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Dual PI therapy: Are all combinations good?
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written by Bruce Polsky, M.D.
published on HIVresistanceWeb: March 15, 1998
The success of recent trials of combination protease inhibitor therapy
using saquinavir and ritonavir has led some researchers to speculate
that a dual protease combinations will be the wave of the future for
HIV therapy. This is based not only on the success of the
ritonavir saquinavir combination in suppressing HIV replication, but
also the possibility of changing the pharmacokinetics of several drugs
and the potential to delay the emergence of resistance.
Combinations of ritonavir with saquinavir, indinavir, and
nelfinavir demonstrate the ability of ritonavir, a potent inhibitor of cytochrome p450 3A, to increase blood levels of the other protease inhibitors. Clearly saquinavir benefits the most, but others are similarly affected. For example, the use of ritonavir with saquinavir 400 mg twice daily results in a more than 20-fold increase in the area under the curve (AUC) of saquinavir. This results in potent suppression of HIV replication for over 48 weeks. Nelfinavir, a less potent inhibitor of cytochrome p450 3A, also has the ability to alter the pharmacokinetics of other protease inhibitors. For example, nelfinavir raises the AUC of saquinavir over 5-fold.
Combinations of protease inhibitors that do not have overlapping resistance mutation profiles would be expected to delay the emergence of resistance. For example, the principal mutations associated with saquinavir resistance are at positions 90 and 48 in the protease protein. Ritonavir, on the other hand, selects for a major resistance mutation at position 82. Theoretically, this would make it harder for the virus to become simultaneously resistant to ritonavir and saquinavir. This may lead to a longer duration of clinical benefit for patients.
However, as pointed out by Merrill and colleagues of Harvard, not all dual protease inhibitor combinations display such characteristics. In the laboratory, Merrill et al have shown that the combination of saquinavir and indinavir is antagonistic. Before we write off this combination, however, it is important to point out that what researchers call antagonism may not be bad for patients.
In the laboratory, various combinations of drugs are mixed, and their ability to suppress HIV replication is measured. Using a mathematical formula, scientists determine whether a particular combination is additive, synergistic or antagonistic. For the sake of argument, let's say one drug has an effect of "1", and another also has an effect of "1". Combinations that yield a result of "2" are considered additive (1 + 1 =2). Combinations that result in values of greater than "2" are considered synergistic (1 + 1 > 2), and combinations that demonstrate values of less than "2" are
considered antagonistic (1 + 1 < 2). In the case of saquinavir and indinavir, the result was 1.7 and so the combination is labeled
antagonistic. But is it?
For patients, a combination of two protease inhibitors that are antagonistic with a value of 1.7 is still better than protease monotherapy. This is because 1.7 is greater than 1. While it is not as good as 2, it is still better than 1. So for clinicians, it is important to "read the fine print". Indinavir and saquinavir are indeed antagonistic in vitro, but for patients the combination could still be clinically useful.
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