Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 92 Antiviral Agents I: Drugs for Non- HIV Viral Infections

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3 Antiviral Therapy  Our ability to treat viral infections remains limited  Viruses use biochemical machinery of host cells to reproduce  Difficult to suppress viral replication without doing significant harm to the host  Antivirals suppress biochemical processes unique to viral reproduction

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.4 Herpesvirus  Herpes simplex virus (HSV)  Causes infection of the genitalia, mouth, face, and other sites  Varicella-zoster virus (VZV)  Cause of varicella (chickenpox) and herpes zoster (shingles)

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6 Acyclovir (Zovirax)  Active only against members of the herpesvirus family  Agent of first choice for HSV or VZV infections  Herpes simplex genitalis  Mucocutaneous herpes simplex infections  Varicella-zoster infections

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.7 Acyclovir (Zovirax)  Herpesvirus develops resistance to acyclovir  Decreased thymidine production  Alteration in thymidine kinase  Alteration of viral DNA polymerase

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.8 Acyclovir (Zovirax) – Adverse Effects  Intravenous therapy  Phlebitis  Reversible nephrotoxicity  Oral therapy  Gastrointestinal  Vertigo  Topical  Stinging sensations

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.9 Valacyclovir (Valtrex)  Prodrug form of acyclovir  Herpes zoster  Herpes simplex genitalis  Herpes labialis  In some immunocompromised patients  Thrombotic thrombocytopenic purpural/hemolytic uremic syndrome (TTP/HUS)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.10 Famciclovir (Famvir)  Prodrug used to treat acute herpes zoster and genital herpes infection  Benefits are equivalent to those of acyclovir  Adverse effects are minimal

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.11 Topical Drugs  Herpes labialis  Penciclovir (Denavir)  Docosanol (Abreva)  Ocular herpes infections  Trifluridine (Viroptic)  Vidarabine (Vir-A)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.12 Cytomegalovirus Infection  CMV – member of herpesvirus group  Transmitted direct contact with body fluids  50%-80% of Americans age 40 and older harbor the virus  Can remain dormant for life  Immunosuppressed patients at high risk to reactivate dormant virus

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.13 Ganciclovir (Cytovene, Vitrasert)  Synthetic antiviral agent  Uses  Herpes simplex viruses – including CMV  Prevention and treatment of CMV infection in immunocompromised patients  Serious side effects  Granulocytopenia  Thrombocytopenia

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.14 Ganciclovir (Cytovene, Vitrasert)  Adverse effects  Granulocytopenia  Thrombocytopenia  Reproductive toxicity  Nausea, fever, rash, anemia, liver dysfunction, confusion, and other CNS symptoms

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.15 Valganciclovir (Valcyte)  Prodrug version of ganciclovir  Used for CMV retinitis  Oral is just as effective as IV  Adverse effects  Blood dyscrasias Bone marrow suppression Bone marrow suppression Granulocytopenia, anemia, thrombocytopenia Granulocytopenia, anemia, thrombocytopenia

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.16 Valganciclovir (Valcyte)  Adverse effects (cont’d)  Diarrhea, nausea, vomiting  Potential for mutagenesis and carcinogenesis  Direct contact with broken tablet should be avoided  Should be disposed of in the same manner as a cytotoxic drug

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.17 Cidofovir (Vistide)  IV with just one indication – CMV retinitis in patients with AIDS who have failed on ganciclovir or foscarnet  Adverse effects  Nephrotoxicity  Neutropenia  Ocular disorders

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.18 Foscarnet (Foscavir)  IV drug active against all known herpesviruses  Compared with ganciclovir  More difficult to give, less well tolerated, much more expensive  CMV retinitis in patients with AIDS  Acyclovir-resistant mucocutaneous HSV and VZV in immunocompromised host

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.19 Fomivirsen (Vitravene)  Unique drug for treating CMV retinitis with HIV-infected patients who are intolerant of or unresponsive to other drugs  Direct injection into the vitreous humor  Adverse effects  Ocular inflammation

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.20 Drugs for Hepatitis  Viral hepatitis is the most common liver disorder  Millions of Americans are infected  Six different viruses can cause acute hepatitis (A, B, C, D, E, and G)  Only B, C, and D can also cause chronic hepatitis

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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.22 Hepatitis C Virus (HCV)  Differences in HCV – 6 genotypes; more than 50 subtypes  Transmission – primarily through exchange of blood; controversy over sexual transmission  No symptoms, but can transmit  Slow progression can lead to liver failure, cancer, and death  Leading reason for liver transplants  Drugs  Pegylated interferon alfa combined with ribavirin

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.23 Interferon Alfa  Interferon family  Alpha, beta, gamma  Alphas used to treat hepatitis  None can be administered orally  Conventional versus long-acting interferons  Adverse effects  Flu-like symptoms  Neuropsychiatric effects, especially depression

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.24 Ribavirin (Rebetol, Copegus)  Used in combination with subQ peginterferon alfa for treatment of chronic hepatitis C  Adverse effects  Hemolytic anemia  Birth defects – category X

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.25 Hepatitis B Virus (HBV)  1.25 million people have chronic hepatitis B  11,000 require hospitalization for deep fatigue, muscle pain, and jaundice  Chronic infection develops in 3%-5% infected adults  Chronic infection can lead to cirrhosis, hepatic failure, hepatocellular carcinoma, and death  Transmission – blood and semen

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.26 Hepatitis B Virus (HBV)  HBV vaccine  Drugs  Interferon alfa-2b (PEG-Intron)  Peginterferon alfa-2a  Lamivudine (Epivir-HBV)  Adefovir (Hepsera)  Entecavir (Baraclude)  Telbivudine (Tyzeka)

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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.28 Influenza  Serious respiratory tract infection  Major cause of morbidity and mortality worldwide  36,000 deaths/year in the United States  Caused by influenza viruses, which are highly variable and undergo constant evolution  Type A – more infectious than B  Type B

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.29 Influenza Management  Influenza managed by vaccination (primary strategy) and drugs  Drugs  Adamantanes and neuraminidase inhibitors  Vaccines  Influenza vaccines change yearly based on identification of strains by CDC, FDA, and WHO.

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.30 Influenza Vaccine  Two types of flu vaccines  Inactivated influenza vaccine  Live, attenuated influenza vaccine  Protection begins 1-2 weeks after vaccination; generally lasts 6 months or more  Small risk for Guillain-Barré syndrome  Five influenza vaccines on the market

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.31 Influenza Vaccine  Precautions and indications  Acute febrile illness – should defer  Minor illnesses with or without fever do not preclude vaccination  Contraindicated for hypersensitivity to eggs – viruses are grown in eggs  Who should be vaccinated  When should vaccines be given

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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.33 Drugs for Influenza  Neuraminidase Inhibitors  Oseltamivir (Tamiflu)  Zanamivir (Relenza)  Adamantanes  Amantadine (Symmetrel)  Rimantadine (Flumadine)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.34 Drugs for Respiratory Syncytial Virus Infection  Ribavirin (inhaled)  Broad-spectrum antiviral drug  Palivizumab (Synagis)  Monoclonal antibody for preventing RSV infection in newborns