Antiviral agents.

Introduction

Viruses present a more difficult problem of chemotherapy than do higher organisms, e.g.

bacteria, for they are intracellular parasites that use the metabolism of host cells. Highly selective

toxicity is, therefore, harder to achieve. In the past 15 years, identification of the molecular

differences between viral and human metabolism has led to the development of many effective

antiviral agents; four were available in 1990, now there are over 40.Antiviral agents are most

active when viruses are replicating. The earlier that treatment is given, therefore, the better the

result. Apart from primary infection, viral illness is often the consequence of reactivation of

latent virus in the body. Patients whose immune systems are compromised may suffer

particularly severe illness. Viruses are capable of developing resistance to antimicrobial drugs,

with similar implications for the individual patient, for the community and for drug development.

Take note: Anti-viral agents are classified according to the agents they are effective against

Agents for Herpes Simplex and Varicella -zoster

Prototype

Acyclovir

Pharmacodynamics: Acyclovir (t½ 3 h) inhibits viral DNA synthesis only after phosphorylation

by virus-specific thymidine kinase. This accounts for its high therapeutic index. Phosphorylated

acyclovir inhibits DNA polymerase and so prevents viral DNA being formed. It is effective

against susceptible herpes viruses if started early in the course of infection, but it does not

eradicate persistent infection because viral DNA is integrated in the host genome.

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Pharmacokinetics: About 20% is absorbed from the gut, but this is sufficient for oral systemic

treatment of some infections. It distributes widely in the body; the concentration in CSF is

approximately half that of plasma and the brain concentration may be even lower. These

differences are taken into account in dosing for viral encephalitis (for which acyclovir must be

given IV). The drug is excreted in the urine unchanged and as such caution should be taken in

patients with renal impairment. For oral and topical use the drug is given five times daily.

Indications: Herpes simplex virus. Both genital and labial and disseminated encephalitis. In

encephalitis, give it IV. Acyclovir-resistant herpes simplex virus has been reported in patients

with AIDS; foscarnet and cidofovir have been used instead. Varicella-zoster virus: i.e. chicken

pox and shingles. In immune compromised patients, give I.V.

Adverse reactions: -The ophthalmic ointment causes a mild transient stinging sensation. Oral or

i.e. use may cause gastrointestinal symptoms, headache and neuropsychiatric reactions.

-Extravasations with i.v. use cause severe local inflammation. Other drugs used include:

Valacyclovir a pro-drug (ester) of acyclovir, i.e. after oral administration the parent acyclovir is

released. The higher bioavailability of valaciclovir (about 60%) allows dosing only 8-hourly. It is

used for treating herpes zoster infections and herpes simplex infections of the skin and mucous

membranes. Famciclovir (t½ 2 h) is a pro-drug of penciclovir, which is similar to acyclovir; it is

used for herpes zoster and genital herpes simplex infections, and a single dose is effective at

reducing the time to healing of labial herpes simplex. It need be given only 8-hourly. Penciclovir

is also available as a cream for treatment of labial herpes simplex.

Agents used in AIDS/HIV infection

Introduction

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We are going to have a fairly long introduction because of the significance of this disease to the

Kenyan population.

The HIV virus attacks the helper T cells within the immune system. It enters the helper T cell

and begins to multiply within the cell. When the cell raptures, many more viruses are released to

attack other T helper cells. This results in destruction of the immune system and leads to

opportunistic infections to include viral infections, some cancers, among others. Some drugs

called antiretroviral (ARV’s) are available to treat HIV infection. The goal of ARV therapy is to

delay disease progression, and prolong survival by suppressing the replication of the virus.

Optimal suppression prevents emergence of drug resistance, reduces risk of transmitting the

virus to one’s sexual partner or to unborn children of HIV mothers. Virological failure is defined

as the inability to reduce plasma HIV viral load to fewer than 400 copies per microliter after 24

weeks, or fewer than 50 copies by 48 weeks. No current antiviral agents or combinations

eliminate HIV infection, but the most effective combinations (so-called 'highly active

antiretroviral therapy', HAART) produce profound suppression of viral replication in many

patients and allow useful reconstitution of the immune system, measured by a fall in the plasma

viral load and an increase in the numbers of Helper T cells. (CD4 count). Rates of opportunistic

infections are reduced when CD4 counts are restored, and life expectancy is markedly increased.

Efficacy of viral suppression comes at the cost of unwanted effects from the multiple drugs used.

