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Antiviral agents

Last updated: March 25, 2021

Summary

Antivirals are a class of medications that are used to treat viral infections. Most viral infections resolve spontaneously in immunocompetent individuals. The aim of antiviral therapy is to minimize symptoms and infectivity as well as to shorten the duration of illness. These drugs act by arresting the viral replication cycle at various stages. Currently, antiviral therapy is available only for a limited number of infections. Most of the antiviral drugs currently available are used to treat infections caused by HIV, herpes viruses, hepatitis B and C viruses, and influenza A and B viruses. Because viruses are obligate intracellular parasites, it is difficult to find drug targets that interfere with viral replication without also harming the host cells. Unlike other antimicrobials, antiviral drugs do not deactivate or destroy the microbe (in this case, the virus) but act by inhibiting replication. In this way, they prevent the viral load from increasing to a point where it could cause pathogenesis, allowing the body's innate immune mechanisms to neutralize the virus. This article provides an overview of the most commonly used antiviral agents. For more information on antiretroviral agents used in the treatment of HIV, which is known as highly active antiretroviral therapy (HAART), see HIV therapy.

Overview of antiviral agents and their mechanisms of action

Overview

Viruses are obligate pathogens, which depend on host-cell machinery for replication. Most antiviral agents target key enzymes required for viral replication (see viral life cycle for details).

Viral replication cycle and targets of antiviral drugs
Viral replication cycle	Target	Antiviral drug
Fusion with host cell	Attachment	CCR5-antagonist (e.g., maraviroc)
Fusion with host cell	Penetration	Fusion inhibitor (e.g., enfuvirtide)
Uncoating	Release of nucleic acid	Amantadine
Replication of viral genome	Reverse transcription	NRTI (e.g., lamivudine) NNRTI (e.g., nevirapine, efavirenz)
	DNA integration (integrase)	Integrase inhibitors (e.g., dolutegravir, elvitegravir, raltegravir)
	Nucleic acid synthesis (DNA polymerase)	Guanosine analogs (e.g., acyclovir, ganciclovir) Viral DNA polymerase inhibitors (e.g., cidofovir, foscarnet) Guanine nucleotide synthesis inhibitor (e.g., ribavirin)
Protein synthesis and assembly of viral components	Protein synthesis (transcription and translation)	Interferon alpha
Protein synthesis and assembly of viral components	Proteolytic processing (protease)	Protease inhibitors (e.g., atazanavir, darunavir, indinavir for HIV, boceprevir for HCV)
Release of new viruses from host cell	Viral budding	Neuraminidase inhibitors (e.g., oseltamivir, zanamivir)

Overview of antiviral agents and their mechanisms of action

Antivirals against influenza viruses

Antiviral against influenza ^[1]^[2]^[3]
Agents	Mechanism of action	Indications	Adverse effects
Amantadine Rimantadine	M2 ion channel blocker Weak NMDA receptor antagonist	Influenza A Parkinson disease: See “Medication for Parkinson disease.”	Neurological Ataxia Anxiety Gastrointestinal Nausea Vomiting Skin: livedo reticularis Other: peripheral edema Amantadine only Orthostatic dysregulation QT interval prolongation
Oseltamivir Zanamivir Peramivir	Neuraminidase inhibitor: blockage of viral budding and prevention of viral dissemination into the bloodstream by inhibiting neuraminidase enzyme	Treatment of influenza A and B (reduces symptom duration if taken within 1–2 days of symptom onset) Prophylaxis of influenza in adults and pediatric patients ≥ 5 years of age	Pulmonary: upper respiratory tract infections Gastrointestinal Nausea Vomiting Other: headache
Baloxavir marboxil	Viral RNA polymerase endonuclease inhibitor: blocks the endonuclease of the viral RNA polymerase → endonuclease cannot remove the 5' cap from host RNA (a process referred to as cap snatching) → without the 5' cap primer, the viral RNA polymerase cannot synthesize RNA → ↓ viral replication	Treatment of influenza A and B (reduces symptom duration if taken within 48 hours of symptom onset)	Gastrointestinal Nausea Diarrhea Pulmonary: bronchitis Other: headache

In influenza A and B, administration of neuraminidase inhibitors within 2 days of symptom onset is vital to reduce the duration of illness and alleviate symptoms.

