Antivirals for Respiratory and Hepatitis Viruses — Questions

a. Influenza (an orthomyxovirus).

b. Start a neuraminidase inhibitor (oseltamivir), continued even beyond 48 hours in severe or hospitalised disease, while recognising that the evidence in critical illness is limited; baloxavir is an alternative. The mainstay is supportive intensive care (oxygenation, lung-protective ventilation), treatment of bacterial co-infection, and appropriate infection-prevention precautions.

• a. Neuraminidase inhibitors. Active-site mutations in the neuraminidase reduce drug binding; the H275Y substitution lowers oseltamivir and peramivir susceptibility but spares zanamivir. Haemagglutinin mutations that reduce dependence on neuraminidase are a second route.
• b. Cap-dependent endonuclease inhibitors. The polymerase acidic (PA) I38T substitution reduces baloxavir susceptibility and emerged in nearly 10% of treated patients in trials, sometimes with viral rebound.

• Zanamivir. A neuraminidase inhibitor given by inhalation; useful where oseltamivir resistance is a concern, since it retains activity against H275Y.
• Peramivir. A neuraminidase inhibitor given intravenously, for patients unable to take the oral or inhaled routes.
• Baloxavir marboxil. Inhibits the polymerase acidic (PA) cap-dependent endonuclease, blocking the polymerase’s cap-snatching; a single oral dose, active against neuraminidase-inhibitor-resistant strains.
• Favipiravir. A broad-spectrum inhibitor of the viral RNA-dependent RNA polymerase, used for influenza in some settings.

• Mechanism. Oseltamivir is an oral prodrug whose active form inhibits the influenza neuraminidase, the enzyme that cleaves sialic acid to release progeny virions, leaving new virus tethered to the cell. It needs no intracellular activation and is active against influenza A and B.
• Clinical use. Treatment and post-exposure prophylaxis of influenza, of most value in severe or complicated disease and in those at high risk of complications; benefit is greatest when started within 48 hours.
• Limitations. The benefit is modest (it shortens symptoms by about a day, with little effect on hospitalisation or mortality), the 48-hour window limits real-world use, gastrointestinal upset is common, and the H275Y neuraminidase mutation can confer resistance.

The H275Y neuraminidase mutation reduces oseltamivir and peramivir binding but spares zanamivir, which remains active.

The adamantanes (amantadine, rimantadine) act on the M2 channel and are not used because of separate near-universal resistance.

Baloxavir inhibits the polymerase acidic (PA) subunit’s cap-dependent endonuclease, blocking the cap-snatching that primes viral messenger RNA synthesis.

Neuraminidase cleavage is the target of oseltamivir and zanamivir, and the M2 channel of the adamantanes; influenza has no reverse transcriptase, and fusion is not the target.

Molnupiravir’s active form is incorporated into viral RNA and base-pairs ambiguously, so mutations accumulate until the genome is no longer viable, a strategy called lethal mutagenesis or error catastrophe.

It is teratogenic and reserved for high-risk patients when alternatives are unsuitable; the other mechanisms belong to other drug classes.

Ritonavir has no useful antiviral activity here; it is a CYP3A inhibitor that blocks the metabolism of nirmatrelvir and props up its levels (pharmacokinetic boosting), which is also the source of Paxlovid’s many drug interactions.

Nirmatrelvir is the active inhibitor of the SARS-CoV-2 main protease (Mpro).

The only meaningful sofosbuvir escape mutation, S282T in the NS5B polymerase, cripples viral replication, so resistant virus is unfit and rarely survives, giving sofosbuvir a high barrier to resistance.

The other explanations are inaccurate.

Entecavir and tenofovir need several mutations to fail, so resistance is slow, whereas lamivudine’s single mutation emerges quickly; this high genetic barrier is why they are first-line.

None of these agents clears covalently closed circular DNA (cccDNA), so therapy stays long-term, and the other statements are incorrect.

A single M2 mutation confers adamantane resistance at no cost to viral fitness, so resistance spread to near-universal levels and the class was abandoned.

The adamantanes acted on the M2 proton channel of influenza A only (not B), and toxicity was not the reason for their fall.

Hepatitis C is an RNA virus with no latent DNA form, so sufficient suppression eradicates it, whereas hepatitis B persists as stable nuclear covalently closed circular DNA (cccDNA) that current drugs cannot clear.

The contrast is the biology of the reservoir, not drug potency, and the other statements are wrong.

• Indication. Intravenous treatment of COVID-19. Its clinical benefit has proved marginal, so use is limited and several authorities, South Africa included, advise against routine use.
• Mechanism. A prodrug of an adenosine analogue whose triphosphate the viral RNA-dependent RNA polymerase (RdRp) incorporates as a delayed chain terminator, stalling RNA synthesis.
• Note. It is incorporated efficiently enough to largely escape the coronavirus proofreading exonuclease, which is why it has any activity against a proofreading virus.

• Mechanism. Tenofovir is an acyclic nucleotide (adenosine monophosphate) analogue activated by cellular kinases to the diphosphate, which the HBV polymerase incorporates as a chain terminator. Its high genetic barrier to resistance makes it first-line; it suppresses replication but does not clear nuclear covalently closed circular DNA (cccDNA), so therapy is long-term.
• Side effects. The disoproxil prodrug (TDF) causes renal tubular toxicity and reduced bone mineral density; the alafenamide prodrug (TAF) has much less renal and bone effect. Tenofovir is also active against HIV, which matters in co-infection.

• Mechanism. A guanosine analogue with a debated, probably several-fold mechanism: depletion of the guanosine pool through inhibition of inosine monophosphate dehydrogenase, interference with messenger RNA capping, direct polymerase inhibition, and lethal mutagenesis (error catastrophe).
• Uses (for context). Now narrow: some viral haemorrhagic fevers (notably Lassa fever) and chronic hepatitis E in the immunocompromised; the historic roles in respiratory syncytial virus and hepatitis C are largely abandoned.
• Side effects. A dose-dependent haemolytic anaemia, and teratogenicity severe enough to contraindicate it in pregnancy and require contraception in both partners.