Antiviral agents

⚫ What do you know about

viruses??
Viruses

⚫ Viruses - no cell wall and made up of nucleic

acid components

⚫ Viruses containing envelope – antigenic in

nature

⚫ Viruses - obligate intracellular parasite

⚫ NO metabolic machinery of their own – uses

host enzymes for nutrition and division
⚫ Multiplication: Nucleus / cytoplasm

⚫ Most multiplication take place before

diagnosis is made

⚫ Undergo mutations – develop resistance

⚫ Virus specific enzymes and multiplication

steps – targets of antiviral agents
⚫ Why do you think treatment
of viral infections is difficult?
Stages of viral replication
⚫ Whatare the possible sites
where antiviral drugs can act?
Anti-Viral drugs

⚫ Many antiviral drugs are Purine or Pyrimidine

analogs

⚫ Usually Prodrugs – need phosphorylation

by viral or cellular enzymes in order to
become active

⚫ Effective Host Immune Response

Antivirus agents

⚫ Anti-Herpes virus - Inhibit Nucleic acid synthesis

⚫ Anti-Influenza virus

⚫ Anti-Hepatitis B virus

⚫ Nonselective antivirals - Act through

immune mechanism
⚫ Anti-retroviral agents
Herpes infection
What are the common clinical
presentations of herpes infection??
Genital herpes
Antiherpes virus agents

⚫ Acyclovir
⚫ Valacyclovir
⚫ Famciclovir
⚫ Ganciclovir
⚫ Foscarnet
⚫ Fomivirsen: Resistant CMV
⚫ Idoxuridine, Trifluridine, Vidarabine (Topical)
Acyclovir and congeners

⚫ Valaciclovir is a prodrug of Acyclovir with better

bioavailability

⚫ Famciclovir is hydrolyzed to Penciclovir and has

greatest bioavailability

⚫ Penciclovir is used only topically whereas

Famciclovir can be administered orally

⚫ Foscarnet – non-nucleoside drug

Antiviral spectrum

⚫ Acyclovir: HSV-1, HSV-2, VZV, EBV

⚫ Ganciclovir / Cidofovir : CMV
(immunocompromised)
⚫ Famciclovir : Herpes genitalis, Weak against HBV
⚫ Foscarnet : HSV, VZV, CMV, HIV
⚫ Penciclovir : Herpes labialis
⚫ Trifluridine : Herpetic keratoconjunctivitis
Acyclovir MOA
Mechanism of action

⚫ Phosphorylation by a viral thymidine-kinase

followed by host cell kinase – Active form

⚫ Inhibits viral DNA-polymerase

⚫ Only actively replicating viruses

⚫ What is good characteristic
of acyclovir?
Acyclovir

⚫ Acyclovir - selectively activated in infected cells

with herpes virus

⚫ Low toxicity – TI = hundred folds

Pharmacokinetics

⚫ Oral bioavailability ~ 20-30%

⚫ Wide Distribution
⚫ Renal excretion: > 80%
⚫ Half lives: 2-5 hours (5 times a day)
⚫ Administration: Topical: 3%,5%,
Oral: 200 mg 5 times/day X 7 days,
IV: 250 mg /ml – meningitis, etc
Adverse effects
⚫ Orally - Nausea, headache, CNS effects

⚫ Topically – stinging, burning

⚫ IV – rashes, sweating, fall in BP, thrombophlebitis

⚫ Nephrotoxicity – crystalluria, haematuria, renal

insufficiency (Foscarnet)

⚫ CNS – tremors, disorientation, hallucinations, convulsions

⚫ Myelosuppression – Neutropenia and thrombocytopenia

(Ganciclovir)
Herpes infections

⚫ Genital (Type II)

⚫ Muco-cutaneous
⚫ Encephalitis, Meningitis
⚫ Keratitis (Type I)
⚫ Herpes zoster
Therapeutic uses