Combination therapy reduces the risks of emergence of resistance to antiretroviral drugs, which

is increasing in incidence even in patients newly diagnosed with HIV. Currently two types of

antiretroviral combination are generally recommended for initial HIV therapy. A non-nucleoside

reverse transcriptase inhibitor plus two nucleoside analogue reverse transcriptase inhibitors. In

this country, this is our first line course. A ritonavir-boosted protease inhibitor plus two

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nucleoside analogue reverse transcriptase inhibitors. This is our second line of drugs currently.

Protease inhibitors are preserved for second line. The decision to begin antiretroviral therapy is

based on: the CD4 cell count (most current recommendations are to start in patients with counts

below 250 cells per microliter, and for pregnant women, treat those with counts below 350 cells

per microliter to reduce the risk of vertical transmission. Secondly, those with rapidly falling

counts or are in stage four according to WHO classifications regardless of their CD4 count.

Thirdly, the plasma viral load (especially if over 100 000 viral genome copies per mL).

Alternative combinations are used if these variables deteriorate or unwanted drug effects occur.

Antiretroviral resistance testing, both genetic (by searching viral RNA for sequences coding for

resistance) and phenotypic (by testing antiretroviral agents against the patient's virus in cell

culture), also guide the choice of drug regimen, especially after Virological failure. Pregnancy

and breast-feeding pose special problems. The objectives of therapy are to minimize drug

toxicity to the fetus while reducing the maternal viral load and the risk of HIV transmission to

the neonate. Prevention of maternal-fetal and maternal-infant spread is the most cost-effective

way of using antiretroviral drugs and available regimens reduce transmission to less than

10% .Combination antiretroviral therapy, especially the thymidine nucleoside analogue reverse

transcriptase inhibitors Zidovudine and stavudine, cause redistribution of body fat in some

patients, the 'lipodystrophy syndrome'. Protease inhibitors can disturb lipid and glucose

metabolism to a degree that warrants a change to drugs with limited effects on lipid metabolism,

e.g. ritonavir-boosted atazanavir, and the introduction of lipid-lowering agents. Improvement in

immune function as a result of antiretroviral treatment may provoke an inflammatory reaction

against residual opportunistic organisms. This is called the immune reconstitution

syndrome.Antiretroviral drugs may also be used in combination to reduce the risks of infection

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with HIV from injuries, e.g. from HIV-contaminated needles. The decision to offer such post-

exposure prophylaxis (PEP), and the optimal combination of drugs used, is as per the national

guidelines. Administration must begin within a few hours of the injury, i.e. within 72 hours.

Let us now examine the classification of these drugs

Nucleoside reverse transcriptase inhibitors

These drugs include; Zalcitabine, Lamivudine, Abacavir, Tenofovir, Didanosine, Atazanavir, and

Zidovudine.

Prototype:

Zidovudine

Pharmacodynamics: The HIV replicates by converting its single-stranded RNA into double-

stranded DNA, which is incorporated into host DNA; this crucial conversion, which is the

reverse of the normal cellular transcription of nucleic acids, is accomplished by the enzyme

reverse transcriptase. Zidovudine has a high affinity for reverse transcriptase and is integrated by

it into the viral DNA chain, causing premature chain termination. The drug must be present

continuously to prevent viral integration to the host DNA, which is permanent once it occurs.

Pharmacokinetic: Zidovudine is well absorbed from the gastrointestinal tract (it is available as

capsules and syrup) and is rapidly cleared from the plasma (t½ 1 h); concentrations in

cerebrospinal fluid (CSF) are approximately half of those in plasma. Zidovudine is also available

i.v. for patients temporarily unable to take oral medications. The drug is inactivated mainly by

metabolism, but 20% is excreted unchanged by the kidney.

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Indications: Zidovudine is indicated for serious manifestations of HIV infection in patients with

acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, i.e. those with

opportunistic infection, or neurological symptoms, or with low CD4 counts; treatment reduces

the frequency of opportunistic infections and prolongs survival when used in effective

combinations.

Adverse reactions: Adverse reactions early in treatment may include anorexia, nausea,

vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually

the dose does not need to be altered. More serious are anemia and neutropenia, which develop

more commonly when the dose is high, with advanced disease, and in combination with

ganciclovir, interferon-α and other marrow suppressive agents. A toxic myopathy (not easily

distinguishable from HIV-associated myopathy) may develop with long-term use. Rarely, a

syndrome of hepatic necrosis with lactic acidosis may occur with Zidovudine (and with other

reverse transcriptase inhibitors).

