Interferons are cytokines (mediators of cell growth and func- tion). They are glycoproteins secreted by cells infected with viruses or foreign double-stranded DNA. They are non- antigenic and are active against a wide range of viruses, but unfortunately they are relatively species specific. Thus, it is necessary to produce human interferon to act on human cells.
Interferon production is triggered not only by viruses but also by tumour cells or previously encountered foreign antigens.
Interferons are important in immune regulation.
Four main types of interferon are recognized:
1. Interferon-α– known previously as leukocyte or lymphoblastoid interferon. Subspecies of the human αgene produce variants designated by the addition of a number, e.g. interferon-α2, or in the case of a mixture of proteins, by Nl, N2, etc. Two methods of commercial production have been developed and these are indicated byrbe(produced from bacteria – typically Escherichia coli– genetically modified by recombinant DNA technology) andlns(produced from cultured lymphoblasts stimulated by Sendai virus). Interferon-α2may also differ in the amino acids at positions 23 and 24 and these are shown by the addition of a letter. Thus, α-2a has Lys–His at these sites, while α-2b has Arg–His. It is not yet clear whether these different molecules have different therapeutic properties;
2. interferon-βfrom fibroblasts;
3. interferon-ωhas 60% homology with interferon-α;
4. interferon-γformerly called ‘immune’ interferon because it is produced by lymphocytes in response to antigens and mitogens.
Commercial production of interferon by cloning of human interferon genes into bacterial and yeast plasmids is now available, facilitating large-scale production.
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-α2b are used to treat Kaposi’s sarcoma in AIDS patients and interferon-α2b is 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 elimination t1/2 is 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 dipivoxil enters cells and is de-esterified to adefovir. Adefovir is 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 adefovir at 30–60% bioavailability. Adefovir is 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.
350 FUNGAL AND NON-HIVVIRAL INFECTIONS
Case history
A 35-year-old female with schizophrenia and insulin-dependent diabetes mellitus developed a severe oral Candidainfection. She was being treated with pimozide for her psychosis and combined glargine insulin with short-acting insulins at meal times. She was started on itraconazole, 100 mg daily, and after a few days her oropharyngeal symptoms were improving. About five days into the treatment, she was brought into a local hospital Accident and Emergency Department with torsades de pointes (polymorphic ventricular tachycar- dia) that was difficult to treat initially, but which eventually responded to administration of intravenous magnesium and direct current (DC) cardioversion. There was no evidence of an acute myocardial ischaemia/infarction on post-reversion or subsequent ECGs. The patient’s cardiac enzymes were not diagnostic of a myocardial infarction. Her electrolyte and magnesium concentrations measured immediately on admission were normal.
Question
What is the likely cause of this patient’s life-threatening dysrhythmia and how could this have been avoided?
Answer
In this case, the recent prescription of itraconazole and the serious cardiac event while the patient was on this drug are temporally linked. It is widely known that all azoles can inhibit CYP3A which happens to be the enzyme responsible for metabolizing pimozide. Pimozide has recently been found (like cisapride and terfenadine – now both removed from prescription) to cause pro- longation of the QT interval in humans in a concentration-dependent manner. Thus, there is an increased likelihood of a patient developing ventricular tachycardia (VT) if the concentrations of pimozide are increased, as occurs when its metabolism is inhibited by a drug (e.g. itraconazole) that inhibits hepatic CYP3A. This is exactly what happened here. Other common drugs whose concen- trations increase (with an attendant increase in their toxicity) if prescribed concurrently with azoles (which should be avoided) are listed in Table 45.4.
In this patient, the problem could have been avoided by either changing to an alternative anti-psychotic with least QTc prolong- ing properties (e.g. clozapine, quetiapine) prior to starting the azole or, if pimozide was such a necessary component of therapy, using a topical polyene, such as amphotericin or nystatin lozenges, to cure her oral Candida. Neither of these polyene antifungal agents inhibit CYP3A-mediated hepatic drug metabolism.
Table 45.4:Important interactions with azole antifungals
Drug or drug class Toxicity caused by azole-mediated reduced hepatic metabolism
Ciclosporin (and Tacrolimus-FK 506) Nephroxicity and seizures
Warfarin Haemorrhage
Benzodiazepines – alprazolam, triazolam Increased somnolence diazepam, etc.
HMG CoA reductase inhibitors (statins, Myositis and rhabdomyolysis except pravastatin)
Calcium channel blockers Hypotension
Sildenafil citrate (Viagra) Protracted hypotension
FURTHER READING
Albengeres E, Le Leouet H, Tillement JP. Systemic antifungal agents:
drug interactions and clinical significance. Drug Safety1998;18:
83–97.
Boucher HW, Groll AH, Chiou CC, Walsh TJ. Newer systemic antifun- gal agents: pharmacokinetics, safety and efficacy. Drugs2004;64:
1997–2020.
Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. New England Journal of Medicine1994;330: 263–72.
De Clercq E. Antiviral drugs in current clinical use. Journal of Clinical Virology2004;30: 115–33.
Francois IE, Aerts AM, Cammue BP, Thevissen K. Currently used antimycotics: spectrum, mode of action and resistance occurrence.
Current Drug Targets2005;6: 895–907.
McCullers JA. Antiviral therapy of influenza. Expert Opinion on Investigational Drugs2005;14: 305–12.
Key points
Anti-influenza and antiviral hepatitis agents
• Influenza virus is susceptible to neuraminidase inhibitors, oseltamivir/zanamivir.
• Neuraminidase inhibitors produce viral aggregation at cell surface and reduce respiratory spread of virus.
• Oseltamivir adverse effects mainly involve gastro- intestinal upsets.
• Interferon-alfa plus ribavirin is effective against chronic hepatitis B and C.
• Resistant hepatitis B or C: use lamivudine or adefovir dipiroxil.
●Introduction 351
●Immunopathogenesis of HIV-1 infection 351
●General principles for treating HIV-seropositive
individuals 352
●Anti-HIV drugs 353
●Opportunistic infections in HIV-1-seropositive patients 357
●Mycobacterium avium-intracellulare complex
therapy 359
●Antifungal therapy 359
●Anti-herpes virus therapy 359
CHAPTER 46