Chemotherapy of
Viral Infections
A virus is made up of a nucleic acid and nucleoproteins, which constitute
the core of viral particle.
This core is enclosed in a protein coat called capsid, which consists of
repeating, identical subunits termed as capsomeres.
Some viruses are, however, more complex and have additional outer lipid
containing coats.
DNA and RNA Viruses
DNA viruses: Herpes simplex virus (HSV), varicella zoster virus
(VZV), smallpox virus, hepatitis B virus (HBV), cytomegalovins (CMV)
and adenovirus
RNA viruses: Rabies virus, measles virus, mumps virus, rubella virus,
dengue virus, yellow fever virus, poliomyelitis virus, human
immunodeficiency virus (HIV), influenza virus and rotavirus
Most viruses survive outside the host cell only for a short time. After
penetration into the target cell, viral replication occurs in the following steps:
1. Uncoating of viral nucleic acid strands
2. Synthesis of early regulatory proteins
3. Replication of viral DNA/RNA
4. Synthesis of late structural proteins
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5. Coating and maturation of viral particle
6. Release from the target cell
Viruses cause cell injury by:
• Direct lysis resulting from viral replication
• Lysis induced by antiviral antibody and the complement system
• Cell-mediated immune mechanisms
• Transforming host cells which proliferate and produce tumours, e.g.
papilloma virus causing cervical cancer
Since the multiplication of a virus is heavily dependent on host cell
mechanisms, an effective antiviral agent must act intracellularly and
selectively.
Classification of Antiviral Drugs
1. Inhibitors of nucleic acid synthesis, e.g. idoxuri-dine, acyclovir,
ribavirin, trifluridine and azidothymidine (AZT)
Il. Inhibitors of attachment/penetration, e.g.
amantadine, rimantadine
Ill.Inhibitors of viral enzymes
i) Reverse transcriptase inhibitors, e.g. lamivudine
ii) Neuraminidase inhibitors, e.g. oseltamivir
iii) Protease inhibitors, e.g. lopinavir
IV. Immunological agents, e.g. interferon, gamma globulin and
monoclonal antibodies
ANTI-HERPES AND ANTI-CMV DRUGS
IDOXURIDINE (5-lodo-2' -Deoxyuridine): Thiscompound, related to
thymidine, acts by competing with it in the synthesis of DNA, and
prevents the utilisation of thymidine. The drug interferes with the
synthesis of host cellular DNA and, hence is too toxic for systemic use.
It has been employed locally as 0.5% drops or ointment in the treatment
of herpetic keratitis.
TRIFLURIDINE: This nucleoside analogue has been used as 0.5%
ophthalmic ointment to treat ocular herpes. It is less specific.
ACYCLOVIR: This guanosine analogue is a potent antiviral drug of low
toxicity.
Mechanism of action: The drug is phosphorylated by viral-specific
thymidine kinase to monophosphate derivative. Further phosphorylation
by host cell kinases leads to the formation of acyclovir triphos-phate,
which specifically inhibits virus induced DNA polymerase and thus
inhibits viral DNA synthesis.
The antiviral spectrum includes Herpes simplex virus (HSV) 1 and 2,
Varicella zoster virus (VZV) and Epstein-Barr virus (EBV). HSV and
VZV can develop resistance to acyclovir.
Absorption, fate and excretion: Given orally, it has a bioavailability of
15%-30%; the CSF level of the drug is 50% that of plasma. Hence,
for viral encephalitis it is given intravenously. Its t½ is 3 h. It is mostly
excreted unchanged in the urine; 15% is metabo-lised in the liver.
Adverse reactions: Locally, it may cause stinging and reversible
superficial keratopathy. Orally, the drug is generally well tolerated.
Given intravenously, it may cause headache, thrombophlebitis and
elevation of blood urea and creatinine (crystalline nephropathy). CNS
toxicity includes lethargy,tremors, abnormal EEG and hallucinations
(neuro-psychiatric reaction).
