Antiviral chemotherapy

ANTIVIRAL CHEMOTHERAPY

12/22/2006

Most clinically useful antiviral agents exert their action on viral replication, either at stage of nucleic synthesis or at stage of late protein synthesis and processing.

With exception of Forscanate, all of drugs are active against herpes virus and against human immuno-deficiency virus (HIV) are antimetabolites with structural similarity to naturally occurring compounds

In order to interfere with viral nucleic synthesis or the late synthesis of viral proteins; they must first undergo conversion to active forms, usually triphoshate derivatives.

For example, drug such as Zidovudine (AZT) undergo phosphorylation by host kinase to form nucleotide analog that may inhibit viral DNA polymerase.

Selective toxicity results because viral DNA polymerase are more sensitive to inhibition by these antimetabolites than are mammalian polymerase.

One of the most important recent trends in antiviral chemotherapy has been the combination therapy.

With the combination therapy there is increase in effectiveness and prevention or delay of emergency of resistance.

The current approach to treatment of infection with H.I.V. is the initiation of treatment with two or three drugs if possible before symptoms appear.

When 3 drugs are used, the combination usually includes 2 inhibitors of reverse transcriptase plus an inhibitor of H.I.V. protease.

Such drug combination can slow or reverse the increase in viral RNA titers that accompany progression of disease

They may delay the emergence of resistant strain of H.I.V.

ANTIHERPES DRUGSACYCLOVIR ( ACYCLO-GUANOSINE)

Is a guanosine analog active against Herpes Simplex Virus (HSV) and Zoster Virus (VZV).

The drug is activated to form Acyclovir triphosphate, a competitive substrate for DNA polymerase leading to chain termination following its incorporation into viral DNA.

Resistant strains lack thymidine kinase; the enzyme involved in initial virus specific phosphorylation of Acyclovir

PHARMACOKINETICS Acyclovir can be administered by the topical, oral and

intravenous routes. Renal excretion is the major route of elimination

CLINICAL USE $ TOXICITY Oral Acyclovir is used for treatment of

mucoteneous and genital Herpes lesions. The oral drug is well tolerated but may cause

G.I.T. distress and headache I/V administration is used for severe Herpes

disease ( including encephalitis) and for neonatal HSV infection.

Toxic effects with parenteral administration include delirium, tremor, seizure, hypotension and nephrotoxicity.

ACYCLOVIR CNGENERSFAMCICLOVIR Is a pro-drug converted PENCICLOVIR by first pass

metabolism in the liver. Used orally in genital herpes and Herpes Zoster. Penciclovir also undergoes activation by Viral

thymidine kinase,and triphosphate form inhibits DNA polymerase but does not cause chain termination.

Valacyclovir is converted to Acyclovir by hepatic metabolism after oral administration and reaches plasma levels three to five times greater than those achieved by Acyclovir.

Valacyclovir has a longer duration of action than acyclovir but is otherwise identical.

FORSCANATE

It is a phosphono-formate derivate that does not require phosphorylation for anti-viral activity.

Though not anti-metabolite,Forscarnate inhibits viral Rna polymerase,DNA polymerase and H.I.V. reverse transcriptase.

PHARMACOKINETICS

Is given intravenously and penetrates well into tissues including CNS.

Up to one third of a dose may be deposited in the bone.

The drug undergoes renal elimination in direct proportion to Creatinine clearance.

CLINICAL USE & TOXICITY

The drug is used for prophylate and treatment of cytomegalo-Virus[CMV] infection…including CMV retinitis.

Forscarnet inhibits herpes DNA polymerase in Acyclovir resistant strains that are thymidine kinase deficient and may suppress such resistant Herpetic infections in patients with AIDS.

ADVERSE EFFECTS

Include nephrotoxicity with disturbance in electrolyte balance[especially calcium and phosphate];genito-urinary ulceration and CNS symptoms[headache,hallucinations,seizures].

GANCICLOVIR

A guanine derivate,is triphosphorylated to form nucleotide that inhibits DNA polymerase of CMV and HSV-infected cells.

PHARMACOKINETICS

Is usually given I/V and penetrates well into tissues,including the eye and CNS.

The drug undergoes renal elimination in direct proportion to creatinine clearance.

Although oral bioavailability is less than 10%;an oral formulation is available for maintenance therapy.

CLINICAL USE & TOXICITY

Used for the prophylaxis and treatment of CMV retinitis and other CMV infection in immunompromised patients.

