(O-med) Lecture 2: Anti-Viral Tx

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  1. Name 3 most common types of viral infections
    • 1. HIV
    • 2. HSV
    • 3. Hepatitis viruses
  2. Primary Herpes Simplex Infection

    - symptomatic/asypmtomatic?
    - types of infection?
    - transmitted through?
    Primary herpes infection is usually asymptomatic


    HSV-seropositives re-infection, superinfection or autoinoculation can occur

    transmitted thorough close personal contact of susceptible host with an infected individual
  3. HSV Primary Infection mech
    • 1. Virion enters epithelial cells
    • 2. DNA replication (15-18hrs)
    • 3. Host cell lysis and HSV release
  4. HSV Primary Infection:

    - how long does the clinical dz last?
    - how long are infectious virions in saliva for?
    - how long does it take for virus to access axon of sensory neurons and the ganglion innervating the inoculation site?
    Clinical disease lasts for 1-3 weeks

    Infectious virions in saliva for 7-10 days

    Virus accesses axon of sensory neurons and then ganglion innervating the inoculation site: Within 2-4 weeks
  5. HSV reactivation due to?
    • - emotional stress
    • - menstruation
    • - transient hyperthermia
    • - fever
    • - IV radiation 
    • - immunosupression
  6. Requirements for HSV Reactivation
    - Deficient humoral (IgG, IgA) & HSV specific cytotoxic T-cell response

    - Viral genome transported down the axon near the site of initial infection

    - Upregulation of viral transcription
  7. Anti-HSV Drugs

    - name 2 major classes
    • 1. Thymidine Kinase (TK) dependent
    • 2. Thymidine Kinase (TK) independent
  8. Thymidine Kinase (TK) dependent

    - mech of action
    - name 4
    - Need phosphorylation by the viral TK; then act as thymidine analogues to terminate DNA replication 

    • Acyclovir (Zovirax)
    • Valacyclovir (Valtrex)
    • Famciclovir (Famvir)
    • - Topical Penciclovir (Denavir)
    • Ganciclovir (Cytovene)
  9. Thymidine Kinase (TK) independent

    - mech of action:
    - name 2
    Directly inhibit viral polymerase enzyme

    • Foscovir (Foscarnet)
    • Cidofovir (Vistide)
  10. treatment of Primary HSV
    Supportive care for primary herpetic gingivostomatitis (Fluids, rest, oral lavage and antipyretics)

    • Oral acyclovir indicated for more severe cases or in immunocompromised patients
    • - Must be initiated shortly after infection to be effective
    • - No serious toxicity; long term use may cause GI disturbances, headaches and vertigo
  11. Acyclovir

    - bioavailability?
    - trade name?
    - used for?
    Zovirax®

    - limited bioavailablility

    - Used for highly susceptible infections (genital herpes)
  12. what is oral acyclovir used for?
    -  prophylaxis and tx of primary or recurrent genital herpes

    - VZV infections (rarely for oral HSV)
  13. What is topical acyclovir used for?
    - non-life threatening recurrent mucocutaneous herpes in immunocompromised patients
  14. What is IV acyclovir used for?
    - disseminated infections
  15. Other Anti-Herpes Drugs
    • 1. Valacyclovir
    • 2. Famciclovir
    • 3. Ganciclovir
  16. Other Anti-Herpes Drug: Valacyclovir

    - related to what drug?
    - used for?
    Related to acyclovir;

    • HSV-1,2 (recurrent genital)
    • VZV (localized shingles) in immunocompetent pts
  17. Other Anti-Herpes Drug:  Famciclovir

    - uses?
    - topical? uses?
    For VZV (acute shingles) and HSV-1,2 (recurrent genital lesions)

    Topical Penciclovir (Denavir) is marketed for Herpes Labialis
  18. Other Anti-Herpes Drug: Ganciclovir

    - used for?
    • - CMV retinitis in HIV infected patients
    • - CMV prophylaxis in transplant recipients

    Occasionally used for tx of acyclovir-resistant HSV infections
  19. Primary HSV Therapies: Acyclovir

    Rx?
    • Acyclovir (Zovirax) capsules 400 mg
    • Disp: 60 capsules
    • Sig: 1 capsules tid 7-10 days
  20. Primary HSV Therapies:Valacyclovir

    Rx?
    • Valacyclovir (Valtrex) caplets 1g
    • Disp: 40 caplets
    • Sig: 1 caplets bid 7-10 days
  21. Primary HSV Therapies:Famciclovir

