Supplementary Notes online) cited in the treatment guidelines14,19, with trial titles given beside each arrow. Solid arrows point towards drugs with superior virologic activity in head-to-head comparisons with the same background regimens. Broken arrows indicate a trend towards superiority not reaching statistical significance. Double-headed arrows indicate equivalent virologic outcomes.