⚫ HSV Genital infections (II) – 400 mg TDS x 10 days

⚫ HSV encephalitis – i.v. then oral therapy

⚫ Mucocutaneous infn (I) – 5% local + systemic

⚫ HS keratitis – 3% oint. 5 times till 3 days after healing

⚫ Chickenpox – immunodeficiency and neonates,

15mg/kg/day i.v. x 7 days
⚫ Herpes zoster: 800 mg 5 times/ day x 10
days
⚫ VZV, Herpes Zoster – immunocompromised
individuals – I.V. acyclovir

⚫ Prophylaxis
⚫ Docosanol - 10 % cream
Cidofovir

• Cytosine analogue – no phosphorylation

• CMV retinitis, molluscum contagiosum in

immunocompromised patients – 5 mg/kg I.V.
weekly

• Nephrotoxicity : Probenecid, prehydration

Foscarnet (Reserved drug)

 An inorganic pyrophosphate analogue

 Directly inhibits viral DNA and RNA -polymerase

and viral reverse transcriptase

 CMV retinitis (ganciclovir resistant / IC)

 HSV infections (acyclovir resistant / IC)

 Hypocalcemia and hypomagnesemia,

Neurotoxicity, Nephrotoxicity
Respiratory viral infections

➢ Influenza
– A : common in all species
– B : Human beings
– H : haemagglutinin
– N : neuraminidase
• H1N1- Swine flu
• H5N1 – Bird flu

➢ Respiratory syncytial virus

Drugs for respiratory viral infections

⚫ Influenza
✓ Viral uncoating & assembly
▪ Amantadine, Rimantadine
✓ Neuraminidase inhibitors
▪ Oseltamivir, Zanamivir

⚫ RSV bronchiolitis
✓ Nucleoside analogue
▪ Ribavirin
Amantadine, Rimantadine

– Inhibition of viral uncoating by inhibiting the viral

membrane protein M2 (ion channel)
– Inhibition of viral assembly
Uses : 100 mg BD x 5 days
✓ Prevention and treatment of Influenza A2
✓ Anti-parkinsonian effects
▪ Dopamine facilitator through NMDA receptor

Adverse effects :
▪ Neuropsychiatric
▪ Ankle oedema
– vasoconstriction due to release of CAs
Oseltamivir, Zanamivir

▪ Influenza :neuraminidase (replication)

MOA: Neuraminidase inhibitors

- Prevent the release of new virions and their
spread from cell to cell
- Effective against both types of influenza A
and B
CI: Pregnancy, Age < 1 year
➢ Do not interfere with immune response to
influenza A vaccine
➢ Prophylaxis and acute treatment (48 hrs)

➢ O – T: 75 mg BD x 5 days, P: 75 mg OD

➢ Z – T : 10 mg BD x 5 days, P : OD
▪ Inhalation via space inhaler

▪ Risk of bronchospasm with zanamivir - asthmatics

Ribavirin

Guanosine analogue
MOA: Inhibition of GTP & RNA polymerase
⚫ Spectrum :
▪ DNA and RNA viruses – RSV (Influenza, HCV)
➢ Anemia and jaundice, teratogenicity (6 months),
mutagenicity, gonadotoxicity
➢ Palivizumab : Prevention of RSV
Anti Hepatitis B drugs

⚫ Adefovir
⚫ Lamivudine
⚫ Entecavir – DNA polymerase
⚫ Telbivudine
⚫ Tenofovir – Resistant cases

⚫ HCV: I-α (sc), Ribavirin (po), Telaprevir (po –

PI) , Boceprevir (- CYP3A4)
Adefovir dipivoxil

 AMP analogue
 Hepatitis B, HIV, herpes (10 mg/day)
MOA:
 Inhibits HBV DNA polymerase – terminates DNA
chain
 Chronic Hepatitis B – Lamivudin resistant
 Nephrotoxicity (dose adj), Lactic acidosis, flu
syndrome, hepatic steatosis
Interferon α (Broad spectrum)

✓ Species specific: LMW glycoprotein cytokines

✓ Induced - viruses, bacteria, parasites, tumor cells
✓ Host specific (α, β, γ)
MOA
▪ Antiviral, immune modulating and anti-
proliferative actions
▪ Antiviral – inhibition of protein synthesis
▪ Affects replication at various stages
Spectrum of action

