Treatment Issues Vol. 11, no. 2

t ISSUES
C
months of AZT but had never before taken a
protease inhibitor or 3TC. The results are summarized in Table 1.
The 65 CD4 count rise at 24 weeks from indinavir monotherapy is surprising given the regimen's poor antiviral performance. The reason
may be that for the first two weeks, the viral load
drop from indinavir alone equaled the reduction
achieved with the triple therapy, about 1.3 logs
(95.0%). The median viral load in the triple therapy arm kept gradually falling at least until week
16, when it essentially stabilized. In those on indinavir alone, the median viral load rebounded
after the second week, and by week 16 was only
about 0.1 log (20.7%) below baseline. (The
AZT/3TC arm's median viral load was stable
from week 2 to week 24.) As for the CD4 counts,
the two indinavir containing arms rose in parallel
Nellinavir has shown through the twelfth week after which the
monotherapy arm declined slightly while
itself to be a respectable those on triple therapy continued their rise.
Other indinavir trials, too, have seen a long
protease inhibitor, but lag between viral load rebound and fall of
i od tCD4 count back to baseline in those on indiit is odd that the navir monotherapy. That process can take
optimum dose is still over a year. (Trial 039 is now continuing
beyond 24 weeks with everyone on open
controversial. Further, label triple combination therapy.)
Another trial looking at people in
it is premature to judge advanced disease was a pilot study conWill. ducted in Vancouver, British Colombia
how nelfinavir Will (abstract 234). This trial followed 21 heavily
be affected by pretreated patients who were failing or
C Coss- intolerant to their nucleoside analog theraresistance. py and seemed to have run out of options
in this drug class. The 21, who were all
naive to indinavir and nevirapine, received those
two drugs in combination with 3TC. Baseline
CD4 count averaged only 28 (everyone was
under 50), and average baseline viral load was
135,000 HIV RNA copies/ml of plasma.
This combination of a potent protease
inhibitor, a rather well tolerated non-nucleoside
reverse transcriptase inhibitor and a relatively
benign nucleoside analog had a surprisingly positive effect as salvage therapy. In the 12 participants who had reached 20 weeks of therapy, CD4
counts were up 100 above baseline and continuing to rise, and viral load had fallen more than
1,000-fold (99.9%). However, so far only two of
the 12 had undetectable viral loads using the new
ultrasensitive PCR assay. Seven (58%) were undetectable by the standard PCR test that goes down

only to 500 copies/ml. Three of the participants
have dropped out, two due to nausea or vomiting and one because of skin rash.
Other indinavir news included the latest
results from protocol 035, a trial of AZT/3TC/
f e br Ua r V199 7

indinavir versus AZT/3TC versus indinavir
alone in 97 adults with at least six months of
prior AZT therapy. Follow-up is now out to 68
weeks in two-thirds of the group. This trial
included a population that was a little less
advanced than the two above: a baseline median
CD4 count of 142 (one eligibility requirement
was a CD4 count between 50 and 400) and a
baseline median viral load of 43,000. Participants
also had to have had at least six months of prior
AZT treatment. The actual average past exposure to AZT was 30 months, with 80% of the participants carrying AZT-resistant HIV (by genetic
analysis). The group was therefore somewhat
representative of a real population with
advanced diseased, in whom HIV has developed
resistance to AZT during past treatment.
Trial participants assigned to receive
AZT/3TC/indinavir from the beginning have
exhibited stable viral load reductions, a median
of 2 logs (99%) or greater, out to a year or a year
and a quarter so far. Of those on treatment for 68
weeks, 18 of 21 (86%) still have plasma viral
loads below the test limit of 500 HIV RNA
copies/ml and 10 of 14 (71%) checked with an
ultrasensitive assay are also below 50 copies/ml.
Nelfinavir: What about Cross-Resistance?
Agouron Pharmaceuticals' protease inhibitor
nelfinavir (brand name Viracept) is now up for
FDA licensing review. Although rumors of its
imminent approval are rampant, the company's
"conservative" prediction is FDA approval by
June of this year. Meanwhile, Agouron
researchers presented a number of reports at the
Retrovirus conference, including information on
the compound's efficacy when combined with
AZT/3TC or d4T. In contrast to the indinavir
studies above, the AZT/3TC/nelfinavir trial
(Agouron protocol 511) included only people
with less than one month prior AZT and no
other past treatment. Their CD4 counts could be
any number, and in many cases were below ten.
The d4T trial (Agouron protocol 506) included
both treatment-naive and -experienced people
(90 naive and 218 experienced with an average
of 27 months prior therapy). The trial required
that their CD4 counts exceed 50. Table 2 summarizes the data from these two trials.
It is risky to compare the studies' data, especially given the two populations' different treatment histories. Still, the triple therapy seems
superior to the double d4T/nelfinavir combination, both in terms of viral load and CD4 cell
response and in the stability of that response:
viral load in the d4T/nelfinavir cohorts reached a

peak decline of about 1.5 logs (96.8%) and then
started gradually rebounding. The viral load