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There are three categories
of HIV antiviral drugs that have FDA approval. (Because HIV
is a retrovirus, these drugs are also called antiretrovirals.)
Nucleosides and non-nucleosides work to stop HIV from infecting
cells and protease inhibitors stop infected cells, from reproducing
the virus. In addition, new classes of drugs to treat HIV/AIDS
are on the horizon. Fusion inhibitors, nucleotide inhibitors
and immune modulators may be available in the near future.
Nucleosides
Nucleoside reverse
transcriptase inhibitors (NRTIs) are also known as nucleoside
analogs, or nukes for short. As their name says, these drugs
inhibit reverse transcriptase, which is an enzyme that HIV
needs in order to infect cells. Retroviruses like HIV use
reverse transcriptase to convert their RNA into DNA. Without
the ability to create its DNA inside the nucleus (core) of
a cell, HIV cannot infect that cell. (An enzyme is a cell
protein that causes chemical reactions in other substances).
The HIV DNA then integrates with the DNA of certain cells
in the body. DNA is the structure containing all of a person’s
genes.
Once proviral DNA has integrated
into the body’s natural DNA, HIV becomes a lifelong infection.
(No virus has ever been cured with medicine. Some are naturally
eliminated by Mother Nature, while others—like HIV and herpes
viruses—are forever. Science continues to work on this.) Generally,
HIV successfully converts into proviral DNA within 72 hours
after infection. Once inside the cell’s DNA, HIV awaits activation
by cytokines and chemokines. In simple terms, these are chemical
substances that tell cells what to do (thus, activating them).
NRTIs are analogs (think
of the word “analogous,” which means “similar”) because they
are imitations of the body’s own nucleosides, which HIV uses
to infect cells. The nukes trick HIV reverse transcriptase
into using the worthless fake nucleosides, thus preventing
the spread of infection to more cells. The virus thinks it
is inserting a natural nucleoside into its DNA chain, but
it’s inserting the drug. This breaks the chain.
The HIV nucleoside analogs
are not as potent as the other antivirals. The nukes interfere
with other enzymes in the body that perform similarly to the
HIV reverse transcriptase enzyme. As with the other drugs,
serious side effects are rare, but need to be closely monitored.
They can, rarely, be fatal. Retrovir (AZT) and Zerit (d4T,
stavudine) cross the blood-brain barrier (see sidebar The
Brain).
Non-nucleosides
Like the nukes, the
non-nucleoside reverse transcriptase inhibitors (NNRTIs, or
non-nukes) also keep HIV from infecting cells by interfering
with the virus’ reverse transcriptase. However, they do it
in a different way. The non-nukes bind directly to reverse
transcriptase, preventing further replication of the virus.
The non-nukes are highly cross-resistant to one another. They
are metabolized in the liver, so therapy needs to take special
consideration of potential interactions with other drugs that
are also processed hepatically (through the liver).
Rescriptor (delavirdine)
is an inhibitor of the cytochrome P450 system (see box), while
Viramune (nevirapine) and Sustiva (efavirenz) are inducers.
Inducers increase drug metabolism, which in some cases results
in lower levels of protease inhibitors. Thus the need for
increased protease inhibitor doses. Sustiva has been placed
in the strongly recommended category of the DHHS guidelines
for treatment of drug naïve patients, along with most of the
protease inhibitors, in combination with two nucleosides.
The non-nukes provide a choice
for people who are intolerant of protease inhibitors, those
who want to save the protease class for the future, or whose
PI therapy failed them. Chances are, if you’ve never had a
non-nuke, you would get beneficial results from adding one
if you’re on your third or fourth regimen. Some of the non-nukes
might be considered a superior choice in that they are easier
to take than the protease inhibitors. Viramune requires two
tablets daily, with or without food. Sustiva requires three
capsules once a day, also without food requirements. Soon,
a single 600 mg Sustiva tablet will be available to simplify
regimens even further. The non-nukes also have fewer short-term
side effects and are generally effective in crossing the blood-brain
barrier (see sidebar Liver Metabolism).
Again, careful monitoring of severe reactions (such as rash)
can prevent illness and even death.
