Copyright © 2017, Elsevier Inc. All rights reserved. Chapter 40 Antiviral Drugs Copyright © 2017, Elsevier Inc. All rights reserved.

General Principles of Virology Viral replication A virus cannot replicate on its own. It must attach to and enter a host cell. It then uses the host cell’s energy to synthesize protein, DNA, and RNA. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Virus replication Copyright © 2017, Elsevier Inc. All rights reserved.

General Principles of Virology (Cont.) Viruses are difficult to kill because they live inside the cells. Any drug that kills a virus may also kill cells. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Viral Illnesses Smallpox (poxviruses) Sore throat Conjunctivitis (adenoviruses) Warts (papovaviruses) Influenza (orthomyxoviruses) Respiratory infections (coronaviruses, rhinoviruses) Gastroenteritis (rotaviruses, Norwalk-like viruses) Human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS) (retroviruses) Herpes (herpesviruses) Hepatitis (hepadnaviruses) Copyright © 2017, Elsevier Inc. All rights reserved.

Viral Illnesses (Cont.) Most viral illnesses are bothersome but survivable. Effective vaccines have prevented some illnesses. Effective drug therapy is available for a small number of viral infections. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Antiviral Drugs Antiviral drugs kill or suppress the virus by destroying virions or inhibiting the ability of viruses to replicate; controlled by current antiviral therapy Immunoglobulins are concentrated antibodies that can attack and destroy viruses. Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Cont.) Viruses controlled by current antiviral therapy Cytomegalovirus (CMV) Hepatitis viruses Herpesviruses HIV Influenza viruses (the “flu”) Respiratory syncytial virus (RSV) Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Cont.) Key characteristics of antiviral drugs Able to enter the cells infected with virus Interfere with viral nucleic acid synthesis, regulation, or both Some drugs interfere with ability of virus to bind to cells. Some drugs stimulate the body’s immune system. Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Cont.) Best responses to antiviral drugs are in patients with competent immune systems. A healthy immune system works synergistically with the drug to eliminate or suppress viral activity. Copyright © 2017, Elsevier Inc. All rights reserved.

Audience Response System Question An 82-year-old woman is unable to take the influenza vaccine because of allergies, but she has been exposed to the virus through a family reunion. She does not yet have symptoms of the flu. Which option would be best for her? She should receive the flu vaccine as soon as possible. She should receive zanamivir (Relenza) in the inhalation form. She should begin oral oseltamivir (Tamiflu) therapy when symptoms begin. She should begin oral oseltamivir (Tamiflu) therapy as soon as possible. Correct answer: D Rationale: Oseltamivir (Tamiflu) is the only one indicated for prophylaxis of influenza infection. Both oseltamivir and zanamivir can be used to treat active influenza illness. Treatment with oseltamivir and zanamivir ideally should begin within 2 days of symptom onset. Copyright © 2017, Elsevier Inc. All rights reserved. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Antiviral Drugs (Cont.) Opportunistic infections Occur in immunocompromised patients Would not normally harm an immunocompetent person Require long-term prophylaxis and antiinfective drug therapy Can be other viruses, fungi, bacteria, or protozoa Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Cont.) Used to treat infections caused by viruses other than HIV Antiretroviral drugs Used to treat infections caused by HIV, the virus that causes AIDS Copyright © 2017, Elsevier Inc. All rights reserved.

Herpes Simplex and Varicella Zoster Virus Infections Herpesviridae HSV-1 (oral herpes) HSV-2 (genital herpes) Chickenpox and shingles (HHV-3 or VZV) Epstein-Barr (HHV-4) CMV (HHV-5) Human herpesviruses 6 and 7 are not especially clinically significant; immunocompromised patients Kaposi’s sarcoma (HHV-8) Copyright © 2017, Elsevier Inc. All rights reserved.

Herpes Simplex and Varicella Zoster Virus Infections (Cont.) Herpesviridae (Cont.) HSV-2 (genital herpes) Highly transmissible “Neonatal” herpes Chickenpox (HHV-3 or VZV): varicella virus vaccine Copyright © 2017, Elsevier Inc. All rights reserved.

