ANTI VIRAL Agents

Kaukab Azim, MBBS, PhD

Viruses

Features of Antiviral Drugs•Purine or pyrimidine analogs

•Prodrugs must be phosphorylated

•Antivirals have a narrow spectrum of action

•Inhibit active replication; do not kill latent viruses, need host immune response

•Resistance is common

•Synergistic effects when given together

•Efficacy relates to con. in infected cells

•Start therapy early for optimal efficacy

A good antiviral drug will

Interfere with a viral specific function

Only kill virus-infected cells

Prevent viral replication

Sites Of Anti Viral Drug Action

Enfuvirtide, maraviroc

Indinavir

Oseltamivir

Reltegravir

Classes

• Class I Antinfluenza agents• Class II Antiherpetic agents• Class III Antiviral for HBV & HCV• Class IV Antiretroviral therapy (ART)• Class V Agents against human Papiloma

virus and RSV

Viruses susceptible to drug therapy

• DNA Viruses1. Herpes virus (HSV 1 & HSV 2)2. Varicella Zoster (VZV)3. Cytomegalovirus (CMV)4. Hepatitis B virus

• RNA Viruses 1. Hepatitis C 2. HIV (Retro virus) 3. Respiratory syncytial virus 4. Influenza A & infl. B viruses

Treatment of Influenza AAMANTADINE

• MOA: Inhibits uncoating no penetration

• Uses: Prophylaxis & treatment, not for Influenza A • S/E: CNS: insomnia & restlessness

Livedo reticularis• dose in renal dysfunction• Good alternative to a vaccine in the elderly or in

immuno compromised patients

OSELTAMIVIR: Tamiflu

• Prophylaxis and treatment of Influenza A and B

• Neuraminidase inhibitor

OSELTAMIVIR: Tamiflu

• Flu virus attaches to host cell membrane – hemagglutinin on viral envelope binds to sialic acid moiety in glycoprotein of cell membranes

• Neuraminidase enzyme cleaves viral attachment

• Neuraminidase inhibitor keep the virus tethered to the host cell membrane; prevent it from being released and thus spreading to other cells

Treatment of HSV, VZV and CMV

• ACYCLOVIR• GANCICLOVIR• FOSCARNET • Compete with dGTP for viral DNA-

polymerase & inhibit viral DNA synthesis • 1st two are purine analogs• Acyclovir and Ganciclovir are prodrugs• Foscarnet acts directly on DNA

polymerase

ACYCLOVIR: guanine analog

MOA: Inhibits HSV replication

Acyclovir

Acyclo-MP

Acyclo-DP

Acyclo-TP

(ACTIVE DRUG)

Viral thymidine kinase

Cell kinase

Cell kinase

Incorporated into growing DNA strand

Chain termination

Stops viral replication

Competes with dGTP for viral

polymerase

USES of ACYCLOVIR

• Genital Herpes: 1st episode viral shedding,

duration of symptoms• Orolabial herpes: Topical/ oral acyclovir

(penciclovir)• Herpes encephalitis: Acyclovir I/V• Varicella zoster: Oral, till all lesions

encrusted I/V in disseminated CNS

or Visceral infection• Cytomegalovirus: Prophylaxis only (prevent

CMV infection in transplant patients)

Use in pregnancy: for 1st episode of genital H. to prevent neonatal herpes (H.pneumonia)

Side effects: NEPHROTOXIC (reversible crystalline nephropathy) Encephalopathy (rare)Resistance:

Mutations occur in the thymidine kinase gene causing an enzyme that does not phosphorylate acyclovir

Occurs more in HIV+ive people

GANCICLOVIR1st drug effective against CMV

Uses: Cytomegalovirus (CMV):

Acute infection (retinitis, pneumonia in AIDS)

Prophylactic (in transplant patients, AIDS)

S/E: Bone marrow toxicity (granulocytopenia & thrombocytopenia)

Drug Interactions:DO NOT give with ZIDOVUDINE (overlapping myelosuppression toxicities)

When acyclovir is effective as CMV prophylaxis why gancyclovir is used?

1. To treat lung, colon infection2. Good in AIDS pt.s3. Has less teratogenicity

FOSCARNET (alternate to Ganciclovir for CMV)

Not a prodrug!

