ANTIVIRAL THERAPY DR FATAI OLUYADI USMLEINCLINED.COM 1

VIRAL INFECTION OVERVIEW  FUSION/RECEPTOR BINDING  UNCOATING  NUCLEIC ACID SYNTHESIS  RELEASE OF PROGENY VIRUS USMLEINCLINED.COM 2

HIV INFECTION  FUSION OF VIRUS  REVERSE TRANSCRIPTION  DNA INTEGRATION  PROTEOLYTIC PROCESSING USMLEINCLINED.COM 3

ANTI HIV THERAPY  ENTRY INHIBITORS  REVERSE TRANSCRIPTASE INHIBITORS  INTEGRASE INHIBITORS  PROTEASE INHIBITORS USMLEINCLINED.COM 4

PROTEASE INHIBITORS  ATAZANAVIR  DARUNAVIR  FOSAMPRENAVIR  INDINAVIR  RITONAVIR  NELFINAVIR  SAQUINAVIR  TIPRANAVIR USMLEINCLINED.COM 5

PROTEASE INHIBITORS(overview)  HIV protease enzyme is required to cleave large polypeptides such as Pol and Gag into functional proteins  Protease inhibitors competitively inhibit this enzyme.  All protease inhibitors can cause insulin resistance leading to Hyperlipidemia(Lipodystrophy), Hyperglycemia, Cushingnoid appearance USMLEINCLINED.COM 6

PROTEASE INHIBITORS UNIQUE SIDE EFFECTS PROTEASE INHIBITORS - HYPERLIPIDEMIA, HYPERGLYCEMIA INDINAVIR - NEPHROLITHIASIS USMLEINCLINED.COM 7

NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR  ZIDOVUDINE  ABACAVIR  DIDANOSINE  STAVUDINE  EMTRICITABINE  LAMIVUDINE  TENOFOVIR (Nucleoside) USMLEINCLINED.COM 8

NRTI (OVERVIEW) NRTIs are analogs of nucleootides/nucleosides that competitively inhibit reverse transcripase. They basically inserts the wrong nucleotides into the transcriptase activity leading to chain termination. They are active against HIV 1 and HIV 2 USMLEINCLINED.COM 9

NRTIs (ADVERSE EFFECTS) MITOCHONDRIAL TOXICITIES Lactic acidosis Hepatitits Pancreatitis Peripheral neuropathies Bone marrow suppression Myopathy USMLEINCLINED.COM 10

NRTIs (Side effect profile) ZIDOVUDINE - Bone marrow suppression(reverse with GM-CSF and Erythropoietin), Myopathy, Liver toxicity STAVUDINE - Peripheral Neuropathy, Pancreatitis,Associated with fat wasting Emtricitabine - Hyperpigmentation of the skin Lamivudine - Least Toxic Didanosine - Peripheral neuropathy, Pancreatitis Tenofovir - Blocks didanosine metabolism Abacavir - Hypersensitivity reactions, Steven Johnson’s reaction, Didanosine/stavudine combinations is contraindicated due to high risk of fatal Pancreatitis, and additive neuropathy. USMLEINCLINED.COM 11

NRTIs USED FOR HEPATITIS B INFECTION  EMTRICITABINE  LAMIVUDINE  TENOFOVIR USMLEINCLINED.COM 12

NON NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS  DELARVIDINE  EFAVIRENZ  NEVIRAPINE  ETRAVIRINE  RILPIVIRINE USMLEINCLINED.COM 13

NON NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS  They are Non competitive inhibitors of reverse transcriptase. They bind at the allosteric site of the enzyme and change conformation of the enzyme.  There is rapid HIV resistance to these drugs if used alone.  They are generally associated with Skin rash, including steven-Johnson syndrome  They are metabolized by the Cytochrome P-450 mechanism USMLEINCLINED.COM 14

NNRTIs (Side effect profile) Nevirapine - Liver Toxicity Efavirenz - CNS symptoms, Nightmares, Psychosis, Contraindicated in pregnancy Delavirdine - Contraindicated in pregnancy Rilpivirine - Depression, Insomnia, Less CNS side effects than efavirenz Rash and Hepatotoxicity is common to all NNRTIs. They are all Cytochrome p-450 unducers and at the same time metabolized by the Cytochrome P-450 USMLEINCLINED.COM 15

ENTRY INHIBITORS These groups of drugs interfere with the communication of the virus and cellular surface proteins which allow viral entry.. ENFURVITIDE: Binds to gp41(fusion protein). Prevents viral fusion with host cell embrane. Has HIV-1 activity only. Given subcutaneously. Injection site reaction with pain and induration can be seen MARAVIROC: Antagonizes CCR-5 on surface of T-cells/monocytes, inhibiting interaction with gp120(Attachment protein) and preventing viral entry. Requires CCR-5 tropism testing. Adverse effects include URTI’s and hepatotoxicity. USMLEINCLINED.COM 16

