Antivirals

Core

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 (and, in retroviruses, reverse transcription and integration).
5. Assembly of new virions.
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, RSV, coronaviruses). The genome type largely determines which polymerase is the drug target.

Influenza Drugs

Influenza A and B are RNA viruses that bind sialic acid receptors on respiratory epithelial cells via their haemagglutinin. 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), oral pro-drug with around 80% bioavailability; 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 seasonal prophylaxis (e.g. during outbreaks in care homes).
  • Side effects: nausea, vomiting, abdominal pain (oseltamivir); bronchospasm with inhaled zanamivir.
• M2 ion channel inhibitors: amantadine and rimantadine. Block influenza A only (M2 is absent in influenza B). 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, immunocompromised patients).

Herpes Family Antivirals

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

HSV and VZV

Aciclovir is the prototype:

• A guanosine analogue.
• Phosphorylated initially by viral thymidine kinase (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, renal excretion.

Valaciclovir is the L-valyl ester pro-drug of aciclovir, with much greater oral bioavailability and convenient twice-daily dosing.

Indications:

• Genital and oral herpes simplex: topical or oral aciclovir/valaciclovir; reduces severity and duration. Suppressive therapy for frequent recurrences.
• HSV encephalitis: intravenous aciclovir; a medical emergency.
• Severe varicella (chickenpox) in adults, immunocompromised patients, and pregnancy.
• Herpes zoster (shingles): aciclovir or valaciclovir within 72 hours of rash onset to reduce post-herpetic neuralgia.

Side effects: nausea, vomiting, headache. Nephrotoxicity particularly with high-dose IV (crystal nephropathy: ensure adequate hydration).

CMV

CMV does not have its own thymidine kinase but uses a different viral kinase (UL97) to activate ganciclovir and valganciclovir (the oral pro-drug). These are nucleoside analogues like aciclovir but more myelosuppressive, 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 and macrophages. The viral life cycle and the targets of each drug class are usefully summarised:

1. Attachment and entry via gp120/CD4 and CCR5 coreceptor: 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) historically used three drugs from at least two classes; current BHIVA-recommended UK first-line regimens are typically an integrase inhibitor plus two NRTIs, with several two-drug regimens (e.g. dolutegravir/lamivudine, or dolutegravir/rilpivirine) now also endorsed for selected patients. The aim is to suppress viral load 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 (less common with newer agents), abacavir hypersensitivity (HLA-B*5701 testing), tenofovir nephrotoxicity, zidovudine bone marrow suppression.
• NNRTIs (non-nucleoside reverse transcriptase inhibitors): efavirenz, nevirapine, rilpivirine. 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 to inhibit their CYP3A4 metabolism). Side effects: GI upset, hyperlipidaemia, insulin resistance, lipodystrophy.
• Entry inhibitors: maraviroc (CCR5 antagonist), enfuvirtide (gp41 fusion inhibitor); niche use.

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

Pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine is highly effective in preventing HIV acquisition in people at risk and is now available on the NHS.

Hepatitis B and C

Hepatitis B (HBV) is a DNA virus. Treatment of chronic HBV uses:

• Tenofovir and entecavir: nucleoside/nucleotide analogues that suppress HBV polymerase. First-line oral therapy.
• Pegylated interferon-α: a finite course (typically 48 weeks) producing seroconversion in a subset of patients.

Treatment usually suppresses, rather than cures, HBV.

Hepatitis C (HCV): an RNA virus. The transformation of HCV treatment by direct-acting antivirals (DAAs) is one of the great recent successes of pharmacology:

• Multiple drug classes: NS3/4A protease inhibitors (-previr suffix), NS5A inhibitors (-asvir), NS5B polymerase inhibitors (-buvir).
• UK first-line oral combinations such as sofosbuvir-velpatasvir achieve sustained virological response (functional cure) in over 95% of patients with an 8-12 week course.
• Replacing the previous interferon-based regimens, which had cure rates around 50% and significant toxicity.

COVID-19 Antivirals

The COVID-19 pandemic prompted rapid development of antivirals against SARS-CoV-2:

• Nirmatrelvir-ritonavir (Paxlovid): protease inhibitor combined with the CYP3A4-inhibitor ritonavir to boost levels. Significantly reduces hospitalisation if started within 5 days of symptoms in high-risk patients. Substantial drug interactions via CYP3A4.
• Molnupiravir: a nucleoside analogue causing viral RNA hypermutation. Modest efficacy.
• Remdesivir: nucleotide analogue inhibiting viral RNA polymerase; given intravenously to hospitalised patients with COVID pneumonitis.
• Monoclonal antibodies (sotrovimab, casirivimab, etc.) had a role but lost efficacy against later viral variants.

Post-Exposure Prophylaxis

Antivirals are also used after potential exposure to limit risk of established infection. Two situations are routinely tested at pre-clinical level:

• HIV PEP: offered after high-risk exposure (needlestick injury, sexual exposure). UK regimen: tenofovir + emtricitabine + raltegravir or dolutegravir for 28 days. Started ideally within 1 hour, no later than 72 hours.
• HBV PEP: hepatitis B immunoglobulin plus active vaccination after exposure in unvaccinated individuals.

Summary

• Antivirals exploit viral-specific steps in the viral life cycle: entry, uncoating, genome replication, assembly, release.
• Influenza: oseltamivir (oral) and zanamivir (inhaled), neuraminidase inhibitors. Effective if started within 48 hours.
• HSV / VZV: aciclovir (and the pro-drug valaciclovir), activated by viral thymidine kinase. Beware nephrotoxicity with IV use.
• CMV: ganciclovir / valganciclovir, more myelotoxic than aciclovir; foscarnet for resistant disease.
• HIV: combination ART with at least three drugs from at least two classes: NRTIs, NNRTIs, integrase inhibitors, protease inhibitors, entry inhibitors. Modern single-tablet regimens are highly effective. PrEP with tenofovir/emtricitabine is available for prevention.
• Hepatitis B: tenofovir or entecavir suppress; hepatitis C: direct-acting antivirals (sofosbuvir-velpatasvir and others) cure over 95% of patients in 8-12 weeks.
• COVID-19: nirmatrelvir-ritonavir (Paxlovid), molnupiravir and remdesivir are in selective use.
• Post-exposure prophylaxis exists for HIV (28-day antiretrovirals) and HBV (immunoglobulin + vaccine).

Drug Summary Table

Reviewed by: Dr. Marcus Judge

Quiz

Preview the Antivirals quiz