Uses: CMV infections Acyclovir-resistant HSV encephalitis

MOA: Directly inhibits DNA polymerase

S. Effect: in Renal function, hypocalcaemia, teratogenic, mutagenic & carcinogenic drugDrug Interactions:Cyclosporine (renal toxicity), Pentamidine (hypocalcaemia), Imipenem (seizures)

Wide Spectrum anti viral RIBAVIRIN: Respiratory Syncytial Virus (given by aerosol only)

Hepatitis C

MOA: Synthetic analogue of nucleoside; inhibits GTP synthesis & , inhibits 5 ̀ capping of viral mRNA, RNA-dependant RNA polymeraseS/ E: Headache, insomnia, anemia, teratogenesisUses: Severe RSV infection with serious underlying respiratory, CV problems or immuno compromisedC.I: Pregnancy

HEPATITIS B: Lamivudine (ARV drug) • Inhibits HBV-DNA polymerase & HIV- reverse-

transcriptase by competing with dCTP • Uses:

1. Chronic Hepatitis B infection with evidence of active viral replication

• 2. HIV infectionSE: N/V, headache, insomnia, fatigue

HEPATITIS B: INTERFERONs

• Interferon -2b & INF- : CytokineBroad spectrum antivirals, Immuno modulator activity, Antiproliferative actions; progression of liverDz in HBVS/E: Many, Flu-like syndrome, Bone marrow suppression

A 10-days old baby girl/ an AIDS pt. e low CD+4/ or bone marrow transplant pt. is suffering from RSV pneumonitis,

what is the treatment of choice?

1. Lamivudine2. Ribavirin3. Oseltamivir

HEPATITIS C: Peg-interferon Ribavirin

PAPILLOMAVIRUS: Imiquimod

For topical treatment of perianal & external genital warts

Stages in Retrovirus development

Why Body Defenses Disappear

Anti retroviral agents• 4-5 big classes

1) Protease Inhibitors 2) Nucleoside reverse transcriptase Inhibitors 3) Non-nucleoside reverse transcriptase inhibitors 4) Fusion Inhibitors

5) Integrase inhibitors

Retrovirus & Anti retroviral agents

Drugs in different classes

NRTIs Non NRTIS Protease inhibitors

Zidovidine NEVIRAPINE SAQUINAVIR

Didanosine DELAVIRDINE INDINAVIR

Stavudine EFAVIRENZ RITONAVIR

Lamivudine ATAZANAVIR

ART• Antiretroviral therapy (ART) is begun when:

Symptomatic disease is present, regardless of CD+4 count and viral load OR

• Patient has CD+4 < 350 cells/mm3 with any value of RNA copies per milliliter– OR

• Plasma HIV RNA viral load>10,000-20,000/ml • HIV infection assoc with lots of symptoms

Malaise, fever, blood disorders, neurological, opportunistic infections etc. difficult to separate these effects from the side effects of the drugs

Zidovudine (NRTIS)• Inhibit reverse transcriptase – prevent conversion of

viral RNA to DNA• All NRTIs nucleoside analogs e.g. Zidovudine

(azidothymidine- AZT) a thymidine analog• NRTIs: narrow therapeutic window, dose limiting

toxicities (mainly due to mitochondrial toxicity and inhibition of cellular DNA polymerases)

• In toxicity– withdraw drug until symptoms clear or become tolerable OR the drug has to be discontinued

AZT

AZTmonophosphate

AZT diphosphate

AZT triphosphate

Thymidine kinase

(host)

Thymidylate kinase

Cell Kinase

Incorporated into

Viral DNA strand

Chain elongation is terminated at thymidine residues

(lack of 3’-OH group)

No viral DNA formed

Resistance• Major cause of treatment failure• Likelihood of resistance:

duration of therapy Advancing disease

• Due to point mutations in reverse transcriptase enzyme

• 33% patients on monotherapy with AZT become resistant within a year

• Use a combination of NRTIs so that there are different point mutations

• R5 viral strains & Maraviroc (new; fusion inhibitor)

Maraviroc is a:

1. Reverse T. Inhibitor2. CCR5 inhibitor3. Protease inhibitor

NRTIs MAJOR TOXIC EFFECT

ZIDOVUDINE Bone marrow suppression, myopathy & lactic acidosis (LA)

LAMIVUDINE LESS TOXIC THAN ABOVE

DIDANOSINE NEUROPATHY, Hepatitis (LA), PANCREATITIS

ABACAVIRHYPERSENSITIVITYREACTIONS, MYOPATHY

STAVUDINENEUROPATHY, Hepatitis (LA)PANCREATITIS (no myopathy)

Maykota, a 42 year old company executive visited his physician complaining of mouth sores. On questioning he stated that he had been feeling unwell for the past couple of weeks. He felt tired and had lost his appetite.

On examination, the physician noted white plaques in his mouth and a generalised lymphadenopathy.

Results

ELISA: HIV positive

CD4+ count: 350 mm3

mouth swab positive for Candida albicans

The physician decided to prescribe antiretroviral drugs for him and clotrimazole or nystatin for the Candida infection.

The antiretroviral drugs he was prescribed were a combination of efavirenz, lamivudine and abacavir (treatment naive patient)

These 3 drugs are typical of the HAART regimen. 2 NRTIs together are synergistic.