Didanosine

Didanosine (ddI) has a short plasma half-life (t½ 1 h) but a much longer intracellular duration

than Zidovudine, and thus prolonged antiretroviral activity. Didanosine is rapidly but

incompletely absorbed from the gastrointestinal tract and is widely distributed in body water; 30-

65% is recovered unchanged in the urine. Didanosine may cause pancreatitis with an incidence

of 7% at a dose of 500 mg/day; a reduced dose may be tolerated after symptoms have resolved.

Other adverse effects include peripheral neuropathy, Hyperuricaemia and Diarrhoea, any of

which may give reason to reduce the dose or discontinue the drug. Didanosine is administered

with a buffer that reduces gastric acidity, and this impairs absorption of a number of drugs

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frequently used in patients with AIDS including dapsone, ketoconazole, quinolones and

indinavir.

Lamivudine

Lamivudine (3TC) is a reverse transcriptase inhibitor with a relatively long intracellular half-life

(14 h; plasma t½ 6 h). In combination with zidovudine, lamivudine appears to reduce viral load

effectively and to be well tolerated, although bone marrow suppression may be produced. Rarely,

pancreatitis may occur. The drug is excreted mainly by the kidney, and dose modification is

necessary in renal impairment. Lamivudine was the first nucleoside analogue to be licensed for

therapy of chronic hepatitis B infection, for which it is sometimes used in combination with

interferon .Emergence of resistant mutants of hepatitis B is troublesome (due to mutations of the

viral reverse transcriptase/DNA polymerase), occurring in up to about 30% patients after 1 year

and 70% after 5 years of therapy.

Abacavir

Abacavir (t½ 2 h) has high therapeutic efficacy; it is usually well tolerated, but adverse effects

include hypersensitivity reactions especially during the first 6 weeks of therapy, affecting about

5% of patients; the drug must be stopped immediately and avoided in future if hypersensitivity is

suspected.

Stavudine

Stavudine (d4T) inhibits reverse transcriptase by competing with the natural substrate

deoxythymidine triphosphate, and additionally is incorporated into viral DNA causing

termination of chain elongation (t½ 1.5 h). Troublesome lipoatrophy has limited its use by most

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authorities outside the developing world. Hepatic toxicity and pancreatitis are reported, and a

dose-related peripheral neuropathy may occur, all probably related to mitochondrial toxicity.

PROTEASE INHIBITORS

Pharmacodynamics

In its process of replication, HIV produces protein and also a protease, which cleaves the protein

into component parts that are subsequently reassembled into virus particles; protease inhibitors

disrupt this essential process.

Protease inhibitors reduce viral RNA concentration ('viral load'), increase the CD4 count and

improve survival when used in combination with other agents.

Pharmacokinetics

They are metabolized extensively by isoenzymes of the Cytochrome P450 system, notably by

CYP 3A4, and most protease inhibitors inhibit these enzymes. They have a plasma t½ of 2-4 h,

except for fosamprenavir (8 h) and atazanavir (7 h with food). The drugs have broadly similar

therapeutic effects. Members of the group include: amprenavir, atazanavir, fosamprenavir (a

prodrug of amprenavir), indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir

Adverse effects include gastrointestinal disturbance, headache, dizziness, sleep disturbance,

raised liver enzymes, neutropenia, pancreatitis and rashes.

Others are abnormal distribution of fat, like central obesity, peripheral and facial wasting, breast

enlargement etc.

Their use is associated with concurrent rise in triglycerides and LDL cholesterol.

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They are also associated with glucose intolerance and insulin resistance.

Interactions

Involvement with the cytochrome P450 system provides scope for numerous drug-drug

interactions. Agents that induce P450 enzymes, e.g. rifampicin, St John's Wort, accelerate their

metabolism, reducing plasma concentration and therapeutic efficacy; enzyme inhibitors, e.g.

ketoconazole, cimetidine, raise their plasma concentration with risk of toxicity.

The powerful inhibiting effect of ritonavir on CYP 3A4 and CYP 2D6 is harnessed usefully by

its combination in low (subtherapeutic) dose with lopinavir; the result is to decrease the

metabolism and increase the therapeutic efficacy of the latter (called ritonavir 'boosting' or

'potentiation'), i.e. a beneficial drug-drug interaction. The effect appears more advantageous in

patients infected with low-level resistant virus. Ritonavir also inhibits the metabolism and

increases the persistence in plasma of amprenavir, atazanavir, indinavir, lopinavir, saquinavir

and tipranavir.

