Perspective: Information, Inspiration and Advocacy for People Living with HIV/AIDS

Strax4tegies fI [r Pn (t]ase Inhi4it mii.]k lILuret

Strategies for
Protease Inhibitor Failure
Project Inform's "Antiviral Strategies" discussion paper previously addressed the question of treatment strategy for people
who have already used and "failed" most existing combination

therapies.
Perhaps the most important rule in such a
situation is to seek highly potent, optimal
uses of available therapies. This means it is
often more important to wait to start two
or more new drugs simultaneously than it
is to take immediate action. In short, using
HIV antiviral drugs correctly is more important than using them at any particular
moment. Simply adding a single new or
different drug is unlikely to help. The most
recent information suggests that even adding two new drugs is seldom sufficient for
people failing on previous regimens. Instead,
the best chance of success may come from
starting a completely new regimen. The
earlier strategies also stressed the opportunity for people in this category to seek out
clinical trials of truly new agents. Unfortunately, there often aren't many clinical trials, or new drugs, to choose from.
Since the initial discussions of antiviral treatment strategies in PI Perspective #19 and
#21, additional options have been identified; but there is only minimal data from
clinical trials to support these approaches.
In some cases, there are little or no data at
all, but the following suggestions represent
the weight of some degree of "expert" opinion or the case experience of primary care
physicians. Since every case of "treatment
failure" represents a unique medication history and different contributing factors, it is
unlikely that any one approach will be
universally successful.
In all of the following suggestions, emphasis is given to the choice of protease inhibitors and other highly potent agents, such
as the non-nucleoside reverse transcriptase
inhibitors (NNRTIs), including nevirapine
(Viramune@), delavirdine (Rescriptor@) and
efavirenz (Sustiva@). These are likely to play
the most important role because of their
potency. Even though powerful new nucleoside analogue reverse transcriptase inhibitors (NARTIs), such as abacavir (1592), are
becoming more available, existing evidence
suggest they will offer little potency in
people who have been heavily pretreated
with other drugs of this type. Nonetheless,
they may play some modest role in overall
therapy when other drugs have failed. Preference should be given to those NARTIs
which have been least used previously by

the individual patient. If all NARTIs have
had similar periods of use, a good strategy
might be to give preference to the ones
known to be slowest to develop resistance.
At the top of this list are ddl (didanosine/
Videx@) and d4T (stavudine/Zerit@).
Possible
Approachas
Changing protease inhibitors (not very
likely to be effective after drug failure).
Assuming a person has developed true resistance to an existing protease inhibitor
therapy, the likely effects of switching to
any other protease inhibitor can be summed
up in a few words. Such a switch is unlikely to result in significant or long-lasting
additional suppression of virus. Switching
protease inhibitors because of side effects
or issues with taking the regimen is not the
same as a switch due to resistance. Switching for reasons other than true resistance
has a reasonable chance of success.
Studies have shown that neither indinavir
(Crixivan@) nor the newly enhanced
saquinavir (Fortovase@) is particularly effective in people previously treated with the
original saquinavir (Invirase@). The same
is likely to be true to switching to ritonavir
(Norvir@) or nelfinavir (Viracept@). Similarly, only a very small percentage of people
who switched from an existing protease
inhibitor to nelfinavir in that company's
expanded access program experienced significant success. A more recent study
showed that, contrary to the manufacturers claims, when nelfinavir fails after being
used as a first protease inhibitor, people do
not respond well to indinavir or ritonavir.
Switching between ritonavir and indinavir
is also unlikely to work in most cases.
Project Inform has argued all along, people
should assume that there will be significant
cross-resistance between any of the currently
available protease inhibitors, and there is
little reason to choose one or another as
the first therapy in hopes of avoiding crossresistance. Clinical data now confirm this
view across all possible sequences of the
known protease inhibitors. There may be
individual, but unpredictable, exceptions to
this. As a general rule, people have only
one good opportunity to use a protease inhibitor.: Combining protease inhibitors (not as easy
as originally thought). The hope of combining two protease inhibitors for people
* who have developed resistance to an initial
protease regimen is to overcome partial resistance by increased drug potency. However, little if any of the clinical experience
has actually tested dual protease inhibitor
combinations in this fashion. Most research
has tested such combinations in people using protease inhibitors for the first time.
Also, protease inhibitors have typically been
combined at lower-than-standard doses in
hopes of reducing toxicity, rather than at
* standard doses in hopes of increasing overall potency. Some specifics:. ritonavir + saquinavir (Invirase@ or. Fortovase@) combination; While this is
commonly used as a "salvage" strategy
after failure of a first protease inhibitor,
almost all the data supporting this combination comes from people who are just
beginning their first use of a protease inhibitor. In the one known study tracking
its use after initial protease failure, the
combination was found to be effective
only about 25% of the time, and even
then, the results were not sustained for
long. The potency of this combination
should be the same whether using the old. version of saquinavir (Invirase@) or the
new version, because both result in the
same levels of drug in the blood when
used along with ritonavir.
E nelfinavir + saquinavir (Fortovase@) combination; Again, this is only supported
by data in people using protease inhibitors for the first time. Its success in treating protease-resistant virus is unknown
(and unlikely).
E ritonavir + indinavir combination; This
is a very new avenue of clinical study,
initially focusing on first-time users of
protease therapy. The hope that might
make this useful after initial protease failure is the sheer potency expected from
combining two of the most powerful protease inhibitors, along with the fact that
ritonavir should also dramatically increase the levels of indinavir. The proper
or safe doses for this combination are not. known and the risk is that when full doses
Sof each drug are used, there may be significant side effects, similar to the effects. of taking higher-than-standard doses.
* Combining therapies for synergy (some an-.ecdotal claims of success). This approach.mixes drugs whose chemical properties or
-absorption into the body are enhanced when
used together. The hope for this approach.is to overpower partial resistance.

4

PI PERSPECTIVE NUIVBER 23 NOVEIVBER 1 997