Antivirals for Respiratory and Hepatitis Viruses

Beyond the herpesviruses and HIV, antivirals exist for the respiratory viruses, influenza and SARS-CoV-2, and for the hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV), with ribavirin as the ageing broad-spectrum agent. Their value, though, is very uneven, and it is worth saying so plainly at the outset. The respiratory-virus antivirals offer modest and often contested benefit: they shorten illness somewhat when started early, but their effect on the outcomes that matter most, hospitalisation and death, is weak. The hepatitis drugs are the opposite, among the most effective agents in all of medicine: entecavir and tenofovir suppress hepatitis B indefinitely, and the hepatitis C direct-acting antivirals cure almost everyone in a few weeks. The difference tracks the biology. Chronic hepatitis B is suppressed for life but not cured, because the virus keeps a stable nuclear reservoir of covalently closed circular DNA (cccDNA); chronic hepatitis C is cured, because it has no such latent form; and the acute respiratory infections are largely over before a drug has much time to act. What a drug can achieve is set by the biology of the infection as much as by the drug itself.

Influenza antivirals

Regarding influenza antiviral therapy, guidelines indicate that these agents exhibit maximal efficacy when initiated within 48 hours of symptom onset, prior to peak viral replication. While historically presumed to offer the greatest clinical benefit in severe or progressive disease, studies evaluating their efficacy in critically ill patients have yielded variable and, at times, conflicting results.

Neuraminidase inhibitors

Influenza enters cells when its haemagglutinin (HA) binds sialic acid; on the way out, the same binding tethers new virions to the cell surface, and the viral neuraminidase (NA) cleaves sialic acid to release them. The neuraminidase inhibitors are transition-state analogues that block that cleavage, so progeny virions stay stuck and cannot spread. They need no intracellular activation and are active against both influenza A and influenza B. Oseltamivir is an oral prodrug and the mainstay for treatment and prophylaxis; zanamivir is inhaled, which limits it in severe disease and can provoke bronchospasm; peramivir is intravenous and reserved for patients who cannot take the oral or inhaled routes. Resistance is most often the H275Y substitution in the neuraminidase, which sharply reduces oseltamivir and peramivir binding but spares zanamivir; a fit H275Y seasonal H1N1 strain spread globally in 2008, showing that such resistance need not carry a fitness cost.

Baloxavir marboxil

Baloxavir attacks the polymerase rather than the surface. The influenza polymerase steals a cap from host messenger RNA to prime its own transcription, a process called cap-snatching, and the PA subunit’s cap-dependent endonuclease performs the cut. Baloxavir inhibits that endonuclease, blocking viral messenger RNA synthesis for influenza A and B, and it works as a single oral dose. It retains activity against neuraminidase-inhibitor-resistant strains. Its weakness is on-treatment resistance: the PA I38T substitution emerged in close to 10% of recipients in the pivotal trial, sometimes with viral rebound, which is why oseltamivir is often still preferred and why combination use is being explored.

The adamantanes

Amantadine and rimantadine were the first anti-influenza drugs. They block the M2 proton channel, which normally admits hydrogen ions to acidify the virion and uncoat it, and they act on influenza A only because influenza B has no M2. They have been abandoned: a single M2 mutation confers resistance at no cost to viral fitness, so resistance became near-universal, and the adamantanes are no longer recommended.

Agent	Target and action	Route	Resistance or limitation
Oseltamivir	Neuraminidase inhibitor: blocks virion release	Oral	H275Y reduces susceptibility
Zanamivir	Neuraminidase inhibitor	Inhaled	Bronchospasm; retains activity against H275Y
Peramivir	Neuraminidase inhibitor	Intravenous	For when oral or inhaled routes are unsuitable
Baloxavir marboxil	PA cap-dependent endonuclease inhibitor: blocks cap-snatching	Oral, single dose	PA I38T in nearly 10% of recipients
Amantadine, rimantadine	M2 proton-channel blocker (influenza A only)	Oral	Abandoned: near-universal, fitness-neutral resistance

The benefit of influenza antivirals is real but modest, and the evidence is weaker than the strength of the recommendations implies. In meta-analyses the neuraminidase inhibitors shorten symptoms by around a day when started within 48 hours, with little or no effect on hospitalisation or mortality, even in high-risk patients; baloxavir may shorten symptoms and perhaps reduce admissions, but the certainty is low. The benefit of treatment begun late, or in a patient already critically ill in intensive care, is especially uncertain, a common reality given how often influenza is recognised only once the patient deteriorates. Current World Health Organization and South African guidance still recommends treating severe or high-risk influenza, but the recommendation rests on a low-certainty evidence base and may change as better trials report.

