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Table 3: Indinavir(IDV)_with AZT + 3TC
VL drop at % <500 % <50 CD4+ cell
IDV Dose 24 weeks HIV RNA HIV RNA increases
800mg / 8 hrs 1.6 logs 45 45 140
1000 mg /112 hrs 2.1 logs 75 70 80
1200 mg / 12 hrs 2.2 logs 75 60 90
Table 4: Hard vs. Soft Gel Saquinavir
Viral load % below CD4+ cell
drop 500 copies increases
NARTIs + HIV RNA
HGC SQV 1.6 logs 43% 120
SGC SQV 2.0 logs 80% 90

HGC = Hard Gel Caplets

SGC = Soft Gel Caplets

Preliminary results from a small study comparing indinavir at the approved dose (800
mg every 8 hours) to two different doses
taken twice daily (every 12 hours) show
that, in the short-term, the every 12 hour
dosing seems as effective initially as taking
indinavir every 8 hours. This study enrolled
87 people who had not used 3TC or protease inhibitors before. Their median viral
load was about 38,000 copies of HIV RNA
and their median CD4+ cell count was 279.
They received indinavir at 800 mg every 8
hours, 1000 mg every 12 hours or 1200
mg every 12 hours. In addition, all participants took AZT + 3TC. All three doses were
generally well tolerated, although there appeared to be slightly more side effects among
people receiving the 1200 mg every 12 hours
dose. The results are shown in Table 3.
It would be a mistake, however, to conclude from these data that taking indinavir
twice daily is as effective or more effective
than the standard thrice daily dosing. The
real test of equivalency in dosing will be
measured in the durability of the treatment
response - how well it holds up over time.
Data after 1 year will be more convincing,
and 2-year data the most convincing of all.
(See "The Science and Marketing of Simpler Dosing" on page 6.)
It is important to stress that these are very
preliminary results with only a few people
reaching the 24-week point of the study.
The long-term effect of indinavir taken every 12 hours is still not known.

Indinavir +u- Ritonavir
(Norvir~)
Interesting results have been reported on
the combination of indinavir + ritonavir. A
very short-term study was conducted in
people who were not HIV-infected, to avoid
the risk of causing protease inhibitor resistance in HIV-infected people. People received either indinavir alone (800 mg every
8 hours), or one of the following twice daily
regimens: 600 mg indinavir + 200 mg
ritonavir; 400 mg indinavir + 300 mg
ritonavir; 600 mg indinavir + 300 mg
ritonavir; or 400 mg indinavir + 400 mg
ritonavir. Results indicate that these two
therapies can be taken together twice a day
and that 400 mg of indinavir + 400 mg of
ritonavir may be the optimal dose. On this
schedule, the peak level of indinavir was
about the same as that seen on the approved
800 mg every 8 hours dose. The trough level
of 400 mg of indinavir with 400 mg
ritonavir was about 4-5 times higher than
that seen when the 800 mg dose is taken
without ritonavir. ("Peak level" refers to the
highest level of the drug seen in the blood
for a given dose and it usually represents
the greatest risk for side effects. The "trough
level" is the lowest level and is associated
with a greater risk of developing resistance
to the drug.) Furthermore, this higher
trough level was seen in spite of taking the
combined drugs within 30 minutes of eating a light meal. In effect, ritonavir slows
the 'breakdown' of indinavir and as a result prolongs and increases the presence of
indinavir in blood - just as it does with
saquinavir. The higher trough levels of

indinavir suggest that a combination of this
sort may help prevent the development of
drug resistance.
Although these data provide encouraging
news about a possible combination of the
two most powerful protease inhibitors, it is
too early to suggest that people try this combination. There is thus far no data at all
about the results of combining the two
drugs in HIV-infected people or any way to
compare this combination to other available treatment regimens.
Hard 'vs. Soft Gel
Saquinavir
Preliminary results from a study comparing the currently approved hard gel (HGC)
formulation of saquinavir (Invirase@) to
Fortovase@, the new soft gel formulation
(SGC), shows that the new formulation has
much better activity than the current version in people who have not been on prior
antiretroviral therapy. The study enrolled
171 people with a median viral load of
63,000 copies of HIV RNA and a CD4+
cell count of about 400. They received either HGC saquinavir (600 mg three times
a day) or SGC saquinavir (1200 mg three
times a day) in addition to two nucleoside
analogue reverse transcriptase inhibitors
(most of the participants chose AZT + 3TC
or d4T + 3TC). The results after 16 weeks
are shown in Table 4.
These results clearly show that SGC
saquinavir is more potent than the currently
approved version. While the dose of SGC
saquinavir is twice that of HGC saquinavir,
the amount of drug that is actually found
in blood is about 10 times higher.
Somewhat surprising results were observed
in a study of SGC saquinavir and nelfinavir
(Viracept@). One hundred and fifty-seven
people with an average of about 300 CD4+
cells and HIV RNA of about 63,000 copies
received one of the following combinations:
M SGC saquinavir (1200 mg three times
daily) + 2 NARTIs,
0 nelfinavir (750 mg three times daily) + 2
SNARTIs,.* nelfinavir + SGC saquinavir (750 and 800
mg respectively three times daily), or
* nelfinavir + SGC saquinavir (750 and 800.mg respectively three times daily) + 2
NARTIs.
About half the participants had not been.on any prior antiretroviral therapy. The.results after 16 weeks of therapy are shown
Sin Table 5 on the following page.

PI PERSPECTIVE

I NUMBER 23 NOVEMBER 1997

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