➢ HBV, HCV and HPV

➢ Anti-proliferative actions inhibit the growth of

certain cancers - Kaposi sarcoma, HCL

➢ 5-10 million units IFN α2B, 3-9 million units IFN

α2A i.m., s.c. – thrice weekly

➢ Pegylated interferon – weekly

Therapeutic uses

⬧ Chronic hepatitis B and C

⬧ CMV, HZV, HSV in immunocompromised patients

⬧ Condylomata acuminata (intralesional injection)

⬧ Hairy cell leukemia (in combination with zidovudine)

⬧ AIDS related Kaposi’s sarcoma

⬧ Chronic myeloid leukemias, lymphomas, multiple

sclerosis
Adverse effects

• Hypersensitivity reactions
• Acute flu-like syndrome (fever, headache)
• Bone marrow suppression
• Neurotoxicity (confusion, seizures)
• Cardiotoxicity - arrhythmia
• Impairment of fertility
• Thyroid dysfunction, Retinopathy
Summary

❑ Acyclovir – DNA viruses - HSV, CMV

❑ Influenza – Amantadine, Oseltamivir

❑ Interferon – Hepatitis, immunocompromised,

tumours

❑ Reduce severity of infection

❑ Blood counts
Thank you !
Antiretroviral drugs
HIV & AIDS

⚫ HIV1, HIV2

Transmission
⚫ Sexual transmission,
⚫ Contaminated syringes, needles, Blood
transfusion, blood products
⚫ Mother to Foetus
Life cycle of HIV

⚫ gp 120 – CD4
⚫ gp41
⚫ RNA→ DNA (Mutations)
⚫ Viral Integrase
⚫ Host DNA polymerase
⚫ Assembly
⚫ Protease
⚫ Incubation period – 1-7 years

⚫ Clinical profile
– Stage 1: short illness – febrile, antibodies in 2-8
weeks
– Stage 2: generalized lymphadenopathy due to
viral replication associated with infections
– Stage 3 (AIDS) – Opportunistic infections, GI
infections, Malignancies, neurological conditions
Aims of Antiviral therapy

– Decrease viral replication

– Improve immunological status
– Delay AIDS
– Prolong survival
Challenges in HIV treatment

⚫ Integration into host T- cell – Dormant cells

⚫ Brain cells
⚫ Toxicity
⚫ Resistance

➢ Guidelines
ARVs and the HIV Lifecycle

53
Classes of Antiretrovirals

⚫ NRTIs – Nucleoside reverse transcriptase

inhibitors (Actively dividing)
⚫ NNRTIs – Non-nucleoside reverse transcriptase
inhibitors
⚫ NTRI – Nucleotide reverse transcriptase
inhibitors
⚫ PIs – Protease inhibitors
⚫ Fusion Inhibitors
⚫ Integrase inhibitors
Nucleoside Reverse Transcriptase
Inhibitors

⚫ Derivatives of Pyrimidine:
– Zidovudine (AZT)
– Zalcitabine (ddC)
– Stavudine (d4T)
– Lamivudine (3TC)
⚫ Derivatives of Purine:
– Didanosine (ddI)
– Abacavir (ABC)
Mechanism of Action

⚫ Intracytoplasmic activation---
phosphorylation → triphosphate form
✓ Competitive inhibition of HIV reverse
transcriptase (100 fold specificity);
✓ Incorporated into the growing viral DNA
chain → cause premature termination
⚫ Active against Rapidly dividing HIV-2 as
well as HIV-1
Zidovudine

▪ Azidothymidine (AZT), Prototype

▪ anti-HIV-1 and HIV-2

▪ Prevents infection of new cells

▪ Action only against retroviruses

o PK: Good absorption, distribution (CSF, milk)

o Renal excretion following glucuronidation

Advantages

• ↓ HIV-RNA titer and ↑ CD4+ count

• Decrease the rate of clinical disease progression and
prolong survival

• Treatment HIV-associated dementia and

thrombocytopenia

• Reduce the rate of vertical transmission of HIV

• Post-exposure prophylaxis
⚫ Adverse effect:
– Myelosuppression → anemia or neutropenia
– GI intolerance, headaches, insomnia, myalgia
– HIV Lipodystrophy Syndrome: Lactic acidosis,
hepatic steatosis
– CNS : convulsions, encephalopathy
⚫ Interactions:
– Paracetamol
– Antifungals
– Stavudine
⚫ Uses:
– First line therapy (HAART)
⚫ 200 mg TDS
– Post-exposure prophylaxis
– Prevention of infection from mother to child
Lamivudine (3TC)

