Ever taken an antiviral that suddenly stops working? That’s what patients and doctors face when acyclovir resistance develops. Below we unpack why it happens, how you might notice it, and what you can do when the usual pills fail.

What is acyclovir resistance?

Acyclovir resistance is a condition where the herpesvirus family no longer responds to the antiviral drug acyclovir. The drug, a nucleoside analogue, normally blocks viral DNA replication, but mutations in the virus can render the blockage ineffective. While resistance is rare in healthy adults, it becomes a real concern for immunocompromised patients, long‑term suppressive therapy users, and certain viral strains.

How does acyclovir work?

Understanding the drug helps explain why resistance emerges. Acyclovir is a synthetic analogue of guanosine. After entering infected cells, a viral enzyme called thymidine kinase (TK) adds a phosphate group, converting acyclovir into acyclovir‑monophosphate. Host enzymes then add two more phosphates, producing acyclovir‑triphosphate, which competitively inhibits viral DNA polymerase, halting DNA chain elongation.

Because the first activation step relies on viral TK, any change in that enzyme can cripple the drug’s effectiveness.

Key causes of resistance

• TK gene mutations: The most common mechanism. Deletions, point mutations, or frameshifts in the UL23 gene (which encodes TK) lead to reduced or absent enzyme activity.
• DNA polymerase mutations: Alterations in the UL30 gene can lower the binding affinity of acyclovir‑triphosphate.
• Prolonged therapy: Continuous suppressive dosing, especially in transplant recipients or HIV‑positive patients, creates selection pressure that favors resistant strains.
• Cross‑resistance: Resistance to acyclovir often predicts reduced susceptibility to related drugs like valacyclovir and famciclovir, because they share the same activation pathway.

Who is most at risk?

Not everyone who takes acyclovir will develop resistance. The highest‑risk groups include:

• HIV patients with low CD4 counts.
• Organ transplant recipients on immunosuppressants.
• Patients with hematologic malignancies undergoing chemotherapy.
• Individuals on long‑term suppressive therapy for recurrent genital herpes or herpes zoster.

Spotting the symptoms

When resistance develops, the classic signs of a herpes outbreak don’t improve despite adequate dosing. Look for:

1. Lesions that persist beyond the usual 7‑10 day healing window.
2. Worsening pain or new satellite lesions.
3. Re‑eruption after a short symptom‑free interval while still on medication.
4. Laboratory confirmation of virus in cultures despite therapy.

In immunocompromised hosts, the disease can spread internally, leading to esophagitis, pneumonitis, or encephalitis that fails to respond to standard acyclovir doses.

Confirming resistance: laboratory testing

Clinical suspicion isn’t enough; you need a lab test. Two main approaches are used:

• Phenotypic drug‑susceptibility assay: Virus isolated from a lesion is grown in cell culture and exposed to increasing concentrations of acyclovir. The lowest concentration that inhibits 50 % of viral replication (IC50) is measured. An IC50 > 10 µg/mL usually indicates resistance.
• Genotypic sequencing: PCR amplifies the TK (UL23) and DNA polymerase (UL30) genes. Sequencing then identifies known resistance‑conferring mutations such as TK‑A200V or DNA‑polymerase‑L500P.

Both methods have pros and cons. Phenotypic assays reflect actual drug response but take 5‑7 days, while genotypic testing is faster (24‑48 h) but may miss novel mutations.

Treatment options when acyclovir fails

If testing confirms resistance, you have several alternatives. Choice depends on the virus involved, organ function, and prior drug exposure.

**Foscarnet** and **cidofovir** are the go‑to IV drugs because they bypass the defective TK step. However, they demand close monitoring of kidney function and electrolytes. Oral options like high‑dose valacyclovir may still work if the resistance is partial, but they’re less reliable.

Practical management algorithm

1. Confirm resistance with phenotypic or genotypic testing.
2. Assess patient’s renal function and electrolyte status.
3. If renal function is adequate, start foscarnet (IV) with pre‑hydration.
4. For patients with poor kidney reserve, consider cidofovir with probenecid and aggressive hydration.
   • Monitor serum creatinine every 48 h.
   • Adjust dose if creatinine clearance < 50 mL/min.
5. Re‑evaluate clinical response after 5‑7 days.
   • Improvement: continue for a total of 14‑21 days.
   • No improvement: reassess for mixed infection, drug levels, or alternative diagnoses.

Prevention strategies

Stopping resistance before it starts is better than fighting it later. Here are proven tactics:

• Limit suppressive therapy: Use the lowest effective dose, and consider drug holidays if the patient’s immune system is stable.
• Rotate antivirals: In transplant protocols, alternating acyclovir with ganciclovir can reduce selection pressure.
• Vaccination: The shingles vaccine (Shingrix) reduces VZV reactivation, cutting the need for antivirals.
• Early detection: Routine viral cultures in high‑risk wards enable swift identification of resistant strains.

Key take‑aways for patients and clinicians

• Resistance is rare in healthy people but common in immunocompromised hosts.
• Persistent lesions despite proper dosing should trigger resistance testing.
• Foscarnet and cidofovir are the mainstays for TK‑deficient viruses, but require kidney monitoring.
• Prevention hinges on judicious antiviral use and immunization.