AIDS Treatment Update

triglycerides amongst the ABT-378/r arm (9%
versus 1%). More people left the nelfinavir
arm than the ABT-378/r arm, however; 24%
versus 17% overall, including 4% versus 2%
for study drug related side-effects, and 9%
versus 1% for virological failure (nelfinavir
versus ABT-378/r respectively).
Where is ABT best placed?
Abbott Labs designed ABT-378/r with the
intention of developing a PI which would be
useful to people with PI resistance. Results
from two studies investigating ABT-378/r use
after other PIs have supported Abbott's theory
that if drug levels are high enough, they can
overcome drug resistance (see AIDS
Treatment Update issue 92). Both involved the
use of ABT-378/r plus an NN RTI in people
who were PI-experienced but NN RTI na've,
but nevertheless, in people with experience of
several different PIs, response rates increased
as baseline sensitivity to ABT-378/r grew'.
So far, there is relatively little information on
how resistance to ABT-378/r develops.
Participants from the nelfinavir comparison
study, who had viral load above 400 copies at
week 24 and week 48, were given a genotypic
resistance test to look for protease drug
resistance mutations. Results were available
for 64 of 78 nelfinavir users and 31 of 42
ABT-378/r users. Mutations were found in 20
nelfinavir users but were not detected in any
ABT-378/r user. Similarly, of four people who
had viral rebound in the M97-720 study, none
had genotypic resistance to ABT-378/r, though
two were resistant to 3TCs.
A report from the VIRADAPT study, (which
looked at the role of resistance testing in the
selection of salvage regimens for people whose
treatment was no longer suppressing their
viral load), found evidence that ritonavir
resistance mutations emerged during
treatment with 100mg ritonavir (given twice
daily with 600mg saquinavir)6. The
VIRADAPT team suggest therefore that the
use of this 'baby-dose' of ritonavir in people
new to treatment - for example those taking
ABT-378/r - might also result in the
development of ritonavir resistance mutations.
This theory too, requires further testing; the

development of resistance mutations in people
who've previously taken several different drugs
could be different to that seen in people new
to treatment.
Despite the absence of ABT-378/r mutations
in people with viral load rebound on ABT-378/
r in clinical trials so far, it would be foolhardy
to assume that this will be repeated in 'realworld' settings, where failure rates are higher,
where monitoring may be less intensive, and
where many people do not come off treatment
at the first hint of a viral load rebound. These
are the ingredients for drug resistance.
For some doctors, ABT-378/r's proven
effectiveness in PI salvage, and the relative
lack of information both on how people who
fail on ABT-378/r will themselves be salvaged,
and on the drug's effect on blood lipids, means
ABT-378/r may be best saved for use after
other PIs have failed.
According to Professor Brian Gazzard, of the
Chelsea and Westminster Hospital, "It's the
outcome of the second treatment - i.e. salvage
- that largely determines what will happen in
ten years time rather than the potency of the
initial regimen. Thus all studies and all drugs
need to be looked at for durability and for
'salvage-ability' as much as for initial potency.
There's uncertainty over ABT-378 mainly
because we don't know why it fails and
therefore what salvage is going to be possible.
It's certainly durable and potent."
Other boosted PIs
A further criticism levelled at ABT-378/r is
that its potency is the result of ritonavirboosting, and as such, it may be no more
effective than other boosted PIs. At present
there are no data from comparative trials,
though a US study called MaxCmin II
comparing ritonavir/saquinavir with ABT-378/
r will begin shortly, a Roche-funded Danish

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