✓ Deoxycytidine analogue

✓ Inhibits HIV and HBV

✓ Long intracellular t1/2

✓ Combination therapy in HIV infection (300 mg

OD)and chronic Hepatitis B (100 mgOD)

✓ AE: headache, Lactic acidosis, anorexia, other

Nucleoside Reverse Transcriptase
Inhibitors

⚫ Derivatives of Pyrimidine:
– Zidovudine (AZT)
– Zalcitabine (ddC): Best tolerated
– Stavudine (d4T) – X ddl
– Lamivudine (3TC)
⚫ Derivatives of Purine:
– Didanosine (ddI) – Long action, P,P
– Abacavir (ABC) - Hypersensitivity
NNRTI
⚫ Delavirdine (IH), Nevirapine (ID)(pregnancy),
Efavirenz (Both)(BBB)
– Bind directly to a distinct site on the viral RTase
– Neither compete with nucleoside triphosphates nor
require phosphorylation to be active
– Blockade of RNA- and DNA-dependent DNA
polymerase activities

⚫ Combination regimens
⚫ Etravirine, Rilpivirine - Resistant cases
⚫ Specific activity against HIV-1.

⚫ Cross-resistance among this class, but not with

NRTI or PI

⚫ Not used as monotherapy

⚫ Inducers / inhibitors of CYP3A4, 2D6

⚫ AE: Rashes, Headache, Hepatotoxicity,
Neuropsychiatric Disturbances, Teratogenicity
Protease inhibitors (PI)

⚫ Ritonavir, Nelfinavir, Saquinavir, Indinavir,

Lopinavir

Gag and Gag-Pol Translate Polyproteins,

gene Immature budding particles
protease

Final structural proteins,

Mature virioncore
▪ Late step – both new and chronically infected
cells
▪ Substrate and Inhibitors of CYP3A4, induce
certain other enzymes
▪ Combination therapy with other agents
✓ Interactions
✓ Large tablet load → compliance
✓ IDV, LPV, SQV combined with Ritonavir – Boosted PI
regimen
Adverse effects
▪ Lipodystrophy - Syndrome of altered body fat
distribution – (buffalo hump and truncal obesity,
with facial and peripheral atrophy)
▪ Hepatotoxicity, Pancreatitis
▪ Neuropathy
▪ Insulin resistance, hyperglycemia
▪ Dyslipidaemia
▪ Renal calculi - Indinavir
NTRI - Tenofovir

⚫ Resistant Infection
⚫ HBV
⚫ OD dosing
⚫ Nephrotoxicity
Fusion inhibitor

⚫ Enfuvirtide
⚫ HIV derived synthetic peptide
⚫ Binds to HIV-1 envelope glycoprotein gp41
↓
Prevents fusion of viral and cellular membranes
⚫ Add on drug – failed patients(SC, BD)
⚫ Lymphadenopathy, PN
⚫ Maraviroc: CCR-5 antagonist
Integrase inhibitor (INSTI)

⚫ Raltegravir, Elvitegravir
⚫ Inhibition of integration of viral DNA strands into host
genome
↓
Inhibits maturation & multiplication of the virus in the
infected cell
⚫ MDR HIV-1
⚫ Elvitegravir – Cobicistat (CYP3A4)