COVID-19 antivirals

Three direct-acting antivirals reached use against SARS-CoV-2, each at a different target, and all are for early treatment of patients at high risk of progression rather than for established severe disease.

Nirmatrelvir is a covalent-reversible inhibitor of the SARS-CoV-2 main protease (Mpro, also called 3CLpro), the cysteine protease that cuts the viral polyproteins into functional units. Nirmatrelvir is itself poorly bioavailable and rapidly metabolised by the liver enzyme CYP3A4, so it is co-formulated with low-dose ritonavir, an old HIV protease inhibitor repurposed purely as a CYP3A4 inhibitor that blocks that metabolism and props up nirmatrelvir levels, the combination marketed as Paxlovid. The crucial caveat follows from the booster: ritonavir’s CYP3A4 inhibition produces extensive drug interactions, raising the levels of many co-medications (several statins, some antiarrhythmics, certain anticoagulants and the calcineurin inhibitors among them), and this interaction burden, not the antiviral itself, is what most limits who can take it.

Remdesivir is a prodrug of an adenosine analogue whose triphosphate the viral RNA-dependent RNA polymerase (RdRp) incorporates as a delayed chain terminator, stalling synthesis a few nucleotides later. It is given intravenously, which confines it to hospital or infusion settings, and its clinical benefit has proved marginal enough that, set against its cost, several authorities including South Africa recommend against its routine use.

Molnupiravir works by a different and striking mechanism: its active form is incorporated into viral RNA and base-pairs ambiguously, so mutations accumulate across the genome until the virus is no longer viable, a strategy called lethal mutagenesis or error catastrophe. Its efficacy is modest, it is reserved for high-risk patients when the alternatives are unsuitable, and because it is teratogenic it is not used in pregnancy or without contraception.

Host-directed treatments for severe COVID-19, such as dexamethasone, the JAK (Janus kinase) inhibitor baricitinib and the interleukin-6 blocker tocilizumab, are immunomodulators rather than antivirals and are not covered here.

Agent	Target and action	Route	Key point
Nirmatrelvir plus ritonavir	Main protease (Mpro) inhibitor, with ritonavir as a CYP3A4 booster	Oral	Extensive drug interactions through ritonavir
Remdesivir	RdRp delayed chain terminator	Intravenous	Hospital or infusion setting
Molnupiravir	Lethal mutagenesis (error catastrophe)	Oral	Modest efficacy; teratogenic

Hepatitis B antivirals

Chronic hepatitis B is controlled, not cured. The first-line agents are the nucleos(t)ide analogues entecavir and tenofovir (given as the prodrugs tenofovir disoproxil or tenofovir alafenamide), which cellular kinases activate and which the HBV polymerase incorporates as chain terminators, suppressing replication to undetectable levels. Both have a high genetic barrier to resistance, needing several mutations to fail, which is why they displaced the low-barrier agent lamivudine (whose single resistance mutation emerges quickly). The reason therapy is usually long-term or lifelong is that none of these drugs clears the cccDNA that persists in the hepatocyte nucleus: stop the drug and replication can resume, sometimes with a dangerous hepatitis flare, so treatment is not interrupted lightly.

One high-yield use is prevention rather than treatment. A patient who is hepatitis B surface antigen positive and is about to receive immunosuppression that can reactivate the virus, such as rituximab, cytotoxic chemotherapy or a stem-cell transplant, is given prophylactic tenofovir or entecavir to prevent a reactivation flare. Tenofovir is also active against HIV, so it does double duty in HIV and HBV co-infection.

Hepatitis C direct-acting antivirals

Hepatitis C is the success story of modern antiviral therapy. The old regimen of injected interferon-alpha with ribavirin was long, toxic and only partly effective; it has been wholly replaced by the direct-acting antivirals (DAAs), oral combinations that cure the great majority of patients in 8 to 12 weeks. Cure is possible, in the way it is not for HBV or HIV, because HCV is an RNA virus with no latent DNA reservoir: suppress replication for long enough and the infection is eradicated, measured as a sustained virological response.