Preparations and dosage
i. Acyclovir tablets 200, 400, 800 mg. Dispersible tablets also
available. Dose 200-400 mg 4-5 times a day.
ii. IV infusion as lyophilized powder 250/500 mg or as solution
25/50 mg/ml. Dose 5-10 mg/kg over 1 h at 8 h interval.
iiiAcyclovir eye ointment 3%
iv.Acyclovir cream 5% for skin application
Indications:
• Herpes simplex virus infection:
a. Primary and recurrent genital infections: It is highly effective in an oral
dose of 200 mg 5 times a day for 7 days. Duration of therapy
increased if new lesions appear during treatment or if healing incomplete.
b. Gingivostomatitis and pharyngitis: also responds to above-mentioned
regime
Keratoconjunctivitis: It is used topically
Meningitis and encephalitis: Acyclovir IV is the treatment of choice
• Varicella zoster virus infection: VZV causes varicella (chicken pox) as
primary infection.
Reactivation of the virus, which remains latent in dorsal root ganglia,
results in herpes zoster.
DOCOSANOL: It is a saturated 22-carbon aliphatic alcohol and an
over-the-counter (OTC) product, available as 10% cream to be applied 5
times a day until healing. It is used for recurrent orolabial herpes simplex.
It blocks the fusion between cellular and viral envelope membranes and
thus inhibits viral replication.
FOSCARNET SODIUM: This drug, an inorganic pyrophosphate
compound, is given by IV infusion to treat CMV retinitis in patients with
AIDS. It has potent activity against HIV as well. It inhibits DNA
polymerase. It does not require activation by viral thymidine kinase and is
effective against acyclovir- and gancielovir-resistant strains. The drug
can cause GI toxicity, nephrotoxicity, anaemia and CNS distur-bances.
Hypocalcaemia, hypokalaemia and hypomas nesemia have also been
reported.
GANCICLOVIR: It is an acyclic nucleoside analogue of guanine with
action similar to that of acyclovir but has higher intracellular
concentration, which remains excreted unchanged in urine.
for 24 h. It is given orally or by IV infusion. It is ADR include GI
disturbances, myelosuppression and aspermatogenesis. CNS symptoms
include headache, behavioural changes and convulsions. It may also cause
liver and renal dysfunction. It is carcinogenic. teratogenic and mutagenic
in animals. Because of its toxicity, its use is limited to immunocompromised
host with serious cytomegalovirus (CMV) infection of the retina and colon.
Valganciclovir is a prodrug for ganciclovir.
CIDOFOVIR: This acyclic cytosine nucleotide has similar mechanism as
ganciclovir, but does not require viral enzymes for phosphorylation; hence,
it is active against resistant CMV and HSV. Its active metabolite
contributes to longer duration of action (intracellular t½ 17-65 h). Its CS
penetration is poor. The drug is eliminated by active renal tubular
secretion.
The drug causes dose dependent renal tubular nephropathy. The other
ADR include uveitis, iritis, ocular hypotony and neutropenia.
It is used intravenously for CMV retinitis.
FOMIVIRSEN, an oligonucleotide agent, is used intravenously for the
treatment of difficult cases of CMV retinitis.
SORIVUDINE is a pyrimidine nucleoside analogue which can be used
in both immunocompromised and immunocompetent patients with
herpes zoster infection.
ANTIHEPATITIS B DRUGS
Hepatitis B virus (HBV) infection is a global public health problem.
Treatment of acute infection is mainly with supportive therapy and not
with antiviral drugs. The therapy of chronic HBV infection depends on
factors like clinical presenta-tion, risk factors, immunological response,
the HBV viral load and genotype. The main goal of therapy is to improve
survival and quality of life by preventing disease progression, and
consequent development of hepatocellular carcinoma.
When the therapy is indicated, there are broadly two treatment options:
1. Nucleoside/nucleotide analogues (NA)
2. Pegylated interferon (IFN) alpha
LAMIVUDINE, an anti-HIV drug, has also been used for treating chronic
HBV infection .
ADEFOVIR is available as a prodrug, adefovir dipiv-oxil. It is
phosphorylated by cellular kinases to active form. It is effective against
HBV, HIV and herpes virus. It has prolonged intracellular t½ and is
administered once daily. It is excreted by kidneys and requires dose
adjustment in renal failure. It is neph-rotoxic. Other ADR include headache,
diarrhoea, asthenia, lactic acidosis and occasionally hepatic ste-atosis. It is
not a preferred drug because of associated ADR and emergence of viral
resistance.
