ANTI VIRAL Agents

1. ANTI VIRAL Agents Kaukab Azim, MBBS, PhD

2. Viruses

3. 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

4. A good antiviral drug will Interfere with a viral specific function Only kill virus-infected cells Prevent viral replication

5. Sites Of Anti Viral Drug Action Enfuvirtide, maraviroc Reltegravir Oseltamivir Indinavir

6. 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

7. 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 Viruses susceptible to drug therapy

8. 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

9. OSELTAMIVIR: Tamiflu • Prophylaxis and treatment of Influenza A and B • Neuraminidase inhibitor

10. 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

11. 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

12. ACYCLOVIR:guanine analog MOA: Inhibits HSV replication Acyclovir Acyclo-MP Acyclo-DP Acyclo-TP (ACTIVE DRUG) Stops viral replication Viral thymidine kinase Competes with dGTP for viral polymerase Cell kinase Chain termination Cell kinase Incorporated into growing DNA strand

13. 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)

14. 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

15. GANCICLOVIR 1st 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 (overlappingmyelosuppression toxicities)

16. When acyclovir is effective as CMV prophylaxis why gancyclovir is used? • To treat lung, colon infection • Good in AIDS pt.s • Has less teratogenicity

17. 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)

18. Wide Spectrum anti viral RIBAVIRIN: Respiratory Syncytial Virus (given by aerosol only) Hepatitis C MOA: Synthetic analogue of nucleoside; inhibits GTP synthesis & , inhibits 5̀ 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

19. 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

20. 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

21. 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? • Lamivudine • Ribavirin • Oseltamivir

22. HEPATITIS C:Peg-interferon  Ribavirin PAPILLOMAVIRUS: Imiquimod For topical treatment of perianal & external genital warts

23. Stages in Retrovirus development

24. Why Body Defenses Disappear

25. 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

26. Retrovirus & Anti retroviral agents

27. Drugs in different classes

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

29. 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

30. No viral DNA formed AZT AZTmonophosphate AZT diphosphate AZT triphosphate Thymidine kinase (host) Chain elongation is terminated at thymidine residues (lack of 3’-OH group) Thymidylate kinase Cell Kinase Incorporated into Viral DNA strand

31. 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)

32. Maraviroc is a: • Reverse T. Inhibitor • CCR5 inhibitor • Protease inhibitor

34. 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

35. 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)

36. 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!

37. Pharmacokinetics Of NNRTIs Well 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

38. Toxicity:Relatively low toxicity, also effect lipid profileToxicities do not overlap with NRTIsMajor toxicity: Skin rashes Drug Interactions Nevirapine INDUCES enzymes:  P.Is  Contraceptives Efavirenz…………….  Zidovudine  Indinavir  Antiepileptics level Delavirdine INHIBITS enzymes: P.Is

39. An HIV positive female developed rash after 3 Months of treatment e efavirenz & switched to nevirapine. She is expected to have: • Impaired lipid profile • Decreased OCP levels • Increased biliary excretion

40. 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

41. Toxicity Saquinavir:GIT disturbances Indinavir:“trunkal obesity” (Cushing-like syndrome) Nephrolithiasis (kidney stones) Hemolytic anemia Ritonavir:Paresthesias

42. 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

43. FUSION INHIBITORS ENFUVIRTIDE, Maraviroc MOA: Prevents the fusion of HIV with the host cell membrane Uses: To treat AIDS which is progressing despite HAART

44. 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

45. 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. NNRTI Option NRTI Options • Tenofovir + emtricitabine** • Zidovudine + lamivudine** • Abacavir + lamivudine OR PI Options +

46. Initial Treatment: Alternative Components NNRTI Option *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 NRTI Options • Abacavir + lamivudine (preffered) • Didanosine + (emtricitabine or lamivudine) OR PI Options

47. Antiretroviral Medications: Not Recommended in Initial Treatment (2)

48. 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

49. 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

50. Antiretroviral Medications: Should not be offered at any time • Antiretroviral components not recommended: • Didanosine + stavudine • Stavudine + zidovudine • Emtricitabine + lamivudine