Antivirals against herpes viruses

Antivirals against herpes ^[4]^[5]^[6]
Agents	Mechanism of action	Indications	Adverse effects	Mechanism of antiviral resistance
Acyclovir Valacyclovir (prodrug of acyclovir with greater oral bioavailability) Penciclovir Famciclovir (prodrug of penciclovir with greater oral bioavailability)	Guanosine analog (nucleoside analog) HSV/VZV-coded thymidine kinase monophosphorylates the guanosine analog to an active intermediate → phosphorylation by cellular kinases → acyclovir triphosphate (ACV-TP) The phosphorylated drug is incorporated into the replicating viral DNA strand → inhibition of viral DNA polymerase via chain termination Selective action in infected cells only with minimal effect on host cells → fewer side effects	Active infection (not effective against latent infections ) Herpes simplex Systemic: HSV encephalitis, and genital herpes Topical: early genital and mucocutaneous herpes Varicella zoster: (e.g., active shingles) treated with systemic acyclovir, especially in immunocompromised adults EBV (weak activity) Prophylaxis in immunodeficient individuals No effect on CMV	Acyclovir Obstructive crystal-induced nephropathy Acute kidney injury Both can be prevented by adequate hydration and dosage adjustment Thrombotic thrombocytopenic purpura Gastrointestinal symptoms (e.g., nausea) ↑ Transaminases	Mutation of viral thymidine kinase
Ganciclovir Valganciclovir (prodrug of ganciclovir with greater oral availability)	Guanosine analog (nucleoside analog) Phosphorylation to 5' monophosphate by the CMV-coded UL97 kinase → further phosphorylation to triphosphate by cellular kinases Incorportaion of the phosphorylated drug into the replicating viral DNA strand → inhibition of viral DNA polymerase → termination of viral DNA synthesis Lower selectivity than acyclovir and penciclovir → inhibition of host cells' DNA replication → higher toxicity	Systemic treatment of choice for CMV retinitis in immunocompromised patients (e.g., patients with AIDS) CMV prophylaxis in transplant recipients	Myelotoxicity: pancytopenia (additive effect when administered with NRTIs) Nephrotoxicity Gastrointestinal symptoms (e.g., nausea) CNS Headache Confusion Paresthesias	Mutation of viral UL97 kinase
Foscarnet (pyrophosphate analog)	Inhibition of DNA/RNA polymerase and HIV reverse transcriptase → direct inhibition of viral DNA polymerases via attachment to the pyrophosphate-binding site of the enzyme Does not require activation by viral kinase	Ganciclovir-resistant CMV retinitis in immunocompromised individuals (e.g., patients with AIDS) Acyclovir-resistant HSV	Nephrotoxicity Gastrointestinal symptoms (e.g., nausea) CNS Headache Confusion Seizures due to electrolyte abnormalities (e.g., hypocalcemia, hypokalemia) Paresthesias Hematological abnormalities Leukopenia Neutropenia	Mutation of viral DNA polymerase
Cidofovir	Viral DNA polymerase inhibitor with a long half-life Direct inhibition of viral DNA polymerases Does not require activation by viral kinase	CMV retinitis in immunocompromised individuals (e.g., patients with AIDS) Acyclovir-resistant HSV	Nephrotoxicity (reduced with administration of probenecid and IV fluids)	Mutation of viral DNA polymerase
Fomivirsen	Antisense antiviral that blocks translation of viral mRNA	Local treatment of CMV retinitis in patients with AIDS (intraocular injection)	Eye infections Increase in intraocular pressure Macular edema	Unknown

Antivirals against hepatitis B and C

See “Antiviral treatment of chronic hepatitis C” and “Antiviral treatment of chronic hepatitis B.”