Systemic toxic effects…include leucopenia;thrombocytopenia;mucositis;hepatic dysfunction and seizures.

CIDOFOVIR

Is activated exclusively by host cell-kinases and inhibits DNA polymerase of HSV;CMV,Adenovirus and papillomavirus.

Resistance is due to mutation in the DNA polymerase gene. The drug has been used by I/V and topical ant by intra-vitreal injection.

Cidofovir undergoes renal elimination in proportion to creatinine clearance.

CLINICAL USE

Effective in CMV retinitis; may be of value in mucocutaneous infection including those resistant to Acyclovir.

Nephrotoxicity is the major dose limiting toxicity.

ANTI-HIV AGENTSREVERSE TRANSCRIPTASE INHIBITORSZIDOVUDINE

Formerly called Azidothymidine. Is an anti-metabolite that requires

phosphorylation by host kinase to form nucleotide analog that inhibits reverse transcriptase and cause chain termination in viral DNA.

PHARMACOKINETICS

Zidovudine is active orally [with 60% bioavailability], and is distributed to most tissues; including CNS.

Elimination of the drug involves both hepatic metabolism to glucuronides and renal excretion.

Dosage reduction is necessary in ureamia patients and those with cirrhosis.

Plasma half-life… ranges from 1 to 3 hours.

CLINICAL USE

Zidovudine temporarily reduces mortality and morbidity in patients with AIDS and AIDS-related complex.

It also of value in prophylaxis against HIV infection through accidental needle sticks and against vertical transmission from mother to neonate.

TOXICITY

The primary toxicity is bone-marrow suppression leading to anaemia and neutropenia,which may require transfusion.

Others…Gastro-intestinal distress;thrombocytopenia;headache,myalgia;hepatitis;agitation and insomnia may occur.

DRUG INTERACTIONS

Drugs undergo hepatic glucuronidation,including acetaminophen,Benzodizepines;Cimetidine and sulphonamides may increase plasma levels of zidovudine.

Metabolism of Zidovudine may also be inhibited by Azole antifungals and Protease inhibitors.

Rifampicin increases clearance of zidovudine.

DIDANOSINE

It is an analoque of deoxyadenosine which is activated by host cell kinases to a triphosphate form that inhibits reverse transcriptase and cause chain termination.

PHARMACOKINETICS AND CLINICAL USE

Oral bioavailability of Didanosine is reduced by food and chelating agents.

The drug is eliminated by glomerular filtration and active tubular secretion.

TOXICITY

Pancreatitis is dose limiting and occurs more frequently in alcoholic patients and those with hyper-triglyceridemia.

Other adverse effects include peripheral neuropathy;diarrhoea;hepatic dysfunction;hyperuricaemia and CNS effects.

ZALCITABINE

MECHANISM…Is pyrimidine nucleotide and its mechanism of action is similar to Zidovudine.

PHARMACOKINETICS & CLINICAL USE

Its bioavailability is high following oral use. Dosage adjustment is needed in patients with

renal insufficiency. Dosage adjustment is needed in patients with

renal insufficiency.

TOXICITY

Dose dependent peripheral neuropathy is major adverse effect.

Others…Pancreatitis;oesaphageal ulceration,stomatitis and arthralgias.

LAMIVUDINE

Like other reverse transcriptase inhibitors; it requires activation by host cell kinases,and the drug is active against HIV-1 including strains resistant to Zidovudine.

The drug is also effective in hepatitis B.

PHARMACOKINETICS & CLINICAL USES

Lamuvidine is used orally in combination regimes with Zidovudine.

Dosage adjustment is needed in patients with renal insufficiency.

TOXICITY

Adverse effects of Lamuvidine are usually mild and include G.I.T.distress,headache,insomnia and fatique.

STAVUDINE

MECHANISM…Is a thymidine analog, its mechanism of inhibition of reverse transcriptase are similar to those of other reverse transcriptase inhibitors.

PHARMACOKINETICS

Stavudine has good oral bioavailability and penetrates most tissues including the CNS.

Dosage adjustment is needed in renal insufficiency.

TOXICITY

Peripheral neuropathy is dose limiting.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS:[NNRTI]

Bind directly to a site on viral reverse transcriptase that is near but is distinct from the binding site of reverse transcriptase inhibitors.

