Antiviral Agents

Chapter: Antiviral Agents
McMaster Section Editor(s): Mark Loeb
Section Editor(s) in Interna Szczeklika: Piotr Zaborowski, Jerzy Stefaniak, Miłosz Parczewski, Weronika Rymer, Agnieszka Wroczyńska
McMaster Author(s): Bahareh Ghadaki, Marek Smieja, Shariq Haider
Author(s) in Interna Szczeklika: Miłosz Parczewski
Additional Information

Pregnancy risk categories: see Table 8.2-1.

Nucleoside and Nucleotide AnaloguesTop

1. Acyclovir (INN aciclovir) (oral, IV) and valacyclovir (INN valaciclovir) (oral):

1) Spectrum of activity: Valacyclovir is an ester prodrug of acyclovir with improved bioavailability compared to acyclovir. These agents are mainly used in the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Their activity against Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) is lower. Cytomegalovirus (CMV) is resistant at clinically achievable levels.

2) Adverse reactions: With intravenous administration, central nervous system (CNS) effects, such as headache, lethargy, confusion, and tremors, seen more commonly in patients with renal insufficiency. Renal toxicity due to crystalline nephropathy and interstitial nephritis. Adequate prehydration may prevent nephrotoxicity. Oral formulations are generally well tolerated. Neurotoxicity and nephrotoxicity are less common.

3) Pregnancy risk: B.

2. Famciclovir (oral):

1) Spectrum of activity: An ester prodrug of penciclovir with improved bioavailability. Activity mainly includes HSV and VZV infections. Activity against EBV is lower. CMV is resistant at clinically achievable levels.

2) Adverse reactions: Oral formulations are generally well tolerated. Toxicity is similar to that of oral acyclovir with neurotoxicity and nephrotoxicity.

3) Pregnancy risk: B.

3. Ganciclovir (IV, ophthalmic) and valganciclovir (IV, oral):

1) Spectrum of activity: Valganciclovir is the prodrug of ganciclovir. These agents are mainly used in the treatment of CMV infections. In vitro activity also exists against other herpesviruses, including HSV, EBV, VZV, and HHV-6, although acyclovir, famciclovir, or valacyclovir are usually preferred over ganciclovir for the treatment of HSV and VZV infections. Ganciclovir is the drug of choice for the treatment of simian herpes B virus.

2) Adverse reactions: Hematologic effects (neutropenia, anemia, and thrombocytopenia) with onset commonly observed in the second week of treatment; the effects tend to be reversible. CNS effects (headache, insomnia, confusion, paresthesia).

3) Pregnancy risk: C.

4. Cidofovir (IV):

1) Spectrum of activity: Cidofovir demonstrates activity against a number of DNA viruses, including CMV, EBV, HHV-6, HHV-8, polyomaviruses (BK virus), and adenoviruses. Clinically, cidofovir is used in the treatment of CMV infections refractory or resistant to ganciclovir and foscarnet.

2) Adverse reactions: The most important toxicity is dose-dependent nephrotoxicity. Cidofovir may cause Fanconi-type syndrome with proteinuria, glucosuria, and metabolic acidosis. It should not be used in patients with creatinine clearance <55 mL/min. Hematologic effects, with the most common adverse effect being neutropenia. Ocular toxicity (iritis, uveitis, reduced intraocular pressure).

3) Pregnancy risk: C.

5. Foscarnet (IV):

1) Spectrum of activity: A pyrophosphate analogue. Foscarnet is principally used in the treatment of ganciclovir-resistant CMV infections. It also shows activity against HSV (acyclovir-resistant strains), VZV, EBV, and HHV-8.

2) Adverse reactions: The most important adverse effects include nephrotoxicity, electrolyte abnormalities (hypocalcemia, hypomagnesemia, and hypokalemia), and infusion-related nausea. Genital ulcerations have been linked to foscarnet therapy and are thought to be caused by high urinary foscarnet concentrations.

3) Pregnancy risk: C.

6. Ribavirin (oral, IV, inhaled):

1) Spectrum of activity: The main use of ribavirin is in the treatment of hepatitis C virus (HCV) infection; for HCV, ribavirin is always used in combination therapy. Clinically, it has also been used for treatment of respiratory syncytial virus (RSV) bronchiolitis and pneumonia (especially in the immunocompromised population) and several hemorrhagic fever syndromes (Lassa, Crimean-Congo).

2) Adverse reactions: In the case of intravenous and oral formulations, the most important adverse effect is dose-dependent hemolytic anemia, which may be exacerbated by cardiac disease and lead to myocardial infarctions. Avoid use in patients with significant/unstable cardiac disease. In the case of inhaled formulations, conjunctival irritation, rash, and bronchospasm may develop.

3) Pregnancy risk: X.

