Treatment Issues Vol. 11, no. 2

treatment
COD

created in the laboratory by exposing HIV to
increasingly high concentrations of ABT-378 had
five mutations and was 338 times less sensitive
to ABT-378. It also was about 20 times less sensitive to ritonavir and indinavir. Four of the five
mutations also appear during analogous culture
tests of Glaxo Wellcome's experimental protease
inhibitor 141W94.
ABT-378 is an interesting new compound, but
it does not represent a radical break with the earlier protease inhibitors. Its structure, mechanism
of action and resistance mutations are comparable to those of other members of its class. A big
remaining question is how feasible it is to
achieve levels within humans that overwhelm
any resistance on HIV's part. There are as yet no
human trials to evaluate what drug levels can be
attained in reality, either with ABT-378 alone or
in combination with ritonavir. No information as
to the new compound's toxicity is available,
either. The data Abbott presented at the Retrovirus Conference at best come from rat studies,
and much of the figures are derived from testtube cell cultures or even straightforward chemical analyses in cell-free solutions.
Combining Protease Inhibitors
Although human trials of ABT-378 plus ritonavir have not yet occurred, a trial of saquinavir
plus ritonavir has been continuing since last
spring (unpublished presentation in session 84
by John Mellors, M.D.). The reason for combining ritonavir with saquinavir is similar to combining ritonavir with ABT-378. In both cases,
ritonavir, which inhibits one of the enzyme pathways in the liver, greatly increases and stabilizes
blood levels of a compound that otherwise
would be rapidly metabolized. The quantities
required for saquinavir are much larger than
those suggested for ABT-378 and are large
enough to have an anti-HIV effect of their own.
This reinforcement helps to delay breakthrough
of drug-resistant HIV, the more so because the
two agents trigger divergent mutational patterns. Results from the ritonavir/saquinavir trial
are now in hand for 20 to 24 weeks of treatment.
This trial includes four arms: 400 mg ritonavir
twice daily plus 400 mg saquinavir twice daily;
600 mg ritonavir twice daily with either 400 or
600 mg saquinavir twice daily; and 400 mg three
times a day of both ritonavir and saquinavir. Initial viral load averaged about 30,000 and average
initial CD4 was about 300. (The trial enrolled 141
participants, all protease inhibitor naive.) For all
four arms, median viral load reductions go below
the limits of the viral load assay (here considered

as 200 copies/ml) at four to eight weeks and stay
there. This represents at least a 2 log (99%) medi
an drop. At week 20 or 24, 60% to 85% of people
on the different trial regimens had no detectable
viral load. CD4 counts were up 75 to 125. There
was no statistically significant difference in the
effect of the various regimens, although by week
20 the group receiving ritonavir and saquinavir
at 600 mg twice daily was lower than the other
three in percent with undetectable viral load and
in CD4 cell count rise. (This group may be less
compliant due to more side effects and a more
complicated dosing schedule.)
Seven participants have been allowed to
add d4T/3TC after their viral loads failed to
become undetectable. Six of these seven are
now undetectable, following four to 16 weeks
of four-drug therapy.
Another trial reported at the Retrovirus Conference (abstract 254) tried a similar four-drug
approach in 32 people with refractory HIV. The
participants had persistent viral loads above
5,000 copies or evidence of disease progression
despite four months on two nucleoside analogs
and one protease inhibitor. They received
ritonavir (600 mg twice a day), saquinavir if
(400 mg twice a day) and two nucleoside
analogs. The week 16 results were as fol- inh
lows: viral load down 2.2 logs (99.4% reduction from a baseline mean of 72,500 do
copies/ml), with 93% of participants having in
undetectable viral load (below 400
copies/ml), CD4 count up an average of 72 cri
(from a baseline average 79). M
Ritonavir/saquinavir by itself frequently Mi
fails to elicit a good response in advanced
patients (see Treatment Issues, December, 1996,
page 4). Throwing two more drugs into the mix
may be helpful for many of these cases, assuming that a patient can absorb and tolerate extra
drugs, that his or her HIV remains sensitive to
these drugs, and that his or her body is still able
to support at least the minimum functioning
needed for survival... There are many factors
that might eventually or immediately interfere,
although in these two small groups, at least,
treatment was initially successful for most individuals.
Should Abbott have lost interest in the
ritonavir/saquinavir combination due to the
arrival of ABT-378, the Hoffmann La Roche
protease inhibitor may have found a new partner: nelfinavir. In a preliminary trial of 13 people on saquinavir plus nelfinavir (abstract 371),
nelf inavir slowed liver metabolism of
saquinavir to the extent that total exposure to
the latter was raised five-fold (compared to a
20-fold average increase with ritonavir). Coin
bination therapy included 750 mg of nelfinavir
thrice daily (note the dose) plus 800 mg three

a two-protease
ibitor combination
esn't work, throwing
two reverse transptase inhibitors
ght help.

vol 11 no 2