NNRTIs neither compete with nucleoside triphosphate nor require phosphorylation to be active, and they usually have specific action against HIV-1.

The binding of NNRTIs to enzymes active site result in blockade of RNA and DNA dependent polymerase activities.

NEVIRAPINE Oral bioavailability is excellent > 90% and is not food dependent. The

drug is highly lipophilic,approximately 60% protein bound, and achieves CSF levels which are 45% of those in plasma.

It is extensively metabolized by CYP3A P 450 isoform to hydroxylated metabolites and then excreted, primarily in the urine.

Single dose of Nevirapine [200 Mg] has recently been shown to be effective in the prevention of transmission of HIV from mother to newborn when administration to women at the onset of labour and followed by a 2 Mg/Kg oral dose given to neonates within 3 days.

Severe and life threatening skin rashes have occurred with or without rashes.

It induces CYP3A drug metabolism of itself co-administration result in a decrease in Indinivar,Ritinovair and Saquinavir levels as well as oral contraceptives.

Nevirapine levels may increase during co-administration with inhibitors CYP3A metabolism such as Cimetidine and macrolide agents.

ADVERSE EFFECTS

Severe and life-threatening skin rashes have occurred during Nevirapine therapy including Stevens-Johnson syndrome and toxic epidermal necrolysis…It occurs in 18 % of patients receiving the drug during the 1st month of therapy

Other adverse effects include headache, fatique, nausea, diarrhoea and increased serum amino transferase levels.

DELAVIRIDINE

Oral bioavailability is good ( 85 % ) but is reduced by antacids.

Extensive bound to plasma proteins ( 98 % ). CSF concentration average only 0.4 % of

those in plasma. Extensively metabolized to inactive

metabolites by the CYP3A and CYP2D6 P 450 enzymes. It also inhibits CYP3A and thus inhibits its own metabolism.

ADVERSE EFFECTS

Skin rashes ( 18 % ) Headache; fatique, nausea; diarrhoea and

increased serum amino transferase levels.

DRUG INTERACTIONS Delaviridine plasma concentrations are reduced in presence of

antacids, Didanosine, Phenytoin, Phenorbarbitone, Carbamazepine, Rifampicin, Nelfinavir and Saquinavir.

Concentrations are increased during co-administration with Clarithromycin; Indinavir; Nelfinavir; Saquinavir; Dapsone; Alprazolam; Midazolam; Triazolam; Nifedipine; Cispride; Quinidine; Warfarin and Ergot derivatives.

Co-administration of Delaviridine with Phenytoin; Phenorbarbitone; Carbamazepine and Rifampicinn is specifically not recommended.

Co-administration with antacids or Didanosine should be separated at least one hour.

Delaviridine has shown to be teratogenic in rats thus pregnancy should be avoided when taking Delaviridine.

EFAVIRENZ

It is given orally; once daily because of its plasma half-life ..approx 50 hours.

It is 99 % bound to plasma albumin and its CSF concentration is ~ 1 % of that in the plasma.

It is inactivated in the liver.

ADVERSE EFFECTS

The unwanted effects are relatively mild and consists mainly of CNS ( dizziness; confusion, dysphoria ), which resolve as therapy is continued.

Skin rashes occur in about 25 % of patients and gastro-intestinal disorders are experienced in 2 %..

Drug interactions could be a hazard and animal studies indicate that foetal abnormalities could occur.

PROTEASE INHIBITOR In HIV, the mRNA transcribed from the provirus is translated into

two biochemically inert polyproteins. A virus-specific protease then converts the polyproteins into

various structural and functional proteins by cleavage at appropriate positions.

Since this protease does not occur in the host, it is a good target for chemotherapeutic intervention.

HIV-specific protease inhibitors bind to the site where cleavage occurs, and their use, in combination with reverse transcriptase inhibitors, has transformed the therapy of AIDS. Examples are Saquinavir (SQV ), Nelfinavir (NFV ); Indinavir (IDV ); Ritonavir ( RTV ) and Amprenavir ( AMP ).

INDINAVIR

MECHANISM….Inhibits HIV-1 protease, an enzyme that cleavases viral precursor proteins and is critical to the production of mature infectious virions.

Resistance to Indinavir is mediated by multiple point mutations.

PHARMACOKINETICS

Oral biovailability is good except in presence of food.

Clearance is mainly via the liver, with about 10 % renal excretion.

