Antivirals

1. Introduction
2. The Viral Life Cycle and Drug Targets
3. Influenza Drugs
4. Herpes Family Antivirals
   • HSV and VZV
   • CMV
5. HIV Antiretroviral Therapy
6. Hepatitis B and C
7. COVID-19 Antivirals
8. Post-Exposure Prophylaxis
9. Summary
10. Drug Summary Table
11. Quiz

• Antivirals are classified by the virus they target and the step in the viral life cycle they block: attachment, entry, uncoating (the virus shedding its protein coat), genome replication, assembly, or release.
• Influenza: oseltamivir and zanamivir (neuraminidase inhibitors, which block a viral enzyme that frees new virus particles from the cell). Earlier treatment is better.
• Herpes (herpes simplex virus, HSV, and varicella zoster virus, VZV): aciclovir and its pro-drug valaciclovir (an inactive form that the body converts to the active drug). Both are nucleoside analogues (fake DNA building blocks that stop viral DNA being copied), activated by viral thymidine kinase (a viral enzyme that switches the drug on). CMV (cytomegalovirus): ganciclovir and valganciclovir.
• HIV: combination antiretroviral therapy. Modern UK first-line regimens are typically an integrase inhibitor (INSTI) plus two NRTIs (nucleoside reverse transcriptase inhibitors, which block the enzyme HIV uses to copy its RNA into DNA). Selected people can instead take a two-drug regimen (e.g. dolutegravir/lamivudine), as recommended by the British HIV Association (BHIVA). Drug classes available: NRTIs, NNRTIs (non-nucleoside reverse transcriptase inhibitors), protease inhibitors, integrase inhibitors, and entry inhibitors. A few other drugs, such as fostemsavir and lenacapavir, are kept for specific circumstances.
• Hepatitis C: direct-acting antivirals (DAAs) such as sofosbuvir-velpatasvir now achieve cure in over 95% of patients.

Introduction

Viruses are obligate intracellular parasites: they hijack host cell machinery to replicate, which makes selective targeting harder than with bacteria. Effective antivirals exploit features of the viral life cycle that have no human equivalent: viral enzymes, viral surface proteins, or unique steps in viral assembly.

The Viral Life Cycle and Drug Targets

The viral life cycle has six broad steps, each a potential drug target:

1. Attachment to the host cell surface.
2. Entry, often by receptor-mediated endocytosis.
3. Uncoating of the viral genome.
4. Replication of the genome. In retroviruses (RNA viruses that copy their genome into DNA) this also includes reverse transcription (copying RNA into DNA) and integration into the host genome.
5. Assembly of new virions (complete virus particles).
6. Release, often by budding from the cell membrane.

Viruses are broadly categorised as DNA viruses (herpes family, hepatitis B, smallpox, papillomavirus) or RNA viruses (influenza, HIV, hepatitis C, respiratory syncytial virus or RSV, coronaviruses). The genome type largely determines which polymerase (the enzyme that copies the viral genome) is the drug target.

Influenza Drugs

Influenza A and B are RNA viruses that bind sialic acid receptors (sugars on the cell surface) on respiratory epithelial cells via their haemagglutinin (a viral surface protein that attaches to the cell). After replication, new virions exit the cell with the help of neuraminidase, which cleaves sialic acid bonds, freeing the virus from the cell surface.

Two main drug classes target this cycle:

• Neuraminidase inhibitors: oseltamivir (Tamiflu), an oral pro-drug (an inactive form that the body converts to the active drug) with around 80% bioavailability (the share of a dose that reaches the bloodstream); zanamivir (Relenza), inhaled because of poor oral absorption. They block release of new virions from infected cells.
  • Active against influenza A and B.
  • Most effective when started within 48 hours of symptom onset.
  • Used for treatment in high-risk patients and for prophylaxis (taking a drug to prevent infection) after exposure, for example during outbreaks in care homes.
  • Side effects: nausea, vomiting, abdominal pain (oseltamivir); bronchospasm (airway narrowing) with inhaled zanamivir.
• M2 ion channel inhibitors: amantadine and rimantadine. Block influenza A only (influenza B has a different channel, called BM2, which they do not block). Largely abandoned because of high resistance and CNS/renal side effects. Amantadine retains a niche use in Parkinson's disease.

Annual vaccination remains the cornerstone of influenza prevention; antivirals are an adjunct, particularly for high-risk groups (older adults, pregnant women, and immunocompromised patients, who have a weakened immune system).

Herpes Family Antivirals

The human herpes viruses include herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 and 7 (HHV-6, HHV-7), and HHV-8 (which causes Kaposi's sarcoma). All are DNA viruses with the characteristic feature of establishing lifelong latency (lying dormant in the body) in specific cell types, with the potential to reactivate.

HSV and VZV

Aciclovir is the prototype:

• A guanosine analogue (a copy of guanosine, one of the DNA building blocks).
• Phosphorylated (has phosphate groups added) initially by viral thymidine kinase (an enzyme only present in infected cells: hence its selectivity for virus over host).
• Further phosphorylated by host kinases to the active triphosphate.
• Acts as a chain terminator on incorporation into viral DNA, halting replication.

Routes: topical, oral, intravenous. Half-life 3 hours (the time for the blood level of the drug to fall by half), renal excretion.

Valaciclovir is the L-valyl ester pro-drug of aciclovir (aciclovir joined to the amino acid valine, which the body removes). It has much greater oral bioavailability. The dose depends on the condition: for example, 1 g three times a day for 7 days for shingles, but 500 mg twice a day for 5 days for a first episode of genital herpes.