Nucleoside and Nucleotide Reverse-Transcriptase InhibitorsTop

Agents used exclusively in the treatment of HIV infection are not included.

1. Adefovir:

1) Spectrum of activity: Used in the treatment of hepatitis B virus (HBV) infections. The main advantage is in the treatment of lamivudine-resistant strains.

2) Adverse effects: Nephrotoxicity. Lactic acidosis and hepatomegaly. Adefovir may cause the development of HIV drug resistance in patients with unrecognized or untreated HIV infection.

3) Pregnancy risk: C.

2. Entecavir:

1) Spectrum of activity: Used in the treatment of HBV infections. Cross-resistance can be seen in patients with lamivudine-resistant strains.

2) Adverse reactions: Lactic acidosis and hepatomegaly. Entecavir may cause the development of HIV drug resistance in patients with unrecognized or untreated HIV infection.

3) Pregnancy risk: C.

3. Lamivudine:

1) Spectrum of activity: Used in the treatment of both HIV and HBV infections. The major limitation for the use of lamivudine in HBV infections is the high rates of resistance that will develop while on therapy.

2) Adverse reactions: Lactic acidosis and hepatomegaly. Lamivudine may cause the development of HIV drug resistance in patients with unrecognized or untreated HIV infection.

3) Pregnancy risk: C.

4. Telbivudine:

1) Spectrum of activity: Used in the treatment of HBV infection, although its role in primary therapy is limited.

2) Adverse reactions: Lactic acidosis and hepatomegaly. Myopathy and peripheral neuropathy.

3) Pregnancy risk: B.

5. Tenofovir disoproxil fumarate:

1) Spectrum of activity: Used in the treatment of both HIV and HBV infections. Considered first-line therapy for treatment-naive patients including those with drug-resistant viruses.

2) Adverse reactions: Decreased bone density. Nephrotoxicity (classically Fanconi syndrome). Lactic acidosis and hepatomegaly.

3) Pregnancy risk: B.

6. Tenofovir alafenamide: A prodrug of tenofovir, converted intracellularly to tenofovir.

1) Spectrum of activity: Used in treatment of both HIV and HBV infections. Considered first-line therapy for treatment-naive patients including those with drug-resistant viruses.

2) Adverse reactions: The advantages over tenofovir disoproxil fumarate are less nephrotoxicity and less effect on bone mineral density.

3) Pregnancy risk: B.

Antivirals Against Influenza VirusTop

1. Neuraminidase inhibitors: Oseltamivir (oral), zanamivir (dry powder inhaler, IV), peramivir (IV):

1) Spectrum of activity: These agents are used in the treatment of or prophylaxis against influenza A and B.

2) Adverse reactions: Rare hypersensitivity reactions, including anaphylaxis and severe cutaneous reactions (Stevens-Johnson syndrome, erythema multiforme). Rare CNS effects, such as confusion, delirium, or hallucinations, have been reported. Inhaled zanamivir has been associated with bronchospasm. Use with caution in patients with obstructive lung disease, such as asthma or chronic obstructive pulmonary disease.

3) Pregnancy risk: C.

2. Adamantanes: Amantadine (oral) and rimantadine (oral):

1) Spectrum of activity: These agents are only active against influenza A infections; however, widespread emergence of adamantane-resistant influenza A strains has limited their use. Adamantanes are no longer recommended for the treatment of influenza A infections.

2) Adverse reactions: CNS effects, such as anxiety, difficulty concentrating, and lightheadedness, have been noted during the first week of treatment. More serious adverse effects, such as seizures and delirium, are associated with high drug levels resulting from renal insufficiency, especially in those with preexisting seizure or psychiatric disorders.

3) Pregnancy risk: C.

Antivirals AGAINST HCVTop

There are 5 main categories of currently available HCV medications (a shift toward interferon-sparing regimens):

1. HCV NS3/4A protease inhibitors: Boceprevir, telaprevir, simeprevir, paritaprevir, grazoprevir, voxilaprevir, glecaprevir, asunaprevir.

2. NS5B RNA-dependent RNA polymerase inhibitors: Sofosbuvir, dasabuvir.

3. NS5A HCV protein inhibitors: Daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir.

4. Pegylated interferon alpha 2a and alpha 2b.

5. Ribavirin (see Nucleoside and Nucleotide Analogues, above).

For more information, please see the chapter on chronic hepatitis C. You may also visit www.hcvguidelines.org.

Other AntiviralsTop

Letermovir is a viral terminase inhibitor.

1. Spectrum of activity: Used in primary prophylaxis for CMV infection in patients treated with hematopoietic stem cell transplantation.

2. Adverse reactions: Nausea, vomiting, cough, peripheral edema, headache, cough, fatigue, abdominal pain, atrial arrythmias.

3. Pregnancy risk: B.

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