Herpes Simplex and Varicella Zoster Virus Infections (Cont.) Herpesviridae (Cont.) Shingles (HHV-3 or VZV) Painful: opioids for pain control Postherpetic neuralgias Acyclovir may speed recovery; best results are generally seen when the antiviral drug is started within 72 hours of symptom onset Zostavax Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Hepatitis B Mild, without symptoms or chronic hepatitis or liver failure and death Transmission of hepatitis B virus occurs through blood and body fluid exposure. Transmission to infants Hepatitis B vaccine Antiviral drug therapy for hepatitis B: lamivudine, tenofovir, and telbivudine, and alfa-interferon Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Hepatitis C Leading cause of liver failure leading to liver transplantation Symptoms Transmission: infected blood and sexual contact Alcoholic disease can lead to development of hepatitis C Treatment: interferon, ribavirin, simeprevir, and sofosbuvir Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV) Mechanism of action Most of the current antiviral drugs work by blocking the activity of a polymerase enzyme that normally stimulates the synthesis of new viral genomes. Used to treat non-HIV viral infections Influenza viruses HSV, VZV CMV Hepatitis Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV) (Cont.) Adverse effects Vary with each drug Healthy cells are often killed also, resulting in serious toxicities. Interactions Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV) (Cont.) Amantadine (Symmetrel) Narrow antiviral spectrum; active only against influenza A Most recent guidelines do not recommend use for treatment or prevention of flu Central nervous system (CNS) effects: insomnia, nervousness, light-headedness Gastrointestinal (GI) effects: anorexia, nausea, others Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV) (Cont.) Rimantadine (Flumadine) Same spectrum of activity, mechanism of action, and indications as amantadine Fewer CNS adverse effects Causes GI upset Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV) (Cont.) Acyclovir (Zovirax) Synthetic nucleoside analog Used to suppress replication of HSV-1, HSV-2, VZV Drug of choice for treatment of initial and recurrent episodes of these infections Oral, topical, parenteral forms Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV) (Cont.) Ganciclovir (Cytovene) Synthetic nucleoside analog Used to treat infection with CMV Oral, parenteral forms CMV retinitis Ophthalmic form surgically implanted (Vitrasert) Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV): Dose-Limiting Toxicities Ganciclovir Bone marrow toxicity Foscarnet and cidofovir Renal toxicity Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV): Neuraminidase Inhibitors Oseltamivir (Tamiflu) and zanamivir (Relenza) Active against influenza types A and B Reduce duration of illness Oseltamivir: causes nausea and vomiting Zanamivir: causes diarrhea, nausea, sinusitis Treatment should begin within 2 days of influenza symptom onset. Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV): Ribavirin (Virazole) Synthetic nucleoside analog Given orally, or by oral or nasal inhalation Inhalation form (Virazole) used for hospitalized infants with RSV infections Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV): Simeprevir (Olysio) Protease inhibitor (PI) Chronic hepatitis C Approved in 2013 Used in conjunction with standard hepatitis C treatments: interferon and ribavirin Not to be used as monotherapy Copyright © 2017, Elsevier Inc. All rights reserved.

Antiviral Drugs (Non-HIV): Sofosbuvir (Solvald) First-in-class RNA polymerase inhibitor for the treatment of chronic hepatitis C Sofosbuvir is considered “break-through” therapy. First drug treatment for hepatitis C that can be given without interferon Used in combination with ribavirin Not to be used as monotherapy Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. HIV and AIDS New cases of HIV have decreased by 33% since 2001 Retrovirus Transmitted by sexual activity, intravenous drug use, perinatally from mother to child The risk for transmission to health care workers via percutaneous (needlestick) injuries is currently calculated at approximately 0.3%. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Human immunodeficiency virus Copyright © 2017, Elsevier Inc. All rights reserved.

Life cycle of the human immunodeficiency virus (HIV) Copyright © 2017, Elsevier Inc. All rights reserved.

Four Stages of HIV Infection* Stage 1: asymptomatic infection Stage 2: early, general symptoms of disease Stage 3: moderate symptoms Stage 4: severe symptoms, often leading to death *World Health Organization model. Copyright © 2017, Elsevier Inc. All rights reserved.

Timeline for the spectrum of untreated HIV infection Copyright © 2017, Elsevier Inc. All rights reserved.