ENTECAVIR is an orally administered guanosine nucleoside that
competitively inhibits HBV DNA polymerase. This reduces the
synthesis of HBV-DNA and its recycling for covalently closed circular
DNA (cccDNA) formation. This results in HBsAg loss.
Bioavailability is 100% but decreases with food. It is eliminated by
kidneys. The ADR include headache, fatigue, nausea, and dizziness. It
can cause drug interactions with drugs that compete for tubular
secretion.
TELBIVUDINE, a thymidine nucleoside analogue, with similar action
as entecavir, has bioavailability unaffected by food. It is widely
distributed and has no documented drug interactions. Adverse effects
are mild like fatigue, headache and GI intolerance.
Lactic acidosis, hepatic steatosis and peripher neuropathy may occur.
TENOFOVIR, an antiretroviral NRTI (Chapter S1 can be used for
chronic HBV infection. It shor netter activity than adefovir. It is useful
ami lamivudine and entecavir resistant organisme Tenofovir is
available as: 1. Tenofovir disoproxil s rate (TDF), 2. Tenofovir
alafenamide fumerate (TAP),
which is prodrug and claimed to have safer kidney and bone profile,
Mechanism of Action of Nucleoside/Nucleotide
Analogues (NA). HBV= Hepatitis B virus; dNTPs = Deoxyri-
bonucleotide triphosphates; cccDNA=covalently closed circular
DNA
ANTIHEPATITIS C DRUGS
Chronic hepatitis C virus (HCV) infection (with virus genotypes 1-6) is a
leading cause of liver cirrhosis and hepatocellular carcinoma. Use of
directly acting antivirals (DAA) orally for 8-12 weeks has improved the
virological response >95% for most genotypes and offered a good
tolerability.
Three nonstructural proteins in the genome of HCV (NS3/4A, NS5A,
and NSSB) play a role in HCV replication, and serve as targets for
drugs.
Classification of Directly Acting Antivirals
Drugs for HCV
I. NS3/4A Protease Inhibitors
Simeprevir, asunaprevir, paritaprevir, grazoprevir
II. NS5A inhibitors: Daclatasvir, ledipasvir, ombi-tasvir, elbasvir,
velpatasvir
III. NSSB RNA-dependent RNA polymerase inhibitors
a. Nucleoside/nucleotide analogues (NPIs):
Sofosbuvir
b. Non-nucleoside analogues (NNPIs): Dasabuvir
I. NS3/4A PROTEASE INHIBITORS
NS3/4A protease impairs induction of IN and thereby prevents viral
elimination by host cells.
NS3/4A protease inhibitors block the NS3 catalytic site or the
NS3/4A interaction. Inhibition of the NS3/4A protease enhances
host immunological response.
SIMEPREVIR: This second-generation NS3/4A protease inhibitor
is effective against HCV genotypes la and Ib. Simeprevir absorption is
increased with food. It is metabolised primarily by CYP3A and
excreted in faeces.
It is a weak inhibitor of intestinal CYP3A4 and P-glycoprotein,
Simeprevir is not recommended with ritonavir, efavirenz, nevirapine
and cyclo-sporine. No dose adjustment is required in renal and mild
hepatic impairment, but is contraindicated in moderate and severe
hepatic impair-ment.
The adverse effects reported when it is combined with RBV/IFN are
nausea, myalgia, rash, photosensitivity, pruritus and dyspnoea.
Other drugs, asunaprevir, paritaprevir, grazo-previr are similar to
simeprevir. All are administered orally with food. Asunaprevir is a
moderate inhibitor of CYP2D6 and weak inducer of CYP3A4 while
grazoprevir is a weak inhibitor of CYP3А. Paritaprevir is neither
enzyme inducer
II. NS5A INHIBITORS
These drugs inhibit both viral RNA replication and virion assembly by
binding to the NS5A (a replication regulator), causing structural
distortions that interfere with its functions. They are potent and
effective across all genotypes, but resistance can develop. The adverse
effect profile is variable.
DACLATASVIR: It is well absorbed orally. Fatty meal decreases its
bioavailability. It is highly bound to plasma protein (99%) and gets
metabolised primarily by CYP3A4 and eliminated in the faeces. Its t½
is about 13 hours.
