STEPTRACKERPHARMACOLOGY + MICROBIOLOGY | ANTIMICROBIALS | HIGH-YIELD REVIEW

Antivirals & Antiretrovirals

Antivirals target virus-specific steps — entry, uncoating, genome copying, assembly or release. HIV therapy combines several of these to stop resistance.

FOCUS ON
Herpesviruses: acyclovir/valacyclovir, famciclovir — guanosine analogs phosphorylated by viral thymidine kinase → chain termination; HSV, VZV; crystal nephropathy (hydrate); resistance = TK mutation → foscarnet (pyrophosphate analog; no activation needed; nephrotoxic, ↓ Ca²⁺/Mg²⁺ → seizures). CMV: ganciclovir/valganciclovir (UL97 kinase; marrow suppression), foscarnet, cidofovir (nephrotoxic; give probenecid), letermovir (prophylaxis). Influenza: oseltamivir, zanamivir (neuraminidase → no release), baloxavir (cap-dependent endonuclease). RSV: nirsevimab/palivizumab. COVID-19: nirmatrelvir-ritonavir (3CL protease; CYP3A4 interactions), remdesivir. HBV: tenofovir, entecavir. HCV: NS3/4A protease (-previr), NS5A (-asvir), NS5B polymerase (sofosbuvir) — cure > 95%. HIV: NRTIs, NNRTIs, integrase inhibitors (-tegravir), protease inhibitors (-navir), entry inhibitors; standard = 2 NRTIs + integrase inhibitor.
DRUG · CLASS
MECHANISM
USE
SIGNATURE TOXICITY
Acyclovir · valacyclovir · famciclovir
Viral TK phosphorylation → DNA polymerase chain termination
HSV (genital, encephalitis), VZV (zoster)
Crystal nephropathy, neurotoxicity (renal failure)
Ganciclovir · valganciclovir
CMV UL97 kinase phosphorylation → DNA polymerase block
CMV retinitis, colitis, transplant prophylaxis
Neutropenia, thrombocytopenia, anemia
Foscarnet
Pyrophosphate analog; directly blocks DNA polymerase
Acyclovir-resistant HSV, ganciclovir-resistant CMV
Nephrotoxicity, ↓ Ca²⁺, ↓ Mg²⁺, ↓ K⁺ → seizures
Cidofovir
Nucleotide analog (no viral kinase needed)
Resistant CMV, adenovirus
Nephrotoxicity (give probenecid + saline), neutropenia
Oseltamivir · zanamivir · baloxavir
Neuraminidase inhibitors (no virion release) · cap-snatching endonuclease block
Influenza A and B (best within 48 h), prophylaxis
GI upset; zanamivir bronchospasm
Nirmatrelvir-ritonavir · remdesivir
SARS-CoV-2 3CL protease (ritonavir boosts) · RNA polymerase
High-risk COVID-19
Major CYP3A4 interactions (ritonavir); dysgeusia
HCV direct-acting antivirals
Sofosbuvir (NS5B), ledipasvir/velpatasvir (NS5A), glecaprevir (NS3/4A)
Chronic hepatitis C (8–12 weeks)
HBV reactivation; amiodarone + sofosbuvir bradycardia
Tenofovir · entecavir
Nucleot(s)ide reverse transcriptase/polymerase inhibitors
Chronic hepatitis B; tenofovir also HIV, PrEP
TDF: renal tubular damage (Fanconi), bone loss; TAF less
NRTIs
tenofovir, emtricitabine, lamivudine, abacavir, zidovudine
Nucleoside analogs → chain termination (need host phosphorylation)
HIV backbone; zidovudine perinatal
Abacavir hypersensitivity (HLA-B*57:01); zidovudine anemia; older NRTIs lactic acidosis, neuropathy, pancreatitis
NNRTIs
efavirenz, rilpivirine, nevirapine, doravirine
Bind RT allosteric site (no phosphorylation)
Alternative HIV regimens
Efavirenz vivid dreams, psychiatric effects; nevirapine hepatotoxicity, SJS
Integrase inhibitors
dolutegravir, bictegravir, raltegravir, cabotegravir
Block strand transfer of viral DNA into host genome
First-line HIV (with 2 NRTIs); long-acting injectable
Weight gain, insomnia, ↑ creatinine (dolutegravir); chelated by cations
Protease inhibitors
darunavir, atazanavir, lopinavir + ritonavir
Block HIV protease → immature virions
Second-line or resistant HIV
Hyperglycemia, lipodystrophy, CYP3A4 inhibition; atazanavir indirect hyperbilirubinemia
Entry · fusion · attachment inhibitors
Maraviroc (CCR5), enfuvirtide (gp41), ibalizumab (CD4), fostemsavir (gp120), lenacapavir (capsid)
Multidrug-resistant HIV
Maraviroc needs CCR5-tropic virus; enfuvirtide injection-site nodules

Mechanism — HIV life cycle targets

Attach / fuseMaraviroc, enfuvirtide
→
Reverse transcribeNRTIs, NNRTIs
→
Integrate-tegravirs
→
MatureProtease inhibitors

Resistance shortcuts

DRUG
RESISTANCE
SWITCH TO
Acyclovir
Viral TK loss
Foscarnet
Ganciclovir
UL97 mutation
Foscarnet, cidofovir
Lamivudine
M184V
Other NRTI combos

How it's tested

COMMON CONFUSIONAcyclovir is safe for host cells because only virus-infected cells (with viral TK) phosphorylate it; foscarnet and cidofovir skip that step and work on TK-deficient strains.
THE TRAPBefore abacavir, test HLA-B*57:01 — a positive result means a potentially fatal hypersensitivity reaction.
YOUR APPROACHVirus → step targeted → activation requirement → signature toxicity → resistance pattern.

If you see… think…

AKI with crystals after IV antiviral for HSV encephalitis → acyclovir
Neutropenia on CMV retinitis treatment → ganciclovir
Seizures with low Ca²⁺ and Mg²⁺ on antiviral → foscarnet
Antiviral given with probenecid → cidofovir
Influenza drug that blocks virion release → oseltamivir
Rash, fever, GI upset days after starting HIV therapy, HLA-B*57:01 → abacavir hypersensitivity
Vivid dreams on HIV regimen → efavirenz
Fanconi syndrome, bone loss on HIV/HBV drug → tenofovir disoproxil
Jaundice with normal LFTs on HIV protease inhibitor → atazanavir (UGT1A1)
CCR5 antagonist → maraviroc