INTEGRASE INHIBITORS  RALTEGRAVIR  ELVITEGRAVIR  DOLUTEGRAVIR Inhibits the integrase enzyme activity and prevents the integration of viral DNA into host DNA. Adverse effects include: Myopathy, Rhabdomyolysis, GI distress. USMLEINCLINED.COM 17

COMBINATION THERAPY FOR HIV  Highly active anti retroviral therapy(HAART) is the recommended approach when HIV is diagnosed.  It is even more recommended for patients with AIDS defining illnesses, Low CD4+ cell count, or High viral load.  The therapy should consist of a 3 drug combination usually to prevent resistance.  The combination should contain at least 2NRTIs + 1 NNRTI or 1 Protease Inhibitor or 1 Integrase Inhibitor.  Most common initial therapy includes Tenofovir/emtricitabine plus any of the following, Efavirenz or rilpivirine, Atazanavir or darunavir with ritonavir boosting, Elvitegravir with cobicistat boosting, raltegravir. USMLEINCLINED.COM 18

HIV PREVENTION  Needle stick cases in Healthcare professionals: Testing should be done immediately(Base line), at 6weeks, at 3 months, at 6 months. Zidovudine + Lamivudine for 4weeks decrease conversion by 79%.  Prevention of Perinatal transmission: Zidovudine administration to the mothe during pregnancy, labor, and delivery and to the newborn decreases the rate of transmission by 2/3. Breastfeeding increases the rate of transmission by 10-20% and should be avoided. Zidovudine administerationfor the baby of an HIV+ patient should be given for 6weeks. If viral load of mother is above 1000 and CD4+ cells are below 350, cesarean section is advised. USMLEINCLINED.COM 19

TREATMENT OF INFLUENZA: NEURAMINIDASE INHIBITORS NEUARMINIDASE INHIBITORS:  OSETALMIVIR  ZANAMIVIR The drugs block the neuraminidase enzyme in Influenza A and B and decrese the release of Viral Progeny. Mostly useful in the first 48hrs after infection. These drugs shorten the duration of the symptoms. If its been more than 48 hours since onset, treat symptomatically with Analgesics, Antipyretics and hydration. USMLEINCLINED.COM 20

TREATMENT OF INFLUENZA: UNCOATING INHIBITORS  AMANTIDINE  RIMANTIDINE They inhibit the uncoating of Influenza A RNA Rimantidine is more potent. May decrease the duration of active flu for 1-2 days. Adverse effects include Atropine-like effects and Livedo reticularis. USMLEINCLINED.COM 21

ANTIHERPETICS: HSV AND VZV ACYCLOVIR: Guanosine Analog prodrug. Requires viral thymidine kinase for phosphorylation. It inhibits Viral DNA polymerase by chain termination. Resistance is via absent or decreased Viral Thymidine kinase. Cross resistance exists with Valacyclovir, famciclovir and Ganciclovir. No cross resistance with Foscarnet, cidofovir and trifluridine. Available in Topical, oral and IV form. Valacyclovir is a pro-drug of acyclovir with better oral Bioavailability Famciclovir is another prodrug like Acyclovir that inhibits Viral DNA polymerase without chain termination. Adverse effects include Nausea, diarrhea and headache. IV form can cause Nephrotoxicity, Neurotoxiciity(Confusion, seizures) and sever thrombocytopenia. USMLEINCLINED.COM 22

ANTIHERPETICS: CMV GANCICLOVIR: Guanosine analog prodrug. Requires viral phosphotransferase UL97 found in CMV. Eventually terminates chain. Available in Oral and IV form. Valganciclovir is a prodrug of ganciclovir with better Oral Bioavailability. Adverse effects include Bone Marrow suppression, CNS toxicity(headache to Seizures) Used for the treatment of CMV especially in Immunocompromised patients. Mechanism of resistance is via Mutation of Viral Kinase USMLEINCLINED.COM 23

FOSCARNET  Inorganic Pyrophosphate analog that bocks Viral DNA and RNA polymerases  Used for Ganciclovir-resistant CMV or Acyclovir resistant HSV/VZV infections  Adverse effects inclide Nephrotoxicity and symptomatic Hypocalcemia. USMLEINCLINED.COM 24

HEPATITIS B TREATMENT Interferon Alpha: Glycoproteins normally synthesized by virus infected cells to prevent protein synthesis in neighbouring cells. Adverse effects include Flu-like symptoms, Neutropenia and Myopathy Entecavir, Tenofovir and Emtricitabine can also be used USMLEINCLINED.COM 25

HEPATITIS C TREATMENT Interferon alpha: See previous slide Ribavirin, Bocepevir and Telaprevir are also used. USMLEINCLINED.COM 26