HAART: Highly Active Anti Retroviral Therapy

NOW: Antiretroviral Therapy (ART)

NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

•NEVIRAPINE

•Delavirdine

•Efavirenz

MOA: Bind directly to reverse transcriptase

Allosteric inhibition of enzyme function

Blocks transcription of viral RNA to DNA

Note: They are NOT pro drugs!

Pharmacokinetics Of NNRTIsWell absorbed orally

Enter CNS (nevirapine more than the others)

Metabolized in the liver by cytochrome P450 enzymes

Excreted by the kidney

Lot of potential (cyp450) for drug interactions

Toxicity: Relatively low toxicity, also effect lipid profileToxicities do not overlap with NRTIsMajor toxicity: Skin rashes

Drug InteractionsNevirapine INDUCES enzymes: P.Is

Contraceptives

Efavirenz……………. Zidovudine

Indinavir

Antiepileptics level

Delavirdine INHIBITS enzymes: P.Is

An HIV positive female developed rash after 3 Months of treatment e efavirenz & switched

to nevirapine. She is expected to have:

1. Impaired lipid profile2. Decreased OCP levels3. Increased biliary excretion

Protease Inhibitors (Do not need to be prodrugs)

• SAQUINAVIR

• Indinavir

• Ritonavir

MOA: Blocks the protease enzyme

Prevent the cleavage of the gag and gag-pol protein precursors causing the formation of immature, non-infectious particles.

Can inhibit cell to cell spread of the virus

ToxicitySaquinavir: GIT disturbances

Indinavir: “trunkal obesity” (Cushing-like syndrome)

Nephrolithiasis (kidney stones)

Hemolytic anemia

Ritonavir: Paresthesias

Drug Interactions

All INHIBIT cytochrome P450 enzymes

High potential for drug interactions!

Ketoconazole: toxicity of saquinavir

Delavirdine: toxicity of saquinavir and indinavir

Rifampin: efficacy of all P.Is

Ritonavir: rifampin toxicity

FUSION INHIBITORS

ENFUVIRTIDE, Maraviroc

MOA: Prevents the fusion of HIV with the host cell membrane

Uses: To treat AIDS which is progressing despite HAART

Integrase inhibitor

• Integration of viral DNA into host DNA• First approved HIV-integrase inhibit. • Raltegravir - integrase inhibitor• Use: Detectable viremia & treatment failure in

pt e triple class experience• Short term efficacy

Initial Treatment: Preferred Components

*Avoid in pregnant women and women with significant pregnancy potential. Alternate is nevirapine.**Emtricitabine can be used in place of lamivudine or vice versa & a fixed dose combination e

tenofovir-efavirenz reduces pill burden.

Efavirenz*

OR

Atazanavir + ritonavirFosamprenavir + ritonavir (BID)Lopinavir/ritonavir (BID)

NNRTI Option

PI Options

Tenofovir + emtricitabine**Zidovudine + lamivudine**Abacavir + lamivudine

+

NRTI Options

Initial Treatment: Alternative Components

*Nevirapine should not be initiated in treatment naïve-women with CD4 counts >250 cells/mm3 or treatment naive-men with CD4 counts >400 cells/mm3

**Atazanavir must be boosted with ritonavir if used in combination with tenofovir

Nevirapine*

OR

Atazanavir** FosamprenavirFosamprenavir + ritonavir (1x/day)Lopinavir/ritonavir (1x/day)

NNRTI Option

PI Options

Abacavir + lamivudine (preffered)

Didanosine + (emtricitabine or lamivudine)

NRTI Options

Antiretroviral Medications: Not Recommended in Initial

Treatment (2)

High pill burden/Dosing- inconvenienceEmer. of resistance

Amprenavir Amprenavir/ritonavir Indinavir (unboosted) Nelfinavir + saquinavir

Lack of data or reserve for specific strains

Tipranavir Darunavir Enfuvirtide

Adherence

• A major determinant of degree and duration of viral suppression

• Poor adherence associated with virologic failure

• Optimal suppression requires 90-95% adherence

• Suboptimal adherence is common

Antiretroviral Medications: Should not be offered at any

time • Regimens not recommended:

– Monotherapy (except possibly zidovudine to prevent perinatal HIV transmission)

3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir

– NRTI-sparing regimens

Antiretroviral Medications: Should not be offered at any time

• Antiretroviral components not recommended:– Didanosine + stavudine– Stavudine + zidovudine– Emtricitabine + lamivudine

CONCLUSIONS

ART:

Delays disease progression

Prolongs survival

Reduces maternal to child transmission.

BUT: Therapy is still suboptimal

Complete suppression of viral replication has not been achieved.

Drugs are toxic

Resistance is a major problem

end