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E D I T O R I A L C O M M E N TA R Y
HIV/AIDS
Instantaneous Inhibitory Potential and Inhibitory Quotient
Show a Modest Association with Virologic Outcome:
Is Either a Useful Surrogate for Clinical Drug Efficacy?
Rodger D. MacArthur
Division of Infectious Diseases, Wayne State University, Detroit, Michigan
(See the article by Henrich et al, on pages 93–98.)
There now are 12 dozen US Food and
Drug Administration–, Health Canada–,
and European Union–approved antiretroviral agents from 6 distinct classes that
are used in combination for the treatment
of human immunodeficiency virus (HIV)
infection. These drugs have been introduced at the rate of ∼1 per year, and that
rate seems likely to continue for at least
the next 5 years. Although guidelines
based largely on results of randomized
clinical trials exist to aid in the selection
of certain combinations under certain circumstances [1], the staggering number of
potential 3- or 4-drug combinations selected from 2 or 3 of the 6 different classes
effectively precludes knowing which combination is the most potent (ie, active).
Indeed, it is not known yet which measure
of “potency” (antiviral activity) correlates
best with the most frequently used outcome in clinical trials: the percentage of
participants with HIV RNA level !50 copies/mL at some time point (typically 6
Received 21 March 2010; accepted 26 March 2010;
electronically published 25 May 2010.
Reprints or correspondence: Dr Rodger D. MacArthur, Div
of Infectious Diseases, Wayne State University, 4201 St
Antoine, UHC 7D, Detroit, MI 48201 ([email protected]
.edu).
Clinical Infectious Diseases 2010; 51(1):99–100
2010 by the Infectious Diseases Society of America. All
rights reserved.
1058-4838/2010/5101-0016$15.00
DOI: 10.1086/653431
months or 1 or 2 years after initiation of
therapy).
In this issue of Clinical Infectious Diseases, Henrich et al [2] compare 2 measures of antiviral activity by correlating differences in predicted inhibitory quotient
(IQ) or instantaneous inhibitory potential
(IIP) with differences in virologic outcome
(percentage of participants with HIV RNA
level !50 copies/mL) at 48 weeks for pairs
of drugs compared in 17 randomized clinical trials. The IQ has been shown to correlate modestly with virologic outcome
[3]; it is the ratio of trough drug concentration to the amount of drug necessary
to inhibit viral activity by 50% in vitro
(IC50). Recently, another measure of antiretroviral activity has been proposed: the
IIP [4], which incorporates the slope
(steepness) of the drug inhibition curve
into a formula also containing the drug
concentration and IC50. The IIP as a measure of antiretroviral activity generated
widespread interest, especially because it
purported to show differences in potency
of the different classes [5]. If either of these
measures could be shown to substantially
correlate with virologic outcome from recently completed clinical trials, then clinicians would have a useful tool to use
when choosing specific combinations of
antiretrovirals, and the pharmaceutical industry might benefit when using the ra-
tio(s) to assess the activity of various drugs
in development.
Unfortunately, neither measure performed particularly well, and the IIP did
not predict antiretroviral activity any
better than did the IQ. Although most
of the measures (IQ-based and IIP-based)
showed a “modest” correlation with HIV
RNA suppression, the results from many
studies fell outside of the 95% confidence
limits of the linear regression curves. In
some cases, as Henrich et al [2] note,
“small differences in treatment outcome
between arms were observed despite substantial differences in IIP or IQ between
the comparator drugs; conversely, in
other studies, significant differences in
outcome were observed despite modest
differences in IIP or IQ.” The meaning
of the observed correlation values, ranging from 0.5 to 0.7, is that these measures of drug potency or antiviral activity explain only ∼25%–50% (r 2) of
the treatment outcome (suppression of
HIV RNA).
Why did the IIP and IQ not work better? The list of possible explanations is
long, starting with pharmacokinetics. The
determination of the IC50, a major component of both the IQ and IIP, is done in
vitro, and there exist some differences of
opinion as to whether to adjust for the
extent of protein-binding in the calculaHIV/AIDS • CID 2010:51 (1 July) • 99
tions. In addition, determination of the
trough drug concentrations is challenging;
reported values typically are derived using
the geometric mean to “correct” for the
substantial variability observed among the
6–20 subjects that contribute to the one
“average” value used in the calculations
[6]. In other words, there is substantially
less precision and considerably more variability in these ratios, when applied at the
individual level, than is suggested by their
formulae.
Another likely explanation for the modest correlation of IIP and IQ with virologic
outcome, as the authors acknowledge, is
that multiple other factors, such as adherence, tolerability, dosing convenience,
and the emergence of drug-limiting resistance, are very important contributors to
the “effectiveness” of the regimens in clinical practice. Indeed, it is probable that
these factors are so important that the incorporation of the slope of drug inhibition
into the IQ (to derive the IIP) did not
significantly improve the correlation with
virologic outcome. Some investigators
have proposed that other ratios, such as
the “normalized” IQ or the genotypic or
virtual IQ, that adjust for resistance and
individual drug concentrations are more
likely to be highly correlated with outcome
[7, 8]. Results for these ratios also have
been disappointing. In fact, adjustment of
drug doses (therapeutic drug monitoring)
to achieve a higher trough concentration
in randomized clinical trials has failed to
give any better results overall, compared
with not making such an adjustment [7,
9]. Thus, despite the popularity of therapeutic drug monitoring in Europe, this
approach has not become the standard of
care in the United States and is filled with
challenges, such as a relative lack of com-
100 • CID 2010:51 (1 July) • HIV/AIDS
mercially available therapeutic drug-monitoring facilities and lack of familiarity
with the principles of pharmacokinetic
monitoring in routine clinical practice
[10].
So, what can we conclude from, and
what are the clinical implications of, the
extensive and thorough comparison of the
IQ and IIP by Henrich et al? First, it seems
clear that neither of these ratios is ready
to be used in routine clinical practice. Although it would be interesting to consistently include both the IQ and the IIP as
metrics in large randomized clinical trials comparing ⭓2 drugs, until it can be
shown that antiretrovirals with moderateto-large IQ or IIP differences consistently
perform better than the comparator
drug(s), it seems unlikely that there will
be much utilization of either of these ratios
for any purpose. Other approaches that
use fuzzy logic or neural network techniques to incorporate variables such as
predicted adherence, tolerability, resistance potential, and dosing ease also need
to be more thoroughly studied in large
clinical trials if they are to gain widespread
acceptance [11]. Thus, there remains
much more work to be done to refine and
evaluate any such ratio or system before
it will be possible to use this approach for
drug development or regimen selection in
clinical practice.
Acknowledgments
2.
3.
4.
5.
6.
7.
8.
9.
10.
Potential conflicts of interest. R.D.M.: no
conflicts.
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