Step 1 · Microbiology

Antivirals: Herpes, Influenza & Hepatitis

Name: Antivirals: Herpes, Influenza & Hepatitis
Creator: Veli Bakalov, MD

Which enzyme switches the drug on, and which organ pays the price

Microbiology·Pharmacology·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Acyclovir, valacyclovir, and famciclovir are guanosine analogs first phosphorylated by HSV/VZV thymidine kinase; they inhibit viral DNA polymerase but cannot touch latent virus.
IV acyclovir can crystallize in renal tubules (prevent with hydration and slow infusion) and is neurotoxic when it accumulates in renal failure.
Acyclovir resistance usually means thymidine kinase loss; switch to foscarnet, which needs no activation.
Ganciclovir/valganciclovir are activated by CMV UL97 kinase and cause dose-limiting neutropenia and thrombocytopenia (additive with zidovudine).
Foscarnet causes nephrotoxicity plus chelation (low ionized Ca2+ and Mg2+, seizures); cidofovir nephrotoxicity is blunted with probenecid and saline.
Letermovir inhibits CMV terminase and is marrow-sparing CMV prophylaxis after allogeneic stem-cell transplant.
Influenza: neuraminidase inhibitors work best within 48 h (inhaled zanamivir can cause bronchospasm), baloxavir blocks cap-dependent endonuclease, and adamantanes are abandoned for resistance.
HCV DAAs (-previr, -asvir, -buvir) cure more than 95%; test HBsAg and anti-HBc first, avoid sofosbuvir with amiodarone, and remember ribavirin (IMPDH inhibitor) causes hemolysis and birth defects.
HBV is suppressed long-term with entecavir or tenofovir; pegylated interferon-α causes flu-like illness, depression, cytopenias, and thyroiditis.

Anti-herpes nucleoside analogs

Acyclovir and its relatives. Acyclovir, valacyclovir, and famciclovir are guanosine analogs aimed at HSV-1, HSV-2, and VZV. Their selectivity comes from the virus itself: HSV/VZV thymidine kinase (TK) performs the first phosphorylation, which uninfected cells barely manage, and host kinases finish the job.

EntryAcyclovir diffuses into infected and uninfected cells alike
Viral thymidine kinaseMakes acyclovir monophosphate, essentially only in infected cells
Host kinasesComplete the triphosphate
Viral DNA polymeraseIncorporates it; with no 3′-OH, the chain terminates

Acyclovir activation

Prodrugs and uses. Oral acyclovir is poorly absorbed. Valacyclovir, its valine ester, delivers 3–5 times the bioavailability, and famciclovir is the oral prodrug of penciclovir; both allow two or three daily doses. Uses: genital herpes (episodic treatment or daily suppression), herpes labialis, and zoster, ideally started within 72 hours of rash onset. IV acyclovir treats HSV encephalitis (started empirically, before the CSF PCR returns), neonatal HSV, and severe VZV in immunocompromised hosts. CMV has no thymidine kinase, so acyclovir does little against it.

These drugs act only on replicating virus. Latent genomes rest in sensory ganglia without replicating, so no antiviral eradicates latency and lesions recur once therapy stops.

Toxicity. Acyclovir is poorly soluble in urine. A rapid high-dose IV infusion, especially in a volume-depleted patient, precipitates needle-shaped crystals in the tubules and causes obstructive acute kidney injury; IV hydration, slow infusion, and renal dosing prevent it. When the drug accumulates (renal failure, old age) it is neurotoxic: tremor, myoclonus, confusion, and hallucinations.

Resistance. Resistance arises almost only in immunocompromised hosts (AIDS, transplant). Most resistant isolates have absent or altered thymidine kinase; fewer carry a DNA polymerase mutation. TK-deficient virus is cross-resistant to valacyclovir, famciclovir, and ganciclovir, so treatment switches to foscarnet, with cidofovir as the alternative.

Anti-CMV drugs and kinase-independent agents

Ganciclovir and valganciclovir. CMV's UL97 protein kinase monophosphorylates ganciclovir, and host kinases produce the triphosphate that inhibits CMV DNA polymerase (UL54). Valganciclovir is the oral valine-ester prodrug. Uses: CMV retinitis (classically AIDS with CD4 <50/mm³), colitis, and pneumonitis, plus prevention after transplant. Resistance usually reflects UL97 mutations (the drug is never activated), less often UL54 mutations.

Ganciclovir's dose-limiting toxicity is myelosuppression (neutropenia, thrombocytopenia), additive with zidovudine and other marrow-toxic drugs. It is also teratogenic.

Foscarnet. A pyrophosphate analog that binds the pyrophosphate site of viral DNA polymerase (and HIV reverse transcriptase) directly, with no kinase step. It is therefore the drug for TK-deficient HSV/VZV and UL97-mutant CMV; only a polymerase mutation confers resistance. It is given IV only. Foscarnet chelates divalent cations: ionized calcium and magnesium fall (even when total calcium looks normal) and potassium and phosphate shift, causing paresthesias, arrhythmias, and seizures. It is also nephrotoxic (acute tubular injury, nephrogenic diabetes insipidus), so saline prehydration and electrolyte monitoring are mandatory.