⚫ Bevirimat: Maturation inhibitor

HAART

⚫ Combination of 3 or more drugs

⚫ Guidelines
– Initiation of treatment

– Therapeutic regimens

– Changing a regimen

– Prophylaxis – indications & regimens

Initiation of treatment
⚫ CD4 cell count – major determinant

⚫ All symptomatic HIV patients – recommended

⚫ Asymptomatic with CD4 count < 200/μl –

recommended
⚫ Asymptomatic with CD4 count > 200/μl –
– 200-350, rate of decline > 100 / μl per annum
– HIV- RNA titer > 50,000 /ml
– Patients adherence to compliance
– Individual risk of drug toxicity and compliance
Therapeutic regimens
 Preferred regimens
2NRTI + 1 NNRTI (PI sparing)
1. Zidovudine +Lamivudine + Efavirenz
2 NRTI + 1 PI
1. Zidovudine +Lamivudine + Lopinavir /r
Alternative regimens
2NRTI + 1 NNRTI (PI sparing)
1. Zidovudine +Lamivudine + Nevirapine
2. Lamivudine + Stavudine + Efavirenz
3. Lamivudine + Stavudine + Nevirapine
4. Lamivudine + Abacavir + Efavirenz
5. Lamivudine + Abacavir + Nevirapine
2NRTI + 1 PI
1. Lamivudine + Zidovudine + Indinavir
2. Lamivudine + Stavudine + Ritonavir
3. Lamivudine + Abacavir + Lopinavir/ r
4. Lamivudine + Abacavir + Nelfinavir
3NRTI - Zidovudine +Lamivudine + Abacavir
Change of regimen

⚫ Adverse reactions
⚫ Drug interactions
⚫ Poor patient compliance
⚫ Pregnancy
⚫ Comorbidity
⚫ Failure
Change of failed regimen

⚫ Viral load reduction < 10 fold in 4 weeks

⚫ Undetectable levels in 6 months
⚫ Repeated detection of virus
⚫ Clinical deterioration, fall in CD4 cell count,
serious opportunistic infections
– Entire regimen
– No replacement from same group
– Viral resistance testing
Prophylaxis

▪ Post-exposure prophylaxis (PEP)

▪ Suppress local viral replication →abort infection

 Needle stick or other sharp injury
 Contact with blood or biological fluids
 Blood transfusion

▪ Within 1-2 hrs of exposure

▪ Two types of regimens

 PEP
Basic 2 drug regimen Low risk
Zidovudine 300 mg + Lamivudine 150 mg Twice daily x 4 weeks
Expanded 3 drug regimen High risk
Zidovudine 300 mg + Lamivudine 150 mg Twice daily x 4 weeks
+
Indinavir 800 mg Thrice daily x 4 weeks
Low risk -

HIV positive – asymptomatic, low HIV-RNA titer, high CD4 cell count

Exposure through MM, scratch, thin solid needles

High risk-

Symptomatic, high HIV-RNA titer, low CD4 cell count

Major splash, large contact area for long duration, abraded skin, large bore needle
Perinatal prophylaxis

➢ Nontreated mother –
➢ AZT 300 mg BD started in 2nd trimester →
postnatal period

➢ Treatment of neonate for 6 weeks

➢ 3 drug ART after 1st trimester

➢ PI - Nevirapine

➢ Breastfeeding - CI
Summary

❑ NRTI, NNRTI, PI

❑ Neurological effects, hepatotoxicity, enzyme

induction and inhibition

❑ HAART

❑ Indications, therapeutic regimens,

prophylaxis
Thank you !
Zalcitabine (ddC)

⚫ Cytosine analog

⚫ Anti-HIV-1

⚫ Zidovudine + Zalcitabine + one protease

inhibitor

⚫ Dose-dependent peripheral neuropathy,

hepatitis, stomatitis
Stavudine
✓ Thymidine analogue (d4T)

✓ Anti-HIV-1 and HIV-2

✓ Rapid, high oral bioavailability (86%) that is not

food-dependent

✓ Combination therapy in HIV (30 mg BD)

✓ AE: Peripheral Neuropathy, Lipodystrophy,

Pancreatitis
Didanosine (ddI)

▪ Competes with ATP for incorporation into viral

DNA, inhibits DNA polymerase

▪ Acid labile - empty stomach

▪ X combination with Stavudine

▪ AE: peripheral neuropathy, pancreatitis, optic

neuritis, retinal depigmentation
Abacavir (ABC)

⚫ Guanosine analogue

⚫ Alternative regimens in HAART

⚫ Hypersensitivity, interaction with alcohol