Prototype

Lopinavir-Ritonavir(Kaletra)

Lopinavir100/ritonavir400 is a combination in which sub therapeutic doses of ritonavir inhibit

theCYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to

lopinavir .The mechanism of action is the same as for other protease inhibitors.

Pharmacokinetics.

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Absorption is enhanced with food. The oral solution contains alcohol. Lopinavir is extensively

metabolized by the CYP3A isoenzyme of the hepatic cytochromep450 system which is inhibited

by ritonavir.

Serum levels of lopinavir may be increased in patients with hepatic impairment.

Adverse effects

They include diarrhoea, abdominal pain, nausea and vomiting.

Interactions

Effavirenz and Nevirapine induces lopinavir metabolism. Thus dosage of lopinavir should be

increased.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Pharmacodynamics

This group is structurally different from the reverse transcriptase inhibitors; members are active

against the subtype HIV-1 but not HIV-2, a subtype encountered mainly in Africa. They bind

directly to HIV reverse transcriptase, blocking both RNA and DNA polymerase activities. They

prevent transfer of information that would allow the virus to replicate.

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Pharmacokinetics

Most have good oral bioavailability.

Non-nucleoside reverse transcriptase inhibitors tend to be inducers of CYP 450 enzymes.

Adverse effects.

GIT intolerance.

Skin rash, which may infrequently be serious (e.g. Stevens-Johnson syndrome.)

Interactions.

They are metabolized by the Cytochrome p450 enzyme system and have potential for many

drug-drug interactions.

Prototype

Effavirenz

Pharmacokinetics

Effavirenz is taken once per day (t½ 52 h).It is moderately well absorbed following oral

administration.(45%).Since toxicity may increase following increased bioavailability after a

heavy meal, it is normally taken with an empty stomach. Peak plasma concentrations normally

occur at3-5hrs after administration of daily doses. Steady state plasma concentrations are reached

after 6-10 days. It is principally metabolized by CYP3A4to inactive hydroxylated metabolites,

the remainde is excreted in faeces as unchanged drug. It is 99% bound to plasma proteins.

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Adverse effects

Rash is relatively common during the first 2 weeks of therapy, but resolution usually occurs

within a further 2 weeks; the drug should be stopped if the rash is severe or if there is blistering,

desquamation, mucosal involvement or fever.

Neurological adverse reactions e.g. dizziness, drowsiness, nightmares, insomnia, etc. occur in

about 50% patients and may be reduced by taking the drug before retiring at night;

gastrointestinal side-effects, and occasional hepatitis and pancreatitis, have also been reported.

Effavirenz is teratogenic, so should be avoided in pregnancy.

Nevirapine is used in combination with at least two other antiretroviral drugs, usually for

progressive or advanced HIV infection, although it also appears to be effective

relatively safe in pregnancy. It penetrates the CSF well, and undergoes hepatic metabolism (t½ 28

h); it induces its own metabolism and the dose should be increased gradually. Nevirapine is taken

once daily, increasing to twice daily if rash is not seen. Rash (including Stevens-Johnson

syndrome) and occasionally fatal hepatitis are the commonest unwanted effects.

Delavirdine (t½ 6 h) is administered thrice daily; rash is the commonest adverse effect, generally

appearing within the first month of therapy and disappearing over a 2-week period, during which

the drug usually does not need to be discontinued

ENTRY INHIBITOR (Fusion inhibitor)

Enfuvirtide is the first antiretroviral agent to target the host cell attachment/entry stage in the

HIV replication cycle.

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Pharmacodynamics;

The linear 36-amino acid synthetic peptide inhibits fusion of the cellular and viral membranes.

Pharmacokinetics

It is given by s.c. injection (t½ 4 h). The drug seems most effective when combined with several

antiretroviral agents to which the virus is susceptible, and in patients whose CD4 counts are

above 100 cells per microlitre

Adverse effects are usually limited to mild injection-site reactions, although hypersensitivity,

peripheral neuropathy and other adverse reactions are reported rarely. HIV isolates with

decreased susceptibility have been recovered from Enfuvirtide-treated patients; these exhibit

mutations in the gp41 outer envelope glycoprotein of the virus (which plays a key role in

infection of CD4 cells by fusing the HIV envelope with the host cell membrane).

Interactions; No interactions have been noted so far.

1. AGENTS FOR TREATING INFLUENZA A VIRUS.

Prototype is amantadine.

(amantadine is not recommended for therapy or prophylaxis of avian influenza)

Amantadine

Amantadine is effective only against influenza A.

