Antiviral Strategies

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Antiviral Strategies
\?Discussion Paper
ing drugs with similar side effects, though sometimes this is impossible. And it is critical to learn about possible drug interactions before mixing any of these drugs together. To help with understanding these issues, Project Inform has Fact Sheets on each
of the antiretrovirals as well as an extensive Drug Interactions
Fact sheet.
Quality of life would improve if combination therapies restore the
immune system enough to make it possible for people to eliminate a person's need for preventative medicines, such as TMP/
SMX (Bactrim or Septra) for PCP, etc. Limited clinical experience suggests that some people who have a good response to antiviral therapy can safely go off preventive therapies they have
used previously, but the majority of others cannot. For now, there
is no way to predict who will and won't be successful. Therefore,
for now, stopping the use of preventive therapies is an unwarranted gamble and preventive treatments should be continued.
Targets for Therapy
Various antiviral drugs work by targeting different stages in the
reproduction of new copies of HIV. No drug has proven to do a
perfect job in stopping its target of HIV viral activity. Researchers
believe the most effective approach to therapy combines drugs
which target two or more different stages of the virus's reproductive cycle. That way, even if one step isn't completely blocked,
treatment can still work by blocking another step in the cycle.
Perhaps the effective therapies will someday prove to be ones which
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block several steps all at the same time. For now, the available
antivirals are capable of stopping two different steps in the viral
life cycles (reverse transcription and protease clipping), and there
are two different ways of stopping reverse transcription.
Reverse Transcriptase Inhibitors
The first general class of antiviral drugs is called reverse transcriptase inhibitors. Reverse transcriptase inhibitors interfere with
HIV's ability to combine its genetic material with that of the cells
it infects. For now, there are two different types of drugs which do
this, in somewhat different ways. The most common approach is
found in drugs called nucleoside analogue reverse transcriptase
inhibitors. Examples of NARTIs include AZT (zidovudine and
Retrovir), ddl (didanosine and Videx), ddC (zalcitabine and Hivid),
d4T (stavudine and Zerit) and 3TC (lamivudine and Epivir), all of
which are approved by the Food and Drug Administration (FDA).
NARTIs were the first to be tried against HIV because they were
better understood and better proven than other antiviral approaches. Also, at least three of the nucleoside analogues, AZT,
3TC and d4T, are effective in crossing the blood-brain barrier and
therefore helpful in managing HIV-associated dementia. For more
information on these specific drugs, please call the Project Inform National HIV/AIDS Treatment Hotline. Other NARTIs that
are in development include 1592U89 and MKC-442.
A second approach is found in the category called non-nucleoside
reverse transcriptase inhibitors (NNRTIs). These work at the same
step of viral replication as the NARTIs, although they use a different mechanism. The NNRTIs are generally effective in crossing
the blood-brain barrier and may be useful in managing HIV-associated dementia. Examples of NNRTIs include nevirapine
(Viramune) and delavirdine (Rescriptor) which are approved by
the FDA. Other NNRTIs that are in development include DMP
266. For more information on specific NNRTIs, please call the
Project Inform Hotline.
A third approach, called nucleotide analogue reverse transcriptase
inhibitors, is currently undergoing clinical trials.
Protease Inhibitors
The second general class of antiviral drugs is called protease inhibitors. These drugs work at a later stage of the virus' life cycle,
after the virus has successfully infected the cell and attempts to
make new copies of itself. Currently, none of the approved protease inhibitors are effective in crossing the blood-brain barrier.
However, newer protease inhibitors may be effective in crossing
the blood-brain barrier. Examples of protease inhibitors include
saquinavir (Invirase), ritonavir (Norvir), indinavir (Crixivan) and
nelfinavir (Viracept) all of which are approved. Other protease
inhibitors that are in clinical development include 141W94 (VX

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