Category:Antivirals

An antiviral is a medicine that interferes with the replication or assembly of a virus in a human host. The category is younger and more pathogen-specific than the antibacterial one: most antivirals act on a single viral family or even a single viral enzyme, because the obligate intracellular life cycle of the virus leaves few molecular targets that are not also targets in the host cell, and selective toxicity must usually be obtained by exploiting an enzyme unique to a particular virus.

The clinical use of antiviral medicines began in 1962 with idoxuridine, a halogenated pyrimidine analogue developed by William Prusoff at Yale as a potential anticancer agent that was found instead to inhibit herpes simplex virus DNA polymerase; it became the first topical treatment for herpetic keratitis. The medicine was too toxic for systemic use, but it established the principle: a nucleoside analogue that the viral enzyme preferentially incorporated into nascent viral DNA, but that the corresponding human enzyme rejected, could selectively kill the virus.

The first effective systemic antiviral was the work of Gertrude Elion and her colleagues at Burroughs Wellcome. Elion had spent decades developing purine and pyrimidine analogues for cancer chemotherapy (6-mercaptopurine, azathioprine, allopurinol); in the 1970s the same screening framework was turned toward viral enzymes. Aciclovir (acyclovir), reported in 1977, was an acyclic guanosine analogue that required phosphorylation by the herpes simplex virus thymidine kinase to its monophosphate, then by cellular kinases to the triphosphate, which selectively inhibited the viral DNA polymerase.^[1] Because the host cell did not phosphorylate the medicine to any meaningful extent, aciclovir was concentrated, by orders of magnitude, in herpes-infected cells. The selectivity was extraordinary, and the medicine remains the standard treatment for herpes simplex and herpes zoster decades later. Elion shared the 1988 Nobel Prize. Valacyclovir (the L-valyl ester prodrug, 1995) and famciclovir (the prodrug of penciclovir, 1994) improved oral bioavailability without changing the underlying pharmacology.

The transformative antiviral event of the late twentieth century was the introduction of antiretroviral therapy for human immunodeficiency virus. Zidovudine (azidothymidine, AZT) had been synthesised by Jerome Horwitz in 1964 as a failed anticancer agent. In 1985 Hiroaki Mitsuya and Samuel Broder at the National Cancer Institute, screening Horwitz's old compound collection, showed that AZT inhibited HIV reverse transcriptase in vitro; the medicine was rushed through trial and approved in 1987, becoming the first antiretroviral.^[2] Monotherapy with zidovudine produced rapid resistance and limited survival benefit; the breakthrough was the 1996 introduction of triple-drug "highly active antiretroviral therapy" (HAART), in which two nucleoside reverse transcriptase inhibitors were combined with either a protease inhibitor (saquinavir, ritonavir, indinavir, nelfinavir) or a non-nucleoside reverse transcriptase inhibitor (nevirapine, efavirenz). HAART converted HIV infection from a uniformly fatal disease (median survival approximately 10 years after seroconversion before 1996) to a chronic manageable condition with near-normal life expectancy on continuous treatment. Subsequent classes (the integrase strand transfer inhibitors raltegravir, dolutegravir, bictegravir; the fusion inhibitors and entry inhibitors maraviroc, enfuvirtide; the capsid inhibitor lenacapavir) and once-daily fixed-dose combination tablets have made modern antiretroviral therapy a single pill, taken once a day, with minimal side effect.

The second great antiviral story of the contemporary period is the cure of hepatitis C. The virus, identified in 1989 by Houghton, Choo, Kuo, and Bradley at Chiron, had been treated with interferon-alpha (combined later with the nucleoside analogue ribavirin) at sustained-virologic-response rates of approximately 50 percent, with substantial flu-like and psychiatric side effects. The introduction of the direct-acting antivirals (DAAs) in 2013-2014 changed the field within two years. Sofosbuvir (Gilead, 2013), an NS5B polymerase nucleotide inhibitor, combined with the NS5A inhibitors ledipasvir, daclatasvir, velpatasvir, and the protease inhibitors simeprevir and grazoprevir, produced sustained-virologic-response rates above 95 percent across all genotypes with 8-to-12-week oral courses and minimal side effects.^[3] The DAA-era hepatitis C cure is one of the rare modern examples of a chronic viral infection rendered eliminable by short-course medicine alone, and the WHO has targeted hepatitis C for elimination as a public-health problem by 2030.