Audience Response System Question A patient with HIV infection is seen in the clinic. The nurse notes the patient is experiencing weight loss, chronic diarrhea, fever, and dropping CD4 counts. The nurse anticipates the patient is in which stage of HIV infection? Stage 1 Stage 2 Stage 3 Stage 4 Correct answer: C Rationale: During stage 3, the infection progresses to a moderately symptomatic state. Weight loss, chronic diarrhea, and fever continue, and CD4 counts continue to drop. Opportunistic infections begin, including severe bacterial pneumonias and pulmonary tuberculosis (TB). Pulmonary TB is usually more severe in persons with AIDS and is currently the leading cause of death worldwide for HIV-infected patients. Copyright © 2017, Elsevier Inc. All rights reserved. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Opportunistic Infections Protozoal Toxoplasmosis of the brain, others Fungal Candidiasis of the lungs, esophagus, trachea Pneumocystis jiroveci pneumonia, others Viral CMV disease, HSV infection, others Copyright © 2017, Elsevier Inc. All rights reserved.

Opportunistic Infections (Cont.) Bacterial Various mycobacterial infections, others Extrapulmonary TB Opportunistic neoplasias Kaposi’s sarcoma, others HIV wasting syndrome Major weight loss, chronic diarrhea, chronic fever Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Antiretroviral Drugs Highly active antiretroviral therapy Includes at least three medications These medications work in different ways to reduce the viral load. Copyright © 2017, Elsevier Inc. All rights reserved.

Antiretroviral Drugs (Cont.) Reverse transcriptase inhibitors (RTIs) Block activity of the enzyme reverse transcriptase, preventing production of new viral DNA PIs Inhibit the protease retroviral enzyme, preventing viral replication Fusion inhibitors Inhibit viral fusion, preventing viral replication Entry inhibitor: CCR5 coreceptor antagonists HIV integrase strand transfer inhibitors Copyright © 2017, Elsevier Inc. All rights reserved.

Antiretroviral Drugs: Adverse Effects Numerous and vary with each drug Drug therapy may need to be modified because of adverse effects. Goal is to find the regimen that will best control the infection with a tolerable adverse effect profile Medication regimens change during the course of the illness. Copyright © 2017, Elsevier Inc. All rights reserved.

Audience Response System Question A patient with active HIV has been taking zidovudine (Retrovir). Which potential adverse effect may limit the length of time this medication can be taken? Lactic acidosis Bone marrow suppression Hepatomegaly Fatigue Correct answer: B Rationale: The major dose-limiting adverse effect of zidovudine (Retrovir) is bone marrow suppression, and this is often the reason a patient with an HIV infection must be switched to another anti-HIV drug. Copyright © 2017, Elsevier Inc. All rights reserved. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Antiretroviral Drugs Enfuvirtide (Fuzeon) Fusion inhibitors Suppresses the fusion process whereby a virion is attached to the outer membrane of a host T cell before entry into the cell and subsequent viral replication Used for treatment of HIV infection in combination with other antiretroviral drugs. Use of this drug in combination with other standard antiretroviral drugs: markedly reduced viral loads Drug is currently available only in injectable form Copyright © 2017, Elsevier Inc. All rights reserved.

Other Viral Infections Avian flu West Nile virus infection Severe acute respiratory syndrome H1N1 influenza virus (“swine flu”) Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Nursing Implications Before beginning therapy, thoroughly assess underlying disease and medical history, including allergies. Assess baseline vital signs and nutritional status. Assess for contraindications, conditions that may indicate cautious use, and potential drug interactions. Copyright © 2017, Elsevier Inc. All rights reserved.

Nursing Implications (Cont.) Be sure to teach proper application technique for ointments, aerosol powders, and so on. Emphasize hand washing before and after administration of medications to prevent site contamination and spread of infection. Instruct patients to wear a glove or finger cot when applying ointments or solutions to affected areas. Copyright © 2017, Elsevier Inc. All rights reserved.

Nursing Implications (Cont.) Instruct patients to consult their prescribers before taking any other medication, including over-the-counter medications. Emphasize the importance of good hygiene. Inform patients that antiviral drugs are not cures but do help to manage symptoms. Copyright © 2017, Elsevier Inc. All rights reserved.