    Rx?
    • Famciclovir (Famvir) 250 mg
    • Disp: 30 tabs
    • Sig: 1 tab tid 7-10 days
  22. Topical HSV Therapies: Acyclovir

    Rx?
    • Acyclovir (Zovirax) cream 5%
    • Disp: 3 gr
    • Sig: apply to lip lesions 5 X per day
  23. Topical HSV Therapies:Penciclovir

    Rx?
    • Penciclovir (Denavir) cream 1%
    • Disp: 2 gr
    • Sig: apply on lesion 5 X per day
  24. Herpes Labialis Prevention

    - when would you prescribe this?
    - Rx?
    application of sunscreen to the lips during sun exposure is the best prophylactic measure for recurrent herpes labialis

    • PreSun lip gel (OTC)
    • Disp: 15 oz
    • Sig: apply to susceptible area 1 hr before sun exposure then every hour thereafter
  25. HZV Treatment
    Systemic therapies for herpes zoster involves the same classes of antiviral agents used for Tx of genital HSV but in higher doses

    For instance, acyclovir is used at 4,000 mg/ day
  26. Thymidine Kinase (TK) Independent Drugs: Foscovir (Foscarnet)

    - used for?
    For CMV retinitis and mucocutaneous acyclovir-resistant HSV in HIV infected patients
  27. Thymidine Kinase (TK) Independent Drugs: Cidofovir (Visitide)
    IV preparation for CMV retinitis in HIV infected patients
  28. Drugs in HIV Disease Management: Main Classes
    • 1. Nucleoside reverse transcriptase inhibitors (NRTI)
    • 2. Non-nucleoside reverse transcriptase inhibitors (NNRTI)
    • 3. Protease inhibitors (PI)
    • 4. Fusion inhibitors
    • 5. Integrase inhibitors
  29. Nucleoside Reverse Transcription Inhibitors (NRTI)

    Advantages and disadvantages
    • Advantage:
    • - Easy dosing schedule
    • - Little food effect
    • - Backbone of combination therapy
    • - Fewer drug interactions

    • Disadvantage:
    • - Serious side effects such as lactic acidosis
  30. Adverse Effects – NRTI Class
    All NRTIs but more likely with older formulations

    Lactic acidosis: Lactate >2-5 mmol/dL plus symptoms–Nausea, vomiting, abdominal pain, muscle weakness

    • Peripheral neuropathy
    • Myopathy, cardiomyopathy & myositis
    • Hepatic steatosis (adiposis)
    • Lipodystrophy
    • Pancreatitis
    • BM suppression
  31. Protease Inhibitors (PI)

    - Advantages and Disadvantages
    Advantage: High genetic threshold (Multiple mutations in the protease gene needed for resistance)

    • Disadvantages:
    • - Complex food requirements
    • - Cross-resistance is common & have severe side effects
    • - CYP3A4 inhibitors and substarte (Drug interaction)
    • - Metabolic complications
  32. Protease Inhibitors

    - name some
    • - aptivus
    • - crixivan
    • - invirase
    • - kaletra
    • - lexiva
    • - norvir
    • - prezista
    • - revataz
    • - viracept
  33. Protease Inhibitors: Adverse effects
    • Metabolic effects
    • - Insulin resistance and relative insulin deficiency
    • - Hyperlipidemia
    • - Osteonecrosis & osteoporosis

    • Lipodystrophy
    • Elevated liver function tests/hepatotoxicity
    • Drug-drug interactions
  34. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)

    Advantages and Disadvantages
    • Advantage
    • - Low toxicity
    • - Impressive long-term results
    • - Less lipid abnormalities
    • - Saves PIs for future use

    • Disadvantage
    • - Low genetic barrier (Requires 1 mutation for high-level drug resistance)
    • - Cross resistance
    • - Potential for CYP450 drug interactions
  35. Name some NNRTIs
    • - Intelence
    • -Rescriptor
    • - Sustiva
    • - Viramune
    • - Edurant
  36. NNRTIs: Adverse Effects
    Rash

    Drug-drug interactions

    • Nevirapine (Viramune)
    • - Severe and life-threatening hepatotoxicity
    • - Stevens-Johnson syndrome
    • Efavirenz (Sustiva)
    • - Neuropsychiatric effects
  37. Drug Regimen Categories ARV Naïve Patients

    INSTI-Based Regimens?
    INSTI-Based Regimens: one INSTI + 2 NRTI

    Dolutegravir + abacavir/lamivudine (Tivicay + Epzicom)

    Dolutegravir + tenofovir/emtricitabine (Tivicay + Truvada)

    Elvitegravir/tenofovir/emtricitabine (Stribid)
  38. Drug Regimen Categories ARV Naïve Patients

    -PI-Based Regimen?
    PI-Based Regimen: two PI + 2 NRTI

    Darunavir + ritonavir + tenofovir/emtricitabine (Prezista + Norvir + Tuvada)

    Atazanavir + ritonavir + tenofovir/emtricitabine (Reyataz + Norvir + Truvada)

    Many pts are still on the older regimen of 1 NNRTI + 2 NRTI (i.e., combination pills like Atripla and Complera or multi-drug regimen)
  39. Maraviroc mech of action?

