Biomedical Engineering Reference
In-Depth Information
24.7 ANTIVIRAL AGENTS IN (PRE)CLINICAL DEVELOPMENT
In addition to the 42 antiviral compounds that by the end of 2006 were available, there are a few
more that are under clinical development, and many more that are under preclinical development.
For HIV (De Clercq, 2004), these include the virus adsorption inhibitors (cosalane derivatives,
cyanovirin-
N
, cyclotriazadisulfonamide [CADA] derivatives, teicoplanin aglycons); the CXCR4
antagonist AMD070; the CCR5 antagonists maraviroc (UK-427857) and vicriviroc (SCH-D);
the NRTIs (
±
)-2
′
-deoxy-3
′
-oxa-4
′
-thiacytidine (dOTC) (apricitabine); racemic (
±
)FTC, amdoxovir
(diaminopurine dioxolane, DAPD), Reverset (
-
D
-d4FC), and alovudine (FddThd); the NNRTIs
etravirine (TMC125), dapivirine (TMC120), and rilpivirine (TMC278); and the integrase inhibitors
Raltegravir (MK-0518) and Elvitegravir (GS-9137). Maraviroc, etravirine, and raltegravir have, in
the mean time, been licensed for clinical use in the treatment of HIV infections.
For HBV, four compounds, namely, lamivudine, adefovir dipivoxil, entecavir, and telbivudine
have been licensed for medical use and TDF will most likely be the next one and has, in the mean
time, been licensed for the treatment of chronic hepatitis B, and for HCV, a variety of compounds
targeted at either the viral protease or RNA-dependent RNA polymerase (RdRp) are currently under
intensive scrutiny. Also for the herpesviruses (i.e., HSV), new antivirals have been described that
target the helicase/primase complex, terminase complex or UL97 protein kinase, and, likewise, new
inhibitors are on the horizon for CMV (De Clercq, 2004b) and VZV (De Clercq, 2003c).
β
24.8 APPRAISAL OF CLINICAL UTILITY
Currently licensed antiviral drugs are particularly focussed on the treatment of HIV, HBV, herpes-
virus, inl uenza virus, and HCV infections, and, so are most of forthcoming antiviral compounds
that are in (pre)clinical development.
For the treatment of HIV/AIDS there are now 22 anti(retro)viral drugs available, and to achieve
the largest possible benei t, these drugs have to be combined in multiple-drug regimens. Numerous
drug combinations could be envisaged. Those that have been generally used consist of two NRTIs,
or one NRTI, and one NtRTI (TDF), to which is then added one NNRTI or one PI. Because of the
long-term side effects (such as lipodystrophy, diabetes, and cardiovascular disturbances) associated
with the PIs that have been longest in use, there is a tendency for starting anti-HIV therapy with
PI-sparing regimens.
One such regimen that has proven to be quite efi cacious in the treatment of HIV infections, and
seems to be well tolerated, is the combination of TDF with (−)FTC (emtricitabine) and efavirenz.
Enfuvirtide represents a new dimension in anti-HIV therapy, which could be added onto any (opti-
mized background) regimen, but, because of the costs involved and the fact it has to be administered
subcutaneously (twice daily), enfuvirtide should be primarily reserved for salvage therapy.
For the treatment of HBV infections, four compounds, lamivudine, adefovir dipivoxil, ente-
cavir, and telbivudine, besides human interferon, are currently available. TDF is recommended
for use in HIV-infected patients who are coinfected with HBV and should soon become avail-
able for the treatment of chronic hepatitis B as well. Whether the treatment of HBV infections
should be based upon multiple-drug regimens (so as to minimize the emergence of virus-drug
resistance), as in the case of HIV/AIDS, needs to be addressed in future studies. A dual-drug
regimen that could be envisaged for the treatment of chronic hepatitis B is that of TDF combined
with emtricitabine.
The treatment for HSV and VZV infections is since many years fairly well consolidated: it is
based on the use of acyclovir, valaciclovir, or famciclovir, and in several European countries, also
brivudin (BVDU). Here, there is no need for drug combination therapy, as virus-drug resistance has
only rarely proved to be a problem, and, if so (in severely immunocompromised patients), therapy
could be switched to, for example, foscarnet or cidofovir. The latter two drugs, which must be
administered intravenously, are also used in the treatment of CMV infections in immunosuppressed
patients, mostly as a second choice following the use of (val)ganciclovir.