Generally, daclatasvir is well tolerated. The most common ADR include
headache, fatigue, nausea and diarrhoea. Severe bradycardia has been
reported when it was co-administered with ami-odarone and sofosbuvir.
It is an inhibitor of P-glycoprotein and organic anion transporting
polypeptide. It is contraindicated with CYP 3A4 inducers like
phenytoin, carbamazepine and rifampicin, whereas a dose reduction is
recommended when it is used with CYP3A4 inhibitors.
No dosage adjustment is required for patients with renal or hepatic
impairment.
The other NS5A inhibitors, Ledipasvir and Vel-patasvir are available
only as a fixed-dose combination with sofosbuvir.
III.NS5B INHIBITORS
NSSB (RNA dependent RNA polymerase) has a catalytic site to
which nucleoside/nucleotide polymerase inhibitors (NPI) bind
causing chain termi-nation.
Non-nucleoside polymerase inhibitors
(NNPI) bind to other sites causing allosteric altera-tions. The
structure of this polymerase enzyme is common across all the CV
genotypes. Thus, the drugs that inhibit NS5B are effective against
all the six genotypes of HCV.
SOFOSBUVIR: This pyrimidine nucleotide analog is
phosphorylated within the cell and gets incorporated into the
growing viral RNA strand and terminates HCV RNA strand
synthesis prematurely.
Sofosbuvir is effective in combination with peglFN and RV. It is an
excellent alterative if IN therapy is contraindicated or stopped
because of adverse effects.
Sofosbuvir can be administrated with/without food. Following a
single 400 mg oral dose, 80% of the drug gets eliminated in the
urine. No dosage adjustments are recommended for hepatic or mild-
to-moderate renal impairment.
The most common ADRs are fatigue, headache, nausea, insomnia,
pruritus, irritability, anaemia, asthenia, and diarrhoea.
ANTI-INFLUENZA DRUGS
RIBAVIRIN (REV): This purine nucleoside analogue has a broad spectrum
antiviral activity against DNA and RNA viruses. It is administered orally or
by inhala rion. Aerosol therapy is generally well tolerated and it systemic
toxicity is less because of poor systemi absorption. It has been shown to be of
some use agains influenza A and B infections, respiratory syncytial vir (RSV)
infection, Lassa fever and hepatitis C.
Adverse reactions: It causes dose dependentanaemia,bone marrow
suppression, cardiac neurological toxicity. Ribavirin has been shown t be
teratogenic, mutagenic, embryotoxic and gonado toxic in small animals, and is
contraindicated ir preonancy A woman must avoid conception for morths
after cessation of ribavirin. Further, passive exposure to aerosolised ribavirin
should be avoidedby pregnant women.
AMANTADINE (1-Admantanamine hydrochlo-ride): This drug acts by
inhibiting uncoating of viral
RNA of influenza A virus within infected cells, thus inhibiting early step in
viral replication. Clinically it is useful in the prophylaxis and treatment of
influenza A, but not of influenza B. Its therapeutic useful-ness, however,
appears to be limited. To be effective, it must be administered within the first
24 48 h after the onset of symptoms.
The drug is administered orally in the dose of 100 mg once or twice daily for
5-7 days.
Adverse reactions: It causes anticholinergic effects (see Chapter 15). It can
also cause confusion, high headedness, slurred speech, insomnia, hallucina-
tions, urinary retention and skin rash.
RIMANTADINE: It has actions similar to those of amantadine but
is 4-10 times more active. It has a long t½ of 24-36 h. No
dosage adjustment is necessary in patients with renal impairment
except in those with end stage renal failure.
OSELTAMIVIR is a prodrug of oseltamivir carboxylate, the first orally
active, specific inhibitor of influenza neuraminidase. This enzyme cleaves
sialic acid residues on new virons to set them free from infected cells.
Oseltamivir, by inhibiting the enzyme, prevents release of progeny virions
and their spread to other cells.
It is effective against both types of influenza viruses including the avian
H5N1, swine origin HIN1 andH9N2 strains). Given orally in a dose of
75 mg b.i.d. within 36 h of onset of symptoms, it can decrease the
severity of influenza and reduces respiratory complications. The duration
of therapy is for 5 days.
For chemoprophylaxis, it can be administered 75 mg once a day for 7
days to contacts of patients within 48 h of the onset of symptoms.