The other antiviral pathogens have produced more limited but real progress. Influenza is treated with the neuraminidase inhibitors oseltamivir (Tamiflu, Gilead/Roche, 1999) and zanamivir, which block release of new viral particles from infected cells, and with the cap-dependent endonuclease inhibitor baloxavir (2018); these medicines shorten symptom duration by approximately one day in immunocompetent adults but have a more substantial benefit in the very young, the elderly, and the immunocompromised. The hepatitis B virus is suppressed (though not cured) by the nucleoside and nucleotide reverse-transcriptase inhibitors tenofovir, entecavir, and (the original) lamivudine. The recently developed antivirals for severe acute respiratory syndrome coronavirus 2 (remdesivir, the RNA-dependent RNA polymerase nucleotide inhibitor, 2020; nirmatrelvir/ritonavir, the 3CL protease inhibitor combination, 2021) provide modest clinical benefit in early COVID-19 in high-risk patients. The cytomegalovirus medicines ganciclovir and valganciclovir, and the recently approved letermovir, treat CMV in transplantation. The smallpox antiviral tecovirimat (2018), originally developed against bioterrorism strains of variola, was repurposed for human mpox in 2022.

What unifies the contemporary antiviral category, in contrast to the antibacterials, is that for many of the historically lethal viral infections there is now either an effective treatment, an effective vaccine, or both. The category remains poor in agents for the respiratory RNA viruses other than influenza (no effective antiviral for respiratory syncytial virus in adults, none for human metapneumovirus, none for the seasonal coronaviruses); for the dengue and other arboviruses; and for the haemorrhagic-fever viruses except Ebola, where the monoclonal antibody cocktail Inmazeb and the single-agent ansuvimab are now first-line. The expansion of the category continues to be driven by the genomic identification of new viral enzymes that have no human counterpart.

By target:

• Herpesvirus medicines (anti-herpesvirus agents, herpes simplex and varicella zoster): aciclovir (acyclovir) and its valyl prodrug valaciclovir; famciclovir (prodrug of penciclovir); for cytomegalovirus the more potent ganciclovir and valganciclovir, with foscarnet for resistant CMV and the recent letermovir
• Influenza medicines (anti-influenza agents and neuraminidase inhibitors): oseltamivir, zanamivir, peramivir (intravenous), baloxavir (cap-dependent endonuclease inhibitor)
• Antiretrovirals (HIV): the nucleoside / nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, abacavir, tenofovir alafenamide and disoproxil fumarate, emtricitabine), the non-nucleoside reverse transcriptase inhibitors (efavirenz, rilpivirine, doravirine), the protease inhibitors (ritonavir as booster, darunavir, atazanavir), the integrase strand transfer inhibitors (raltegravir, dolutegravir, bictegravir, cabotegravir), the entry and fusion inhibitors (maraviroc, enfuvirtide), the capsid inhibitor lenacapavir, and the long-acting injectable cabotegravir/rilpivirine
• Hepatitis C direct-acting antivirals: NS5B polymerase inhibitors (sofosbuvir), NS5A inhibitors (ledipasvir, velpatasvir, daclatasvir, pibrentasvir), NS3/4A protease inhibitors (glecaprevir, voxilaprevir, grazoprevir); the fixed-combinations sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, sofosbuvir/velpatasvir/voxilaprevir
• Hepatitis B (suppressive): tenofovir, entecavir, lamivudine; pegylated interferon-alfa for selected patients
• SARS-CoV-2 (COVID-19): remdesivir (intravenous, hospitalised patients), nirmatrelvir/ritonavir (oral, outpatient), molnupiravir (oral, outpatient, modest benefit)
• Other viral families: tecovirimat for mpox/variola; ribavirin (broad-spectrum guanosine analogue, used for hepatitis C in older regimens, for respiratory syncytial virus in selected paediatric cases, and for selected haemorrhagic fevers); the Ebola monoclonal antibodies Inmazeb and ansuvimab; the broad-spectrum unproven amantadine and rimantadine (now largely retired for influenza because of universal M2 channel resistance)

The boundary of this category is "medicine that inhibits replication of a virus pathogenic to humans." The vaccines that prevent viral infection (the influenza vaccines, the SARS-CoV-2 mRNA and adenovirus-vectored vaccines, the hepatitis A and B vaccines, the human papillomavirus vaccine, the measles-mumps-rubella vaccine, and many others) are an entirely different pharmacological category, although they accomplish similar clinical aims; they are collected under biologics and under their specific vaccine indications. The monoclonal antibodies used in pre-exposure or post-exposure prophylaxis of viral disease (the RSV agents palivizumab and nirsevimab; the SARS-CoV-2 agents in the changing succession that resistance has produced; the Ebola Inmazeb and ansuvimab) are biologic medicines and are listed here when used as treatment and under monoclonal antibodies otherwise. Interferons (interferon-alpha for hepatitis B and historically hepatitis C; interferon-beta for multiple sclerosis) are collected under immunomodulators when their indication is autoimmune.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.