Treatment Issues Vol. 11, no. 2

-It UMR 2 AY 17a
GAY EN' HE LTH RISS ' S U E NE SLE TE O LUP ME1 NUMB ASTERPEBR1 S

Protease Inhibitors: Resistance, Resistance,
Resistance
by Dave Gilden, with John Falkenberg and Gabriel Torres, M.D.

Nothing at the Retrovirus Conference changed the
fact that all the HIV drugs now available or in
advanced development operate by interfering with
either HIV's reverse transcriptase or protease
enzymes. Protease inhibitors are potent drugs in their
own right, and combining them with reverse transcription inhibitors makes for a synergistic "one-two
punch" against the virus. In examining the various
combinations described below, bear in mind that it is
very difficult to obtain greater than a 99% (2 log) average reduction in HIV viral load over the first month
or two, or more than 99.7% (2.5 logs) over the first six
months. The reasons for this lie in both the drugs'
mode of action and the dynamics of HIV infection. All
the present drugs stop the infection of new cells.
None can kill or inhibit infected cells in any way, nor
do they affect the HIV-driven metabolic processes
within them. Since 99% of the new virus comes from
actively producing cells with a short lifespan on average, viral load can drop quickly only by that percentage. Further, limits in the sensitivity of viral load
assays (commonly considered to be 400 to 500, sometimes 200, HIV RNA copies/ml of plasma-or 20 to
50 copies/ml for the new ultrasensitive tests) reduce
the observable viral load reductions. It is impossible
with these tests to tell directly how close to zero a person's viral load has fallen.
Similarly, the dynamics of CD4 cell proliferation
tend to limit the average initial rises in CD4 counts to
100 to 150 cells/mm3 of blood. The differences
between combinations are most observable in the
long-term viral load endpoints and the stability of
those endpoints.
The present HIV drugs are plagued by resistance.
These drugs are very specific in their action, which
helps to protect the body from side effects but also
makes it possible for HIV to slightly alter its enzyme
structures and render the drugs ineffective. Combinations of drugs require HIV to mutate at more points in
its genes before it can resist all the drugs and rebound
to previous viral loads. Besides a drug regimen's immediate impact on viral load, the ease with which resistance can develop is a crucial factor in determining

durability of response. Reports at the conference proposed various ways to use protease inhibitor-containing combinations to build a sufficiently high "genetic
barrier" against HIV breakthrough. Creating this barrier is easier in people with no prior treatment. Those
with advanced disease and/or long treatment history
present a more difficult problem. Their circumstances,
including high viral loads, mean that the HIV within
them likely has already spawned many mutants at least
partially resistant to various drugs. Plus, large residual
HIV levels after initiating therapy are a breeding
ground for more resistance.

C)
LC)
LO)
LO)

Table 1: AZT/3TC/Indinavir in Advanced AIDS

baseline group size
size at 24 weeks
median baseline viral load
median viral load
change at 24 weeks*
percent with viral load
below detection*
median baseline CD4
median CD4 change
at 24 weeks

Indinavir
alone
107
81
94,000
-0.15 log
(-28.6%)
2%
17
+65

AZT/3TC
105
60
94,200

Triple
Combo
108
85
76,400

-0.20 log -2.19 log
(-36.7%) (-99.4%)

0%
14
0

65%
15
+84

*Lower limit of viral load assay = 500.
HAART Therapy in Advanced Disease
Nonetheless, potent HAART (for highly active antiretroviral therapy) combination therapies can be of benefit even to people with advanced AIDS and with
extensive past exposure to anti-HIV therapy. This was
confirmed by two studies at the Retrovirus Conference. In one (Merck protocol 039-abstract LB7), 320
volunteers with CD4 cell counts of less than 50
received either AZT/3TC/indinavir, indinavir alone
or just AZT/3TC. All participants had at least six