Cidofovir. A cytosine nucleotide (phosphonate) analog. Because it already carries a phosphate mimic, host kinases alone make the active diphosphate, so it covers CMV (including UL97 mutants), TK-deficient HSV, and adenovirus. Proximal tubular nephrotoxicity is dose-limiting; each dose is given with probenecid, which blocks organic-anion uptake into tubular cells, plus IV saline.

Letermovir. Inhibits the CMV DNA terminase complex (pUL56), which cuts concatemeric DNA into unit genomes and packages them into capsids; UL56 mutations confer resistance. This non-polymerase target spares the marrow, so letermovir is CMV prophylaxis for seropositive allogeneic stem-cell transplant and high-risk kidney transplant recipients. It has no HSV or VZV activity, so acyclovir prophylaxis continues.

Herpesvirus and CMV drugs

Drug	Activation	Main use	Signature toxicity
Acyclovir, valacyclovir, famciclovir	HSV/VZV thymidine kinase	HSV, VZV	Crystal nephropathy, neurotoxicity (IV)
Ganciclovir, valganciclovir	CMV UL97 kinase	CMV disease, transplant prevention	Neutropenia, thrombocytopenia
Foscarnet	None (pyrophosphate analog)	Resistant HSV/VZV and CMV	Nephrotoxicity; low Ca²⁺/Mg²⁺ → seizures
Cidofovir	Host kinases only (nucleotide)	CMV, resistant HSV, adenovirus	Nephrotoxicity (probenecid + saline)
Letermovir	None (terminase inhibitor)	CMV prophylaxis after transplant	Marrow-sparing; no HSV/VZV coverage

Influenza antivirals

Neuraminidase inhibitors. Oseltamivir (oral), zanamivir (inhaled), and peramivir (single IV dose) are sialic acid analogs. Neuraminidase normally cleaves sialic acid so budding virions can detach; blocked, the progeny stay clumped on the cell surface. They cover influenza A and B and help most when started within 48 hours of symptom onset, although hospitalized and high-risk patients are treated regardless of timing. Inhaled zanamivir can trigger bronchospasm and is avoided in asthma or COPD.

Baloxavir marboxil. A single oral dose inhibits the cap-dependent endonuclease in the PA subunit of the viral polymerase. Influenza steals 5′ caps from host mRNAs (cap-snatching) to prime its own transcription, so blocking this step stops viral mRNA synthesis.

Adamantanes. Amantadine and rimantadine block the M2 proton channel needed for uncoating. They never covered influenza B, and nearly all circulating influenza A strains carry the S31N M2 mutation, so they are no longer used for influenza. Amantadine persists as a Parkinson disease drug (livedo reticularis).

48 hwindow for the greatest benefit from neuraminidase inhibitors

Hepatitis C: direct-acting antivirals and ribavirin

HCV direct-acting antivirals

Class	Examples	Target's job
NS3/4A protease inhibitors (-previr)	Glecaprevir, grazoprevir, voxilaprevir	Cleaves the viral polyprotein
NS5A inhibitors (-asvir)	Velpatasvir, ledipasvir, pibrentasvir	Organizes replication and virion assembly
NS5B polymerase inhibitor (-buvir)	Sofosbuvir	RNA polymerase; sofosbuvir is a uridine nucleotide chain terminator

Protease inhibitors are avoided in decompensated (Child-Pugh B/C) cirrhosis.

Regimens and cure. Pangenotypic combinations dominate: sofosbuvir-velpatasvir for 12 weeks or glecaprevir-pibrentasvir for 8 weeks. Cure, a sustained virologic response (undetectable HCV RNA 12 weeks after therapy), exceeds 95%.

Sofosbuvir with amiodarone can cause severe, even fatal, bradycardia. Because clearing HCV can unleash a coexisting hepatitis B infection (a boxed warning for all DAAs), HBsAg and anti-HBc are checked before any DAA is started.

Ribavirin. A guanosine analog that inhibits IMP dehydrogenase (the enzyme mycophenolate also targets), depleting GTP and impairing viral RNA synthesis and capping. It is now added to DAAs only in select cases (such as decompensated cirrhosis) and is used for severe RSV. Ribavirin phosphates accumulate in red cells, which cannot remove them, causing ATP depletion, oxidative damage, and dose-dependent hemolytic anemia. It is strongly teratogenic: both partners use contraception during therapy and for 6 months afterward.

Hepatitis B therapy and interferon-α

Nucleos(t)ide analogs. The HBV polymerase has reverse-transcriptase activity. Entecavir (guanosine analog) and tenofovir (adenosine nucleotide analog) inhibit it with a high barrier to resistance. Covalently closed circular DNA (cccDNA) persists in hepatocyte nuclei, so therapy is usually indefinite, and stopping it can provoke a flare. Tenofovir is preferred in pregnancy and HIV coinfection.

Pegylated interferon-α. A finite 48-week course of weekly injections that induces antiviral proteins through JAK-STAT signaling. Its drawbacks: flu-like illness, depression (including suicidality), neutropenia and thrombocytopenia, and thyroiditis with hypo- or hyperthyroidism.

Interferon is contraindicated in decompensated cirrhosis, pregnancy, and severe psychiatric illness.