Nursing Implications (Cont.) Instruct patients on the importance of taking these medications exactly as prescribed and for the full course of treatment. Instruct patients to start therapy with antiviral drugs at the earliest sign of recurrent episodes of genital herpes or herpes zoster. Copyright © 2017, Elsevier Inc. All rights reserved.

Audience Response System Question The nurse administers maraviroc (Selzentry) to a patient with HIV infection. It is most important for the nurse to monitor which of the following? CD4 count Bone marrow suppression Urinary output Liver function tests Correct answer: D Rationale: The antiretroviral drug maraviroc requires assessment of allergies and liver function, as well as review of the list of medications the patient is taking, because of the lengthy list of interacting drugs. Copyright © 2017, Elsevier Inc. All rights reserved. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Nursing Implications (Cont.) Monitor for adverse effects: Effects are varied and specific to each drug. Monitor for therapeutic effects: Effects vary depending on the type of viral infection. Effects range from delayed progression of AIDS and other viruses to a decrease in flulike symptoms, decrease in frequency of herpes-like flare-ups, or crusting over of herpetic lesions. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Case Study (Cont.) When teaching patients about treatment of viral infection with Acyclovir (Zovirax), which of the following statements will the nurse include? The drug is used mainly to suppress the replication of HSV-1, HSV-2, and VZV. Acyclovir (Zovirax) is only effective for initial viral infections. Acyclovir (Zovirax) is available in topical form only. Acyclovir (Zovirax) is taken once daily. Correct answer: A Rationale: Acyclovir (Zovirax) is a synthetic nucleoside analogue that is used mainly to suppress the replication of HSV-1, HSV-2, and VZV. Acyclovir is considered the drug of choice for the treatment of both initial and recurrent episodes of these viral infections. Acyclovir is available in oral, topical, and injectable formulations. Acyclovir (Zovirax) is taken five times daily. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Case Study (Cont.) When reviewing the antiviral medications oseltamivir (Tamiflu) and zanamivir (Relenza) used for treatment of the flu, which of the following statements should the nurse include? These drugs are effective only for influenza A. These drugs decrease the effects of the flu by 12 hours. Zanamivir is currently indicated only for treatment of active influenza. The most commonly reported adverse events with oseltamivir are diarrhea, nausea, and sinusitis. Correct answer: C Rationale: Zanamivir is currently indicated only for treatment of active influenza. These drugs are active against influenza virus types A and B. They have been shown to reduce the duration of influenza infection by several days. The most commonly reported adverse events with oseltamivir are nausea and vomiting. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Case Study (Cont.) Which of the following drugs does the nurse include when teaching caregivers about treatment of neonates with RSV? Telbivudine (Tyzeka) Sofosbuvir (Solvald) Ganciclovir (Cytovene) Ribavirin (Virazole) Correct answer: D Rationale: Telbivudine (Tyzeka) is a nucleoside analogue RTI indicated for chronic hepatitis B. Sofosbuvir (Solvald) is the first-in-class RNA polymerase inhibitor for the treatment of chronic hepatitis C. Ganciclovir (Cytovene) is indicated for the treatment of infections caused by CMV. The inhalational form (Virazole) is used primarily in the treatment of hospitalized infants with severe lower respiratory tract infections caused by RSV. Copyright © 2017, Elsevier Inc. All rights reserved.

Copyright © 2017, Elsevier Inc. All rights reserved. Case Study (Cont.) Which statement should the nurse include when teaching the patient about Indinavir (Crixivan) therapy? The drug must be taken with food. Patients taking the drug should be encouraged to drink at least 48 ounces of liquid daily. This drug is best absorbed in an alkaline environment. Indinavir decreases CD4 cell counts. Correct answer: B Rationale: Patients who take indinavir are encouraged to drink at least 48 oz of liquids every day to maintain hydration and help avoid nephrolithiasis. This drug is best dissolved and absorbed in an acidic gastric environment, and the presence of high-protein and high-fat foods reduces its absorption. Therefore, it is recommended that it be administered in a fasting state. Indinavir therapy produces increases in CD4 cell counts and significant reductions in viral load. Copyright © 2017, Elsevier Inc. All rights reserved.