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

Strteg(ies I [4. rcotes e (1Inhll.] or Fa1il I a

M delavirdine + indinavir combination; Although delavirdine has not been proven
very effective in any clinical trial to date,
it can effect the absorption of other drugs
and increase their potency, much like
ritonavir. It does a good job of increasing the levels of indinavir. A number of
physicians report anecdotal success with
this combination in people who have
failed initial protease combination
therapy. The two drugs are typically taken
at their standard doses, though it is unclear what affect this has on toxicity.
Particular care should be taken to watch
for an increase in potential liver toxicity
and kidney toxicity. Proponents of this
approach report a fair degree of success
in returning patients to undetectable viral load and sustaining this for 6 months
or longer, even after initial failure on
indinavir.
" efavirenz + indinavir combination; Studies in people first initiating protease inhibitor therapy have found this combination to be highly effective in suppressing HIV RNA levels. Although it hasn't
yet been tested in people with protease
resistant HIV, the high potency offers the
hope that it might be capable of overcoming partial resistance. It is likely that
efavirenz will combine usefully with almost any other protease inhibitor as well.
" nevirapine + a previously unused protease
inhibitor or dual protease combination;
When employed along with one or two
additional nucleoside analogue drugs, this
approach seeks to overpower partially resistant virus.
" ddl + hydroxyurea + single or dual protease inhibitor combination, with or without a NNRTI (nevirapine, delavirdine, or
efavirenz); Small studies have continued
to confirm that the ddl/hydroxyurea combination offers unique properties and
might work even in people with highly
drug resistant virus. Of the NARTI drugs,
ddl is perhaps the slowest to develop resistance and there is no known pattern
of resistance affecting hydroxyurea. Some
researchers also believe that d4T is slow.
to develop resistance and combines par-.
ticularly well with ddl and hydroxyurea.
Experimental.
Approaches.
* GWl4l (a new Glaxo Wellcome/ Vertex.
protease inhibitor) plus abacavir (1592,.
a new Glaxo Wellcome NARTI) plus.
efavirenz (a new Dupont Merck NNRTI). -
A small nationwide clinical trial of this
combination will begin before year's end,.

targeting people who have failed all existing therapies. In laboratory studies,
GW141 does not demonstrate cross-resistance with other protease inhibitors,
and abacavir shows only partial crossresistance to 3TC and ddl. Thus, this
combination theoretically offers hints of
good potential, even in a protease inhibitor resistant population. However, an
early pilot arm of this study combining
just the GW141 and abacavir did not
appear to work well. Only time will tell if
adding the third new drug, efavirenz, will
change the outcome.
N AR177 (Zintevir@, an integrase inhibitor from Aronex) plus adefovir
(Preveon@, a new type of RT inhibitor
from Gilead Sciences) plus efavirenz.
While this approach sounds intriguing because it combines two new classes of
drugs (an integrase inhibitor and a nucleotide analogue), neither AR177 nor
adefovir has shown much potency as individual therapy. Nonetheless, the overall combination still warrants careful study.
A Final Wordl
Virologic failure doesn't necessarily mean
clinical failure. Were this the case, we should
already be seeing a great reduction in the
clinical benefits of treatment, but this is not
the case. Rates of new opportunistic infections and death remain at an all-time low,
despite the growing incidence of virologic
treatment failure. Many people assume that
when they run out of options capable of
completely suppressing viral load, they
might as well go off their current antiviral
therapies. Some even believe this will be
helpful, based on the theory that this will
permit their virus to regain sensitivity to
the drugs. Most researchers dispute this
view, pointing out that once resistance occurs, some quantity of virus with the resistant properties will always be retained and
will quickly reassert itself. Many researchers also believe it is a mistake to discontinue therapy even when all possible combinations no longer seem able to suppress
viral load below pre-treatment levels. They
argue that even when all available therapy
options have failed to suppress virus, it may
still have an important effect. In this situation, therapy continues to shape or control
the pool of virus, permitting only the growth
of the mutated, resistant strains while blocking growth of more potent "wild-type" virus. The "wild type" is the natural state of
HIV, the condition it prefers and in which
it is most potent. Virologists believe that
for each mutation a virus accumulates in
the body, it pays a "price," forcing it to

deviate from its preferred, natural state.
While highly mutated virus may still be able
to replicate to some degree, it is not clear
that it is still as capable of harming the
immune system.
However, other virologists worry that continuing on therapy when it appears to be
"failing" virologically, may encourage the
accumulation of even more mutations. This
could make it more difficult for future drugs
of the same classes to work, should such
drugs come along. These arguments make
sense only if new drugs of the same classes
come along which aren't cross-resistant to
existing drugs. So far, in protease inhibitors, this has never been the case. In situations like this, people are forced to make a
gamble, choosing between effects of the
known, available drugs and the unknown
effects of future drugs. Just which choice
results in the longest survival is unknown.
There is considerable initial evidence that
people retain immunologic benefits from
therapy long after losing the battle for complete viral suppression. Also, some virologists suspect that when patients see only a
modest and stable return of measurable
virus, without returning to the pretreatment
levels, the PCR test may be measuring defective, mutated copies of virus rather than
productive virus capable of reproducing itself. For any of these reasons, it may be
important to continue to use therapy to
keep virus in its "unhappy" state. True loss
of virologic control still does not imply
complete return to the devastation of AIDS.
In short, even when all options "fail" (by
today's definitions), hope is not lost. 0

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PI PERSPECTIVE I NUIVBER 23 NOVEIVBER 1 997

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