Protease inhibitors
Protease inhibitors,
like the name says, inhibit protease. Almost every living
cell has a form of protease, a digestive enzyme that breaks
down protein. HIV protease is only one of several enzymes
the virus uses to reproduce itself. The HIV protease works
by cutting up long chains of the virus’ proteins and enzymes
into smaller pieces that go on to infect new cells. By blocking
HIV protease—or as some people say, by gumming up the HIV
protease scissors—these drugs keep the virus from making copies
that can infect cells. Thus the drugs keep immature non-infectious
virus particles from becoming mature infectious particles.
HIV protease works near the end of the replication cycle of
the virus. As shown by the way in which antiviral drugs work,
the HIV protease inhibitors can slow virus production in both
newly infected cells and cells that have been infected for
a long time, compared to the nukes and non-nukes which do
not work on longtime infected cells.
The protease inhibitors are
for the most part very powerful in relation to the nucleosides
and have received major public attention. The protease inhibitors
also do not generally have overlapping toxicities with the
other two classes. However, they may be difficult to tolerate
because of side effects like gastrointestinal symptoms. As
with the nukes and non-nukes, some long-term side effects
are still not understood. Researchers are working to understand
the obvious relationship between protease inhibitors and very
serious long-term side effects such as hypercholesterolemia
and fat redistribution. Other abnormalities include the development
of heart disease and diabetes in people who are predisposed
to these conditions. The nukes and non-nukes are also potentially
involved in the development of these problems.
As with the non-nukes, there
is a lot of cross-resistance among the protease inhibitors
despite different patterns of drug resistance among them.
For this reason many specialists once believed that people
with HIV may have only one shot at taking a protease inhibitor.
With the introduction of Kaletra (lopinavir/ritonavir) and
the increased usage of dual protease combinations, this may
no longer be true. The protease inhibitors also have poor
penetration into the cerebral spinal fluid (CSF), although
again, the clinical benefits of this are unclear. Crixivan
(indinavir) has the highest penetration of CSF of all the
protease inhibitors. The PIs are highly protein bound. This
means they are attached to proteins in the bloodstream. It
is unbound drug that is active (gets absorbed), so the higher
the protein binding the less drug is available to work. This
creates a bioavailability
problem. Protein binding, bioavailability, and metabolism
in the liver (which can cause drug interactions with other
drugs metabolized in the liver) all can lower the concentration
of protease inhibitors in the body. However, most people achieve
adequate drug levels at the doses prescribed. Some clinics
are now using Therapeutic Drug Monitoring (TDM) to measure
how much drug is available in your blood. At some time in
the future, we may be ready to prescribe “Designer Drugs”
and customize doses of drugs for each individual.
A note about adherence:
A discussion of “How
Drugs Work” must include a mention about adherence. Because
the amount of drug needed to suppress the virus must be above
a certain level at all times, missing doses will allow the
virus to fight back and reduce the effectiveness of the drug
therapy. Think of the drugs as a dam holding back a river
(the virus). If the dam is not tall enough (not enough drug),
the water will just pour right over the wall (viral replication).
Food is also important in making sure there is enough drug
to fight the virus. Most protease inhibitors (except Crixivan)
must be taken with food to be absorbed into the blood. Other
drugs like Videx and Crixivan require an empty stomach because
stomach acid destroys the medication before it is absorbed
into the bloodstream. [See “Adherence
101” and “To Start
or not Start?”.]
Some HIV drugs will require
closer monitoring, and sometimes dose reductions, to decrease
the risk of side effects or toxic levels of drugs in the blood.
Other HIV drugs can have the opposite effect, and may require
increase in dosage in order to achieve adequate blood levels.
Liver disease such as hepatitis, inherited deficiencies in
the CYP genes, and multiple medications can cause problems
with drug metabolism. Doctors use information on how drugs
affect the different CYP450 enzymes (there are more than three
hundred of them) to help determine which drugs to use in combination
therapy and the doses to be used.
See Positively
Aware 2001 Drug Guide for a complete listing of currently
available HIV antivirals.
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