Indications:

• Genital herpes simplex: oral aciclovir or valaciclovir, started within 5 days of the start of a first episode or while new lesions are forming. Topical antivirals are not recommended. Suppressive therapy (a regular low dose to prevent recurrences) is offered for frequent recurrences (six or more a year).
• Oral herpes simplex (cold sores): healthy people are not routinely given oral or topical antivirals.
• HSV encephalitis (inflammation of the brain): intravenous aciclovir; a medical emergency.
• Chickenpox (varicella): oral aciclovir is considered for an immunocompetent (normal immune system), non-pregnant adult or adolescent aged 14 or over who presents within 24 hours of the rash starting. It is not recommended for otherwise healthy children with uncomplicated chickenpox. Immunocompromised and pregnant people need specialist advice, and may need intravenous aciclovir.
• Herpes zoster (shingles): oral aciclovir, valaciclovir or famciclovir within 72 hours of rash onset for people who are immunocompromised, aged 50 or over, have non-truncal involvement (a rash away from the trunk, for example on the face or limbs), or have moderate or severe pain or rash. Treatment can be considered up to one week after onset in people at higher risk of complications. Severely immunocompromised people are referred for intravenous aciclovir. Oral aciclovir has not been shown to reduce post-herpetic neuralgia (nerve pain that lasts after the rash has healed).

Side effects: nausea, vomiting, headache. Nephrotoxicity (kidney damage) is a particular risk with high-dose IV treatment. In crystal nephropathy, crystals can block the kidney tubules, so ensure adequate hydration (a good fluid intake).

CMV

CMV does not have its own thymidine kinase but uses a different viral kinase (an enzyme encoded by the UL97 gene) to activate ganciclovir and valganciclovir (the oral pro-drug). These are nucleoside analogues like aciclovir but more myelosuppressive (more likely to suppress the bone marrow), and are reserved for serious CMV disease in immunocompromised patients (transplant recipients, HIV).

Foscarnet and cidofovir are alternatives in ganciclovir-resistant disease, both with significant nephrotoxicity.

HIV Antiretroviral Therapy

HIV is a retrovirus that infects CD4 T cells (immune cells that coordinate the response to infection) and macrophages. The list below shows the HIV life cycle and the drug class that targets each step:

1. Attachment and entry via the viral surface protein gp120, which binds the CD4 receptor and then a coreceptor on the host cell (CCR5 in most infections, CXCR4 in some): targeted by entry inhibitors.
2. Reverse transcription of viral RNA to DNA by viral reverse transcriptase: targeted by NRTIs and NNRTIs.
3. Integration into host genome by viral integrase: targeted by integrase inhibitors.
4. Maturation of viral proteins by viral protease: targeted by protease inhibitors.

Modern combination antiretroviral therapy (cART) usually uses three drugs from at least two classes. Current BHIVA-recommended UK first-line regimens are typically an integrase inhibitor plus two NRTIs. Dolutegravir/lamivudine, a two-drug regimen, is also recommended for selected people starting treatment (not, for example, those with a very high viral load above 500,000 copies/mL or hepatitis B that needs tenofovir). Dolutegravir/rilpivirine is a two-drug option only for switching people whose virus is already suppressed. The aim is to suppress viral load (the amount of virus in the blood) to undetectable levels and restore immune function. The standard pre-clinical drug class summary:

• NRTIs (nucleoside reverse transcriptase inhibitors): tenofovir, emtricitabine, abacavir, lamivudine, zidovudine. Backbone of most regimens. Side effects: lactic acidosis (a dangerous build-up of lactic acid in the blood; less common with newer agents), abacavir hypersensitivity (a severe allergy; HLA-B*5701 testing is a genetic test that identifies people at high risk of it), tenofovir nephrotoxicity, zidovudine bone marrow suppression.
• NNRTIs (non-nucleoside reverse transcriptase inhibitors): efavirenz, nevirapine, rilpivirine, doravirine. Efavirenz is now a first-line choice only in pregnancy or during TB treatment, and nevirapine is used only to maintain people already taking it (BHIVA). Side effects: rash, hepatitis, CNS effects (efavirenz: vivid dreams, dizziness).
• Integrase strand transfer inhibitors (INSTIs): dolutegravir, raltegravir, bictegravir. Increasingly first-line because of high efficacy and good tolerability.
• Protease inhibitors: darunavir, atazanavir, lopinavir (always boosted with ritonavir or cobicistat, which inhibit CYP3A4, a liver enzyme that breaks down many drugs, and so raise protease inhibitor levels). Side effects: gastrointestinal (GI) upset, hyperlipidaemia (high blood fats), insulin resistance, lipodystrophy (abnormal fat distribution).
• Entry inhibitors: maraviroc (CCR5 antagonist), enfuvirtide (gp41 fusion inhibitor); niche use.

UK practice now uses single-tablet, once-daily co-formulations (several drugs combined in one tablet) such as bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy).

Pre-exposure prophylaxis (PrEP) means taking antivirals before a possible exposure to prevent infection. Tenofovir/emtricitabine PrEP is highly effective in preventing HIV acquisition in people at risk. It is available from NHS sexual health clinics.

Long-acting injectable PrEP also exists. In England, NICE recommends cabotegravir (an integrase inhibitor), given as an injection every 2 months after the starting (initiation) injections, alongside safer sex practices. Cabotegravir PrEP is recommended only for adults and young people at high risk of HIV who weigh at least 35 kg and cannot have oral PrEP (the daily tablets). The UK medicines regulator (the MHRA) has also approved lenacapavir for PrEP, given as an injection every 6 months, but NICE is still appraising it for NHS use.

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