Antiviral Strategies

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478), DMP-450, PNU-140690, BMS-234475 and ABT-378. For
more information on specific protease inhibitors, please call the
Project Inform HIV/AIDS Treatment Hotline.
Other approaches, some of which are in clinical testing, will try to
inhibit HIV from replicating at other stages in its life cycle.
Cellular Targets
Unlike all other antiviral drugs, which target the virus itself, this
class of compounds inhibits factors inside the cell that are necessary for viral replication. Attacking cellular targets, instead of targets on the virus itself, offers hope of slowing or avoiding viral
resistance because the cellular target does not rapidly mutate like
the virus. In general, these drugs work by suppressing compounds
inside the cell that the virus needs to replicate. In the laboratory
setting, this requires only a small reduction in the level of these
compounds, not enough to hurt the cell's own reproductive cycle
or function. The most researched of this class of drugs is called
hydroxyurea (HU).
Nucleoside Analogue Considerations
The five available nucleoside analogues have different side effects
and have different levels of activity when used in combination.
Resistance to 3TC occurs almost universally in people who use it
for 2 months or longer when the drug is used alone or in a typical
two-drug combination. When 3TC is used initially in an effective
three-drug combination, typically including a protease inhibitor,
the treatment regimen usually suppresses viral load below the
limit of detection. This appears to suppress the development of
resistance to 3TC, which allows the drug to then make a large and
long-lasting contribution to therapy. Once resistance is present
though, 3TC loses its ability to directly produce large reductions
in viral load. As a result, most researchers and the new Federal
Guidelines argue against using two drug conbinations like AZT
+ 3TC or d4T + 3TC as first line therapy. Instead, these make
excellent and long-lasting contributions when employed as part
of a 3-drug regimen. In short, 3TC has a lot to offer, but only if it
is used wisely.
The best results from combinations using AZT + 3TC + protease
inhibitors (or any other combinations) seem to occur in people
who initiate all three drugs for the first time or for people who
initiate at least two of the drugs for the first time when they start
the protease inhibitor.
A recent study of AZT + d4T in people who have been on prolonged AZT therapy showed that people on this combination fared
significantly worse than people who received AZT + ddl, d4T alone
or ddl alone. A second study also tested the AZT + d4T combination but in people who had not taken any prior antiretroviral drugs.

Antiviral Strategies
DiScussion Paper
This study found that people on the AZT + d4T combination did
not fare any worse than people receiving other antiretroviral regimens. The use of other combinations should be seriously considered before initiating this particular combination.
Some NARTI's, like ddl, d4T, and ddC, have the potential for creating similar side effects. Therefore, many researchers believe it
is unwise to combine them, fearing that the combination will increase the risk of the side effects common to both drugs. Therefore, a good general rule is to try to mix drugs with different,
rather than overlapping, side effects.
As with any other class of drugs, the most effective combinations
will include drugs that do not have cross resistance, that is, resistance to one does not confer resistance to the other. Among
NARTI's, AZT and d4T have somewhat different patterns of resistance than ddl, ddC, and 3TC, while ddl, ddC, and 3TC have at
least some degree of overlap when resistance develops. Resistance
to 3TC may affect a person's response to ddl, for example, but is
unlikely to affect AZT or d4T.
Since many people have used some or all of the NARTI's previously, the choice of a drug in this class when starting 3-drug combination therapy is often dictated by a person's individual drug
history. The most potent NARTIs to use in combination are likely
to be those that haven't been used before, or that have been used
for the shortest time.
Non-Nucleoside Reverse Transcriptase Inhibitor
Considerations
The NNRTIs have very potent activity against HIV. However, these
drugs can be rendered ineffective by a single, easily attained mutation in HIV. They can go from being highly potent to totally
ineffective in a short time unless a wise strategy is used to prevent
the development of resistance.
The NNRTIs should not be used alone or in two drug combinations. Even in a 3-drug combination, it is important that all three
drugs be new to the user.
A potential role for the NNRTIs may be for people with early stage
HIV disease, where the results have been very encouraging. By
using an NNRTI early in place of a protease inhibitor in a 3-drug
combination, it may be possible to save the protease inhibitors
for later use. If, instead, people begin immediately using a protease combination, there are few or no places left to turn when
the resistance eventually develops to the protease inhibitor since
there is some cross-resistance between all currently available protease inhibitors. In contrast, use of 3-drug combination including an NNRTI does not cause development of mutations which
could lead to resistance to protease inhibitors.

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