Antivirals against both hepatitis B and C

Antivirals against both hepatitis B and C ^[7]^[8]
Agents	Mechanism of action	Indications	Contraindications	Adverse effects
Pegylated interferon-α and interferon-α	Antiviral and immunomodulatory effect via intercellular and intracellular mechanisms Inhibition of viral protein synthesis Promotion of breakdown of viral RNA Increased expression of MHC class I molecules	Monotherapy in acute hepatitis C and chronic active hepatitis B As a combination treatment in chronic hepatitis C	Decompensated cirrhosis Psychiatric conditions Pregnancy Autoimmune conditions Leukopenia or thrombocytopenia	Flu-like symptoms Bone marrow suppression CNS Depressive mood Seizures Induction of autoantibodies Myopathy

Antivirals against hepatitis B

Antivirals against hepatitis B only ^[8]

Agents

Mechanism of action

Indications

Adverse effects

Tenofovir

Adefovir

Nucleotide analog (adenosine analog): phosphorylated to triphosphate in hepatic cells (activation) → binds to viral DNA polymerase → causes premature termination of DNA transcription

Chronic active hepatitis B, HIV

Nephrotoxicity (e.g., Fanconi syndrome)
Headache and abdominal pain
Disease exacerbation is possible.

Entecavir

Lamivudine

Telbivudine

Nucleoside analog: inhibition of reverse transcriptase

Chronic active hepatitis B
HIV

Occasional
- Gastrointestinal symptoms
- Fever
- Headache
Rare
- Vasculitides
- Neuropathies
- Neutropenia
- Lactic acidosis

Antivirals against hepatitis C

Antivirals against hepatitis C only ^[7]
Agents		Mechanism of action	Indications	Adverse effects
Ribavirin		Guanosine analog (nucleoside inhibitor) Competitive inhibition of IMP dehydrogenase → prevention of guanine nucleosides synthesis	Adjunct in combination treatment of hepatitis C refractory to direct-acting antivirals for all HCV genotypes Viral hemorrhagic fever RSV bronchiolitis	Hemolytic anemia Highly teratogenic Nausea
Direct acting antivirals (DAAs)	Glecaprevir	NS3/4A protease inhibitors Inhibition of NS3/4A (an HCV serine protease required for viral replication) → ↓ viral replication	Chronic hepatitis C infection (all genotypes)	Headache Fatigue Nausea
	Grazoprevir		Chronic hepatitis C infection (genotypes 1a, 1b, and 4)	Headache Fatigue Nausea
	Paritaprevir		Chronic hepatitis C infection (genotype 1 or 4)	Headache Fatigue Nausea Insomnia Asthenia Pruritus Allergic skin reactions
	Simeprevir		Chronic hepatitis C infection	Photosensitivity Rash Fatigue Headache Abdominal pain Diarrhea
	Voxilaprevir		Chronic hepatitis C infection (all genotypes)	Headache Fatigue Diarrhea Nausea
	Daclatasvir	Non-nucleoside NS5A polymerase inhibitors Exact mechanism of action is unknown Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication	Chronic hepatitis C infection (genotype 1, 3, or 4)
	Elbasvir		Chronic hepatitis C infection (genotype 1 and 4)
	Ledipasvir		Chronic hepatitis C infection (genotypes 1a and 1b)
	Ombitasvir		Chronic hepatitis C infection (genotypes 1a, 1b, and 4)	Headache Diarrhea Fatigue Nausea Insomnia Asthenia Pruritus Skin reactions
	Pibrentasvir		Chronic hepatitis C infection (all genotypes)	Headache Fatigue Nausea Diarrhea
	Velpatasvir		Chronic hepatitis C infection (all genotypes)	Headache Diarrhea Fatigue
	Dasabuvir	NS5B inhibitors Inhibition of NS5B (a RNA-dependent RNA polymerase) → chain termination and disruption of RNA synthesis → prevention of HCV replication	Chronic hepatitis C infection (genotypes 1a and 1b)	Fatigue Headache Insomnia Pruritus Asthenia Nausea
	Sofosbuvir		Chronic hepatitis C infection (all genotypes)	Fatigue Headache Insomnia Pruritus Asthenia Nausea

Protease inhibitors used to treat HIV end in ”navir.” Protease inhibitors used to treat HCV end in “previr.”

References

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He Z, He YS, Kim Y, et al. The human cytomegalovirus UL97 protein is a protein kinase that autophosphorylates on serines and threonines.. J Virol. 1997; 71 (1): p.405-11.
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/AASLD-IDSA_HCVGuidance_August_27_2020.pdf. Updated: August 27, 2020. Accessed: December 3, 2020.
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