TOXICITY

Nausea; diarrhoea; thrombocytopenia; hyper-bilirubinemia and nephro-lithiasis occur.

To reduce renal damage, it is important to maintain good hydration.

It is a substrate for and inhibitor of the cytochrome P 450 isoenzyme CYP3A4 and is implicated in drug interactions.

Serum levels of Indinavir are increased By Azole antifungals and decreased by Rifampicin.

RITONAVIR

MECHANISMS..of action and resistance are quite similar to those of Indinavir.

PHARMACOKINETICS

Oral biovailability is good, and the drug should be taken with meals.

Clearance is mainly via the liver and dosage reduction is necessary in patients with hepatic impairment.

TOXICITY Most common G.I.T. irritation and bitter taste. Paraesthesias and elevation of hepatic amino-

transferases and triglycerides in plasma also occur. DRUG INTERACTIONS:…Are of major concern. Drugs that inhibit the activity of cytochrome P 450

e.g. Erythromycin; Azole anti-fungals; Cimetidine etc..elevate serum levels of antiviral drugs.

Ritonavir inhibits the metabolism of a wide range of drugs including Dronabinol; Erythromycin; Ketoconazolee; Prednisolone; Rifampicin and Saquinavir.

SAQUINAVIR

Must be taken with meals to avoid gastro-intestinal distress and has only 4 % oral bioavailability.

The drug has additive or synergistic effects against HIV-1 when used in combination with Reverse transcriptase.

TOXICITY

Marked gastro-intestinal effects; also cause headache and neutropenia…Serum levels may be increased by ingestion of Ketoconazole; Ritonavir or grape-fruits.

NELFINAVIR

Has a higher absorption in fed state; is extensively protein bound (> 98 % ).

Undergoes metabolism by CYP3A and is excreted primarily in the faeces.

Plasma half-life is 3 to 5 hours,

ADVERSE EFFECTS

Diarrhoea and flatulence

DRUG INTERACTIONS Nelfinavir is both an inducer and inhibitor of the

CYP3A system…Multiple drug interactions. Nelfinavir’s AUC is increased by …Indinavir;

Ritonavir; Saquinavir, Delaviridine; Efavirenz; Ketoconazole…etc

Nelfinazir’s AUC is decreased by Rifampicin; Cabamazepine; Phenytoin ; Pheno barbitone …etc.

Nelfinavir increases the levels of Lamuvidine; Indinavir; Saquinavir; Amprenavir and Rifabutin.

Nelfinavir decreases the AUC of Zidovudine, Delaviridine and Ethinyl-oestradiol.

AMPRENAVIR

Rapidly absorbed from the gut. Can be taken with food or without food. High-fat meal may decrease absorption. Plasma half-life range from 7 to 10.6 hours.

ADVERSE EFFECTS

Nausea, vomiting; diarhoea; peri-oral paraesthesia…rash.

DRUG INTERACTIONS

It inhibits CYP3A4 enzyme activity. It can increase the serum levels of midazolam;

Triazolam; Ergotamine, Cisapride, Amiodarone; Warfarin; Tricyclic antidepressants; Lovastatin; Simstatavin and Sildenafil.

It serum concentration could be decreased by Rifampicin and Efavirenz.

Its serum concentration could be increased by Ritonavir

NEW PROTEASE INHIBITORS:(PI ) FOS-AMPRENAVIR:…Calcium phosphate ester

of Amprenavir with better solubility and resorption than the parent compound.

ATAZANAVIR…Is a once-daily Pi with favourable lipid profile and anti-viral potency which seems comparable to that of Nelfinavir.

TIPRANAVIR..First non- peptide PI and shows good efficacy against PI-resistant viruses..Oral bioavailability is not very good and it always require Ritonavir boosting.

MOZENAZIR….A cyclic PI with good solubility but with a short half-life ..3 daily doses required.

ENTRY INHIBITORS

There are 3 crucial steps for entry of HIV into CD4+ T cells-:

Binding of HIV to the CD4 receptor ( ‘attachment ‘- target for attachment inhibitors ).

Binding to co-receptors ( target of co-receptor antagonists)

Fusion of virus and cell ( target of fusion inhibitors )

ATTACHMENT INHIBITORS

Various compounds have been developed. BMS- 806 –‘ An early’ attachment inhibitor

binds to HIV gp 120 specifically and reversibly and so prevents the attachment of HIV to CD4+ T –lymphocyte.