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Pharmacodynamics.

it acts by interfering with the uncoating and release of viral genome into the host cell.

Pharmacokinetics

It is well absorbed from the gastrointestinal tract and is eliminated in the urine (t½ 3 h).

Amantadine may be used orally for the prevention and treatment of infection with influenza A

virus: if commenced within 48 h of the onset of symptoms, it reduces the duration of symptoms

by an average of 1 day. Those most likely to benefit include the debilitated, persons with

respiratory disability or those living in crowded conditions, especially during an influenza

epidemic. Amantadine reduces the risk of acquiring influenza A by 70-90% if started before

exposure. Natural resistance is very rare, but may emerge on treatment, and the resistant virus is

fully pathogenic and transmissible; it remains susceptible to oseltamivir and zanamivir.

Adverse reactions include dizziness, nervousness, lightheadedness and insomnia. Drowsiness,

hallucinations, delirium and coma may occur in patients with impaired renal function.

Convulsions may be induced, and amantadine should be avoided in epileptic patients.

2. AGENTS FOR CYTOMEGALOVIRUS

Ganciclovir

Ganciclovir resembles acyclovir in its mode of action, but is much more toxic.

Pharmacokinetics

It is given orally or i.v. and is eliminated in the urine, mainly unchanged (t½ 4 h).

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Uses

Ganciclovir is active against several types of virus but toxicity limits its i.v. use to life- or sight-

threatening CMV infection in immunocompromised patients. A ganciclovir-releasing intraocular

implant is more effective than i.v. ganciclovir for CMV retinitis and avoids systemic toxicity. It

is given by mouth for maintenance suppressive treatment of retinitis in patients with AIDS, and

to prevent CMV disease in patients receiving immunosuppressive therapy following organ

transplantation (especially liver transplants

Ganciclovir-resistant CMV isolates have been reported, and require treatment with foscarnet or

cidofovir)

Adverse reactions include neutropenia and thrombocytopenia, which are usually but not always

reversible. Concomitant use of potential marrow-depressant drugs, e.g. co-trimoxazole,

amphotericin B, azathioprine, zidovudine, should be avoided, and co-administration of

granulocyte colony-stimulating factor may ameliorate the myelosuppressive effects. Other

reactions are fever, rash, gastrointestinal symptoms, confusion and seizure (the last especially

when imipenem is co-administered).

Valganciclovir is an oral prodrug of Ganciclovir that provides systemic concentrations almost as

high as those following i.v. therapy

Foscarnet

Foscarnet finds use i.v. for CMV retinitis in patients with HIV infection when ganciclovir is

contraindicated, and for acyclovir-resistant herpes simplex virus infection (see p. 225). It is

15
generally less well tolerated than ganciclovir; adverse effects include renal toxicity (usually

reversible), nausea and vomiting, neurological reactions and marrow suppression.

Hypocalcaemia is seen especially when foscarnet is given with pentamidine, e.g. during

treatment of multiple infections in patients with AIDS.

Cidofovir

Cidofovir is given by i.v. infusion (usually every 1-2 weeks) for CMV retinitis in patients with

AIDS when other drugs are unsuitable or resistance is a problem. It has also been used i.v. and

topically to produce resolution of molluscum contagiosum skin lesions in immunosuppressed

patients and it may be effective in other poxvirus infections. Nephrotoxicity is common with i.v.

use, but is reduced by hydration with i.v. fluids before each dose and co-administration with

probenecid. Other unwanted effects include bone marrow suppression, nausea and vomiting, and

iritis and uveitis, and cause about 25% patients to discontinue therapy.

3. RESPIRATORY SYNCYTIAL VIRUS (RSV)

Ribavirin (Tribavirin) is a synthetic nucleoside used for RSV bronchiolitis in infants and

children, inhaled by a special ventilator. As therapeutic efficacy for this indication is

controversial, it is usually reserved for the most severe cases and those with co-existing illnesses,

such as immunosuppression.

Pharmacokinetics

Systemic absorption by the inhalational route is negligible.

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Ribavirin is effective by mouth (t½ 45 h) for reducing mortality from Lassa fever and hantavirus

infection (possibly also other viral haemorrhagic fevers and West Nile virus) and, when

combined with interferon α-2b or peg-interferon, for chronic hepatitis C infection (see below). It

does not cross the blood-brain barrier, so is unlikely to be effective in viral encephalitis.

Adverse effects

Systemic Ribavirin is an important teratogen, and it may cause cardiac, haematological,

gastrointestinal and neurological adverse effects

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