Biomedical Engineering Reference
In-Depth Information
Principal indication(s)
: As a small size droplet aerosol, in the treatment of RSV infections in
high-risk infants, and in combination with interferon-
α
(Intron A
®
, as in Rebetron
®
) or pegylated
(PEG-INTRON
®
or Pegasys
®
) in the treatment of HCV infections.
Administered
: Orally at doses of 800-1200 mg/day, in the treatment of HCV infections; or by
aerosol (solution of 20 mg/mL), which has proved superior to placebo aerosol in the treatment of
RSV infections.
interferon-
α
24.6 CURRENT STATE OF THE ART
Almost 50 antiviral compounds (not including interferons or immunoglobulins) have momentarily
been licensed for the treatment of HIV, HBV, herpesvirus, inl uenza virus, and/or HCV infections. In
the preceding sections these compounds have been discussed from the following viewpoints: chemical
structure, activity spectrum, mechanism of action, principal clinical indication(s), route(s) of admin-
istration and dosage. Other points that need to be considered before the full clinical potential of any
given drug could be appreciated are: (1) duration of treatment, (2) single- versus multiple-drug therapy,
(3) pharmacokinetics, (4) drug interactions, (5) toxic side effects, and (6) development of resistance.
As to the duration of treatment, this may vary from a few days (HSV, VZV, inl uenza virus
infections) to several months or years (HIV, HBV, and HCV infections), depending on whether
we are dealing with an acute (primary [i.e., inl uenza] or recurrent [i.e., HSV, VZV]) infection or
chronic, persistent (i.e., HIV, HBV, and HCV) infection.
While the short-term treatment (5-7 days) of HSV, VZV, and inl uenza virus infections, and
even the more prolonged treatment of CMV infections, can be based on single-drug therapy, for
the long-term treatment of HIV infections a combination of several drugs in a triple-drug cocktail
(also referred to as HAART for “highly active antiretroviral therapy”) has become the standard
procedure. For HIV infection, this triple-drug combination therapy can now be given as a single,
once-daily oral pill, i.e., Atripla, containing three active ingredients: TDF, emtricitabine, and efa-
virenz (De Clercq, 2006b).
Pharmacokinetic parameters to be addressed, when evaluating the therapeutic potential, include
bioavailability (upon either topical, oral, or parenteral administration), plasma protein binding afi n-
ity, distribution through the organism (penetration into the CNS, when this is needed), metabolism
through the liver (i.e., cytochrome P-450 drug-metabolizing enzymes) and elimination through
the kidney. Particularly when concocting the multiple-drug combinations for the treatment of HIV
infection, possible drug-drug interactions should be taken into account: i.e., some compounds act as
P-450 inhibitors and others as P-450 inducers, and this may greatly inl uence the plasma drug levels
achieved, especially in the case of NNRTIs and PIs.
Toxic side effects, both short- and long-term, must be considered when the drugs have to be
administered for a prolonged period, as in the treatment of HIV infections. These side effects may
seriously compromise compliance (adherence to drug intake), and could, at least in part, be circum-
vented by reducing the pill burden to, ideally, once-daily dosing.
Finally, resistance development may be an important issue, again for those compounds that have
to be taken for a prolonged period, as is generally the case for most of the NRTIs, NNRTIs, and
PIs currently used in the treatment of HIV infections. Yet, the nucleoside phosphonate analogues
(NtRTIs) tenofovir and adefovir do not readily or rapidly lead to resistance development, even after
several years of therapy (as for HIV and HBV infections). Increasing resistance has been noted
with HBV against lamivudine after 1 or more years of treatment, but, even if resistant to lamivu-
dine, HBV infections remain amenable to treatment with adefovir dipivoxil. As has been occasion-
ally observed in immunosuppressed patients, HSV may develop resistance to acyclovir, and CMV
to ganciclovir, but, if based on ACV TK or CMV PK dei ciency, these resistant viruses remain
amenable to treatment with foscarnet and/or cidofovir. In immunocompetent patients, treated for
an acute or episodic HSV, VZV, or inl uenza virus infection, short-term therapy is unlikely to
engender any drug resistance problems.