CO-RECEPTOR ANTAGONISTS

SCH-C and SCH-D…are ccR5 receptor antagonists with oral bioavailability and potent in vitro activity against numerous HIV isolates.

FUSION INHIBITORS

T-20 ( Enfuvirtide, Fuzeon®…Large peptide, comprised of 36 AA and must therefore be given by S/C injection like Insulin.

It binds to an intermediate structure of HIV gp 41 protein; which appears during entry of HIV into the target cell i.e. during fusion.

RECOMMENDED ARV DRUGS IN TANZANIA: 1ST Line ARV combination regimen: (1) Zidovudine ( ZDV ) 300 Mg twice daily (NRTI ) (2) Lamuvidine ( 3TC ) 150 Mg twice daily (NRTI ) (3) Efavirenz ( EFV ) 600 Mg once daily. (NNRTI ) There is a combined Zidovudine + Lamivudine

Tablet= Combivir [ 300 Mg ZDV + 150 Mg 3TC ]

Second line combination in Tanzania

Didanosine (ddI ) 200 Mg bd for bodt weight greater >60Kg

125 Mg bd for body weight < 60 Kg Stavudine ( d4T ) 40 Mg bd for bw > 60 Kg 30 Mg bd for bw < 60 Kg Saqinavir 800 Mg tds ( to be taken with fatty

meal) Lopinavir 400 Mg bd ( where Saquinavir is

not indicated ) Abacavir (NRTI) 300 Mg bd ( where listed

NRTI listed are not indicated ).

ARV THEPAPY IN HIV PREGNANT WOMEN

Zidovudine 300 Mg bd Lamuvidine 150 Mg bd. Nevirapine 200 Mg od for the first two

weeks then 200 Mg twice daily.

RECOMMENDED PAEDIATRIC HAARTCOMBINATIONREGIMENS IN TANZANIA

FIRST LINE; Nevirapine 200 Mg / M2 ( not more than 400

Mg/ day ) given bd. Zidovudine 180 Mg/ M2 bd Lamuvidine 4 Mg/Kg bd. For children who can swallow capsules

replaca Nevirapine with Efavirenz capsules…14 Mg/Kg od.

SECOND LINE

Didanosine 30 Mg ( 90 to 150 mg/ M2) bd. Stavudine 1 Mg/Kg bd. Nelfinavir 20 to 30 / Kg tds.

MISCELLANEOUS ANTIVIRAL AGENTS

AMANTADINE & RIMANTIDINE: Inhibits the 1st steps in the replication of the

Influenza A and rubella viruses. These steps involve viral adsorption of the

host membrane, penetration into the cell via endocytosis and virus particle uncoating.

Also binds to a specific protein in the surface coat of the influenza virus to prevent fusion.

CLINICAL USES & TOXICITY

Drugs are prophylactic with 80 % efficacy against Influenza A virus infection.

They can reduce the duration of symptoms if given within 48 hours after contact.

TOXIC EFFECTS

Include G.I.T. irritation; dizziness; ataxia and slurred speech.

Rimantadine has activity equal to Amantadine but it has a longer half-life and require no dosage adjustment in renal failure.

INTERFERONS

Are glcoproteins produced in human leucocytes; fibroblasts and immune cells.

They exert multiple actions that affect viral RNA and DNA synthesis.

Interferons induce the formation of enzymes, including a protein-kinase that phosphorylates a factor that blocks peptide chain initiation, a phosphodiestrase that degrades terminal nucleotides of tRNA.

CLINICAL USES & TOXICITY

Approved for use in chronic hepatitis A and B infections; Kaposi’s sarcoma, papillomatosis and topically for genital warts.

Also to prevent Herpes Zoster virus dissemination in cancer patients.

TOXIC EFFECTS

Dose limiting neutropenia, G.I.T. irritation; fatique, mylagia, mental confusion and a reversible cardiomyopathy.

RIBAVIRIN

Precise antiviral mechanism is not known. The drug inhibits Guanosine triphosphate

formation prevents capping of viral mRNA and can block RNA dependent RNA polymerase.

CLINICAL USE & TOXICITY

Used in aerosol form for respiratory syncytical virus infections and may shorten the symptoms of Influenzae A and B infections.

Early I/V administration decrease mortality in lass fever and other viral haemorrhagic fevers…

Side effects according to route of administration

Aerosol route..conjunctival & bronchial irritation.

Systemic use…..Myelosuppression.