Treatment Issues Vol. 11, no. 2

* ISSUES
C
ed the results of several studies that she has con* ducted (abstract 10). The HIV isolates involved
all came from participants in either the combination studies described above or earlier monotherapy studies. In the nelfinavir monotherapy trials,
36 of 54 (56%) participants analyzed had HIV
with the protease codon 30 mutation by week 16.
By contrast, only three of 49 (6%) of the people on
AZT/3TC/nelfinavir had this mutant HIV. Sixteen such individuals who were maintained on
nelfinavir for another 28 weeks (44 weeks on nelfinavir in all) had no detectable codon 84 mutation, but other, supplementary mutations did
tend to accumulate. Six viral clones isolated from
five people with the 30 mutation were five to 93 -fold less susceptible to nelfinavir than wild type
virus (the range in resistance probably arises
from the supplementary mutations). All of these
isolates were fully susceptible to other proABT-378 seems to tease inhibitors.
But, the question remains, if someone's
HIV is resistant to nelfinavir, will their
resistance by its HIV more rapidly become resistant to
other protease inhibitors to which that
sheer potency- person might be switched? One specific
cause of concern: the supplementary
at least in the lab. mutations at codons 36, 46 and 71 are frequently seen from exposure to other protease inhibitors as well as to nelfinavir. Their
presence could facilitate the development of
resistance to protease inhibitors that follow nelfinavir.
And what about nelfinavir as a second-line
protease inhibitor? People on one of the currently approved compounds would like to know
that they can switch to nelfinavir if they start
failing their present therapy. Dr. Patick presented
an analysis of 23 HIV isolates obtained from people failing on indinavir, ritonavir or saquinavir.
Fourteen (61%) of these isolates were still susceptible to nelfinavir in culture. The catch is that
the protease inhibitor resistant HIV that had
only one identified mutation was still sensitive
to nelfinavir (with one mild eight-fold exception), but the virus found with two mutations
(most at codon 90 plus either 82 or 84) was
seven- to 75-fold resistant. Indeed, multiple
mutations are more common than single ones
after prolonged protease inhibitor therapy.
These data led Dr. Patick to conclude (however tentatively), "Nelfinavir failures are treatable
by other protease inhibitors. Failures on other
protease inhibitors with one mutation are treat
able with nelfinavir, but more than one mutation
is a problem-so there is a need to switch early."
Emilio Emini, M.D., who led the effort to
develop indinavir at Merck would exercise
greater caution about nelfinavir as either first- or
t eb r u ar Y I1

second-line therapy: "You cannot say that if you
start on protease inhibitor A and become resistant, the virus will still be susceptible to B, C or
D," he declared. "You will get varying degrees of
cross-resistance up to 100%. It all depends on the
mutations generated. You don't get just one
mutation. You alter the genetic background in
ways that you can't see [in lab tests] because the
mutations are present at too low a level. And it is
from this background of minor mutations that
resistance to new drugs appears."
Nelfinavir has shown itself to be a respectable
protease inhibitor, but it is odd that at this late
stage, with the drug before the FDA, the optimum dose is still controversial. Further, it is premature to judge how nelfinavir will be affected
by cross-resistance. Certainly it is intemperate to
draw conclusions on optimum protease inhibitor
sequencing on the basis of 23 isolates. Further
information on nelfinavir's place as follow-on
protease inhibitor in the case of treatment failure
may be available in the near future: Agouron is
tracking the viral load response in a group of protease inhibitor treatment failures now enrolled in
the nelfinavir expanded access programs.
And lest anyone think that there is no money
to made from AIDS drugs: Agouron's stock price
has skyrocketed from the high twenties to the
mid-nineties in the past year, almost entirely on
the perceived strength of nelfinavir.
Abbott Labs Tries Again
Abbott Laboratories in the meantime surprised the conference by unveiling its new protease inhibitor ABT-378 with much fanfare
(abstracts 14 and 206-213). This compound has
remained hidden from public view for some time
(see Treatment Issues, May, 1996, page 5). It is highly active against HIV, about three or four times
more so than Abbott's original protease inhibitor,
ritonavir. The structure of ABT-378 also circumvents some of the drug-resistance mutations that
afflict other protease inhibitors. For example, its
activity is hardly impaired by a protease gene
mutation at codon 82 that confers considerable
resistance to both ritonavir and indinavir.
In general, though, ABT-378 seems to overwhelm drug resistance by its sheer potency. In
combination with small amounts of ritonavir,
which blocks the relatively rapid breakdown of
ABT-378 by the liver, it is easy to obtain drug levels that are 50 times the levels that are effective
against wild type (non-drug resistant) HIV and
ten to 20 times higher than HIV with a single
mutation like that at codon 82. It is nevertheless
possible to generate HIV that is not inhibited by

ABT-378 and is considerably less sensitive to
other protease inhibitors as well. One mutant