The agents come in three classes, each named by a suffix that signals its target. Treatment always combines classes, which raises the barrier to resistance and underpins the pangenotypic regimens that work across all HCV genotypes.

Class (suffix)	Target	Examples	Note
Protease inhibitors (-previr)	NS3/4A serine protease	glecaprevir, grazoprevir, voxilaprevir	Resistance at NS3 positions R155, A156, D168
NS5A inhibitors (-asvir)	NS5A replication-complex protein	velpatasvir, pibrentasvir, ledipasvir	Among the most potent antivirals known; resistance at Y93H
Polymerase inhibitors (-buvir)	NS5B RNA-dependent RNA polymerase	sofosbuvir	High barrier: the S282T mutation replicates poorly

In practice the regimens are fixed-dose combinations: sofosbuvir with velpatasvir, and glecaprevir with pibrentasvir, are the two pangenotypic backbones, with a protease inhibitor added for re-treatment after failure. Sofosbuvir illustrates why resistance is rarely a clinical problem: its only real escape mutation, S282T, cripples the polymerase, so it almost never survives.

Broad-spectrum agents

Ribavirin is an old guanosine analogue with genuinely broad activity in culture and a mechanism that has never been fully settled, variously attributed to depletion of the cellular guanosine pool through inhibition of inosine monophosphate dehydrogenase, interference with messenger RNA capping, direct polymerase inhibition and error catastrophe (ribavirin was the original drug for which lethal mutagenesis was proposed). Its place has narrowed sharply. It was once given, aerosolised, for severe respiratory syncytial virus infection and, with interferon, for chronic hepatitis C, both now largely abandoned; its remaining roles are in some viral haemorrhagic fevers (notably Lassa fever) and chronic hepatitis E in the immunocompromised. Two toxicities define its use: a dose-dependent haemolytic anaemia, and teratogenicity severe enough that it is contraindicated in pregnancy and requires contraception in both partners. Favipiravir, another broad-spectrum polymerase inhibitor, has been used for influenza and studied in other RNA-virus infections without establishing a firm place.

South African context

The South African public-sector picture reflects where antiviral benefit is clearest and where cost and logistics bite. For influenza, the National Institute for Communicable Diseases recommends oseltamivir or baloxavir for severe or complicated influenza and for those at very high risk of hospitalisation or death, started within 48 hours, while stating plainly that the evidence behind the recommendation is of low certainty. For hepatitis B, tenofovir is widely available, dovetailing with the large antiretroviral programme. For hepatitis C, the Essential Medicines List defers chronic infection to a specialist and names no direct-acting antiviral, so the curative regimens are reached through specialist and programmatic routes rather than routine prescribing. For COVID-19, care is largely supportive: the national therapeutics committee recommends against remdesivir on the balance of marginal benefit, cost and equity, and the oral agents are not part of routine public-sector care. The consistent pattern is that the cheap, high-impact interventions, tenofovir and influenza vaccination, are embedded, while the expensive newer agents sit behind specialist access or are not used at all.

References and recommended reading

• Coen DM, Namchuk MN, Kuritzkes DR. Antiviral Agents. In: Fields Virology, 7th edition (Fundamentals), Chapter 14. Wolters Kluwer; 2022. The current reference for the mechanism, spectrum, resistance and selectivity of the influenza, hepatitis B, hepatitis C and SARS-CoV-2 antivirals, and for ribavirin.
• National Department of Health, South Africa. Hospital Level (Adults) Standard Treatment Guidelines and Essential Medicines List, 6th edition; 2024. The reference for South African public-sector availability of these agents: tenofovir for hepatitis B, the specialist pathway for hepatitis C, and the supportive-care framing of COVID-19.
• National Institute for Communicable Diseases, South Africa. Influenza: NICD recommendations for the diagnosis, management, prevention and public health response, version 1.8; April 2026. The current South African source for influenza antiviral use, including its candid summary of the low-certainty evidence behind treatment.
• National Essential Medicines List Committee, South Africa. Remdesivir for COVID-19: evidence review of the clinical benefit and harm. Ministerial Advisory Committee on COVID-19 Therapeutics; 15 February 2022. The basis for the South African recommendation against routine remdesivir use.