    When would you use Maraviroc?
    Use of Maraviroc a CCR5 receptor antagonist, in the newly infected with the R5 strain
  40. Lipodystrophy

    - mech?
    - what is it?
    Mechanism not understood

    - Peripheral fat wasting more associated with NRTIs

    - Central fat accumulation perhaps more associated w/ PIs

    - Switch to other agents

    - Polymer injections (Scluptra)
  41. Lipodystrophy associated with?
    Associated with dyslipidemia

    Elevations in total cholesterol, LDL, and triglycerides
  42. Dx of HCV infection
    • + anti-HCV
    • elevated serum ALT levels
    • measurable HCV RNA level
  43. What is HCV?

    How many genotypes and which is least amenable to tx?

    clearance?
    Chronic disease: liver biopsy indicative of portal fibrosis, inflammation and necrosis

    Of the six HCV genotypes, genotype 1 is least amenable to treatment

    Sustained viral suppression < 15 IU/ml (assay’s detection limit) after 12 weeks = clearance
  44. HCV Management

    - 2011 approved tx?
    - 3 classes of new drugs
    Until 2011, pegylated interferon (PegIFN-α) + ribavirin for 24 or 48 weeks was the approved treatment = 40-50% showed suppression

    Three classes of drugs since 2011 – viral protease inhibitors (targeting NS3-4A, NS3-5A region) and polymerase inhibitors (against NS5B)
  45. HCV Managment: Combo Therapy
    Elbasvir/grazoprevir, Ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir
  46. HCV Regimens
    Boceprevir (VICTRELIS®) & Telaprevir (INCIVEK®

    Simeprevir (OLYSIO®) & Sofosbuvir (SOVALDI®)

    Daclatasvir (DAKLINZA®)
  47. Boceprevir (VICTRELIS®) & Telaprevir (INCIVEK®
    - HCV regimen

    early PIs used in combo w/ Peg-IFN/RBV therapy, not used today
  48. Simeprevir (OLYSIO®) & Sofosbuvir (SOVALDI®)
    - HCV regimen

    - a PI and a Poli
  49. Daclatasvir (DAKLINZA®)
    - HCV regimen

    – a recently approved Poli
  50. HCV Regimens: Combo made of what?


    Ex?
    Combination once a day tablets made of a PI and a Poli used   w/ or w/out ribavirin (depending on genotype)


    Ledipasvir/sofosbuvir (HARVONI®)

    Ombitasvir/paritaprevir/ritonavir (VIEKIRA PAK® and TECHNIVIE®)

    Elbasvir/grazoprevir (ZEPATIER®)
  51. HCV Regimen Side Effects
    • blood cell reductions
    • liver damage
    • taste alterations
    • HAs
    • flu like symptoms
    • nausea
    • depression
  52. Management of Hepatitis B

    - recommendations
    Only recommended w/ acute liver damage or severe cirrhosis
  53. Management of Hepatitis B: Agents
    • Pegylated interferons
    • Ribavirin (Rebetol®)
    • Nucleoside Analogs
  54. Management of Hepatitis B: Side effects

    Interferons?
    other agents?
    Interferons lead to neuropsychiatric side effects (depression/anxiety disorder), neutropenia & thrombocytopenia;

    Other agents can cause liver damage, HAs, flu like symptoms, nausea & depression
  55. Summary: Management of herpes infections?
    TK dependent and TK independent drugs
  56. Summary: Tx of Oral HSV
    treated with topical agents unless disease is invasive or host is immune compromised
  57. Summary: NRTIs are associated w/ what abnormalities?
    NRTIs are associated with lipid abnormalities while PIs can lead to endocrine changes including hyperglycemia
  58. Summary: Describe HCV tx and its side effects
    HCV tx involves protease or polymerase inhibitors that can cause blood cell reductions, liver damage & taste alterations
  59. Summary: Describe HBV tx and its side effects?
    HBV tx may involve the used of interferons that can lead to pancytopenia and nucleoside analogs that may cause liver abnormalities
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(O-med) Lecture 2: Anti-Viral Tx
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