Adverse reactions: The ADR include GI disturbances e.g. nausea,
vomiting, diarrhoea and abdominal pain.
It should be taken with food. Rarely, it may cause hepatitis, allergic rash,
toxic epidermal necrolysis, seizures, and confusion. In high risk pregnant
patient it may be preferred to zanamivir.
Is decreased in patients with renal damage to 30 mg b.i.d. or OD.
Peramivir, another potent viral neuraminidase inhibitor is available for IV
administration. Its efficacy and safety is comparable to oseltamivir.
Baloxavir, is an oral selective inhibitor of influenza capsid dependent
endonuclease. It blocks influenza proliferation by inhibiting the initiation of
mRNA synthesis. It is active against both, type A and type B influenza. It is
indicated for the treatment of acute uncomplicated influenza in patients, who
have been symptomatic for up to 2 days and for those at high risk of
developing influenza-related complications. It is also approved for post-
exposure prophylaxis of influenza.
INTERFERONS
Interferons (IFNs) are species specific cellular glyco-proteins, produced
naturally by virus-infected cells, and have antiviral protective action. They can
inter-fere with a wide variety of DNA and RNA viruses.
They are considered as potent, broad spectrum, antiviral compounds with a
high therapeutic ratio. The INs vary from species to species but each species
produces at least three types of IFNs:
• Alpha and Beta from nearly all cell types induced by viruses, double
stranded RNA and cytokines like II-1, II-2 and TNF.
• Gamma from immunologically stimulated T lymphocytes and NK cells.
Mechanism of action: IFNs act by binding to specific,
cell-surface receptors and inducing the production of new cellular RNA and
proteins, which in turn inhibit protein synthesis of viruses. They inhibit several
steps of viral reproduction. IFNs also act as an immune modulator, thus
increasing cytotoxic T lymphocyte activity, enhancing NK cell activity and
activating mac-rophages. IFNs have no effect on extracellular virus.
Adverse reactions: These include hypersensitivity reactions, fever, flu-
like syndrome, lethargy, myalgia, arthralgia and ocular
symptoms.Dose-related myelosuppression, nephrotoxicity and
hepatotoxic-ity have also been reported. Larger doses cause alo-pecia,
neurotoxicity, personality changes, depression, reversible hearing loss,
retinopathy, thyroid dysfunc-tion, azotaemia and impaired fertility.
Antibodies to INs can decrease their therapeutic effect.
Preparations and dosage:
• IN-alpha 2a and 2b are available as only pegylated IFN-alpha 2a
and 2b. They have prolonged absorption and reduced clearance
resulting into increased t½.
The higher and
more sustained plasma levels allow once weekly dosages. They are
administered subcutaneously as a single dose once a week.
• IEN-beta la: It is a glycosylated recombinant product from
mammalian cells available for IM or SC administration.
• Peginterferon-beta la: It is available as SC injection.
• IFN-beta Ib: It is a nonglycosylated recombinant product from
mammalian cells available for SC injection.
• IFN-gamma 1b: It is administered subcutane-ously.
• IFN-alpha n3: is available for intralesional administration of twice
weekly for a maximum of 8 weeks.
Indications:
• Chronic hepatitis B: Recombinant IFN-alpha 2b to prevent progressive
liver damage
• Chronic hepatitis C and D: All forms of IFNs
• Condyloma acuminata: Intralesional IFN-alpha
n3
• Hairy cell leukaemia: IFN-alpha 2a and 2b
• Chronic myelogenous leukaemia to induce remission: IFN-alpha 2a
• Kaposi sarcoma (in patients with HIV): IFN-alpha 2a and 2b
• Multiple sclerosis: IFN-beta la and Ib are currently recommended for
relapsing/remitting MS
• Chronic granulomatous disease and malig
nant osteopetrosis: IN gamma 1b
• All severe viral infections: IFNs are give
empirically.
Partially purified IFNs have shown. Antitumou effects in osteogenic
sarcoma, multiple myeloma lymphoma and breast cancer nodules.
GAMMA GLOBULIN: It prevents viral adsorption + and their
penetration into the target cell
T, topical; O, oral; IV intravenous; SC subcutaneous; CMV,
cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes
simplex virus.
