A Textbook of Clinical Pharmacology and Therapeutics

INTERFERONS ANDANTIVIRALHEPATITISTHERAPY 349

Uses

Interferon-αwhen combined with ribavirin(see above) pro-
vides effective therapy for chronic hepatitis C infection
(Chapter 34). Regular interferon-αis given three times a week
(orpegylated interferon-αis given once weekly) by subcuta-
neous injection, for 6–12 months. Interferon-βis of some bene-
fit in patients with relapsing multiple sclerosis. Interferon-αis
used to treat condylomata acuminata by intralesional injection.
All three interferons are used to treat hairy cell leukaemia.
Interferon-α2aandinterferon-α2bare used to treat Kaposi’s
sarcoma in AIDS patients and interferon-α2bis effective in
recurrent or metastatic renal cell carcinoma (Chapter 48).
Recombinantinterferon-γhas been used for the treatment of
chronic granulomatous disease. Interferon therapy is also bene-
ficial in chronic myelogenous leukaemia, multiple myeloma,
refractory lymphoma and metastatic melanoma.

Mechanism of action

Interferons bind to a common cell-membrane receptor, except
interferon-γ, which binds to its own receptor. Following recep-
tor binding, interferons activate the JAK-STAT signal transduc-
tion cascade and lead to nuclear translocation of a cellular
protein complex that binds to genes containing IFN-specific
response elements and stimulating synthesis of enzymes with
antiviral activity, namely 25-oligoadenylate synthetase (which
activates ribonuclease L, which preferentially cuts viral RNA); a
protein kinase activity (important in apoptosis) and a phospho-
diesterase that cleaves tRNA. The onset of these effects takes
several hours, but may then persist for days even after plasma
interferon concentrations become undetectable. Interferon also
increases the presentation of viral antigens in infected cells and
upregulates macrophage activation and T cell and natural killer
cell cytotoxicity, thereby increasing viral elimination. The inter-
feron concentrations needed to produce antiviral effects are
lower than those required for their antiproliferative effects.

Adverse effects

These include:

• fever, malaise, chills – an influenza-like syndrome, and
  neuropsychiatric symptoms similar to a postviral syndrome;


• lymphocytopenia and thrombocytopenia are reversible,
  and tolerance may occur after a week or so;


• anorexia and weight loss;


• alopecia;


• transient loss of higher cognitive functions, confusion,
  tremor and fits;


• transient hypotension or cardiac dysrhythmias;


• hypothyroidism.

Pharmacokinetics

Most clinical experience has been gained with interferon-α,
administered subcutaneously. Following subcutaneous admin-
istration, peak plasma concentrations occur at between four
and eight hours and decline over one to two days. The mean
eliminationt1/2is three to five hours. Polyethylene glycol

(PEG)-conjugated (PEG-ylated) interferons are now used clini-

cally, have protracted half-lives and may be administered

weekly. Elimination of interferons is complex. Inactivation

occurs in the liver, lung and kidney, but interferons are also

excreted in the urine.

ADEFOVIR DIPIVOXIL

Adefovir dipivoxilis a prodrug diester of adefovir, an acyclic

phosphonate nucleotide analogue of adenosine monophos-

phate. It is used in the treatment of chronic hepatitis B, espe-

cially if interferon-αtreatment has failed or is not tolerated. It

is given orally once a day until seroconversion occurs (or indef-

initely in patients with uncompensated liver disease or cirrho-

sis).Adefovir dipivoxilenters cells and is de-esterified to

adefovir. Adefoviris converted by cellular kinases to its

diphosphate which is a competitive inhibitor of viral DNA

polymerase and reverse transcriptase. Hepatitis B DNA poly-

merase has a higher affinity for the adefovir diphosphatethan

other cellular enzymes. Adverse effects include dose-related

reversible nephrotoxicity and tubular dysfunction, gastro-

intestinal upsets and headaches. It is genotoxic, nephrotoxic

and hepatotoxic at high doses. The parent compound has low

bioavailability, but the prodrug is rapidly absorbed and

hydrolysed by blood and gastro-intestinal hydrolases to yield

adefovirat 30–60% bioavailability. Adefoviris eliminated

unchanged by the kidney with a mean elimination t1/2of 5–7.5

hours. Dose reduction is needed in patients with renal dys-

function. Drugs that reduce renal function or compete with

tubular secretion may increase systemic drug exposure.

LAMIVUDINE (3-THIACYTIDINE)

Lamivudineis a nucleoside analogue reverse transcriptase/

DNA polymerase inhibitor. It is used as chronic oral therapy

for hepatitis B and HIV. Oral administration twice daily is well

tolerated in hepatitis B patients and the most common adverse

effects are worsening hepatic transaminases during and after

therapy (Chapter 46).

A number of newer oral nucleoside reverse transcriptase/

DNA polymerase inhibitors for hepatitis B are in late clinical

development.

IMMUNOGLOBULINS

For information related to immunoglobulins, see Chapter 50.

Key points

Non-HIV antiviral drugs

• Specific anti-CMV agents are ganciclovir (valganciclovir)
  and foscarnet.


• Both are active against aciclovir-resistant herpes viruses.


• Ganciclovir and foscarnet are best given intravenously,
  poorly or not absorbed orally, both are renally excreted.


• Valganciclovir is a prodrug ester of ganciclovir and
  yields 60% bioavailable ganciclovir with oral dosing.


• Ganciclovir (bone marrow suppression) and foscarnet
  (nephrotoxicity) are much more toxic than aciclovir.