Fact Sheet Number 402
REVERSE TRANSCRIPTASE INHIBITORS
- REVERSE TRANSCRIPTASE INHIBITORS
- A. NUCLEOSIDE ANALOGS (NUKES)
- B. NON-NUKES (NNRTIs)
- DRUGS NO LONGER IN DEVELOPMENT
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PrintNOTE: Fact Sheets 402 through 405 describe drugs that
are being tested against HIV. See Fact
Sheet 403 for information on protease inhibitors, Fact
Sheet 404 for information on new classes of drugs, and Fact Sheet 405 on immune stimulators.
These drugs have not been approved by the Food and Drug Administration
(FDA) for use against HIV.
INHIBITORS
These drugs stop HIV from multiplying by blocking the reverse
transcriptase enzyme. This enzyme changes HIV’s genetic material
(RNA) into the form of DNA. This step has to occur before HIV’s
genetic code gets combined with an infected cell’s own genetic
codes. There are two types of reverse transcriptase inhibitors:
- Nucleoside analogs (often called “nukes”).
These drugs mimic the building blocks used by reverse transcriptase
to make copies of the HIV genetic material. These fake building
blocks disrupt the copying.
- Non-nucleoside reverse transcriptase inhibitors, called
NNRTIs, physically prevent the reverse transcriptase enzyme from
working.
ANALOGS (NUKES)
Nucleoside analogs (nukes) in development include ACH-126,443,
DAPD, FTC and MIV-310. Tenofovir is a closely-related nucleotide
analog.
ACH-126,443 (Beta-L-Fd4C) by Achillion Pharmaceuticals
is a once-daily drug with activity against HIV that is resistant
to several other nukes. It is also effective against hepatitis
B.
DAPD (amdoxovir) by Triangle Pharmaceuticals is being
studied in twice-daily doses. It appears to be effective against
HIV that is resistant to other nukes and against hepatitis B.
DAPD is in Phase I/II trials.
Emtricitabine (Coviracil®, formerly FTC)
by Triangle Pharmaceuticals is closely related to the drug 3TC.
FTC was much stronger than 3TC in the laboratory but is not stronger
in humans. It is taken once a day and is in Phase III trials.
A recent study comparing FTC to d4T was halted when FTC showed
superior effectiveness.
NUCLEOTIDE ANALOGS
Tenofovir (bis-poc PMPA, Viread®) by Gilead was
approved by the FDA in October 2001. See fact
sheet 428 for more information.
(NNRTIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in
development include Calanolide A, Capravirine, DPC083, Emivirine,
MIV-150, TMC120 and TMC125.
(+)-Calanolide A by Sarawak MediChem Pharmaceuticals
was derived from a rain forest plant. It can easily cross the
blood-brain barrier, and seems to stay in the bloodstream for
a long time. It is in Phase I human trials. There are no recent
reports on its status.
Capravirine (AG1549, formerly S-1153) by Agouron Pharmaceuticals
appears to be about 10 times stronger than nevirapine or delavirdine
against wild type virus. HIV needs 2 or 3 mutations to develop
resistance to capravirine, compared to just one mutation for current
NNRTIs. The dose will probably be two 700 mg tablets twice a day.
Development was put on hold due to toxicity in dogs but has been
resumed. It is in Phase II trials.
DPC083 by Bristol-Myers Squibb is closely related to
Efavirenz (Sustiva®). It has a very long half-life, so it
will probably be dosed once a day. It can suppress HIV with some
resistance to NNRTIs. It is in Phase I/II trials.
MIV-150 by Medivir and Chiron shows good results in
the laboratory against HIV that is resistant to other NNRTIs.
It takes a long time for HIV to develop resistance to MIV-150.
Phase II trials are scheduled.
TMC120 and TMC125 by Tibotec Virco are active against
some strains of HIV that are resistant to other NNRTIs. It takes
longer for HIV to develop resistance to TMC120 or 125 than to
the first NNRTI drugs. They are being studied in Phase II trials.
IN DEVELOPMENT
The following drugs are no longer being developed for use against
HIV:
Nukes:
- Adefovir dipivoxil (bis POM PMEA) by Gilead Sciences
- dOTC (BCH-10652) by BioChem Pharma
- FddA (Beta-fluoro-ddA, Lodenosine®) by US Bioscience
- GW420867X by GlaxoSmithKline
- Lobucavir by Bristol-Myers Squibb
NNRTIs:
- Atevirdine by Upjohn
- Emivirine (Coactinon) by Triangle Pharmaceuticals
- Loviride by Janssen Pharmaceuticals
- HBY-097 by Hoechst-Bayer
- PNU142721 by Pharmacia & Upjohn
Revised August 7, 2002
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